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7,001 | be evident. Parents often report that the child looks ill or pale and has a decreased appetite. The underlying etiology also produces accompa nying symptoms. Although the underlying etiologies can manifest in varied ways clinically, there are some predictable features. For example, fever with petechiae in an ill appearing patient indicates the high pos sibility of life threatening conditions such as meningococcemia, Rocky Mountain spotted fever, or acute bacterial endocarditis. The unusual symptom of loss of smell and taste can accompany fever in COVID 19. Changes in heart rate, most frequently tachycardia, accompany fever. Normally heart rate rises by 10 beatsmin per 1C (1.8F) rise in temperature for children 2 months old. Relative tachycardia, when the pulse rate is elevated disproportionately to the temperature, is usu ally caused by noninfectious diseases or infectious diseases in which a toxin is responsible for the clinical manifestations. Relative brady cardia (temperature pulse dissociation), when the pulse rate remains low in the presence of fever, can accompany typhoid fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of fever also may be a result of a conduction defect resulting from cardiac involve ment with acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis. EVALUATION Most acute febrile episodes in a normal host can be diagnosed by a careful history and physical examination and require few, if any, labo ratory tests. Because infection is the most likely etiology of acute fever, the evaluation should initially be geared to discovering an underlying infectious cause (Table 219.2 and Chapter 220). The details of the his tory should include the onset and pattern of fever and any accompany ing signs and symptoms. The patient often displays signs or symptoms that provide clues to the cause of the fever. Exposures to other ill per sons at home, daycare, and school should be noted, along with any recent travel, animal exposures, or medications. The past medical his tory should include information about underlying immune deficien cies or other major illnesses and receipt of childhood vaccines. Physical examination should begin with a complete evaluation of vital signs, which should include pulse oximetry, because hypoxia may indicate lower respiratory infection. In the acutely febrile child, the physical examination should focus on any localized complaints, but a complete head to toe screen is recommended, because clues to the underlying diagnosis may be found. For example, palm and sole lesions may be discovered during a thorough skin examination and provide a clue for infection with coxsackievirus. If a fever has an obvious cause, laboratory evaluation may not be required, and management is tailored to the underlying cause with as needed reevaluation. If the cause of the fever is not apparent, further diagnostic evaluation should be considered on a case by case basis. The history of presentation and abnormal physical examination find ings guide the evaluation. The child with respiratory symptoms and hypoxia may require a chest radiograph, rapid antigen testing for respi ratory syncytial virus or influenza, or polymerase chain reaction (PCR) |
7,002 | testing for SARS CoV 2. The child with pharyngitis can benefit from PCR testing for group A Streptococcus and a throat culture. Dysuria, back pain, or a history of vesicoureteral reflux should prompt a urinaly sis and urine culture, and bloody diarrhea should prompt a stool cul ture. A complete blood count and blood culture should be considered in the ill appearing child, along with cerebrospinal fluid studies if the child has neck stiffness or if the possibility of meningitis is considered. Well defined high risk groups require a more extensive evaluation on the basis of age, associated disease, or immunodeficiency status and might warrant prompt antimicrobial therapy before a pathogen is iden tified. Fever in neonates and young infants (0 3 months old), fever in older children, and fever of unknown origin are discussed in Chapters 220, 221, and 222, respectively. MANAGEMENT Although fever is a common parental worry, no evidence supports the belief that high fever can result in brain damage or other bodily harm, except in rare instances of febrile status epilepticus and heat stroke. Treating fever in self limiting illnesses for the sole reason of bringing the body temperature back to normal is not necessary in the otherwise healthy child. Most evidence suggests that fever is an adaptive response and should be treated only in select circumstances. In humans, increased temperatures are associated with decreased microbial replication and an increased inflammatory response. Although fever can have benefi cial effects, it also increases oxygen consumption, carbon dioxide pro duction, and cardiac output and can exacerbate cardiac insufficiency in patients with heart disease or chronic anemia (e.g., sickle cell disease), pulmonary insufficiency in patients with chronic lung disease, and metabolic instability in patients with diabetes mellitus or inborn errors of metabolism. Children between 6 months and 5 years of age are at increased risk for simple febrile seizures. The focus of the evaluation and treatment of febrile seizures is aimed at determining the underlying cause of the fever. Children with idiopathic epilepsy also often have an increased frequency of seizures associated with a fever. High fever dur ing pregnancy may be teratogenic. Fever with temperatures 39C (102.2F) in healthy children gen erally does not require treatment. However, as temperatures become higher, patients tend to become more uncomfortable, and treatment of fever is then reasonable. If a child is included in one of the high risk groups previously discussed or if the childs caregiver is concerned that the fever is adversely affecting the childs behavior and causing dis comfort, treatment may be given to hasten the resolution of the fever. Table 219.2 Evaluation of Acute Fever Thorough history: onset, other symptoms, exposures (daycare, school, family, pets, playmates, other ill individuals), travel, medications, other underlying disorders, immunizations Physical examination: complete, with focus on localizing symptoms Laboratory studies on a case by case basis: Blood: complete blood count, culture, C reactive protein, procalcitonin, sedimentation rate Cerebrospinal fluid: cell count, culture, glucose, Gram stain, NAAT for herpes simplex virus, protein Nasopharyngeal: NAAT |
7,003 | for respiratory viruses Pharyngeal: NAAT and culture for group A Streptococcus Stool: calprotectin, culture, NAAT for enteric pathogens Urine: culture, gross and microscopic analysis, NAAT for genital pathogens Others (such as chest radiograph or other radiologic imaging) NAAT, Nucleic acid amplification test. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1642 Part XV u Infectious Diseases Other than providing symptomatic relief, antipyretic therapy does not change the course of infectious diseases. Encouraging good hydration is the first step to replacing fluids that are lost related to the increased metabolic demands and insensible losses of fever. Antipyretic therapy is beneficial in high risk patients and patients with discomfort. Hyper pyrexia (41C 105.8F) indicates high probability of a hypotha lamic disorder or central nervous system injury (hemorrhage, other etiology) and should be treated with antipyretics. Some studies show that hyperpyrexia may be associated with a significantly increased risk of serious bacterial infection, but other studies have not substanti ated this relationship. The most common antipyretics are acetamino phen 10 15 mgkgdose every 4 hours and ibuprofen in children 6 months old at 5 10 mgkgdose every 8 hours. Antipyretics reduce fever by reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibu profen). To reduce fever most safely, the caregiver should choose one type of medication and clearly record the dose and time of administra tion so that overdosage does not occur, especially if multiple caregiv ers are involved in the management. Physical measures such as tepid baths and cooling blankets are not considered effective to reduce fever. Evidence is also scarce for the use of complementary and alternative medicine interventions. Fever caused by specific underlying etiologies resolves when the condition is properly treated. Examples include administration of intravenous immunoglobulin to treat Kawasaki disease or the admin istration of antibiotics to treat bacterial infections. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 220 Fever Without a Focus in the Neonate and Young Infant Laura Brower and Samir S. Shah Fever is a common reason for neonates and young infants to undergo medical evaluation in the hospital or ambulatory setting. For this age group (0 3 months), fever without a focus refers to a rectal temper ature of 38C (100.4F) or greater without other presenting signs or symptoms. The evaluation of these patients can be challenging because of the difficulty distinguishing between a serious infection (bacterial or viral) and a self limited viral illness. The etiology and evaluation of fever without a focus depend on the age of the child. Three age groups are typically considered: neonates 0 28 days, young infants 29 90 days, and children 3 36 months. ETIOLOGY AND EPIDEMIOLOGY Serious bacterial infection (SBI) occurs in 713 of neonates and young infants with fever. In this group, the most common SBIs |
7,004 | are urinary tract infection (UTI; 513), bacteremia (12), and men ingitis (0.20.5). The risk for SBI is highest in those appearing ill (in contrast to well appearing) and those with risk factors and is inversely related to postnatal age. The term invasive bacterial infection (IBI), which refers to bacteremia and meningitis, recognizes that infants with UTIs may be managed differently (e.g., often with oral antibiotics) than those with bacteremia or meningitis. Escherichia coli is the most com mon organism causing SBI, followed by group B Streptococcus (GBS). The frequency of GBS infections has decreased as a consequence of increased screening of pregnant women and use of intrapartum anti biotic prophylaxis. Other, less common organisms include Klebsiella spp., Enterococcus spp., Streptococcus pneumoniae, Neisseria meningiti dis, and Staphylococcus aureus (Table 220.1). Listeria monocytogenes is a rare cause of neonatal infections, potentially related to changes in public health education and improvements in food safety. Additional details about specific bacteria are available in the following chapters: E. coli (see Chapter 246), GBS (see Chapter 230), S. pneumoniae (see Chapter 228), N. meningitidis (see Chapter 237), S. aureus (see Chap ter 227.1), and L. monocytogenes (see Chapter 234). Specific bacte rial infections that can present with fever in this age group, although often with symptoms other than isolated fever, include pneumonia (see Chapter 449), gastroenteritis (see Chapter 387), osteomyelitis (see Chapter 725), septic arthritis (see Chapter 726), omphalitis (see Chap ter 144), cellulitis, and other skin and soft tissue infections (see Chapter 706). Herpes simplex virus (HSV) infections (see Chapter 299) should also be considered in febrile neonates, particularly those under 28 days old, given the high rate of mortality and significant morbidity among survivors. Neonatal HSV is rare, with a prevalence of 0.20.3 among febrile neonates. Most of these infections are caused by HSV type 2, though HSV type 1 can also cause neonatal infection. Neonates with disseminated disease and skin, eye, and mouth (SEM) disease typi cally present at 5 12 days of life. Neonates with central nervous system (CNS) disease generally present at 16 19 days. Perinatally acquired HSV occasionally manifests beyond 28 days of age, although most cases beyond 28 days of age represent postnatal acquisition. In febrile infants who appear well, viral illnesses are much more common than bacterial or serious viral infections. The most common viruses include respiratory syncytial virus (RSV; see Chapter 307), enteroviruses (see Chapter 297), influenza viruses (see Chapter 305), parainfluenza viruses (see Chapter 306), human metapneumovirus (see Chapter 308), adenovirus (see Chapter 309), parechoviruses (see Chapter 297), and rhinovirus (see Chapter 310). CLINICAL MANIFESTATIONS In neonates and young infants, bacterial and viral infections can pres ent with isolated fever or nonspecific symptoms, making diagnosis of serious illnesses challenging. Some neonates and young infants will have signs of systemic illness at presentation, including abnormal temperature (hypothermia 36C 96.8F, fever 38C 100.4F), abnormal respiratory examination (tachypnea 60 breathsmin, respi ratory distress, apnea), abnormal circulatory examination (tachycardia 180 beatsmin, delayed capillary refill 3 seconds, weak or bound ing |
7,005 | pulses), abnormal abdominal examination, abnormal neurologic Table 220.1 Bacterial Pathogens in Neonates and Young Infants with Urinary Tract Infection, Bacteremia, or Meningitis FREQUENCY URINARY TRACT INFECTION BACTEREMIA AND MENINGITIS Common Escherichia coli Escherichia coli Group B Streptococcus Less common Klebsiella spp. Enterococcus spp. Listeria monocytogenes Streptococcus pneumoniae Staphylococcus aureus Klebsiella spp. Rare Group B Streptococcus Staphylococcus aureus Pseudomonas aeruginosa Enterobacter spp. Citrobacter spp. Proteus mirabilis Neisseria meningitidis Salmonella spp. Enterobacter spp. Enterococcus spp. Cronobacter sakazakii Haemophilus influenzae Citrobacter Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1642 Part XV u Infectious Diseases Other than providing symptomatic relief, antipyretic therapy does not change the course of infectious diseases. Encouraging good hydration is the first step to replacing fluids that are lost related to the increased metabolic demands and insensible losses of fever. Antipyretic therapy is beneficial in high risk patients and patients with discomfort. Hyper pyrexia (41C 105.8F) indicates high probability of a hypotha lamic disorder or central nervous system injury (hemorrhage, other etiology) and should be treated with antipyretics. Some studies show that hyperpyrexia may be associated with a significantly increased risk of serious bacterial infection, but other studies have not substanti ated this relationship. The most common antipyretics are acetamino phen 10 15 mgkgdose every 4 hours and ibuprofen in children 6 months old at 5 10 mgkgdose every 8 hours. Antipyretics reduce fever by reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibu profen). To reduce fever most safely, the caregiver should choose one type of medication and clearly record the dose and time of administra tion so that overdosage does not occur, especially if multiple caregiv ers are involved in the management. Physical measures such as tepid baths and cooling blankets are not considered effective to reduce fever. Evidence is also scarce for the use of complementary and alternative medicine interventions. Fever caused by specific underlying etiologies resolves when the condition is properly treated. Examples include administration of intravenous immunoglobulin to treat Kawasaki disease or the admin istration of antibiotics to treat bacterial infections. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 220 Fever Without a Focus in the Neonate and Young Infant Laura Brower and Samir S. Shah Fever is a common reason for neonates and young infants to undergo medical evaluation in the hospital or ambulatory setting. For this age group (0 3 months), fever without a focus refers to a rectal temper ature of 38C (100.4F) or greater without other presenting signs or symptoms. The evaluation of these patients can be challenging because of the difficulty distinguishing between a serious infection (bacterial or viral) and a self limited viral illness. The etiology and evaluation of fever without a focus depend on the age of the child. Three age groups are typically considered: neonates 0 |
7,006 | 28 days, young infants 29 90 days, and children 3 36 months. ETIOLOGY AND EPIDEMIOLOGY Serious bacterial infection (SBI) occurs in 713 of neonates and young infants with fever. In this group, the most common SBIs are urinary tract infection (UTI; 513), bacteremia (12), and men ingitis (0.20.5). The risk for SBI is highest in those appearing ill (in contrast to well appearing) and those with risk factors and is inversely related to postnatal age. The term invasive bacterial infection (IBI), which refers to bacteremia and meningitis, recognizes that infants with UTIs may be managed differently (e.g., often with oral antibiotics) than those with bacteremia or meningitis. Escherichia coli is the most com mon organism causing SBI, followed by group B Streptococcus (GBS). The frequency of GBS infections has decreased as a consequence of increased screening of pregnant women and use of intrapartum anti biotic prophylaxis. Other, less common organisms include Klebsiella spp., Enterococcus spp., Streptococcus pneumoniae, Neisseria meningiti dis, and Staphylococcus aureus (Table 220.1). Listeria monocytogenes is a rare cause of neonatal infections, potentially related to changes in public health education and improvements in food safety. Additional details about specific bacteria are available in the following chapters: E. coli (see Chapter 246), GBS (see Chapter 230), S. pneumoniae (see Chapter 228), N. meningitidis (see Chapter 237), S. aureus (see Chap ter 227.1), and L. monocytogenes (see Chapter 234). Specific bacte rial infections that can present with fever in this age group, although often with symptoms other than isolated fever, include pneumonia (see Chapter 449), gastroenteritis (see Chapter 387), osteomyelitis (see Chapter 725), septic arthritis (see Chapter 726), omphalitis (see Chap ter 144), cellulitis, and other skin and soft tissue infections (see Chapter 706). Herpes simplex virus (HSV) infections (see Chapter 299) should also be considered in febrile neonates, particularly those under 28 days old, given the high rate of mortality and significant morbidity among survivors. Neonatal HSV is rare, with a prevalence of 0.20.3 among febrile neonates. Most of these infections are caused by HSV type 2, though HSV type 1 can also cause neonatal infection. Neonates with disseminated disease and skin, eye, and mouth (SEM) disease typi cally present at 5 12 days of life. Neonates with central nervous system (CNS) disease generally present at 16 19 days. Perinatally acquired HSV occasionally manifests beyond 28 days of age, although most cases beyond 28 days of age represent postnatal acquisition. In febrile infants who appear well, viral illnesses are much more common than bacterial or serious viral infections. The most common viruses include respiratory syncytial virus (RSV; see Chapter 307), enteroviruses (see Chapter 297), influenza viruses (see Chapter 305), parainfluenza viruses (see Chapter 306), human metapneumovirus (see Chapter 308), adenovirus (see Chapter 309), parechoviruses (see Chapter 297), and rhinovirus (see Chapter 310). CLINICAL MANIFESTATIONS In neonates and young infants, bacterial and viral infections can pres ent with isolated fever or nonspecific symptoms, making diagnosis of serious illnesses challenging. Some neonates and young infants will have signs of systemic illness |
7,007 | at presentation, including abnormal temperature (hypothermia 36C 96.8F, fever 38C 100.4F), abnormal respiratory examination (tachypnea 60 breathsmin, respi ratory distress, apnea), abnormal circulatory examination (tachycardia 180 beatsmin, delayed capillary refill 3 seconds, weak or bound ing pulses), abnormal abdominal examination, abnormal neurologic Table 220.1 Bacterial Pathogens in Neonates and Young Infants with Urinary Tract Infection, Bacteremia, or Meningitis FREQUENCY URINARY TRACT INFECTION BACTEREMIA AND MENINGITIS Common Escherichia coli Escherichia coli Group B Streptococcus Less common Klebsiella spp. Enterococcus spp. Listeria monocytogenes Streptococcus pneumoniae Staphylococcus aureus Klebsiella spp. Rare Group B Streptococcus Staphylococcus aureus Pseudomonas aeruginosa Enterobacter spp. Citrobacter spp. Proteus mirabilis Neisseria meningitidis Salmonella spp. Enterobacter spp. Enterococcus spp. Cronobacter sakazakii Haemophilus influenzae Citrobacter Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 220 u Fever Without a Focus in the Neonate and Young Infant 1643 examination (lethargy, irritability, alterations in tone), or abnormal skin examination (rash, petechiae, cyanosis). Infants with septic arthritis or osteomyelitis may appear well except for signs around the involved joint or bone or may only manifest with pseudoparaly sis (disuse) and paradoxical irritability (infant experiences pain during attempts to comfort the child). DIAGNOSIS Historically, all neonates 60 or 90 days of age were hospitalized; underwent laboratory evaluation of the blood, urine, and cerebrospinal fluid (CSF); and received empirical antibiotics. Additionally, some patients had stool cultures, had chest radiographs, had HSV evalua tion, andor received empirical antiviral agents. Under this approach, many infants without SBI or serious viral infection received evaluation, treatment, and hospitalization. Protocols were subsequently developed to identify infants at lower risk of SBI, who may be managed outside the hospital setting. The most current protocol is the American Academy of Pediatrics (AAP) guideline, which considers UTIs separately from bacteremia and meningitis (Table 220.2). Despite protocols, substan tial variation continues to exist in the approach to and management Table 220.2 Management of Fever Without Source in Infants 0 36 Months Old GROUP MANAGEMENT Any toxic appearing child 036 mo and temperature 38C (100.4F) Hospitalize, cultures (blood, urine, CSF) plus other tests, parenteral antibiotics WELL APPEARING CHILD Child 22 days and temperature 38C (100.4F) Hospitalize, cultures (blood, urine, CSF) plus other tests, parenteral antibiotics Child 2260 days and temperature 38C (100.4F) Three Step Process 1. Determine risk based on history, physical examination, and laboratory studies. Low risk: Uncomplicated medical history Well appearing physical examination Normal laboratory studies Urine: negative leukocyte esterase and nitrite, 5 WBChpf centrifuged and 10 WBChpf uncentrifuged Inflammatory markers: temperature 38.5C, procalcitonin 0.5 ngmL, CRP 20 mgL, absolute neutrophil count 4,000 5,200mm3 Stool studies if diarrhea (no RBC and 5 WBChpf) 2. If child fulfills all low risk criteria, use age to determine need for LP, parenteral antimicrobials, and hospital observation. Age 22 28 days: Obtain UA, blood culture, inflammatory markers. May perform LP. May administer parenteral antimicrobials. Observe in hospital. Age 29 60 days old: |
7,008 | Obtain UA, blood culture, inflammatory markers. Need not perform LP. Need not administer antimicrobials. Observe closely at home with follow up within 24 36 hr. 3. If child does not fulfill all low risk criteria, use age and lab results to determine need for LP, antimicrobials, and hospital observation. Age 22 28 days with abnormal UA and normal inflammatory markers: May perform LP. Administer parenteral antimicrobials. Observe in hospital. Age 22 28 days with abnormal inflammatory markers: Perform LP. If CSF pleocytosis, CSF uninterpretable, or abnormal UA, administer parenteral antimicrobials and observe in hospital. If CSF and UA are normal, may observe at home after parenteral antimicrobials or observe in the hospital with or without parenteral antimicrobials. Age 29 60 days with abnormal UA and normal inflammatory markers: Administer oral antimicrobials. May observe closely at home with follow up in 12 24 hr. Age 29 60 days with abnormal inflammatory markers: May perform LP. If CSF pleocytosis, administer parenteral antimicrobials and observe in hospital. If CSF is normal, may administer parenteral or oral antimicrobials and may observe closely in hospital or at home. If CSF is not available or uninterpretable, administer parenteral antimicrobials and may observe closely in hospital or at home. Child 2 36 mo and temperature 3839C (100.4102.2F) Reassurance that diagnosis is likely self limited viral infection, but advise return with persistence of fever, temperatures 39C (102.2F), andor new signs and symptoms. Child 2 36 mo and temperature 39C (102.2F) Two Step Process 1. Determine immunization status. 2. If received conjugate pneumococcal and Haemophilus influenzae type b vaccines, obtain urine studies (urine WBC, leukocyte esterase, nitrite, and culture) for all females, all males 6 mo old, all uncircumcised males 2 yr, and all children with recurrent urinary tract infections. If did not receive conjugate pneumococcal and H. influenzae type b vaccines, manage according to the 1993 Guidelines (see Baraff et al. Ann Emerg Med. 1993;22:11981210). Other tests may include chest radiograph, stool studies, herpes simplex and other virus polymerase chain reaction. CSF, Cerebrospinal fluid; hpf, high powered field; LP, lumbar puncture; RBC, red blood cell; UA, urinalysis; WBC, white blood cell. Modified from Huppler A. Fever. In: Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table 52.5, p. 971; with data from Pantell RH, Roberts KB, Adams WG, et al. Evaluation and management of well appearing febrile infants 8 to 60 days old. Pediatrics. 2021;148(2):e2021052228. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1644 Part XV u Infectious Diseases of the febrile infant. It must be emphasized that these criteria apply to the well appearing child; those who appear critically ill (septic) require prompt evaluation, resuscitation, and empiric antibiotic therapy (within 1 hour). In the past, experts advocated that all neonates 28 days old undergo a complete evaluation for serious infection, |
7,009 | receive empirical antimi crobials, and be hospitalized. In prior risk criteria, one allowed neo nates 28 days to be designated as low risk and managed outside the hospital without antimicrobials. In one study, 1 of low risk infants 28 days old had SBI; however, in another study applying the other criteria to neonates, 34 of those classified as low risk had SBI. In the current protocols, neonates 22 28 days who meet certain low risk criteria can be managed outside the hospital; in one study, the risk of bacteremia in this age group was lower than in infants 22 days (1.6 vs 3.35.3). Young febrile infants 29 days old who appear ill (with signs of systemic illness) require complete evaluation for serious infection, empiric antimicrobials, and hospitalization; however, well appearing infants can be managed safely as outpatients using low risk criteria as indicated in Table 220.2. With each of these approaches, infants must have a normal physical examination, must be able to reliably obtain close follow up, and must meet certain laboratory andor radiographic criteria. Based on these protocols, all infants meeting the previous criteria would undergo lumbar puncture (LP), whereas low risk infants meeting other criteria and following the current pro tocols would not. There is substantial variation in clinical practice in the performance of LPs in well appearing infants 28 days. When deciding whether to perform an LP in this age group, clinicians should consider multiple factors, including the home situation and the ability to contact the family. The protocols discussed in Table 220.2 were initially developed for use in the emergency department (ED). Infants evaluated in the office setting may warrant a different approach when a relationship between the physician and family already exists to facilitate clear communi cation and timely follow up. In one large study of febrile infants 3 months old who were initially evaluated for fever in the office setting, clinicians hospitalized only 36 of infants but initiated antibiotics in 61 of the 63 infants with bacteremia or bacterial meningitis. These findings suggest that, with very close follow up (including multiple in person visits or frequent contacts by telephone), some febrile infants perceived to be at low risk for invasive bacterial infection (bacteremia and meningitis) on the basis of history, physical exami nation, and normal but limited laboratory testing can be managed in an office based setting. It is important to note that 3 of infants with SBI did not initially receive empiric antibiotics, necessitating careful consideration of risks and benefits of selective rather than universal testing and empiric antibiotic treatment of febrile infants evaluated in the office setting. Viral Respiratory Illness Several studies have demonstrated a decreased risk of SBI in infants with positive testing for influenza, RSV, and other respiratory viral ill nesses, although the risk of UTI remains significant. In one prospective study, the risk of SBI in neonates 28 days old was not altered by RSV status. Given these data, young febrile infants with bronchiolitis may not require LP, particularly |
7,010 | if they can be closely observed or have close follow up. Urinary Tract Infection and Bacterial Meningitis In the past, infants with abnormal findings on urinalysis (UA) would undergo complete evaluation for infection, including LP. In well appearing infants 28 days old with an abnormal UA, some evidence suggests that the risk of bacterial meningitis is extremely low: 0.5. For neonates 0 28 days, the risk of concomitant bacterial meningitis with UTI is 12. CSF pleocytosis in the absence of bacterial meningitis (i.e., sterile pleocytosis) has been reported in 23 infants with UTI. The cause is uncertain, with some studies attributing this phenomenon to traumatic LPs or undetected viral infection rather than inflammation in the con text of systemic illness. LABORATORY DIAGNOSIS Complete Blood Count The peripheral complete blood cell count (CBC) and differential are frequently obtained by providers when evaluating febrile neonates and infants. The white blood cell (WBC) count alone cannot accu rately predict SBI risk. In one series, isolated use of the WBC cutoffs of outside 5,000 15,000 WBCsmm3 would miss at least 33 of infants with bacteremia and 40 of those with meningitis. A prospective study found no increased risk of SBI in febrile, well appearing infants with leukopenia (WBC count 5,000mm3). The WBC count com bined with other factors may help determine an infants risk of SBI, but it should not be used in isolation to predict infection risk. The absolute neutrophil count (ANC) has also been used in evaluating the risk of serious infection. Two recent large studies derived ANC cutoffs of greater than 4,000 and 5,200 per mm3 for use in specific protocols; however, these protocols used ANC in conjunction with other markers. Blood Culture The ability to identify pathogens in the blood depends on the volume of blood, the timing of the blood culture in relation to antimicrobial administration, and, to a lesser degree, the number of blood cultures obtained. A negative blood culture does not exclude the possibility of bacterial meningitis; in one study, 38 of infants with culture proven bacterial meningitis had negative blood cultures. For additional infor mation on the time to positivity of blood cultures in neonates and young infants, see Discharge from the Hospital. Urinalysis Different methods can assist in making a presumptive diagnosis of UTI while awaiting results of a urine culture. Traditional UA con sists of dipstick biochemical analysis of urine for nitrites or leukocyte esterase (LE) and microscopic examination of the urine for WBCs and bacteria. One study found that the traditional UA had a higher nega tive predictive value (NPV) than dipstick alone (99.2 vs 98.7), but that dipstick alone had a higher positive predictive value (PPV, 66.8 for dipstick alone vs 51.2 for traditional UA). Enhanced UA includes hemocytometer cell count (to decrease variability of urine cell counts) and Gram stain on uncentrifuged urine. The enhanced UA has a higher sensitivity but comparable specificity to traditional UA. However, the enhanced UA has not been studied in the most common protocols for evaluation |
7,011 | of the febrile infant, and many institutionsoffice practices do not perform this test. Cerebrospinal Fluid CSF evaluation consists of culture and Gram stain, cell count, glucose, and protein. Polymerase chain reaction (PCR) testing may also be sent based on the clinical scenario, usually for enterovirus or HSV (some include bacterial pathogens). Normal CSF parameters vary by age of the infant and should be interpreted in combination with other clinical and historical risk factors, given that some infants with normal CSF parameters may rarely have CNS infections (Table 220.3). The CSF Gram stain can be a useful adjunct to other CSF parameters given the high specificity of the test (99.399.9; i.e., relatively few false positive results), although the range of reported sensitivity is much broader (6794.1). The interpretation of CSF can be challenging in the setting of a trau matic LP, where the CSF is contaminated with peripheral blood. Some clinicians assume a ratio of WBCs to red blood cells (RBCs) of 1:500 in the CSF. Others advocate calculating the expected CSF WBCs based on the peripheral blood WBCs and RBCs and then using the observed to predicted ratio of CSF WBCs to aid in the identification of bacterial meningitis. This calculation assumes that the ratio of WBCs to RBCs in the peripheral blood remains constant after introduction into the CSF. Next generation molecular testing is helpful in identifying the most Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 220 u Fever Without a Focus in the Neonate and Young Infant 1645 common bacterial and viral pathogens despite a traumatic LP; results are often available within a few hours. One retrospective cohort study concluded that an observedpre dicted CSF WBC ratio of 0.01 was helpful in predicting the absence of bacterial meningitis; however, another retrospective cohort study and one case series of traumatic LPs concluded that adjustment of CSF WBC count does not improve the accuracy of diagnosis of meningitis in patients with traumatic LPs. Clinicians may consider hospitalization and empirical antimicrobials in patients with traumatic LPs given the challenge of interpreting the CSF WBC count when there is blood con tamination of the specimen. Treatment with antibiotics before LP can complicate the interpre tation of CSF cultures. CSF cultures are negative relatively rapidly after antibiotic administration, within 2 hours for N. meningitidis and 4 24 hours for S. pneumoniae. Next generation molecular testing is not affected by prior antibiotic treatment, thus enhancing a diagnosis despite prior antibiotic therapy. In patients with bacterial meningitis, CSF glucose increases to normal range, often within 4 24 hours of antibiotic administration, whereas CSF protein concentrations, despite decreasing, remain abnormal for 24 hours after antibiotic administra tion. Changes in CSF WBC count and ANC are minimal in the first 24 hours of antibiotic therapy. Therefore CSF findings can provide rel evant management information even in the setting of |
7,012 | antibiotic admin istration before LP. Herpes Simplex Virus Testing No consensus exists on which neonates should be tested and empiri cally treated for HSV infection. Historical and clinical features that CSF WHITE BLOOD CELL COUNTS CELLSMM3 Upper limit of normal by age 1 28 days 18 29 60 days 8.5 61 90 days 8.5 Upper limit of normal by age 0 28 days 15 29 60 days 9 90th percentile by age 0 7 days 26 8 28 days 8 9 29 56 days 6 8 95th percentile by age 0 28 days 19 29 56 days 9 95th percentile by age 0 28 days 16 29 60 days 11 CSF PROTEIN MGDL Upper limit of normal by age 1 28 days 131 29 60 days 105.5 61 90 days 71 Upper limit of normal by age 0 28 days 127 29 60 days 99 Table 220.3 Values of Cerebrospinal Fluid (CSF) Studies in Neonates and Infants by Age CSF PROTEIN MGDL 90th percentile by age 0 7 days 153 8 28 days 84 106 29 56 days 84 105 95th percentile by age 0 14 days 132 15 28 days 100 29 42 days 89 43 56 days 83 95th percentile by age 0 28 days 118 29 60 days 91 CSF GLUCOSE MGDL Lower limit of normal by age 1 28 days 30 29 60 days 30.5 61 90 days 33.5 Lower limit of normal by age 0 28 days 25 29 60 days 27 10th percentile for infants 0 56 days 38 43 10th percentile by age 0 28 days 37 29 60 days 39 Data from Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr. 2011;158(1):130134. All infants had nontraumatic lumbar puncture (LP) and no evidence of bacterial or viral infection. Data from Chadwick SL, Wilson JW, Levin JE, Martin JM. Cerebrospinal fluid characteristics of infants who present to the emergency department with fever: establishing normal values by week of age. Pediatr Infect Dis J. 2011;30(4):e63e67. All infants were excluded if they had identified viral or bacterial meningitis, positive blood or urine cultures, a ventriculoperitoneal shunt, recent neurosurgeryantibioticsseizure, or a traumatic LP. Data from Kestenbaum LA, Ebberson J, Zorc JJ, et al. Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants. Pediatrics. 2010;125(2):257 264. Infants were excluded for traumatic LP, serious bacterial infection, congenital infection, seizure, presence of ventricular shunt, or positive CSF testing for enterovirus. Data from Shah SS, Ebberson J, Kestenbaum LA, et al. Age specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med. 2011;6(1):2227. Infants were excluded for traumatic LP, serious bacterial infection, congenital infection, seizure, presence of a ventricular shunt, positive CSF testing for enterovirus, or elevated serum bilirubin. Data from Thomson J, Sucharew H, Cruz AT, et al. Cerebrospinal fluid reference values for young infants undergoing lumbar puncture. Pediatrics. 2018;141(3):e20173405. Infants were excluded for missing any component of the CSF profile, traumatic LP, |
7,013 | serious bacterial infection, viral CNS infection, non CNS HSV disease, or prolonged hospital length of stay. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1646 Part XV u Infectious Diseases should raise concern for HSV include exposure to individuals infected with HSV, particularly mothers with primary HSV infections or first time genital infections, seizure or abnormal neurologic examination, vesicular rash, ill appearance, apnea, hypothermia, petechial rash excessive bleeding, hepatic failure, or a history of a scalp electrode. However, neonates with HSV can present without any high risk clini cal or historical features, particularly with early isolated CNS dis ease. Published approaches to neonatal HSV include (1) testing and empirical treatment of all neonates 21 days old who are evaluated for infection; (2) testing and empirical treatment of neonates with the presence of high risk clinical features for HSV; and (3) testing and empirical treatment for all neonates with high risk features plus testing the CSF of all neonates 21 days old while deferring empiri cal acyclovir in those without high risk features, unless the CSF HSV PCR test is positive. The AAP Committee on Infectious Diseases recommends that neonates undergoing evaluation for HSV have the following labora tory studies performed: surface cultures or PCR of the conjunctiva, mouth or nasopharynx, rectum, and any vesicles; CSF PCR (sensitivity: 75100); whole blood PCR; and serum levels of alanine transaminase (ALT). HSV PCR testing of the mouth, conjunctiva, nasopharynx, rec tum, and vesicles has been shown to be more sensitive than culture, with comparable specificity, although no direct comparisons have been performed in neonates. Enterovirus Testing Enterovirus is a common and typically benign cause of fever in febrile infants, although it can be difficult to distinguish from SBI on initial presentation. Enterovirus PCR testing of the CSF is a sensitive and rapid means to diagnose infection. One retrospective study of patients with CSF enterovirus testing found no cases of bacterial meningitis in patients with positive enterovirus PCR; this study did not include neo nates 28 days old. Several studies have demonstrated shorter length of stay, fewer antibiotics, and lower cost among infants with positive CSF enterovirus test results. These results suggest that during local enterovi rus seasons, and if PCR testing is available, testing for enterovirus may be of benefit in the evaluation of febrile infants and neonates. Some centers have implemented multiplex PCR panels, which permit test ing for multiple viruses, including enterovirus and HSV (and bacteria) simultaneously. Other Inflammatory Markers Investigations have examined the utility of inflammatory markers such as C reactive protein (CRP) and serum procalcitonin (PCT) in the diagnosis of SBI and, more specifically, IBI (bacteremia and meningitis) (see Table 220.2). One meta analysis reported that PCT is superior to WBC count and CRP for the detection of IBI in chil dren 3 years old, whereas another found that PCT was inferior to |
7,014 | prediction rules in identifying SBI in young infants. A prospective multicenter cohort study of febrile infants 7 91 days old determined that the PCT was better at identifying patients with IBI than CRP, WBC count, or ANC. Building on these results, clinical prediction rules for febrile infants, such as the Step by Step approach, incor porate PCT and CRP, along with age 21 days, ill appearance, ANC 10,000mm3, and pyuria in a stepwise approach to determine which patients are at high risk for IBI; only 0.7 of infants who met none of those criteria had IBI. In the approach from the AAP, inflammatory markers are recommended for all infants 22 days and older as part of risk stratification. If available, this approach recommends PCT along with either CRP or ANC. If PCT is unavailable, then CRP, ANC, and elevation in temperature should be considered as markers of inflam mation (see Table 220.2). Other Diagnostic Studies Older infants with positive RSV and influenza testing have a very low risk of SBI beyond UTI. One large case based survey demonstrated decreased admission rates and antibiotic use for infants with positive respiratory viral tests, and another study demonstrated that implemen tation of a care algorithm incorporating viral testing led to a shorter length of stay and antibiotic course. Chest radiographs are unlikely to be clinically useful in the evalu ation of the febrile infant without respiratory symptoms. Studies that have examined routine use of radiographs have found limited utility because in infants without respiratory symptoms, most results will be normal and abnormal results can be difficult to interpret. TREATMENT Antimicrobials Ill appearing and high risk infants and those 22 days old hospitalized for evaluation for SBI should receive antimicrobial therapy. Commonly used regimens include (1) a third generation cephalosporin (typically cefepime or ceftazidime), (2) a third generation cephalosporin and ampicillin, or (3) an aminoglycoside and ampicillin. Ampicillin is the preferred treatment of GBS and covers L. mono cytogenes and many Enterococcus spp. and some E. coli. For neonates 0 28 days, options 2 or 3 have been recommended, given the risk of L. monocytogenes. For young infants 28 days, option 1 (third generation cephalosporin: ceftriaxone) is a reasonable choice. For ill appearing infants or those with positive CSF Gram stains, additional antibiotics may include vancomycin or broad spectrum antibiotics such as car bapenems. Local epidemiology and resistance patterns may assist in these choices. Neonates with concern for HSV should be empirically treated with high dose acyclovir (60 mgkgday). Treatment duration and route of antimicrobial administration depend on the infection. Additional details based on specific infections and organisms are available in the following chapters: meningitis (see Chapter 148), UTI (see Chapter 575), E. coli (see Chapter 246), GBS (see Chapter 230), and HSV (see Chapter 299). Discharge from the Hospital Traditionally, infants remained in the hospital receiving antimicrobial therapy until bacterial cultures were negative for 48 hours or even lon ger. Multiple studies have suggested that shorter culture observation periods (i.e., 24 or 36 |
7,015 | hours) may be reasonable because most patho gens in the blood grow within this time frame when automated blood culture monitoring systems are used. In one multicenter retrospective cross sectional study, 91 of blood cultures were positive by 24 hours and 96 by 36 hours. Fewer studies have evaluated the time to positivity of CSF and urine cultures, but in one large study of febrile infants 28 90 days old, all positive CSF cultures grew within 24 hours (median time to positivity, 18 hours). For blood cultures, 1.3 grew after 24 hours (median time to positivity, 16 hours), and for urine cultures, 0.9 grew after 24 hours (median time to positivity, 16 hours). In one multicenter study including infants 60 days old, 82 of CSF cultures were positive by 24 hours and 86 by 36 hours. For neonates undergoing evalua tion for HSV, it is reasonable to await results of HSV testing before discharge to home. For patients with identified bacterial infections or HSV infections, the duration of the hospital stay will be determined by the specific pathogen and site of infection. PROGNOSIS Most well appearing neonates and young infants with fever recover completely and relatively quickly, depending on the etiology of the fever. Most infection related mortality and long term morbidity result from HSV infection and bacterial meningitis. For HSV, reported mor tality rates range from 27 to 31 for disseminated disease and from 4 to 6 for CNS disease. Of those who survive, 83 of patients with disseminated disease and 31 of those with CNS disease will have nor mal development at 12 months old. The mortality of bacterial menin gitis varies by pathogen but ranges from 4 to 15. In one study of children who had meningitis as infants, 84 had normal development at age 5 years. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 221 u Fever in the Older Child 1647 Fever is the most common reason for a child to seek medical care. While most infants and children have benign viral causes of fever, a small proportion will have more serious infections. Unlike fever in young infants, pediatricians can rely more readily on symptoms and physical examination findings to establish a diagnosis in older chil dren. Laboratory testing and radiographic studies are not routinely indicated but may be helpful when diagnostic uncertainty exists or the patient appears critically ill. Occult infections, such as urinary tract infection (UTI), may be present, and testing for such infections should be guided by demographic and contextual factors such as patient age, patient gender, and environmental exposures. DIAGNOSIS The many potential causes of fever in older infants and children can be broadly categorized into viral and bacterial infections, further orga nized by body region, as well as the less common inflammatory, onco logic, endocrine, and |
7,016 | medication induced causes (Table 221.1). Viral Infections Viral infections are the most common cause of fever, and the prevalence of specific viral infections varies by season. Typically, in the summer and early fall, enteroviruses (e.g., coxsackieviruses) predominate, usually presenting as hand foot and mouth disease, herpangina, aseptic men ingitis, or a variety of other manifestations. In the late fall and winter, viral upper and lower respiratory tract infections caused by respiratory viruses such as respiratory syncytial virus (RSV) and influenza and gas troenteritis caused by gastrointestinal (GI) viruses such as norovirus and rotavirus are common. Parainfluenza viruses are a common cause of laryngotracheobronchitis (croup) and occur primarily in the fall and spring, affecting mostly infants and toddlers. Varicella is a less common cause of fever than in the past because of childhood vaccination but still occurs, with the highest incidence in winter and early spring. Coronavi rus disease 2019 (COVID 19) caused by SARS CoV 2 can cause fever alone or with either upper or lower respiratory tract symptoms in young children, though asymptomatic infections also occur. Bacterial Infections Common bacterial infections include acute otitis media and streptococ cal pharyngitis (strep throat). Acute otitis media is diagnosed by the presence of a bulging, erythematous, and nonmobile tympanic membrane upon insufflation. Streptococcal pharyngitis occurs most frequently in the late fall and winter and is uncommon before age 3 years. The pres ence of focal auscultatory findings, including crackles, suggests a lower respiratory tract infection, such as bacterial pneumonia, but may also be present among children with bronchiolitis and viral pneumonia. Atypical pneumonia caused by mycoplasma typically occurs in school age children and is often associated with headache, sore throat, malaise, and low grade fever. The presence of neck pain (especially with neck extension for those with retropharyngeal abscess), drooling, or muffled voice may indicate a deep neck infection such as a retropharyngeal abscess, which occurs in infants and young children, or a peritonsillar abscess, which typically affects older children. Skin and soft tissue infections such as cellulitis and abscess may also present with fever, with the buttocks a common area for abscesses in young children. Bone and joint infections such as osteomyeli tis and septic arthritis may present with fever and refusal to bear weight or limp in the young child. Invasive bacterial infections, including sepsis and bacterial meningitis, must be considered in young children present ing with fever. Although uncommon, these infections are potentially life threatening and require prompt recognition and treatment. Ill appearance, lethargy, and tachycardia are typically present among children with severe sepsis, and petechiae may be an early finding among children with menin gococcemia or other invasive bacterial diseases. Figures 221.1 and 221.2 show age related diagnoses and organisms producing bacterial sepsis in infants and children. Children with fever who are immunosuppressed, such as children receiving chemotherapy or those with sickle cell disease, are at higher risk for invasive bacterial infection. Infants and children age 2 24 months merit special consideration because they have limited verbal skills, |
7,017 | are at risk for occult bacterial infections, and may be otherwise asymptomatic except for fever (see Chapter 220). Occult Urinary Tract Infection Among children 2 24 months old without symptoms or physical examination findings that identify another focal source of infection, the prevalence of UTI may be as high as 510. The highest risk of UTI occurs in females and uncircumcised males, with a very low rate of infection (0.5) in circumcised males. Table 221.2 lists clinical risk factors for UTI. Occult Bacteremia Occult bacteremia is defined as a positive blood culture for a pathogen in a well appearing child without an obvious source of infection. In the 1990s, before vaccination programs against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, up to 5 of young children age 2 to 24 (up to 36) months with fever 39C (102.2F) had occult bacteremia, most often caused by S. pneumoniae. Currently, the preva lence of occult bacteremia is far less than 1 in febrile, well appearing young children. Most cases of pneumococcal occult bacteremia are transient, with a minority of these children developing new focal infections, sepsis, or other sequelae. Unimmunized and incompletely immunized young children remain at higher risk for occult bacteremia because of pneumococcus (see Chapter 228). Bacteremia caused by Hib or meningococcus should not be considered benign because sub sequent serious invasive infection may rapidly follow the bacteremia. GENERAL APPROACH The general approach to fever in the older child begins with an assess ment of the childs overall appearance and vital signs. A detailed history of the present illness and a thorough physical examination should be performed to identify the cause of the fever. Overall Appearance and Vital Signs Children who are ill or appear toxic or who have abnormal vital signs (e.g., tachycardia, tachypnea, hypotension) require rapid assessment, including a focused physical examination to evaluate for the possibility of an invasive bacterial infection. A more detailed history and physical exam can be performed in the well appearing child. Symptoms A thorough history should be obtained from the caregiver (and patient, when appropriate), including a characterization of the fever and any other associated symptoms. The degree and duration of the fever should be assessed, and the method of taking the temperature should be ascer tained (e.g., forehead, axillary, oral, rectal). For children with prolonged fever, it is important to determine whether the fever has been episodic or persistent. Patients with prolonged fever may harbor occult infections, UTI, or bone or soft tissue infections or may have an inflammatory or oncologic condition. Additionally, Kawasaki disease and multisystem inflammatory syndrome in children (MIS C) should be considered among children with prolonged fever, and a careful evaluation for other stigmata associated with these conditions is warranted (see Chapter 208). After characterizing the fever, it is important to ask systemati cally about the presence of symptoms that may identify an etiol ogy for the fever, including symptoms of common viral infections such as rhinorrhea, cough, vomiting, and diarrhea. Additionally, symptoms should be elicited |
7,018 | for each body system: headache, ear pain, sore throat, neck pain or swelling, difficulty breathing, chest pain, abdominal pain, rash or changes in skin color, extremity pain or difficulty with ambulation (including refusal to bear weight in a Chapter 221 Fever in the Older Child Laura Brower and Samir S. Shah Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1648 Part XV u Infectious Diseases young child), and overall activity level. In older children, the pres ence of dysuria, urinary frequency, or back pain may indicate UTI. Assessment of oral intake and urine output is also critical because dehydration may accompany common childhood infections and is associated with higher rates of morbidity. The presence of weight loss or night sweats may indicate leukemia, lymphoma, or tubercu losis. Additionally, a thorough social history should be performed, inquiring about attendance at daycare, any travel, and any sick con tacts at daycare, school, or in the household. Physical Examination A complete physical examination includes particular attention to body systems with associated symptoms (e.g., thorough exam of oropharynx for child with sore throat). A complete physical Table 221.1 Etiologies of Fever in Children 2 Mo of Age INFECTIOUS Central Nervous System Bacterial meningitis Viral meningitis Viral encephalitis Epidural abscess Brain abscess Ear, Nose, and Throat Acute otitis media Mastoiditis Viral upper respiratory infection (i.e., common cold) Acute bacterial sinusitis Acute streptococcal pharyngitis Acute viral pharyngitis Retropharyngeal abscess Ludwig angina Peritonsillar abscess Herpangina Herpes simplex virus gingivostomatitis Acute bacterial lymphadenitis Viral laryngotracheobronchitis (i.e., croup) Bacterial tracheitis Epiglottitis Lemierre syndrome Face and Ocular Parotitis (viral and bacterial) Erysipelas Preseptal cellulitis Orbital cellulitis Lower Respiratory Tract Acute viral bronchiolitis Pneumonia (viral and bacterial) Complicated pneumonia (e.g., empyema, pleural effusion) Tuberculosis Cardiac Pericarditis Myocarditis Endocarditis Gastrointestinal Gastroenteritis (viral and bacterial) Mesenteric adenitis Acute appendicitis Hepatitis Pancreatitis Gallbladder disease (e.g., cholecystitis, cholangitis) Intraabdominal abscess Genitourinary Urinary tract infectionpyelonephritis Renal abscess Epididymitis Pelvic inflammatory disease Tubo ovarian abscess Skin, Soft Tissue, and Muscle Viral exanthemas (e.g., varicella, coxsackievirus, roseola, measles) Scarlet fever Syphilis Cellulitis Abscess Necrotizing fasciitis Myositis (viral and bacterial and immune) Bone and Joint Osteomyelitis Septic arthritis Transient synovitis Spondylodiscitis Toxin Mediated Toxic shock syndrome Staphylococcal scalded skin syndrome Invasive Bacterial Infections Occult bacteremia Bacterial sepsis Bacterial meningitis Disseminated gonococcal infection Systemic Infection EBV CMV HIV Cat scratch disease Brucellosis Influenza Others (see Chapter 222) Vector Borne (Tick, Mosquito) Lyme disease Rickettsiae (e.g., Rocky Mountain spotted fever Ehrlichiosis Arboviruses (e.g., West Nile virus) Dengue fever INFLAMMATORY Kawasaki disease Acute rheumatic fever Systemic lupus erythematosus Inflammatory bowel disease Juvenile idiopathic arthritis IgA vasculitis (Henoch Schnlein purpura) Other rheumatologic diseases (e.g., dermatomyositis) Periodic fever syndromes Serum like sickness syndrome Multisystem inflammatory syndrome in children (MIS C) ONCOLOGIC Leukemia Lymphoma Solid tumors (e.g., neuroblastoma) ENDOCRINE Thyrotoxicosisthyroid storm MEDICATION INDUCED Serotonin syndrome Anticholinergic toxidrome (e.g., antihistamines) Sympathomimetic toxidrome (e.g., cocaine) Salicylate toxicity OTHER Hemophagocytic lymphohistiocytosis Macrophage |
7,019 | activation syndrome Ectodermal dysplasia Dysautonomia Factitious Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 221 u Fever in the Older Child 1649 examination is particularly important in young children 24 months old who have limited verbal skills to communicate localized pain. In older children the physical exam may proceed systematically from head to toe, but in younger children, who may be fearful of the exam, it is important to auscultate the heart and lungs first before proceeding to potentially painful or distressing aspects of the examination (e.g., inspection of ears or oropharynx). In addition to a careful evaluation of each body system, a complete examination should include an assess ment of neck pain and mobility, which may be limited in children with meningitis. Additionally, the examiner should palpate carefully for the presence of lymphadenopathy, which may be present with infectious and oncologic causes of fever. Erythema and exudate of the tonsils with palatal petechiae suggest streptococcal pharyngitis. Erythema, bulging, and decreased mobility of the tympanic membrane are the cardinal signs of acute otitis media. Diffuse crackles and wheezes on auscul tation of the lungs occur with acute viral bronchiolitis, whereas focal crackles or decreased breath sounds are more consistent with bacterial pneumonia. Focal tenderness in the right lower quadrant of the abdo men suggests appendicitis, and suprapubic tenderness may indicate UTI (cystitis). Any focal bony tenderness may reflect a diagnosis of osteomyelitis, whereas erythema, swelling, and limitation of range of motion suggest a diagnosis of septic arthritis. Abnormal gait or pain with ambulation without focal findings may also reflect a bone or joint infection. A careful skin examination should also be performed. The presence of petechiae may suggest meningococcal or other invasive bacterial infection, whereas viral exanthems are typically associated with a blanching macular or maculopapular rash. EVALUATION Laboratory Testing Laboratory testing is not routinely indicated in the well appearing child without a focus of infection on examination. Urine testing should be considered based on the childs age, duration of fever, and risk factors for UTI (see Table 221.2). In general, the decision to perform labora tory testing should be guided by the overall appearance and vital signs of the child, the presence of specific symptoms or physical examination findings, and the childs age. For children who are ill or appear toxic or who have vital sign abnor malities indicative of an invasive bacterial infection (tachycardia, hypo tension), rapid laboratory evaluation should be performed. Testing may include a blood culture and possibly urine and cerebrospinal fluid (CSF) cultures, depending on the age of the child and the presence or absence of physical exam findings indicative of UTI or bacterial menin gitis. Markers of inflammation, such as procalcitonin or C reactive pro tein may also be considered. Complete blood counts (CBCs) identify leukocytosis or leukopenia, anemia, and thrombocytosis or thrombo cytopenia. Children with infectious |
7,020 | mononucleosis may have lympho cyte predominance and the presence of atypical lymphocytes. Children 0 25 50 75 100 Prev iou sly he alt hy ch ild ren Neo na tes Chil dre n w ith co morb idi tie s Patient group P ro po rt io n of e pi so de s ( ) 28 3 65 da ys 1 4 y ea rs 5 9 y ea rs 10 1 6 y ea rs Age group Neo na tes (2 8 d ay s) Neo na tes (2 8 d ay s) 28 3 65 da ys 1 4 y ea rs 5 9 y ea rs 10 1 6 y ea rs Age group Abdominal infection Bone and joint infection CNS infection CLABSI Other infection type Pneumonia Primary bloodstream infection Urinarytract infection A B C Fig. 221.1 Age distribution of sites of infection causing blood cultureproven bacterial sepsis in children. Sites of infection are shown for (A) the three patient groups together and separately for (B) previously healthy children 28 days old and (C) neonates and children with comorbidities 28 days old. CLABSI, Central lineassociated bloodstream infection; CNS, central nervous system. Skin infection, wound infection, endocarditis, toxic shock syndrome; ear, nose, and throat infection; other, nonspecified focal infection. (From Agyeman PKA, Schlapbach LJ, Giannoni E, et al. Epidemiology of blood culture proven bacterial sepsis in children in Switzerland: a population based cohort study. Lancet Child Adolesc. 2017;1:124133, Fig. 3.) 0 25 50 75 100 P ro po rt io n of e pi so de s ( ) 28 3 65 da ys 1 4 y ea rs 5 9 y ea rs 10 1 6 y ea rs Neo na tes (2 8 d ay s) Neo na tes (2 8 d ay s) 28 3 65 da ys 1 4 y ea rs 5 9 y ea rs 10 1 6 y ea rs Prev iou sly he alt hy ch ild ren Neo na tes Chil dre n w ith co morb idi tie s Patient group Age groupAge group Coagulasenegative staphylococci Escherichia coli Group A streptococci Group B streptococci Other Gramnegative pathogens Other Grampositive pathogens Staphylococcus aureus Streptococcus pneumoniae A CB Fig. 221.2 Age distribution of pathogens causing blood cultureproven bacterial sepsis in children. Pathogens isolated in blood culture are shown for (A) the three patient groups together and separately for (B) previously healthy children 28 days old and (C) neonates and children with comorbidities 28 days old. Pseudomonas aeruginosa, Klebsiella spp., Neisseria meningitidis, Haemophilus influenzae, other gram negative pathogens. Enterococcus spp., viridans group streptococci, other gram positive pathogens. (From Agyeman PKA, Schlapbach LJ, Giannoni E, et al. Epidemiology of blood culture proven bacterial sepsis in children in Switzerland: a population based cohort study. Lancet Child Adolesc. 2017;1:124133, Fig. 4.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All |
7,021 | rights reserved. 1650 Part XV u Infectious Diseases who are immunosuppressed or who have a central venous catheter should also undergo diagnostic testing and receive prompt antimicro bial therapy, given their higher risk of invasive bacterial infection. For well appearing children with symptoms or signs indicative of a viral upper respiratory or GI infection, routine viral testing is not gen erally indicated. Influenza testing may be indicated within 48 hours of symptom onset in certain higher risk populations, with immuno suppression, chronic respiratory or cardiac disease, sickle cell disease, hospitalization, and age 2 years influencing the decision to treat with an antiviral agent. Testing for SARS CoV 2 may be indicated based on local prevalence and symptoms (fever, cough, congestion, loss of taste or smell, shortness of breath, body aches, fatigue, headache, sore throat, nausea, vomiting, or diarrhea). Viral testing may also be useful with pro longed fever to identify a source of the fever and avoid extensive evalu ation for inflammatory conditions such as Kawasaki disease or MIS C. Rapid strep testing of the oropharynx is indicated for children 3 years old with signs of streptococcal pharyngitis on examination. Although strep throat is uncommon in children 3 years old, this group should undergo rapid strep testing if they have signs of strep throat on exam and a household contact with streptococcal pharyngitis (see Chapter 229). Febrile children 2 months to 2 years old with several of the risk factors for UTI listed in Table 221.2, particularly females and uncir cumcised males, should undergo evaluation with urine dipstick, urine microscopy, and urine culture. Females and uncircumcised males 2 6 months old with high fever or fever that lasts 2 days may undergo urine testing even in the presence of respiratory tract infection, given the higher risk of UTI in this younger group (see Chapter 575). Given the very low risk of occult bacteremia, routine performance of blood testing (e.g., CBC, blood culture) is not indicated in the vast majority of immunized children with fever. Unimmunized and underimmunized children 2 years old remain at higher risk of occult pneumococcal bacteremia, and CBC, blood culture, andor inflamma tory markers may be considered in this population in the absence of another source of infection. Imaging The presence of focal crackles or decreased breath sounds on ausculta tion in the febrile child is suggestive of pneumonia. Current guidelines recommend presumptive antibiotic treatment for pneumonia based on clinical grounds and reserve the use of chest radiography for children with hypoxemia or significant respiratory distress and for those who fail outpatient therapy. Chest radiography is indicated for hospitalized children to assess for complicated pneumonia, including empyema. The performance of other imaging should be dictated by physical exam find ings. The presence of drooling and neck or throat pain in an infant or toddler may be suggestive of a retropharyngeal abscess, which is usually confirmed by imaging that may include a lateral radiograph of the soft tissue of the neck or computed tomography (CT) if clinical suspicion |
7,022 | is high. Ultrasonography (US) may be performed to assess for appendicitis in children with fever and focal right lower quadrant pain or abdominal pain that is severe. However, definitive imaging, including CT or MRI, may be required if US is nondiagnostic or if clinical suspicion is high. MANAGEMENT General Management Principles Management should be guided by the presence of specific symptoms by history or signs on physical examination. Based on the childs age and duration of fever, management may also be guided by focused diagnostic testing, such a urinalysis and selective urine culture testing among young febrile children (Fig. 221.3 and see Table 221.2). Supportive care, includ ing the use of antipyretics and adequate hydration, should be reviewed with the patient and caregiver for all children with fever. Children with viral infections generally require supportive care only, except for chil dren at higher risk of severe or complicated disease with influenza virus (see Chapter 305) or SARS CoV 2 (see Chapter 311). Antibiotics should Toxicappearing or signs of sepsis? Obvious source of infection 24 months of age? Immunocompromised? Risk factors for urinary tract infection (Table 221.2) Yes Treatment for sepsis (e.g. broadspectrum antibiotics, intravenous fluids) Chapter 85 No Yes Evaluation and management discussed in Chapter 223 No Yes No Yes Management guided by physical examination findings No Yes Urinalysis and urine culture; treatment based on results of urinalysis No Unimmunized or underimmunized against pneumococcus or Hib? Yes Consider complete blood count and blood culture; ceftriaxone if WBC 15,000microL No Supportive care, followup Management guided by physical examination findings Fig. 221.3 Algorithm for evaluation and management of fever in in fants and children 2 mo of age. Hib, Haemophilus influenzae type b; WBC, white blood cell count. Table 221.2 Risk Factors for Urinary Tract Infection in Children AMERICAN ACADEMY OF PEDIATRICS CLINICAL PRACTICE GUIDELINE CHILDREN 2 24 MO OF AGE Female Age 1 yr Temperature 39C (102.2F) Fever duration 2 days No obvious source of infection Male Uncircumcised males at higher risk Temperature 39C (102.2F) Fever duration 1 day No obvious source of infection UNIVERSITY OF PITTSBURGH UTICALC CHILDREN 2 23 MO OF AGE Age 12 mo Maximum temperature 39C History of UTI Female or uncircumcised male Duration of fever 48 hr No other source of fever Adapted from Subcommittee on Urinary Tract Infection, et al. Urinary tract infection clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595610. Adapted from Shaikh N, Hoberman A, Hum SW, et al. Development and validation of a calculator for estimating the probability of urinary tract infection in young febrile children. JAMA Pediatr. 2018;172(6):550556 and UTICalc Version 3.0, University of Pittsburgh 2021, https:uticalc.pitt.edu Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 222 u Fever of Unknown Origin 1651 be reserved for children with evidence of |
7,023 | bacterial infection on physical examination. A wait and see approach can be considered for children with acute otitis media, in whom a prescription for antibiotics can be provided to the family but instructions given to not fill the prescrip tion unless severe or worsening symptoms develop (see Chapter 680). Oral antibiotics can be prescribed to young children with UTI, although children who cannot tolerate oral intake, are vomiting or dehydrated, or appear toxic require parenteral antibiotics and hospitalization. Blood tests, including CBC and blood culture, should be consid ered to evaluate for occult bacteremia in the unimmunized child. One management strategy for these children is to administer a parenteral antibiotic (e.g., ceftriaxone) if leukocytosis (white blood cell count 15,000L), elevated absolute neutrophil count (10,000L), or ele vated inflammatory markers (procalcitonin 0.5 ngmL) are present while awaiting results of blood culture. Children who appear toxic or who have signs of either sepsis or bacterial meningitis require emer gent treatment with parenteral antibiotics as well as adjunct therapies to support the childs hemodynamics (see Chapter 85). Importantly, anticipatory guidance should be provided to all families of children with fever, including the criteria to return to care and the importance of fever control and adequate hydration. Other Considerations Children who are unimmunized or underimmunized are at higher risk of invasive bacterial infection, as are children who are immunocom promised. Management of fever in these children is described further in Chapter 223. Additionally, the approach to fever in the returning traveler should be focused on identifying commonly encountered infections based on the region of travel (see Chapter 218). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 222 Fever of Unknown Origin Andrew P. Steenhoff Fever of unknown origin (FUO) is a diagnostic dilemma for pedia tricians because it is often difficult to distinguish clinically between benign and potentially life threatening causes. Pediatricians face the important challenge of not missing the diagnosis of a serious illness or an easily treatable condition that can result in increased morbidity. Fortunately, FUO is usually an uncommon presentation of a common disease, with most of these common diseases being easily treatable. The classification of FUO is best reserved for children with a tem perature 38C (100.4F) documented by a healthcare provider and for which the cause could not be identified after at least 8 days of evalu ation (Table 222.1). It is important to differentiate FUO from fever without a source (FWS). FWS is fever where the source has not yet been identified and is differentiated from FUO by the duration of the fever. FWS can progress to FUO if no cause is elicited after 7 days of evaluation. ETIOLOGY The many causes of FUO in children are infectious, rheumatologic (connective tissue or autoimmune), autoinflammatory, oncologic, neurologic, genetic, factitious, and iatrogenic processes (Table 222.2). Although oncologic disorders should be seriously considered, most children with malignancies do not have fever alone. The possibility of drug fever should be considered if the patient is receiving any drug. Drug fever is usually |
7,024 | sustained and not associated with other symp toms. Discontinuation of the drug is associated with resolution of the fever, generally within 72 hours, although certain drugs, such as iodides, are excreted for a prolonged period, with fever that can persist for as long as 1 month after drug withdrawal. Most fevers of unknown origin result from atypical presentations of common diseases. In some cases, the presentation as an FUO is characteristic of the disease (e.g., juvenile idiopathic arthritis), but the definitive diagnosis can be established only after prolonged observa tion, because initially there are no associated or specific findings on physical examination, and all laboratory results are negative or normal. In the United States the systemic infectious diseases most commonly implicated in children with FUO are bacterial enterocolitis, including salmonellosis, as well as tuberculosis, rickettsial diseases, syphilis, Lyme disease, cat scratch disease, atypical prolonged presentations of common viral diseases such as adenovirus infection, Epstein Barr virus (EBV) infection, cytomegalovirus (CMV) infection, viral hepati tis, coccidioidomycosis, histoplasmosis, malaria, Angiostrongylus can tonensis infection, and toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and rat bite fever. Acquired immunodeficiency syndrome (AIDS) alone is not usually responsible for FUO, although febrile illnesses often occur in patients with AIDS as a result of opportunistic infections (see Table 222.1). Juvenile idiopathic arthritis (JIA) and systemic lupus erythemato sus (SLE) are the connective tissue diseases most often associated with FUO. Inflammatory bowel disease (IBD) and Kawasaki disease are also frequently reported as causes of FUO. If factitious fever (inocula tion of pyogenic material or manipulation of the thermometer by the patient or parent) is suspected, the presence and pattern of fever should be documented in the hospital. Prolonged and continuous observation of the patient, which can include electronic or video surveillance, is imperative. FUO lasting 6 months is uncommon in children and suggests granulomatous, autoinflammatory, or autoimmune disease. Repeat interval evaluation is required, including history, physical examination, laboratory evaluation, and imaging studies. Historically, 90 of pediatric FUO cases in the United States had an identifiable cause: approximately 50 infectious, 1020 colla gen vascular, and 10 oncologic. Other studies had variable results: 2044 infectious, 07 collagen vascular, 23 oncologic, and up to 67 undiagnosed. The reason for the paradoxical increase in undiag nosed cases of FUO ironically is likely caused by improved infectious and autoimmune diagnostic techniques. The advent of polymerase chain reaction (PCR), improved culture techniques, and better under standing of atypical viral and bacterial pathogenesis and autoimmune processes likely contribute to earlier diagnosis of these conditions and fewer children with these conditions advancing to the category of FUO. By contrast, causes of FUO remain primarily infectious in low and middle income settings where there is a higher infectious disease bur den and advanced diagnostic techniques are more limited. DIAGNOSIS The evaluation of FUO requires a thorough history and physical exami nation supplemented by a few screening laboratory tests and additional laboratory and imaging evaluation informed by the history or abnormal ities on examination |
7,025 | or initial screening tests (see Table 222.2). Occasion ally the fever pattern helps make a diagnosis (Fig. 222.1). Nonetheless, most diseases causing an FUO do not have a typical fever pattern. History A detailed fever history should be obtained, including onset, fre quency, duration, response or nonresponse to therapy, recurrence, and associated symptoms. Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause), par ticularly when associated with kidney disease, liver or biliary disease, infective endocarditis, malaria, brucellosis, rat bite fever, or a locu lated collection of pus. The age of the patient is helpful in evaluating FUO. Children 6 years old often have a respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JIA, or rarely, leukemia. Adolescent patients are more likely to have IBD, autoimmune pro cesses, lymphoma, or tuberculosis in addition to the causes of FUO found in younger children. A history of exposure to wild or domestic animals should be solic ited. The incidence of zoonotic infections in the United States is Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 222 u Fever of Unknown Origin 1651 be reserved for children with evidence of bacterial infection on physical examination. A wait and see approach can be considered for children with acute otitis media, in whom a prescription for antibiotics can be provided to the family but instructions given to not fill the prescrip tion unless severe or worsening symptoms develop (see Chapter 680). Oral antibiotics can be prescribed to young children with UTI, although children who cannot tolerate oral intake, are vomiting or dehydrated, or appear toxic require parenteral antibiotics and hospitalization. Blood tests, including CBC and blood culture, should be consid ered to evaluate for occult bacteremia in the unimmunized child. One management strategy for these children is to administer a parenteral antibiotic (e.g., ceftriaxone) if leukocytosis (white blood cell count 15,000L), elevated absolute neutrophil count (10,000L), or ele vated inflammatory markers (procalcitonin 0.5 ngmL) are present while awaiting results of blood culture. Children who appear toxic or who have signs of either sepsis or bacterial meningitis require emer gent treatment with parenteral antibiotics as well as adjunct therapies to support the childs hemodynamics (see Chapter 85). Importantly, anticipatory guidance should be provided to all families of children with fever, including the criteria to return to care and the importance of fever control and adequate hydration. Other Considerations Children who are unimmunized or underimmunized are at higher risk of invasive bacterial infection, as are children who are immunocom promised. Management of fever in these children is described further in Chapter 223. Additionally, the approach to fever in the returning traveler should be focused on identifying commonly encountered infections based on the region of travel (see Chapter 218). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 222 Fever of Unknown Origin Andrew P. Steenhoff Fever |
7,026 | of unknown origin (FUO) is a diagnostic dilemma for pedia tricians because it is often difficult to distinguish clinically between benign and potentially life threatening causes. Pediatricians face the important challenge of not missing the diagnosis of a serious illness or an easily treatable condition that can result in increased morbidity. Fortunately, FUO is usually an uncommon presentation of a common disease, with most of these common diseases being easily treatable. The classification of FUO is best reserved for children with a tem perature 38C (100.4F) documented by a healthcare provider and for which the cause could not be identified after at least 8 days of evalu ation (Table 222.1). It is important to differentiate FUO from fever without a source (FWS). FWS is fever where the source has not yet been identified and is differentiated from FUO by the duration of the fever. FWS can progress to FUO if no cause is elicited after 7 days of evaluation. ETIOLOGY The many causes of FUO in children are infectious, rheumatologic (connective tissue or autoimmune), autoinflammatory, oncologic, neurologic, genetic, factitious, and iatrogenic processes (Table 222.2). Although oncologic disorders should be seriously considered, most children with malignancies do not have fever alone. The possibility of drug fever should be considered if the patient is receiving any drug. Drug fever is usually sustained and not associated with other symp toms. Discontinuation of the drug is associated with resolution of the fever, generally within 72 hours, although certain drugs, such as iodides, are excreted for a prolonged period, with fever that can persist for as long as 1 month after drug withdrawal. Most fevers of unknown origin result from atypical presentations of common diseases. In some cases, the presentation as an FUO is characteristic of the disease (e.g., juvenile idiopathic arthritis), but the definitive diagnosis can be established only after prolonged observa tion, because initially there are no associated or specific findings on physical examination, and all laboratory results are negative or normal. In the United States the systemic infectious diseases most commonly implicated in children with FUO are bacterial enterocolitis, including salmonellosis, as well as tuberculosis, rickettsial diseases, syphilis, Lyme disease, cat scratch disease, atypical prolonged presentations of common viral diseases such as adenovirus infection, Epstein Barr virus (EBV) infection, cytomegalovirus (CMV) infection, viral hepati tis, coccidioidomycosis, histoplasmosis, malaria, Angiostrongylus can tonensis infection, and toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and rat bite fever. Acquired immunodeficiency syndrome (AIDS) alone is not usually responsible for FUO, although febrile illnesses often occur in patients with AIDS as a result of opportunistic infections (see Table 222.1). Juvenile idiopathic arthritis (JIA) and systemic lupus erythemato sus (SLE) are the connective tissue diseases most often associated with FUO. Inflammatory bowel disease (IBD) and Kawasaki disease are also frequently reported as causes of FUO. If factitious fever (inocula tion of pyogenic material or manipulation of the thermometer by the patient or parent) is suspected, the presence and pattern of fever should be documented in |
7,027 | the hospital. Prolonged and continuous observation of the patient, which can include electronic or video surveillance, is imperative. FUO lasting 6 months is uncommon in children and suggests granulomatous, autoinflammatory, or autoimmune disease. Repeat interval evaluation is required, including history, physical examination, laboratory evaluation, and imaging studies. Historically, 90 of pediatric FUO cases in the United States had an identifiable cause: approximately 50 infectious, 1020 colla gen vascular, and 10 oncologic. Other studies had variable results: 2044 infectious, 07 collagen vascular, 23 oncologic, and up to 67 undiagnosed. The reason for the paradoxical increase in undiag nosed cases of FUO ironically is likely caused by improved infectious and autoimmune diagnostic techniques. The advent of polymerase chain reaction (PCR), improved culture techniques, and better under standing of atypical viral and bacterial pathogenesis and autoimmune processes likely contribute to earlier diagnosis of these conditions and fewer children with these conditions advancing to the category of FUO. By contrast, causes of FUO remain primarily infectious in low and middle income settings where there is a higher infectious disease bur den and advanced diagnostic techniques are more limited. DIAGNOSIS The evaluation of FUO requires a thorough history and physical exami nation supplemented by a few screening laboratory tests and additional laboratory and imaging evaluation informed by the history or abnormal ities on examination or initial screening tests (see Table 222.2). Occasion ally the fever pattern helps make a diagnosis (Fig. 222.1). Nonetheless, most diseases causing an FUO do not have a typical fever pattern. History A detailed fever history should be obtained, including onset, fre quency, duration, response or nonresponse to therapy, recurrence, and associated symptoms. Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause), par ticularly when associated with kidney disease, liver or biliary disease, infective endocarditis, malaria, brucellosis, rat bite fever, or a locu lated collection of pus. The age of the patient is helpful in evaluating FUO. Children 6 years old often have a respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JIA, or rarely, leukemia. Adolescent patients are more likely to have IBD, autoimmune pro cesses, lymphoma, or tuberculosis in addition to the causes of FUO found in younger children. A history of exposure to wild or domestic animals should be solic ited. The incidence of zoonotic infections in the United States is Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1652 Part XV u Infectious Diseases increasing, and these infections are often acquired from pets that are not overtly ill. Immunization of dogs against specific disorders such as leptospirosis can prevent canine disease but does not always pre vent the animal from carrying and shedding leptospires, which may be transmitted to household contacts. A history of ingestion of rabbit or squirrel meat might provide a clue to the diagnosis of oropharyngeal, glandular, or typhoidal tularemia. A history |
7,028 | of tick bite or travel to tick or parasite infested areas should be obtained. Any history of pica should be elicited. Ingestion of dirt is a partic ularly important clue to infection with Toxocara canis (visceral larva migrans) or Toxoplasma gondii (toxoplasmosis). A history of unusual dietary habits or travel as early as the birth of the child should be sought. Tuberculosis, malaria, histoplasmosis, and coccidioidomycosis can reemerge years after visiting or living in an endemic area. It is important to identify prophylactic immunizations and precautions taken by the patient against ingestion of contaminated water or food during foreign travel. Rocks, dirt, and artifacts from geo graphically distant regions that have been collected and brought into the home as souvenirs can serve as vectors of disease. A medication history should be pursued rigorously. This his tory should elicit information about nonprescription preparations and topical agents, including eyedrops, that may be associated with atropine induced fever. The genetic background of a patient also is important. Descen dants of the Ulster Scots may have FUO because they are afflicted with nephrogenic diabetes insipidus. Familial dysautonomia (Riley Day syndrome), a disorder in which hyperthermia is recurrent, is more common among Jews than among other population groups. Ancestry from the Mediterranean region should suggest familial Mediterra nean fever. Both familial Mediterranean fever and hyper IgD syn drome are inherited as autosomal recessive disorders. Tumor necrosis factor receptorassociated periodic syndrome and Muckle Wells syn drome are inherited as autosomal dominant traits. Pseudo FUO is defined as successive episodes of benign, self limited infections with fever that the parents perceive as one prolonged fever episode. This needs to be carefully ruled out before undertaking an unnecessary evaluation. Usually, pseudo FUO starts with a well defined infection (frequently viral) that resolves but is followed by other febrile viral illnesses that may be less well defined. Diagnosis of pseudo FUO usually requires a careful history, focusing on identifying afebrile periods between febrile episodes. If pseudo FUO is suspected and the patient does not appear ill, keeping a fever diary can be helpful. Table 222.1 Summary of Definitions and Major Features of Four Subtypes of Fever of Unknown Origin (FUO) FEATURE CLASSIC FUO HEALTHCARE ASSOCIATED FUO IMMUNE DEFICIENT FUO HIV RELATED FUO Definition 38C (100.4F), 3 wk, 2 visits, or 1 wk in hospital 38C (100.4F), 1 wk, not present or incubating on admission 38C (100.4F), 1 wk, negative cultures after 48 hr 38C (100.4F), 3 wk for outpatients, 1 wk for inpatients, HIV infection confirmed Patient location Community, clinic, or hospital Acute care hospital Hospital or clinic Community, clinic, or hospital Leading causes Cancer, infections, inflammatory conditions, undiagnosed, habitual hyperthermia Healthcare associated infections, postoperative complications, drug fever Majority caused by infections, but cause documented in only 4060 HIV itself, typical and atypical mycobacteria, CMV, lymphomas, toxoplasmosis, cryptococcosis, immune reconstitution inflammatory syndrome (IRIS) History emphasis Travel, contacts, animal and insect exposure, medications, immunizations, family history, cardiac valve disorder Operations and procedures, devices, anatomic considerations, drug treatment Stage of chemotherapy, |
7,029 | drugs administered, underlying immunosuppressive disorder Drugs, exposures, risk factors, travel, contacts, stage of HIV infection Examination emphasis Fundi, oropharynx, temporal artery, abdomen, lymph nodes, spleen, joints, skin, nails, genitalia, rectum or prostate, lower limb deep veins Wounds, drains, devices, sinuses, urine Skinfolds, IV sites, lungs, perianal area Mouth, sinuses, skin, lymph nodes, eyes, lungs, perianal area Investigation emphasis Imaging, biopsies, sedimentation rate, skin tests Imaging, bacterial cultures CXR, bacterial cultures Blood and lymphocyte count; serologic tests; CXR; stool examination; biopsies of lung, bone marrow, and liver for cultures and cytologic tests; brain imaging Management Observation, outpatient temperature chart, investigations, avoidance of empirical drug treatments Depends on situation Antimicrobial treatment protocols Antiviral and antimicrobial protocols, vaccines, revision of treatment regimens, good nutrition Time course of disease Months Weeks Days Weeks to months Tempo of investigation Weeks Days Hours Days to weeks CMV, Cytomegalovirus; CXR, chest radiograph; HIV, human immunodeficiency virus; IV, intravenous line. Adapted from Mackowak PA, Durack DT. Fever of unknown origin. In: Mandell GL, Bennett, JE, Dolin R, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 7th ed. Philadelphia: Elsevier; 2010: Table 51 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 222 u Fever of Unknown Origin 1653Table 222.2 Etiology of Fever of Unknown Origin (FUO) in Children ABSCESSES Brain Hepatic Intraabdominal Odontogenic (dental) Pelvic Perinephric and renal Psoas Rectal Subphrenic BACTERIAL DISEASES Actinomycosis Bartonella henselae (cat scratch disease) Brucellosis Campylobacter Chlamydia Francisella tularensis (tularemia) Fusobacterium (Lemierre syndrome) Leptospirosis Listeria monocytogenes (listeriosis) Lymphogranuloma venereum Meningococcemia (chronic) Mycoplasma pneumoniae Psittacosis Rat bite fever (Streptobacillus moniliformis; streptobacillary form of rat bite fever) Salmonella Tuberculosis Whipple disease Yersiniosis LOCALIZED INFECTIONS Bacterial endocarditis Cholangitis Ludwig angina Mastoiditis Osteomyelitis Pericarditis Pneumonia Pyelonephritis Sinusitis Spondylodiskitis SPIROCHETES Borrelia burgdorferi (Lyme disease) Leptospirosis Rat bite fever (Spirillum minus; spirillary form of rat bite fever) Relapsing fever (Borrelia recurrentis, Borrelia miyamotoi) Syphilis FUNGAL DISEASES Blastomycosis (extrapulmonary) Coccidioidomycosis (disseminated) Cryptococcosis Histoplasmosis (disseminated) RICKETTSIAE LIKE ORGANISMS Anaplasmosis Ehrlichiosis Q fever Rocky Mountain spotted fever Tick borne typhus VIRUSES Arboviruses Chikungunya Cytomegalovirus Epstein Barr virus Hantavirus Hepatitis viruses HIV Human herpesviruses (HHV 6 and HHV 7) Lymphocytic choriomeningitis Respiratory viruses (especially, adenovirus and enteroviruses) Zika virus PARASITIC DISEASES Amebiasis Babesiosis Baylisascaris Malaria Naegleria Toxoplasmosis Trichinosis Trypanosomiasis Visceral larva migrans (Toxocara) RHEUMATOLOGIC DISEASES Autoimmune hepatitis Behet syndrome Chronic noninfectious osteomyelitis (CNO) Juvenile dermatomyositis Juvenile idiopathic arthritis macrophage activation syndrome Rheumatic fever Systemic lupus erythematosus Vasculitis syndromes (granulomatous, nongranulomatous) HYPERSENSITIVITY DISEASES Drug fever, including DRESS Hypersensitivity pneumonitis Hypersensitivity vasculitisreactive arthritis Serum sickness Weber Christian disease NEOPLASMS Atrial myxoma Cholesterol granuloma Hodgkin lymphoma Inflammatory pseudotumor Langerhans cell histiocytosis Leukemia Lymphoma Pheochromocytoma Neuroblastoma Wilms tumor GRANULOMATOUS DISEASES Crohn disease Granulomatous hepatitis Polyangiitis with granulomatosis Sarcoidosis FAMILIAL AND HEREDITARY DISEASES Anhidrotic ectodermal dysplasia Autoimmune lymphoproliferative syndrome (ALPS) Autonomic neuropathies Fabry disease Familial dysautonomia Familial Hibernian fever Familial Mediterranean fever and the many other autoinflammatory (periodic |
7,030 | fever) diseases (see Chapter 204) Hypertriglyceridemia Ichthyosis Sickle cell crisis Spinal cordbrain injury MISCELLANEOUS Addison disease Allergic alveolitis Castleman disease Cyclic neutropenia Diabetes insipidus (non nephrogenic and nephrogenic) Erythema multiforme Factitious fever Hemophagocytic lymphohistiocytosis (HLH) Hypereosinophilia syndromes Hypothalamic central fever Infantile cortical hyperostosis Inflammatory bowel disease Kawasaki disease Kikuchi Fujimoto disease Metal fume fever Multisystem inflammatory syndrome in children (MIS C) Pancreatitis Poisoning Pulmonary embolism Rosai Dorfman disease Thrombotic thrombocytopenia purpura Thrombophlebitis Thyrotoxicosis, thyroiditis Most common identified causes of FUO in children. DRESS, Drug reaction with eosinophilia and systemic symptoms. Modified from Huppler AR. Fever. In: Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023: Table. 52.9, pp. 980981. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1654 Part XV u Infectious Diseases Fig. 222.1 Distinctive fever patterns. A, Malaria. B, Typhoid fever (demonstrating relative bradycardia). C, Hodgkin disease (Pel Ebstein fever pat tern). D, Borreliosis (relapsing fever pattern). (From Woodward TE. The fever pattern as a clinical diagnostic aid. In Mackowiak PA, ed. Fever: Basic Mechanisms and Management, 2nd ed. Philadelphia: Lippincott Raven; 1997:215236.) Table 222.3 Subtle Physical Findings with Special Significance in Patients with Fever of Unknown Origin BODY SITE PHYSICAL FINDING DIAGNOSIS Head Sinus tenderness Sinusitis Temporal artery Nodules, reduced pulsations Temporal arteritis Oropharynx Ulceration Disseminated histoplasmosis, SLE, IBD, Behet syndrome, periodic fever syndromes Tender tooth Periapical abscess, sinus referred pain Loose teeth Langerhans cell histiocytosis, leukemia Fundi or conjunctivae Choroid tubercle Disseminated granulomatosis Petechiae, Roth spots Endocarditis Thyroid Enlargement, tenderness Thyroiditis Heart Murmur Infective or marantic endocarditis Relative bradycardia Typhoid fever, malaria, leptospirosis, psittacosis, central fever, drug fever Abdomen Enlarged iliac crest lymph nodes, splenomegaly Lymphoma, endocarditis, disseminated granulomatosis Audible abdominal aortic or renal artery bruit Large vessel vasculitis such as Takayasu arteritis Costovertebral tenderness Chronic pyelonephritis, perinephric abscess Rectum Perirectal fluctuance, tenderness Abscess Prostatic tenderness, fluctuance Abscess Genitalia Testicular nodule Periarteritis nodosa, cancer Epididymal nodule Disseminated granulomatosis Spine Spinal tenderness Vertebral osteomyelitis Paraspinal tenderness Paraspinal collection Lower extremities Deep venous tenderness Thrombosis or thrombophlebitis Upper or lower extremities Pseudoparesis Syphilitic bone disease Skin and nails Petechiae, splinter hemorrhages, subcutaneous nodules, clubbing Vasculitis, endocarditis Includes tuberculosis, histoplasmosis, coccidioidomycosis, sarcoidosis, granulomatosis with polyangiitis, and syphilis. Adapted from Mackowak PA, Durack DT. Fever of unknown origin. In: Mandell GL, Bennett, JE, Dolin R, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 7th ed. Philadelphia: Elsevier; 2010: Table 51 8. Physical Examination A complete physical examination is essential to search for any clues to the underlying diagnosis, and often it is worthwhile to repeat a detailed examination on different days to detect signs that may have changed or been missed (Tables 222.3 222.5). The childs general appearance, including sweating during fever, should be noted. The continuing absence of sweat in the presence of an elevated or changing body tem perature |
7,031 | suggests dehydration caused by vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should suggest anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to atropine. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 222 u Fever of Unknown Origin 1655 Table 222.4 Examples of Potential Diagnostic Clues to Infections Presenting as Fever of Unknown Origin ETIOLOGY HISTORICAL CLUES PHYSICAL CLUES Anaplasmosis Transmitted by bite of Ixodes tick in association with outdoor activity in northern central and eastern United States Fever, headache, arthralgia, myalgia, pneumonitis, thrombocytopenia, lymphopenia, elevated liver enzymes Babesiosis Transmitted by bite of Ixodes tick in association with outdoor activity in northeastern United States Arthralgias, myalgias, relative bradycardia, hepatosplenomegaly, anemia, thrombocytopenia, elevated liver enzymes Bartonellosis Recent travel to Andes Mountains (Oroya fever; Bartonella bacilliformis), association with homelessness in urban settings (Bartonella quintana) or scratch of infected kitten or feral cat (Bartonella henselae) Conjunctivitis, retroorbital pain, anterior tibial bone pain, macular rash, nodular plaque lesions, regional lymphadenopathy Blastomycosis Contact with soil adjacent to Mississippi and Ohio River valleys, Saint Lawrence River in New York and Canada, and North American Great Lakes or exposure to infected dogs Arthritis, atypical pneumonia, pulmonary nodules, and or fulminant adult respiratory distress syndrome; verrucous, nodular, or ulcerative skin lesions; prostatitis Brucellosis Associated with contact or consumption of products from infected goats, pigs, camels, yaks, buffalo, or cows and with abattoir work Arthralgias, hepatosplenomegaly, suppurative musculoskeletal lesions, sacroiliitis, spondylitis, uveitis, hepatitis, pancytopenia Coccidioidomycosis Exposure to soil or dust in southwestern United States Arthralgias, pneumonia, pulmonary cavities, pulmonary nodules, erythema multiforme, erythema nodosum Ehrlichiosis Transmitted by bite of Amblyomma, Dermacentor, or Ixodes tick in association with outdoor activity in midwestern and southeastern United States Pneumonitis, hepatitis, thrombocytopenia, lymphopenia Enteric fever (Salmonella enterica serovar Typhi) Recent travel to a low or middle income country (LMIC) with consumption of potentially contaminated food or water Headache, arthritis, abdominal pain, relative bradycardia, hepatosplenomegaly, leukopenia Histoplasmosis Exposure to bat or blackbird excreta in roosts, chicken houses, or caves in region surrounding Ohio and Mississippi River valleys Headache, pneumonia, pulmonary cavities, mucosal ulcers, adenopathy, erythema nodosum, erythema multiforme, hepatitis, anemia, leukopenia, thrombocytopenia Leptospirosis Occupational exposure among workers in sewers, rice and sugarcane fields, and abattoirs; recreational water sports and exposure to contaminated waters or infected dogs Bitemporal and frontal headache, calf and lumbar muscle tenderness, conjunctival suffusion, hepatic and renal failure, hemorrhagic pneumonitis Leishmaniasis (visceral disease) Associated with recent travel to areas endemic for sand flies Hepatosplenomegaly, lymphadenopathy, and hyperpigmentation of face, hand, foot, and abdominal skin (kala azar) Malaria Recent travel to endemic areas in Asia, Africa, and CentralSouth America Fever, headaches, nausea, emesis, diarrhea, hepatomegaly, splenomegaly, anemia Psittacosis (Chlamydia psittaci) Associated with contact with birds, especially psittacine birds Fever, pharyngitis, hepatosplenomegaly, pneumonia, blanching maculopapular eruptions; erythema multiforme, marginatum, and nodosum Q fever (Coxiella burnetii) Associated with farm, veterinary, or abattoir work; consumption of unpasteurized |
7,032 | milk; contact with infected sheep, goats, or cattle Atypical pneumonia, hepatitis, hepatomegaly, relative bradycardia, splenomegaly Rat bite fever (Streptobacillus moniliformis) Recent bite or scratch by rat, mouse, or squirrel; ingestion of food or water contaminated by rat excrement Headaches, myalgias, polyarthritis, and maculopapular, morbilliform, petechial, vesicular, or pustular rash over the palms, soles, and extremities Relapsing fever (Borrelia recurrentis) Associated with poverty, crowding, and poor sanitation (louse borne) or with camping (tick borne), particularly in the Grand Canyon High fever with rigors, headache, delirium, arthralgias, myalgias, and hepatosplenomegaly Rocky Mountain spotted fever Associated with outdoor activity in the South Atlantic or southeastern United States and exposure to Dermacentor tick bites Headache, petechial rash involving the extremities, palms, and soles Tuberculosis Recent contact with tuberculosis; recent immigration from endemic country; work or residence in homeless shelters, correctional facilities, or healthcare facilities Night sweats, weight loss, atypical pneumonia; on chest xray, hilar adenopathy is most common in younger children, with cavitary pulmonary lesions seen in youth. Tularemia Associated with bites by Amblyomma or Dermacentor ticks, deer flies, and mosquitoes or direct contact with tissues of infected animals such as rabbits, squirrels, deer, raccoons, cattle, sheep, and swine Ulcerated skin lesions at a bite site, pneumonia, relative bradycardia, lymphadenopathy, conjunctivitis Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1656 Part XV u Infectious Diseases Table 222.5 Discriminating Features of Noninfectious Causes of Fever of Unknown Origin CAUSES OF FEVER EXPOSURE OR CONDITION FEATURES DIAGNOSTIC METHOD Kikuchi Fujimoto disease Regional or generalized lymphadenopathy; elevated inflammatory markers Biopsy or histology Inflammatory pseudotumor History of nonspecific illness (presumed host controlled infection) Insidious; malaise, weight loss, vague abdominal pain or tenderness; anemia; elevated inflammatory markers Abdominal CT; biopsy or histology Kawasaki disease (incomplete) Asynchronous or incomplete features of Kawasaki disease; elevated inflammatory markers; thrombocytosis Clinical constellation; echocardiogram Juvenile idiopathic arthritis Familial, sporadic Hepatosplenomegaly, lymphadenopathy, exanthem; anemia, elevated inflammatory markers Clinical constellation Systemic lupus erythematosus Familial, sporadic Malaise, weight loss; then multisystem involvement (kidneys, joints, skin) Serum antinuclear antibody, antidouble stranded DNA, antismooth muscle antibody Hemophagocytic lymphohistiocytosis Familial, virus, or rheumatologic (macrophage activation syndrome) induced Severe, rapidly progressive illness; hepatomegaly, lymphadenopathy, exanthem; cytopenias; extreme elevations of inflammatory markers Ferritin, triglyceride levels, gene panel, other diagnostic criteria; erythrophagocytosis by macrophages; natural killer cell, CD8 T lymphocyte dysfunction Vasculitis syndromes Familial, sporadic Specific hallmarks (renal, neurologic, stomatitis or perianal ulcers, uveitis, pulmonary) Clinical constellation; specific autoantibodies; biopsy or histology Sarcoidosis Geography; race Fatigue, weight loss, leg pain; anemia; elevated inflammatory markers; mediastinal lymphadenopathy; uveitis Clinical constellation; biopsy or histology; soluble interleukin 2 receptor level Inflammatory bowel disease Familial; sporadic Linear growth failure, subtle gastrointestinal symptoms or abdominal tenderness; perirectal skin tag; iron deficiency anemia; elevated inflammatory markers Abdominal CT; barium study Lymphoreticular malignancy Weight loss, fatigue; nonarticular bone pain; lymphadenopathy; cytopenias Bone marrow or tissue biopsy Drug hypersensitivity Prescription or nonprescription drug exposure |
7,033 | Preserved sense of well being; exanthems; eosinophilia; organ dysfunction (renal, cardiac, pulmonary) Clinical constellation; withdrawal of drug Factitious fever or Munchausen syndrome by proxy Predisposing parent patient dynamic Discordant temperature and vital signs; discordant parent measured temperature and urine temperature; normal inflammatory markers Clinical constellation; verification of temperature in medical setting Hypothalamic dysfunction, diabetes insipidus, dysautonomia, or absent corpus callosum Underlying condition; genetic syndrome; anatomic abnormality Normal inflammatory markers; hypernatremia; no response to nonsteroidal antiinflammatory drugs Clinical constellation; laboratory tests and imaging Modified from Long SS, Prober CG, Fischer M, eds. Principles and Practice of Pediatric Infectious Diseases, 5th ed. Philadelphia: Elsevier; 2018: Table 15.2, p. 121. Table 222.4 Examples of Potential Diagnostic Clues to Infections Presenting as Fever of Unknown Origincontd ETIOLOGY HISTORICAL CLUES PHYSICAL CLUES Whipple disease (Tropheryma whipplei) Potential association with exposure to sewage Chronic diarrhea, arthralgia, weight loss, malabsorption, malnutrition Adapted from Wright WF, Mackowiak PA. Fever of unknown origin. In: Bennett JE, Blaser MJ, Dolin R, et al., eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Saunders; 2015: Table 56 9. The general activity of the patient and the presence or absence of rashes should also be noted. A careful ophthalmic examination is important. Red, weeping eyes may be a sign of connective tissue disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a febrile patient may be a clue to measles, coxsackievirus infection, tuberculosis, infectious mononucle osis, lymphogranuloma venereum, or cat scratch disease. In contrast, bulbar conjunctivitis in a child with FUO suggests Kawasaki disease or leptospirosis. Petechial conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests sarcoidosis, JIA, SLE, Kawasaki disease, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 222 u Fever of Unknown Origin 1657 Behet disease, and vasculitis. Chorioretinitis suggests CMV, toxo plasmosis, and syphilis. Proptosis suggests an orbital tumor, thyrotoxi cosis, metastasis (neuroblastoma), orbital infection, granulomatosis with polyangiitis, or orbital pseudotumor. The ophthalmoscope should also be used to examine nail fold cap illary abnormalities that are associated with connective tissue diseases such as juvenile dermatomyositis and systemic scleroderma. Immersion oil or lubricating jelly is placed on the skin adjacent to the nailbed, and the capillary pattern is observed with the ophthalmoscope set on 40. FUO is sometimes caused by hypothalamic dysfunction. A clue to this disorder is failure of pupillary constriction because of absence of the sphincter constrictor muscle of the eye. This muscle develops embryologically when hypothalamic structure and function also are undergoing differentiation. Fever resulting from familial dysautonomia may be suggested by lack of tears, an absent corneal reflex, or a smooth tongue with absence of fungiform papillae. Tenderness to tapping over the sinuses or the upper teeth suggests sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the immune system, especially involving the T lymphocytes. Hyperactive deep tendon reflexes can suggest thyrotoxi cosis as the |
7,034 | cause of FUO. Hyperemia of the pharynx, with or without exudate, suggests strepto coccal infection, EBV infection, CMV infection, toxoplasmosis, salmonel losis, tularemia, Kawasaki disease, gonococcal infection, or leptospirosis. The muscles and bones should be palpated carefully. Point tender ness over a bone can suggest occult osteomyelitis or bone marrow invasion from neoplastic disease. Tenderness over the trapezius muscle may be a clue to subdiaphragmatic abscess. Generalized muscle ten derness suggests dermatomyositis, trichinosis, polyarteritis, Kawasaki disease, or Mycoplasma or arboviral infection. Rectal examination can reveal perirectal lymphadenopathy or ten derness, which suggests a deep pelvic abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should be obtained; occult blood loss can suggest granulomatous colitis or ulcerative colitis as the cause of FUO. Laboratory Evaluation The laboratory evaluation of the child with FUO and whether inpatient or outpatient are determined on a case by case basis. Hospitalization may be required for laboratory or imaging studies that are unavailable or impractical in an ambulatory setting, for more careful observation, or for temporary relief of parental anxiety. The tempo of diagnostic evaluation should be adjusted to the tempo of the illness; haste may be imperative in a critically ill patient, but if the illness is more chronic, the evaluation can proceed in a systematic manner and can be carried out in an outpatient setting. If there are no clues in the patients history or on physical examination that suggest a specific infection or area of suspicion, it is unlikely that diagnostic studies will be helpful. In this common scenario, continued surveillance and repeated reevaluations of the child should be employed to detect any new clinical findings. Although ordering a large number of diagnostic tests in every child with FUO according to a predetermined list is discouraged, certain stud ies should be considered in the evaluation. A complete blood cell count (CBC) with a white blood cell (WBC) differential and a urinalysis should be part of the initial laboratory evaluation. An absolute neutrophil count (ANC) of 5,000L is evidence against indolent bacterial infection other than typhoid fever. Conversely, in patients with a polymorphonuclear leukocyte (PMN) count of 10,000L or a nonsegmented PMN count of 500L, a severe bacterial infection is highly likely. Direct examina tion of the blood smear with Giemsa or Wright stain can reveal organ isms of malaria, trypanosomiasis, babesiosis, or relapsing fever. An erythrocyte sedimentation rate (ESR) 30 mmhr indicates inflammation and the need for further evaluation for infectious, autoimmune, autoinflammatory, or malignant diseases, tuberculosis, Kawasaki disease, or autoimmune disease. A low ESR does not elimi nate the possibility of infection or JIA. C reactive protein (CRP) is another acute phase reactant that becomes elevated and returns to nor mal more rapidly than the ESR. Experts recommend checking either ESR or CRP, because there is no evidence that measuring both in the same patient with FUO is clinically useful. Blood cultures should be obtained aerobically. Anaerobic blood cul tures have an extremely low yield and should be obtained only if there |
7,035 | are specific reasons to suspect anaerobic infection. Multiple or repeated blood cultures may be required to detect bacteremia associated with infective endocarditis, osteomyelitis, or deep seated abscesses. Poly microbial bacteremia suggests factitious or self induced infection or gastrointestinal (GI) pathology. The isolation of leptospires, Fran cisella, or Yersinia requires selective media or specific conditions not routinely used. Therefore it is important to inform the laboratory what organisms are suspected in a particular case. Urine culture should be obtained in all cases. Next generation sequencing of tissue or whole blood or plasma may identify undetected or unculturable bacteria, fungi, or viruses. Tuberculin skin testing (TST) should be performed with intrader mal placement of 5 units of purified protein derivative that has been kept appropriately refrigerated. In children 2 years old, it is reasonable to test for tuberculosis using an interferon release assay (IGRA). Imaging studies of the chest, sinuses, mastoids, or GI tract may be indicated by specific historical or physical findings. Radiographic evaluation of the GI tract for IBD may be helpful in evaluating selected children with FUO and no other localizing signs or symptoms. Examination of the bone marrow can reveal leukemia; metastatic neoplasm; mycobacterial, fungal, or parasitic infection; histiocytosis; hemophagocytosis; or storage diseases. If a bone marrow aspirate is performed, cultures for bacteria, mycobacteria, and fungi should be obtained. Serologic tests can aid in the diagnosis of EBV infection, CMV infection, toxoplasmosis, salmonellosis, tularemia, brucellosis, lepto spirosis, cat scratch disease, Lyme disease, rickettsial disease, and on some occasions JIA. The clinician should be aware that the reliability and the sensitivity and specificity of these tests vary; for example, sero logic tests for Lyme disease outside of reference laboratories have been generally unreliable. MRI scans may be helpful in detecting abdominal abscesses and osteomyelitis, especially if the focus cannot be localized to a specific limb or multifocal disease is suspected. 18F fluorodeoxyglucose posi tron emission tomography (PET) combined with MRI or CT is a help ful imaging modality and contributed to an ultimate diagnosis in 48 of children in a Dutch study. Echocardiograms can demonstrate veg etation on the leaflets of heart valves, suggesting infective endocarditis. Ultrasonography (US) can identify intraabdominal abscesses of the liver, subphrenic space, pelvis, or spleen. Total body CT or MRI (both with contrast) is usually the first imag ing study of choice; both permit detection of neoplasms and collections of purulent material without the use of surgical exploration or radio isotopes. CT and MRI are helpful in identifying lesions of the head, neck, chest, retroperitoneal spaces, liver, spleen, intraabdominal and intrathoracic lymph nodes, kidneys, pelvis, and mediastinum. CT or US guided aspiration or biopsy of suspicious lesions has reduced the need for exploratory laparotomy or thoracotomy. MRI is particularly useful for detecting osteomyelitis or myositis if there is concern about a specific limb. Diagnostic imaging can be helpful in confirming or evaluating a suspected diagnosis. With CT scans, however, the child is exposed to large amounts of radiation. PET CT or MRI may help |
7,036 | localize an occult tumor. Biopsy is occasionally helpful in establishing a diagnosis of FUO. Bronchoscopy, laparoscopy, mediastinoscopy, and GI endoscopy can provide direct visualization and biopsy material when organ specific manifestations are present. When employing any of the more invasive testing procedures, the riskbenefit ratio for the patient must always be considered before proceeding further. A diagnostic approach to an FUO is noted in Figure 222.2. MANAGEMENT The ultimate treatment of FUO is tailored to the underlying diagnosis. Fever and infection in children are not synonymous, and antimicro bial agents should only be used when there is evidence of infection, with avoidance of empirical trials of medication. An exception may be the use of antituberculous treatment in critically ill children with Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1658 Part XV u Infectious Diseases suspected disseminated tuberculosis. Empirical trials of other anti microbial agents may be dangerous and can obscure the diagnosis of infective endocarditis, meningitis, parameningeal infection, or osteo myelitis. After a complete evaluation, antipyretics may be indicated to control fever associated with adverse symptoms. PROGNOSIS Children with FUO have a better prognosis than adults. The outcome in a child depends on the primary disease process. In many cases, no diagnosis can be established, and fever abates spontaneously. In as many as 25 of children in whom fever persists, the cause of the fever remains unclear even after thorough evaluation. In a series of 69 patients referred for prolonged unexplained fever, 10 were not actually having fever, and 11 had diagnoses that were readily apparent at the initial visit. The remaining 48 were classified as having FUO. The median duration of reported fever for these patients was 30 days. Fifteen received a diagnosis, and 10 (67) had confirmed infections: acute EBV or CMV infection (n 5; with 1 patient develop ing hemophagocytic lymphohistiocytosis), cat scratch disease (3), and histoplasmosis (2). The other 5 patients had inflammatory conditions (systemic JIA, 2; IBD, 1), central fever (1), or malignancy (acute lym phoblastic leukemia, 1). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 222.2 Algorithmic approach to the evaluation of fever of unknown origin (FUO). EBV, Epstein Barr virus; HLH, hemophagocytic lymphohistiocytosis; LDH, lactate dehydrogenase; LFT, liver function test; PPD, purified protein derivative; STIR, short tau inversion recovery rapid MRI; UTI, urinary tract infection. (Modi fied from Huppler AR. Fever. In Kliegman RM, Toth H, Bordini BJ, Basel D, eds. Nelson Pediatric Symptom Based Diagnosis, 2nd ed. Philadelphia: Elsevier; 2023, Fig. 52.2, p. 982.) FEVER 38.3 C for 14 Days Thorough history Identify: Pneumonia UTI Consider history, physical, and screening labs for clues to diagnosis Clues absent or nonspecific and fever still present Physical examination including growth chart Screening laboratory studies: CBC, CRP, ESR, UA culture, blood culture, chest xray Clues present Pursue Clues present Clues absent or nonspecific and fever still present Repeat history |
7,037 | and physical exam Repeat screening labs: CBC, ESR, CRP, UA, blood culture, urine culture LFTs, LDH, uric acid, BUN, creatinine Stool heme PPD, interferon release assay Tube to hold Next generation sequencing on tissue or blood for pathogen genome Consider EBV, Bartonella, other serologies Consider abdominal CT, STIR MRI or MRIPET scan Consider genetic testing for HLH, recurrent fever syndrome Avoid empiric antibiotic therapy without clear indication Consider: hospitalization if: Clinically worrisome Labs worrisome Fever history suspect Need for evaluation by multiple subspecialists Perform serial physical exams Consider as appropriate: Pediatric infectious diseases consult Hematologyoncology consult Rheumatology consult Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 223 u Infections in Immunocompromised Persons 1659 Infection develops when the host immune system fails to protect ade quately against potential pathogens (see also Chapters 165, 166, and 180). For individuals with an intact immune system, infection occurs in the setting of navet to the microbe and absence of or inadequate preexisting microbe specific immunity, or when protective barriers of the body such as the skin have been breached. Healthy children are able to meet the challenge of most infectious agents with an immuno logic armamentarium capable of preventing significant disease. Once an infection begins to develop, an array of immune responses is set into action to control the disease and prevent it from reappearing. In con trast, immunocompromised children might not have this same capa bility. Depending on the level and type of immune defect, the affected child might not be able to contain the pathogen or develop an appro priate immune response to prevent recurrence. Primary immunodeficiencies are compromised states that result from genetic defects affecting one or more arms of the immune system. Acquired, or secondary, immunodeficiencies may result from infec tion (e.g., infection with HIV), from malignancy, or as a consequence of immunomodulating or immunosuppressing medications. The lat ter include medications that affect T cells (corticosteroids, calcineurin inhibitors, tumor necrosis factor TNF inhibitors, chemotherapy), neutrophils (myelosuppressive agents, idiosyncratic or immune mediated neutropenia), specific immunoregulatory cells (TNF block ers, interleukin 2 inhibitors), or all immune cells (chemotherapy). Perturbations of the mucosal and skin barriers or the normal microbial flora can also be characterized as secondary immunodeficiencies, pre disposing the host to infections, if only temporarily. The pathogens causing infections among immunocompetent hosts are also responsible for infections among children with immunodefi ciencies. In addition, less virulent or opportunistic organisms, including normal skin flora, commensal bacteria of the oropharynx or gastro intestinal (GI) tract, environmental fungi, and common community viruses of low level pathogenicity, can cause severe, life threatening illnesses in immunocompromised patients (Table 223.1). Close com munication with the diagnostic laboratory is critical to ensure that the laboratory does not disregard normal flora and organisms normally considered contaminants as being unimportant. 223.1 Infections Occurring with Primary Immunodeficiencies Marian G. Michaels, Hey Jin Chong, and |
7,038 | Michael Green Currently, more than 450 genes involving inborn errors of immunity have been identified, accounting for a wide array of diseases presenting with susceptibility to infection, allergy, autoimmunity, and autoinflam mation, as well as malignancy (see Chapters 165 and 166). ABNORMALITIES OF THE PHAGOCYTIC SYSTEM Children with abnormalities of the phagocytic and neutrophil system have problems with bacteria and environmental fungi. Disease mani fests as recurrent infections of the skin, mucous membranes, lungs, liver, and bones. Dysfunction of this arm of the immune system can be a result of inadequate numbers, abnormal movement properties, or aberrant function of neutrophils (see Chapter 168). Neutropenia is defined as an absolute neutrophil count (ANC) of 1,000 cellsmm3 and can be associated with significant risk for devel oping severe bacterial and fungal disease, particularly when prolonged or when the ANC is 500 cellsmm3. Although acquired neutropenia secondary to bone marrow suppression from a virus or medication is common, practitioners should be cognizant of genetic causes of neutropenia. Primary congenital neutropenia most often manifests during the first year of life with cellulitis, perirectal abscesses, or sto matitis from Staphylococcus aureus or Pseudomonas aeruginosa. Epi sodes of severe disease, including bacteremia or meningitis, are also possible. Bone marrow evaluation shows a failure of maturation of myeloid precursors. Many of the neutropenic syndromes respond to colony stimulating factor. Cyclic neutropenia can be associated with autosomal dominant inheritance or de novo sporadic gene variations Chapter 223 Infections in Immunocompromised Persons Marian G. Michaels, Hey Jin Chong, and Michael Green Table 223.1 Most Common Causes of Infections in Immunocompromised Children BACTERIA, AEROBIC Acinetobacter Bacillus Burkholderia cepacia Citrobacter Corynebacterium Enterobacter spp. Enterococcus faecalis Enterococcus faecium Escherichia coli Klebsiella spp. Listeria monocytogenes Mycobacterium spp. Neisseria meningitidis Nocardia spp. Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus, coagulase negative Streptococcus pneumoniae Streptococcus, viridans group BACTERIA, ANAEROBIC Bacillus Clostridium Fusobacterium Peptococcus Peptostreptococcus Propionibacterium Veillonella FUNGI Aspergillus Candida albicans Other Candida spp. Cryptococcus neoformans Fusarium spp. Pneumocystis jirovecii Zygomycoses (Mucor, Rhizopus, Rhizomucor) VIRUSES Adenoviruses Cytomegalovirus Epstein Barr virus Herpes simplex virus Human herpesvirus 6 Polyomavirus (BK) Respiratory and enteric community acquired viruses Varicella zoster virus PROTOZOA Cryptosporidium parvum Giardia lamblia Toxoplasma gondii Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1660 Part XV u Infectious Diseases and manifests as fixed cycles of severe neutropenia between periods of normal granulocyte numbers. Often the ANC has normalized by the time the patient presents with symptoms, thus hampering the diagno sis. The cycles classically occur every 21 days (range: 14 36 days), with neutropenia lasting 3 6 days. Most often the disease is characterized by recurrent aphthous ulcers and stomatitis during the periods of neu tropenia. However, life threatening necrotizing myositis or cellulitis and systemic disease can occur, especially with Clostridium septicum or Clostridium perfringens. Leukocyte adhesion deficiencies (LADs) are caused by defects of neutrophil aggregation and attachment to endothelial surfaces, render ing |
7,039 | them unable to enter sites of infection (see Chapter 168). In the most severe form, there is a total absence of CD18, seen in LAD type 1, but genetic defects in fucose metabolism (LAD type 2) and FERMT3 (LAD type 3) have also been described. Generally, children with LAD have a history of delayed cord separation and recurrent infections of the skin, oral mucosa, and genital tract beginning early in life. Ecthyma gangreno sum also occurs. Because the defect involves leukocyte migration and adherence, the ANC in the peripheral blood is usually extremely elevated, but a key hallmark of LAD is that pus is not found at the site of infec tion. The mainstay of treatment is aggressive antibiotic use, with curative therapy being hematopoietic stem cell transplantation (HSCT). Chronic granulomatous disease (CGD) is an inherited neutro phil dysfunction syndrome, which can be either X linked or autoso mal recessive, although spontaneous genetic changes can also occur (see Chapter 170). Neutrophils and other myeloid cells have defects in their nicotinamide adenine dinucleotide phosphate oxidase function, decreasing superoxide production and thereby impairing intracellular killing. Accordingly, microbes that destroy their own hydrogen perox ide (S. aureus, Serratia marcescens, Burkholderia cepacia, Nocardia spp., Aspergillus) cause recurrent infections in these children. Less common but considered pathognomonic are Granulibacter bethesdensis, Fran cisella philomiragia, Chromobacterium violaceum, and Paecilomyces infections. Infections have a predilection to involve the lungs, liver, and bone. Mulch pneumonitis can be seen in patients with known CGD but also can be a unique presenting feature in adults with autosomal recessive CGD. Mulch pneumonitis can resemble hypersensitivity pneumonitis, and bronchoscopy may yield Aspergillus but often may not identify a clear organism. Treatment with antifungals and cortico steroids for the inflammation is recommended. S. aureus abscesses can occur in the liver despite prophylaxis. In addition, these children can present with recurrent abscesses affecting the skin, perirectal region, or lymph nodes. Sepsis can occur but is more common with certain gram negative organisms such as C. violaceum and F. philomiragia. Prophylaxis with trimethoprim sulfamethoxazole (TMP SMX), recombinant human interferon , and oral antifungal agents with activity against Aspergillus spp., such as itraconazole or newer azoles, substantially reduces the incidence of severe infections. Patients with life threatening infections are also reported to benefit from aggressive treatment with white blood cell transfusions along with antimicrobial agents directed against the specific pathogen. In addition, HSCT can be curative, and gene therapy trials are also a consideration. It is important to remember that patients with CGD do not make pus, and thus drain age alone for liver abscesses is not effective. Instead, patients should be treated with intravenous (IV) antibiotics as well as IV corticosteroids, with surgical resection considered if these measures fail. DEFECTIVE SPLENIC FUNCTION, OPSONIZATION, OR COMPLEMENT ACTIVITY Children who have congenital asplenia or splenic dysfunction associ ated with polysplenia or hemoglobinopathies, such as sickle cell disease, as well as those who have undergone splenectomy are at risk for serious infections from encapsulated bacteria and blood borne protozoa |
7,040 | such as Plasmodium and Babesia. Prophylaxis against bacterial infection with penicillin or amoxicillin should be considered for these patients, par ticularly children 5 years of age. The most common causative bacterial organisms include Staphylococcus pneumoniae, Haemophilus influenzae type b (Hib), and Salmonella, which can cause sepsis, pneumonia, men ingitis, and osteomyelitis. Defects in the early complement components, particularly C2 and C3, may also be associated with severe infection from these bacteria. Terminal complement defects (C5, C6, C7, C8, and C9) are associated with recurrent infections with Neisseria. Patients with complement deficiency also have an increased incidence of autoimmune disorders. Vaccines for S. pneumoniae, Hib, and N. meningitidis should be administered to all children with abnormalities in opsonization or complement pathways (see Chapters 173 and 174). B CELL DEFECTS (HUMORAL IMMUNODEFICIENCIES) Antibody deficiencies account for the majority of primary immuno deficiencies among humans (see Chapters 165 and 166). Patients with defects in the B cell arm of the immune system fail to develop appro priate antibody responses, with abnormalities that range from complete agammaglobulinemia to isolated failure to produce antibody against a specific antigen or organism. Complete antibody deficiencies found in children with X linked agammaglobulinemia (XLA) or other rarer autosomal recessive agammaglobulinemia predispose to infections with encapsulated organisms such as S. pneumoniae and Hib. Other bac teria can also be problematic in these children (see Table 223.1). Patients with XLA can also have neutropenia, with one case series showing 12 of 13 patients with XLA having neutropenia as part of the initial presenta tion. Because of the neutropenia, patients with XLA can present with Pseudomonas septicemia. Viral infections can also occur, with rotavirus leading to chronic diarrhea. Enteroviruses can disseminate and cause a chronic meningoencephalitis syndrome in these patients. Paralytic polio can develop after immunization with live polio vaccine. Protozoan infec tions such as giardiasis can be severe and persistent. Children with agammaglobulinemia are usually asymptomatic until 5 6 months of age, when maternally derived antibody levels begin to wane. Around 6 months of age these children begin to develop recur rent episodes of otitis media, bronchitis, pneumonia, bacteremia, and meningitis. Many of these infections respond quickly to antibiotics, delaying the recognition of antibody deficiency, with studies showing some patients diagnosed in their teens. Children with B cell defects can develop bronchiectasis over time after chronic or recurrent pulmo nary infections and require lifelong IgG replacement therapy. Careful physical examination identifies lack of tonsils in these children, and lymphocyte subsets should confirm the lack of circulating B cells. Selective IgA deficiency is the most common antibody deficiency and leads to a lack of production of secretory antibody at the muco sal membranes (see Chapter 166). Even though most patients have no increased risk for infections, some have mild to moderate disease at sites of mucosal barriers. Accordingly, recurrent sinopulmonary infection and GI disease are the major clinical manifestations. These patients also have an increased incidence of allergies and autoimmune disorders compared with the normal population. Common variable immunodeficiency (CVID) is |
7,041 | considered an antibody deficiency, with 30 of cases found to have a monogenic cause. Diagnosis can be made in children over the age of 4, with low IgG as well as low IgM or IgA and lack of protective vaccine titers. These patients develop sinopulmonary and GI infections with com mon organisms, although they can have more severe presentations than their immunocompetent counterparts. They also have increased risk of autoimmunity and malignancy and often require IgG replacement. Hyper IgM syndrome encompasses a group of genetic defects associ ated with immunoglobulin class switch recombination. The most com mon type is caused by a defect in the CD40 ligand on the T cell, leading to inability of the B cell to class switch (see Chapter 166). Similar to other patients with humoral defects, these patients are at risk for bacterial sinopulmonary infections. However, unlike a true pure antibody defect, besides being important in T cellB cell interactions, CD40 ligand is also important in the interaction between T cells and macrophages monocytes, predisposing to opportunistic infections such as Pneumocys tis jirovecii pneumonia (PJP) and Cryptosporidium intestinal infection. T CELL DEFECTS (CELL MEDIATED IMMUNODEFICIENCIES) Children with primary T cellmediated immunodeficiencies can present early in life and are susceptible to viral, fungal, and proto zoan infections. Clinical manifestations include chronic diarrhea, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 223 u Infections in Immunocompromised Persons 1661 mucocutaneous candidiasis, and recurrent pneumonia, rhinitis, and otitis media. In thymic hypoplasia (DiGeorge syndrome), hypoplasia or aplasia of the thymus and parathyroid glands occurs during fetal development in association with the presence of other congenital abnormalities. Hypocalcemia and cardiac anomalies can be the pre senting features of DiGeorge syndrome, which should prompt evalua tion of the T cell system. Chronic mucocutaneous candidiasis (CMC) is a group of immu nodeficiencies leading to susceptibility to fungal infections of the skin, nails, oral cavity, and genitals. Most frequently caused by Can dida spp., dermatophyte infections with Microsporum, Epidermophy ton, and Trichophyton have also been described. Interestingly, patients with CMC do not have an increased risk for histoplasmosis, blasto mycosis, or coccidioidomycosis. Despite chronic cutaneous and muco sal infection with Candida spp., these patients often lack a delayed hypersensitivity to skin tests for Candida antigen. Several gene defects have been identified in people with CMC, including STAT1 gain of function pathologic gene variations, IL17R defects, CARD9 deficiency, and ACT1 deficiency. Although patients with CMC generally do not develop invasive candidiasis, patients with CMC as a feature of an inborn error or immunity certainly do develop invasive Candida infec tion. Endocrinopathies, autoimmunity, and life threatening vascular abnormalities can be seen as well, making genetic testing important in the prognosis and management of patients with CMC. COMBINED B CELL AND T CELL DEFECTS Patients with defects in both the B cell and T cell components of the immune |
7,042 | system have variable manifestations depending on the extent of the defect (see Chapter 165). Complete or almost complete immu nodeficiency is found with severe combined immunodeficiency dis order (SCID), whereas partial defects can be present in such states as ataxia telangiectasia, Wiskott Aldrich syndrome, hyper IgE syn drome, and X linked lymphoproliferative disorder. Rather than one disorder, SCID represents a heterogeneous group of genetic defects that present in the first year of life with recurrent and typically severe infections caused by a variety of bacteria, fungi, and viruses. Failure to thrive, chronic diarrhea, mucocutaneous or systemic candidiasis, PJP, or cytomegalovirus (CMV) infections are common early in life. Passive maternal antibody is relatively protective against the bacterial pathogens during the first few months of life, but thereafter patients are susceptible to both gram positive and gram negative organisms. Exposure to live virus vaccines can also lead to disseminated disease; accordingly, the use of live vaccines (including rotavirus vaccine) is contraindicated in patients with suspected or proven SCID. Without stem cell transplantation or gene therapy, most affected children suc cumb to infections within the first year of life. Children with ataxia telangiectasia develop recurrent sinopulmo nary infections from both bacteria and respiratory viruses and are particularly susceptible to chronic lung infections because of their immunodeficiency and their muscular weakness leading to poor air way clearance. In addition, these children experience an increased incidence of malignancies and neurologic complications, with most patients being wheelchair bound by the second decade of life. Wiskott Aldrich syndrome is an X linked recessive disease associated with eczema, thrombocytopenia, reduced number of CD3 lymphocytes, moderately suppressed mitogen responses, and impaired antibody response to polysaccharide antigens. Accordingly, infections with S. pneumoniae or Hib can be seen. Hyper IgE syndrome (HIES) is characterized by elevated levels of IgE, infections, and eczema, with the most common cause being the result of dominant negative gene variation in STAT3. Pathogenic gene variants in TYK2, PGM3, ZNF341, CARD11, and IL6ST have also been reported to cause this phenotype. Patients can present with recurrent episodes of S. aureus abscesses of the skin, lungs, and musculoskel etal system. These abscesses were initially described as cold in that they did not have the characteristic warmth and rubor typically seen in immunocompetent patients and thereby are easily missed, delaying therapy. Patients can also develop infections caused by Candida and, depending on the gene defect, severe viral infections. Patients with STAT3 HIES should receive prophylaxis against S. aureus with aggres sive management of eczema as well. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 223.2 Infections Occurring with Acquired Immunodeficiencies Marian G. Michaels, Hey Jin Chong, and Michael Green Immunodeficiencies can be secondarily acquired from infections or other underlying disorders, such as malignancy, cystic fibrosis, diabe tes mellitus, sickle cell disease, or malnutrition. Immunosuppressive medications used to prevent rejection after organ transplantation, to prevent graft versus host disease (GVHD) after stem cell transplan tation, or to treat malignancies may also leave the host vulnerable to infections. Similarly, medications used to |
7,043 | control rheumatologic or other autoimmune diseases may be associated with an increased risk for developing infection. Surgical removal of the spleen likewise puts a person at increased risk for infections. Further, any process that disrupts the normal mucosal and skin barriers (e.g., burns, surgery, indwelling catheters) may lead to an increased risk for infection. ACQUIRED IMMUNODEFICIENCY FROM INFECTIOUS AGENTS Infection with HIV, the causative agent of AIDS, remains globally an important infectious cause of acquired immunodeficiency (see Chap ter 322). Left untreated, HIV infection has profound effects on many parts of the immune system but in particular T cellmediated immu nity that leads to susceptibility to the same types of infections as with primary T cell immunodeficiencies. Other organisms can also lead to temporary alterations of the immune system. Very rarely, transient neutropenia associated with community acquired viruses can lead to significant disease with bac terial infections. Secondary infections can occur because of impaired immunity or disruption of normal mucosal immunity, as exemplified by the increased risk for pneumonia from S. pneumoniae or S. aureus after influenza infection and group A streptococcal cellulitis and fasci itis after varicella. MALIGNANCIES The immune systems of children with malignancies are compromised by the therapies used to treat the cancer and, at times, by direct effects of the cancer itself. The type, duration, and intensity of anticancer therapy remain the major risk factors for infections in these children and often affect multiple arms of the immune system. The presence of mucous membrane abnormalities, indwelling catheters, malnutrition, prolonged exposure to antibiotics, and frequent hospitalizations adds to the risk for infection in these children. Even though several arms of the immune system can be affected, the major abnormality predisposing to infection in children with cancer is neutropenia. The depth and duration of neutropenia are the primary predictors of the risk of infection in children being treated for cancer. Patients are at particular risk for bacterial and fungal infections if the ANC decreases to 500 cellsmm3, and the risk is highest in those with counts 100 cellsmm3. Counts of 500 cellsmm3 but 1,000 cellsmm3 incur some increased risk for infection, but not nearly as great. The lack of neutrophils can lead to a diminution of inflammatory response, limiting the ability to localize sites of infection and potentially leaving fever as the only manifestation of infection. Accordingly, the absence of physical signs and symptoms does not reliably exclude the pres ence of infection, resulting in the need for empirical antibiotics (Fig. 223.1). Because patients with fever and neutropenia might only have subtle signs and symptoms of infection, the presence of fever warrants an intensive investigation, including a thorough physical examination with careful attention to the oropharynx, lungs, perineum and anus, skin, nailbeds, and intravascular catheter insertion sites (Table 223.2). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1662 Part XV u Infectious |
7,044 | Diseases A comprehensive laboratory evaluation, including a complete blood cell count, serum creatinine, blood urea nitrogen, and serum trans aminases, should be obtained. Blood cultures should be taken from each port of any central venous catheter (CVC) and from a peripheral vein and repeated if the original culture is negative. Although periph eral vein sampling is often omitted with continued fevers and neutro penia, it should be obtained before the initial antibiotic administration and reconsidered in children with one or more positive cultures from a CVC, facilitating localization (line vs systemic) of the source of the infec tion. Other microbiologic studies should be done if there are associated clinical symptoms, including a nasal aspirate for viruses in patients with upper respiratory findings; stool for viruses such as rotavirus or noro virus and for Clostridium difficile toxin in patients with diarrhea; uri nalysis and culture in young children or in older patients with symptoms of urgency, frequency, dysuria, or hematuria; and biopsy and culture of cutaneous lesions. Chest radiographs should be obtained in any patient with lower respiratory tract symptoms, although pulmonary infiltrates may be absent in children with severe neutropenia. Sinus films should be obtained for children 2 years of age if rhinorrhea is prolonged. Abdominal CT scans should also be considered in children with pro found neutropenia and abdominal pain to evaluate for the presence of typhlitis. Chest CT scan should be considered for children not respond ing to broad spectrum antibiotics who have continued fever and neutro penia for 96 hours. Although some have considered the use of fungal biomarkers (e.g., galactomannan, d glucan, fungal polymerase chain reaction PCR), these assays have poor positive predictive values, and their use is not routinely recommended. Biopsies for cytology, Gram stain, and culture should be considered if abnormalities are found during endoscopic procedures or if lung nodules are identified radiographically. Past studies demonstrated that before the routine institution of empirical antimicrobial therapy for fever and neutropenia, 75 of children with fever and neutropenia were ultimately found to have a documented site of infection, suggesting that most children with fever and neutropenia will have an underlying infection (see Table 223.2). Current data suggest that bacteremia is present in 20 of febrile neutropenic pediatric patients with leukemia; 90 have bacterial disease (Fig. 223.2). Currently, gram positive cocci are the most com mon pathogens identified in these patients; however, gram negative organisms such as P. aeruginosa, Escherichia coli, and Klebsiella can cause life threatening infection and must be considered in the empiri cal treatment regimen. Other multidrug resistant Enterobacterales are increasingly recovered in these children. Although coagulase negative staphylococci often cause infections in these children in association with CVCs, these infections are typically indolent, and a short delay in treatment usually does not lead to a detrimental outcome. Other gram positive bacteria, such as S. aureus and S. pneumoniae, can cause more fulminant disease and require prompt institution of therapy. Viridans streptococci are particularly important potential pathogens in patients with the oral mucositis that |
7,045 | is often associated with use of cytarabine and in patients who experience selective pressure from treatment with certain antibiotics such as quinolones. Infection caused by this group of organisms can present with an acute septic shock syndrome. Also, patients with prolonged neutropenia are at increased risk for oppor tunistic fungal infections (fungemia or tissue invasion), with Candida spp. and Aspergillus spp. being the most commonly identified fungi. Other fungi that can cause serious disease in these children include zygomycetes, Fusarium spp., and dematiaceous molds. In patients with repeatedly negative blood cultures but persistent fevers, next generation sequencing in blood or plasma may help identify bacterial, viral, fungal, or protozoan pathogens. FEVER AND NEUTROPENIA The use of empirical antimicrobial treatment as part of the management of fever and neutropenia decreases the risk of progression to sepsis, sep tic shock, acute respiratory distress syndrome, organ dysfunction, and death. In 2017 the International Pediatric Fever and Neutropenia Guide line Panel updated a comprehensive guideline for the management of neutropenic children with cancer or after HSCT (see Fig. 223.1). First line antimicrobial therapy should take into consideration the types of microbes anticipated and the local resistance patterns encoun tered at each institution as well as the level of risk for severe infection asso ciated with a given patient. In addition, antibiotic choices may be limited by specific circumstances, such as the presence of drug allergy and renal or hepatic dysfunction. Guidelines for the management of fever and neu tropenia in children with cancer andor undergoing HSCT conclude that the use of oral antimicrobial therapy as either initial or stepdown therapy can be considered in low risk children who can tolerate oral antibiotics and in whom careful monitoring can be ensured. However, the guide line emphasizes that oral medication use may present major challenges in children, including the availability of liquid formulations of appropriate antibiotics, cooperation of young children, and the presence of mucositis potentially interfering with absorption. Accordingly, decisions to imple ment this approach should be reserved for a select subset of these children presenting with fever and neutropenia and institutions with an appropri ate infrastructure to follow them as outpatients. The decision to initially use IV monotherapy versus an expanded regimen of antibiotics depends on the severity of illness of the patient, history of previous colonization with resistant organisms, and obvious presence of catheter related infection. Glycopeptide addition (such as vancomycin) to the initial empirical regimen should be implemented if the patient has hypotension or other evidence of septic shock, an obvi ous catheter related infection, a history of colonization with methicillin resistant S. aureus, or the patient is at high risk for infection with viridans streptococci (severe mucositis, acute myelogenous leukemia, or prior use of quinolone prophylaxis). Otherwise, use of monotherapy with an antipseudomonal lactam, such as piperacillin tazobactam, a fourth generation cephalosporin, or a carbapenem can be consid ered. Ceftazidime should not be used as monotherapy if concern exists for gram positive organisms or resistant gram negative bacteria. The addition of |
7,046 | a second antigram negative bacterial agent (e.g., amino glycoside) for empirical therapy can be considered in patients who are clinically unstable when multidrug resistant organisms are suspected. Fig. 223.1 Algorithm for the initial management of the febrile neutropenic patient. Monotherapy can be consid ered with cefepime, imipenemcilastatin, meropenem, piperacillin tazobactam, or ticarcillinclavulanic acid. Ami noglycoside antibiotics should be avoided if the patient is also receiving nephrotoxic, ototoxic, or neuromuscular blocking agents; has renal or severe electrolyte dysfunc tion; or is suspected of having meningitis (because of poor blood brain perfusion). (Adapted from Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56e93.) Sefepime Ceftazidime Carbapenem Fever (?38.3?C) and Neutropenia (?500mm3) Evaluate Is vancomycin needed? Reassess after 3 days Duotherapy Aminoglycoside ? Antipseudomonal ?lactam Monotherapy Indications Severe mucositis Quinolone prophylaxis Colonized with: methicillinresistant Staphylococcus aureus Obvious catheterrelated infection Hypotension Vancomycin ? Ceftazidime, Cefepime, or Carbapenem No indications Cefepime or Ceftazidime or Carbapenem Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 223 u Infections in Immunocompromised Persons 1663 Regardless of the regimen chosen initially, it is critical to evaluate the patient carefully and continually for response to therapy, develop ment of secondary infections, and adverse effects. Management recom mendations for these children are evolving. Patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of bone marrow recovery can have all antibi otics discontinued. However, if symptoms persist or evolve, IV anti biotics should be continued. Continuation of antibiotics in children whose fever has abated and who are clinically well but continue to have depression of neutrophils is more controversial. Pediatric guidelines advocate for discontinuing antibiotics in low risk patients at 72 hours for children who have negative blood cultures and who have been afe brile for at least 24 hours regardless of bone marrow recovery, as long as careful follow up is ensured. Nextgeneration sequencing (NGS) during episodes of fever and neutropenia may enhance pathogen detection when blood cultures and other tests are negative. NGS has the advantage of detecting bac teria, fungi, viruses and polymicrobial infections. When fever persists despite empiric antibiotics, NGS results may help modify antimicrobial therapy based on the pathogens identified. Patients without an identified etiology but with persistent fever should be reassessed daily. At day 3 5 of persistent fever and neutropenia, those remaining clinically well may continue on the same regimen, although consideration should be given to discontinuing vanco mycin or double gram negative bacterial coverage if they were included initially. Patients who remain febrile with clinical instability warrant esca lation of therapy with the addition of a glycopeptide, if it was not included initially and risk factors exist, and modification |
7,047 | of the empirical antibac terial regimen to cover potential antimicrobial resistance and anaerobic infections in these children. If fever persists for 96 hours, the addition of an antifungal agent with antimold activity should be considered, partic ularly for those at high risk for invasive fungal infection (those with acute myelogenous leukemia or relapsed acute lymphocytic leukemia or who are receiving highly myelosuppressive chemotherapies for other cancers or with allogeneic HSCT). Liposomal amphotericin products and echi nocandins have been studied in children; voriconazole, itraconazole, and posaconazole have been successfully used in adults, with increasing expe rience in children. Azoles may have substantial drug drug interactions; however, their use has not been thoroughly evaluated. Studies comparing caspofungin with liposomal amphotericin for children with malignancies and fever and neutropenia have shown that caspofungin is noninferior. The use of antiviral agents in children with fever and neutropenia is not warranted without specific evidence of viral disease. Active herpes simplex or varicella zoster lesions merit treatment to decrease the time of healing; even if these lesions are not the source of fever, they are poten tial portals of entry for bacteria and fungi. CMV is a rare cause of fever in children with cancer and neutropenia. If CMV infection is suspected, assays to evaluate viral load in the blood and organ specific infection should be obtained. Ganciclovir, foscarnet, or cidofovir may be consid ered while evaluation is pending, although ganciclovir can cause bone marrow suppression and foscarnet and cidofovir can be nephrotoxic. If influenza is identified, specific treatment with an antiviral agent (osel tamivir, zanamivir) should be administered. The possibility of severe acute respiratory syndromecoronavirus type 2 (SARS CoV 2) infection should be evaluated by PCR, and treatment should be considered based on current recommendations and local availability of antiviral therapies. The use of hematopoietic growth factors shortens the duration of neutropenia but has not been proved to reduce morbidity or mortality. Accordingly, guidelines do not endorse the routine use of hematopoietic growth factors in patients with established fever and neutropenia, although the recommendations do note that hematopoietic growth factors can be considered as prophylaxis in those with neutropenia at high risk for fever. Prophylaxis with levofloxacin has been shown to decrease bactere mia for children with acute leukemia receiving intensive chemotherapy and may also be effective in those undergoing allogenic HSCT. How ever, monitoring for breakthrough bacteremia and for quinolone resis tance is important. Table 223.2 Host Defense Defects and Common Pathogens by Time After Bone Marrow or Hematopoietic Stem Cell Transplantation TIME PERIOD HOST DEFENSE DEFECTS CAUSES COMMON PATHOGENS Pretransplant Neutropenia Abnormal anatomic barriers Underlying disease Prior chemotherapy Aerobic gram negative bacilli Preengraftment Neutropenia Abnormal anatomic barriers Chemotherapy Radiation Indwelling catheters Aerobic gram positive cocci Aerobic gram negative bacilli Candida Aspergillus Herpes simplex virus (in previously infected patients) Community acquired viral pathogens Postengraftment Abnormal cell mediated immunity Abnormal anatomic barriers Chemotherapy Immunosuppressive medications Radiation Indwelling catheters Unrelated cord blood donor Gram positive cocci Aerobic gram negative bacilli Cytomegalovirus Adenoviruses Community acquired viral pathogens |
7,048 | Pneumocystis jirovecii Late posttransplant Delayed recovery of immune function (cell mediated, humoral, and abnormal anatomic barriers) Time required to develop donor related immune function Graft versus host disease Varicella zoster virus Streptococcus pneumoniae Unclassified 13.8 Others 1.8 Viruses 3.2 Fungi 4.8 Gram 42.1 Gram 34.3 Fig. 223.2 Pathogens involved in the microbiologically documented infections in pediatric oncology patients with febrile neutropenia. (From Boeriu E, Borda A, Dumitru D, et al. Diagnosis and management of febrile neutropenia n pediatric oncology patients a systematic review. Diagnostics. 2022;12:1800.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1664 Part XV u Infectious Diseases FEVER WITHOUT NEUTROPENIA Infections occur in children with cancer in the absence of neutropenia. Most often, these infections are viral in etiology. However, P. jirovecii can cause pneumonia regardless of the neutrophil count. Adminis tration of prophylaxis against Pneumocystis is an effective preventive strategy and should be provided to all children undergoing active treatment for malignancy. First line therapy remains TMP SMX, with second line alternatives including pentamidine, atovaquone, dapsone, or dapsone pyrimethamine. Environmental fungi such as Cryptococ cus, Histoplasma, and Coccidioides can also cause disease. Toxoplasma gondii is an uncommon but occasional pathogen in children with can cer. Infections caused by pathogens encountered in healthy children (S. pneumoniae, group A streptococcus) can also occur in children with cancer regardless of the granulocyte count. TRANSPLANTATION Transplantation of hematopoietic stem cells and solid organs (includ ing heart, liver, kidney, lungs, pancreas, and intestines) is increas ingly used as therapy for a variety of disorders. Children undergoing transplantation are at risk for infections caused by many of the same microbial agents that cause disease in children with primary immu nodeficiencies. Although the types of infections after transplantation generally are similar among all recipients of these procedures, some differences exist between patients depending on the type of transplan tation performed, the type and amount of immunosuppression given, and the childs preexisting immunity to specific pathogens. Stem Cell Transplantation Infections after HSCT can be classified as occurring during the pre transplantation period, preengraftment period (0 30 days after transplantation), postengraftment period (30 100 days), or late post transplantation period (100 days). Specific defects in host defenses predisposing to infection vary within each of these periods (see Table 223.2). In addition, risk is affected by type of transplant (autologous, allogeneic, T cell depleted, cord blood) along with the quality of the donor recipient match. Neutropenia and abnormalities in cell mediated and humoral immune function occur predictably during specific periods after transplantation. In contrast, breaches of anatomic barriers caused by indwelling catheters and mucositis secondary to radiation or chemotherapy create defects in host defenses that may be present any time after transplantation. Pretransplantation Period Children come to HSCT with a heterogeneous history of underlying diseases, chemotherapy exposure, degree of immunosuppression, and previous infections. Approximately 12 of all infections among adult HSCT |
7,049 | recipients occur during the pretransplantation period. These infections are often caused by aerobic gram negative bacilli and mani fest as localized infections of the skin, soft tissue, and urinary tract. Importantly, the development of infection during this period does not delay or adversely affect the success of engraftment. Preengraftment Period Bacterial infections predominate in the preengraftment period (0 30 days). Bacteremia is the most common documented infection and occurs in as many as 50 of all HSCT recipients during the first 30 days after transplantation. Bacteremia is typically associated with the pres ence of either mucositis or an indwelling catheter but may also be seen with pneumonia. Similarly, 40 of children undergoing HSCT expe rience one or more infections in the preengraftment period. Gram positive cocci, gram negative bacilli, yeast, and, less frequently, other fungi cause infection during this period. Aspergillus has been identified in 420 of HSCT recipients, most often after 3 weeks of neutrope nia. Infections caused by the emerging fungal pathogens Fusarium and Pseudallescheria boydii are associated with the prolonged neutropenia during the preengraftment period. Viral infections also occur during the preengraftment period. Among adults, reactivation of herpes simplex virus (HSV) is the most common viral disease observed, but this is less common among children. A history of HSV infection or seropositivity indicates the need for prophylaxis. Nosocomial exposure to community acquired viral pathogens, including SARS CoV 2, respiratory syncytial virus (RSV), influenza virus, adenovirus, rotavirus, and norovirus, repre sents another important source of infection during this period. There is growing evidence that community acquired viruses cause increased morbidity and mortality for HSCT recipients during this period. Ade novirus is a particularly important viral pathogen that can occur early, although it typically presents after engraftment. Postengraftment Period The predominant defect in host defenses in the postengraftment period is altered cell mediated immunity. Accordingly, organisms historically categorized as opportunistic pathogens predominate during this period. The risk is especially accentuated 50 100 days after transplantation, when host immunity is lost and donor immunity is not yet established. P. jirovecii presents during this period if patients are not maintained on appropriate prophylaxis. Reactivation of T. gondii, a rare cause of disease among HSCT recipients, can also occur after engraftment. Hepatosplenic candidiasis often presents during the postengraftment period, although seeding likely occurs during the neutropenic phase. Cytomegalovirus (CMV) is an important cause of morbidity and mor tality among HSCT recipients. Unlike patients undergoing solid organ transplantation (SOT), where primary infection from the donor causes the greatest harm, CMV reactivation in an HSCT recipient whose donor is nave to the virus can also cause severe disease. Disease risk from CMV after HSCT is also increased in recipients of cord blood transplants or matched unrelated T celldepleted transplants and those with GVHD. Adenovirus, another important viral pathogen, has been recovered from up to 5 of adult and pediatric HSCT recipients and causes invasive dis ease in approximately 20 of cases. Children receiving matched unrelated donor organs or unrelated cord blood cell transplants have |
7,050 | an incidence of adenovirus infection as high as 14 during this early postengraftment period. Polyomaviruses such as BK virus have been increasingly recog nized as a cause of renal dysfunction and hemorrhagic cystitis after bone marrow transplantation. Infections with other herpesviruses (Epstein Barr virus EBV and human herpesvirus 6) as well as community acquired pathogens are associated with excess morbidity and mortality during this period, similar to the preengraftment period. Late Posttransplantation Period Infection is unusual after 100 days in the absence of chronic GVHD. However, the presence of chronic GVHD significantly affects anatomic barriers and is associated with defects in humoral, splenic, and cell mediated immune function. Viral infections, including primary infection with or reactivation of varicella zoster virus (VZV), are responsible for 40 of infections during this period. This may decrease over time, as the Oka varicella vaccine strain has a lower rate of reactivation than wild type varicella. Pandemic SARS CoV 2 has also been noted to have more severe outcomes in children after HSCT. Bacterial infections, particularly of the upper and lower respiratory tract, account for approximately 30 of infections. These infections may be associated with deficiencies in immu noglobulin production, especially IgG2. Fungal infections account for 20 of confirmed infections during the late posttransplantation period. Solid Organ Transplantation Factors predisposing to infection after organ transplantation include those that either existed before transplantation or are secondary to intra operative events or posttransplantation therapies (Table 223.3). Some of these additional risks cannot be prevented, and some risks acquired dur ing or after the operation depend on decisions or actions of members of the transplant team. Organ recipients are at risk for infection from potential exposure to pathogens in the donor organ. Although some donor derived infections can be anticipated through donor screening, many pathogens are not routinely screened for, and strategies defining when and how to screen for all but a small subset of potential patho gens have not been identified or implemented. Similar to other children who have undergone surgical procedures, surgical site infections are a frequent cause of infection early after transplantation. Beyond this, the need for immunosuppressive agents to prevent rejection is the major factor predisposing to infection after transplantation. Despite efforts to Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 223 u Infections in Immunocompromised Persons 1665 optimize immunosuppressive regimens to prevent or treat rejection with minimal impairment of immunity, all current regimens interfere with the ability of the immune system to prevent infection. The primary target of the majority of these immunosuppressive agents in organ recipients is the cell mediated immune system, but regimens can and do impair many other aspects of the transplant recipients immune system as well. Timing The timing of specific types of infections is generally predictable, regardless of which organ is transplanted. Infectious complications typ ically develop in one of three |
7,051 | intervals: early (0 30 days after transplan tation), intermediate (30 180 days), or late (180 days); most infections present in the first 180 days after transplantation. Table 223.4 should be used as a general guideline to the types of infections encountered, but the timing of the presentation may be modified with the introduction of newer immunosuppressive therapies and by the use of prophylaxis. Early infections are usually the result of a complication of the trans plant surgery itself, the unexpected acquisition of a bacterial or fungal pathogen from the donor, or the presence of an indwelling catheter. In contrast, infections during the intermediate period typically result from a complication of the immunosuppression, which tends to be at its greatest intensity during the first 6 months after transplantation. This is the period of greatest risk for infections caused by opportunistic pathogens such as CMV, EBV, and P. jirovecii. Anatomic abnormalities, such as bronchial stenosis and biliary stenosis, that develop as a result of the transplant sur gery can also predispose to recurrent infection in this period. Infections developing late after transplantation typically result from uncorrected anatomic abnormalities, chronic rejection, or exposure to community acquired pathogens. Augmented immunosuppres sion as treatment for late acute cellular rejection or chronic rejec tion can increase the risk for late presentations with CMV, EBV, and other potential opportunistic infections. Acquisition of infection from community acquired pathogens such as RSV can result in severe infec tion secondary to the immunocompromised state of the transplant recipient during the early and intermediate periods. Compared with the earlier periods, community acquired infections in the late period are usually benign because immunosuppression is typically maintained at significantly lower levels. However, certain pathogens such as VZV and EBV may be associated with severe disease even at this late period. Bacterial and Fungal Infections Although there are important graft specific considerations for bacte rial and fungal infections after transplantation, some principles are generally applicable to all transplant recipients. Bacterial and fungal infections after organ transplantation are usually a direct consequence of the surgery, a breach in an anatomic barrier, a foreign body, or an abnormal anatomic narrowing or obstruction. With the exception of infections related to the use of indwelling catheters, sites of bacterial infection tend to occur at or near the transplanted organ. Infections after abdominal transplantation (liver, intestine, or renal) usually occur in the abdomen or at the surgical wound. The pathogens are typi cally enteric gram negative bacteria, Enterococcus, and occasionally Candida. Infections after thoracic transplantation (heart, lung) usually occur in the lower respiratory tract or at the surgical wound. Pathogens associated with these infections include S. aureus and gram negative bacteria. Patients undergoing lung transplantation for cystic fibrosis Table 223.3 Risk Factors for Infections After Solid Organ Transplantation in Children PRETRANSPLANTATION FACTORS Age of patient Underlying disease, malnutrition Specific organ transplanted Previous exposures to infectious agents Previous immunizations Presence of infection in the donor INTRAOPERATIVE FACTORS Duration of transplant surgery Exposure to blood products Technical problems Organisms transmitted with |
7,052 | donor organ POSTTRANSPLANTATION FACTORS Immunosuppression Induction immunosuppression type Maintenance immunosuppression Augmented treatment for rejection Indwelling catheters Nosocomial exposures Community exposures Table 223.4 Timing of Infectious Complications After Solid Organ Transplantation EARLY PERIOD (0 30 DAYS) Bacterial Infections Gram negative enteric bacilli Small bowel, liver, neonatal heart Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes Cystic fibrosis lung Gram positive organisms All transplant types Fungal Infections All transplant types Viral Infections Herpes simplex virus All transplant types Nosocomial respiratory viruses All transplant types MIDDLE PERIOD (1 6 MO) Viral Infections Cytomegalovirus All transplant types Seronegative recipient of seropositive donor Epstein Barr virus All transplant types (small bowel the highest risk group) Seronegative recipient Varicella zoster virus All transplant types Opportunistic infections Pneumocystis jirovecii All transplant types Toxoplasma gondii Seronegative recipient of cardiac transplant from a seropositive donor are highest risk group Bacterial Infections Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes Cystic fibrosis lung Gram negative enteric bacilli Small bowel LATE PERIOD (6 MO) Viral Infections Epstein Barr virus All transplant types, but less risk than middle period Varicella zoster virus All transplant types Community acquired viral infections All transplant types Bacterial Infections Pseudomonas, Burkholderia, Stenotrophomonas, Alcaligenes Cystic fibrosis lung Lung transplants with chronic rejection Gram negative bacillary bacteremia Small bowel Fungal Infections Aspergillus Lung transplants with chronic rejection Adapted from Green M, Michaels MG. Infections in solid organ transplant recipients. In: Long SS, Prober CG, Fischer M, eds. Principles and Practice of Pediatric Infectious Diseases, 5th ed. Philadelphia: Elsevier; 2018: Table 95 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1666 Part XV u Infectious Diseases experience a particularly high rate of infectious complications because they are often colonized with P. aeruginosa or Aspergillus before trans plantation. Even though the infected lungs are removed, the sinuses and upper airways remain colonized with these pathogens, and sub sequent reinfection of the transplanted lungs can occur. Children receiving organ transplants are often hospitalized for long periods and receive many antibiotics; thus recovery of multidrug resistant bacteria is common after all types of organ transplantation. Infections caused by Aspergillus are less common but occur after all types of organ transplan tation and are associated with high rates of morbidity and mortality. Viral Infections Viral pathogens, especially herpesviruses, are a major source of mor bidity and mortality after SOT. In addition, BK virus is a major cause of renal disease after kidney transplantation. Although SARS CoV 2 has affected pediatric SOT recipients less than adult recipients, disease severity is increased compared with nonimmunosuppressed children. The patterns of disease associated with individual viral pathogens are generally similar among all organ transplant recipients. However, the incidence, mode of presentation, and severity differ according to the type of organ transplanted and, for many viral pathogens, pretrans plant serologic status of the recipient. Viral pathogens can be generally categorized as latent pathogens, which cause infection through reactivation in the |
7,053 | host or acquisition from the donor (e.g., CMV, EBV) or as community acquired viruses (e.g., SARS CoV 2, RSV, influenza). For CMV and EBV, primary infec tion occurring after transplantation is associated with the greatest degree of morbidity and mortality. The highest risk is seen in a nave host who receives an organ from a donor who previously was infected with one of these viruses. This mismatched state is frequently associ ated with severe disease. However, even if the donor is negative for CMV and EBV, primary infection can be acquired from a close con tact or through blood products. Secondary infections (reactivation of a latent strain within the host or superinfection with a new strain) tend to result in milder illness unless the patient is highly immunosuppressed, which can occur in the setting of treatment of significant rejection. CMV is one of the most commonly recognized transplant viral patho gens. Disease from CMV has decreased significantly with the use of preventive strategies, including antiviral prophylaxis, most commonly using ganciclovir or oral valganciclovir, as well as viral load monitoring to inform preemptive antiviral therapy. Some centers have implemented a sequential approach where surveillance viral load monitoring follows a relatively short period of chemoprophylaxis. Clinical manifestations of CMV disease can range from a syndrome of fatigue and fever to tissue invasive disease that most often affects the liver, lungs, and GI tract. Infection caused by EBV is another important complication of SOT. Clinical symptoms range from a mild mononucleosis syndrome to disseminated posttransplant lymphoproliferative disorder (PTLD). EBV associated PTLD is more common among children than adults, because primary EBV infection in the immunosuppressed host is more likely to lead to uncontrolled proliferative disorders, including post transplant lymphoma. Other viruses, such as adenovirus, also have the capacity to be donor associated, but appear to be less common. The unexpected develop ment of donor associated viral pathogens, including hepatitis B virus, hepatitis C virus, and HIV, is rare today because of intensive donor screening. However, the changing epidemiology of some viruses (e.g., dengue, chikungunya, Zika) raises concerns for the donor derived transmission of these emerging viral pathogens. Community acquired viruses, including those associated with respi ratory tract infection (SARS CoV 2, RSV, influenza virus, adenovirus, parainfluenza virus) and GI infection (enteroviruses, norovirus, and rotavirus), can cause important disease in children after organ trans plantation. In general, risk factors for more severe infection include young age, acquisition of infection early after transplantation, and augmented immune suppression. Infection in the absence of these risk factors frequently results in a clinical illness that is comparable to that seen in immunocompetent children. However, some community acquired viruses, such as adenovirus, can be associated with graft dys function even when acquired late after transplantation. Although children with SARS CoV 2 infection after transplantation fare better than adult counterparts, they are at risk for more severe symp toms early after transplant and if they have comorbidities. Immunization remains one of the best preventive strategies against severe disease even though |
7,054 | efficacy is less compared to nonimmunosuppressed children. Opportunistic Pathogens Children undergoing SOT are also at risk for symptomatic infections from pathogens that do not usually cause clinical disease in immuno competent hosts. Although these typically present in the intermedi ate period, these infections can also occur late in patients, requiring prolonged and high levels of immunosuppression. P. jirovecii is a well recognized cause of pneumonia after SOT, although routine prophy laxis has essentially eliminated this problem. T. gondii can complicate cardiac transplantations because of tropism of the organism for cardiac muscle and risk for donor transmission; less often, it complicates other types of organ transplantation. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 223.3 Prevention of Infection in Immunocompromised Persons Marian G. Michaels, Hey Jin Chong, and Michael Green Although infections cannot be completely prevented in children who have defects in one or more arms of their immune system, measures can be taken to decrease the risks for infection. Replacement immuno globulin is a benefit to children with primary B cell deficiencies. Inter feron (IFN) , TMP SMX, and oral antifungal agents have long been used to reduce the number of infections occurring in children with CGD, although the relative benefit of INF has been questioned. Chil dren who have depressed cellular immunity resulting from primary diseases, advanced HIV infection, or immunosuppressive medications benefit from prophylaxis against P. jirovecii. Strategies for safe living for all children with immunocompromising conditions should be empha sized, including hand hygiene, avoidance of community members with communicable infections, and attention to local environmental risk factors. These strategies were stressed and employed during the era of pandemic SARS CoV 2 circulation. Immunizations prevent many infections and are particularly important for children with compro mised immune systems who do not have a contraindication or inabil ity to respond. For children rendered immunocompromised because of medication or splenectomy, immunizations should be administered before treatment whenever possible. This timing allows for superior response to vaccine antigens, avoids the risk of live vaccines, which may be contraindicated depending on the immunosuppression, and impor tantly, provides protection before the immune system is compromised. Although immunodeficient children are a heterogeneous group, some principles of prevention are generally applicable. The use of inac tivated vaccines does not lead to an increased risk for adverse effects, although their efficacy may be reduced because of an impaired immune response. In most cases, children with immunodeficiencies should receive all the recommended inactivated vaccines. Live attenuated vac cinations can cause disease in some children with immunologic defects, and therefore alternative immunizations should be used whenever pos sible, such as inactivated influenza vaccine rather than live attenuated influenza vaccine or inactivated typhoid vaccine rather than the oral live typhoid vaccine for travelers. In general, live virus vaccines should not be used in children with primary T cell abnormalities; efforts should be made to ensure that close contacts are all immunized to decrease the risk of exposure. In some patients in whom wild type viral infection can be severe, immunizations, |
7,055 | even with live virus vaccine, are warranted in the immunosuppressed child. For example, children with HIV infection and a CD4 level of 15 should receive vaccinations against measles and varicella. In addition, growing evidence suggests that select transplant recipients can safely receive live vaccines as well. Some vaccines should be given to children with immunodeficiencies in addition to routine Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 224 u Infection Associated with Medical Devices 1667 vaccinations. As an example, children with asplenia or splenic dysfunc tion should receive meningococcal vaccine and both the conjugate and the polysaccharide pneumococcal vaccines. Influenza and SARS CoV 2 vaccination is recommended for all eligible individuals (6 months old for influenza) and should be emphasized for immunocompromised chil dren and all household contacts to minimize risk for transmission to the immunocompromised child. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 224 Infection Associated with Medical Devices Hana Hakim and Joshua Wolf Use of implanted synthetic and prosthetic devices has revolutionized pediatric practice by providing long term venous access, limb salvage surgery, and successful treatment of hydrocephalus, urinary reten tion, and renal failure. However, infectious complications of these devices remain a major concern and account for a significant number of healthcare acquired infections (HAIs) and attributable morbidity and mortality among hospitalized patients. Several federal and hospi tal programs in the United States and elsewhere focus on prevention initiatives to reduce device related HAI rates, most frequently central lineassociated bloodstream infection (CLABSI), catheter associated urinary tract infection (CAUTI), and ventilator associated pneumonia (VAP). HAIs are typically defined as infections that occur at least 2 days after admission to the hospital and that were not incubating at the time of admission. Device associated infections are related to the develop ment of biofilms, organized communities of microorganisms on the device surface protected from the immune system and from antimicro bial therapy. A number of factors are important to the development of infection, including host susceptibility, device composition, duration of implantation, and exposure to colonizing or contaminating organisms. INTRAVASCULAR ACCESS DEVICES Intravascular access devices range from short, stainless steel needles or plastic cannulae inserted for brief periods to multilumen, implant able, synthetic plastic catheters that are expected to remain in use for years. Infectious complications include local skin and soft tissue infec tions, such as exit site, tunnel tract, and device pocket infections, and catheter related bloodstream infections (CRBSIs). The use of central venous devices has improved the quality of life of high risk patients but has also increased the risk of infection. Catheter Types Short term peripheral cannulae are most often used in pediatric patients, and infectious complications occur infrequently. The rate of peripheral CRBSIs in children is 0.15. Patient age 1 year, dura tion of use 144 hours (6 days), and some infusates are associated with increased risk for catheter related |
7,056 | infection. Catheter associated phle bitis is more common (16) but is rarely infective and can be treated conservatively by cannula removal. Central venous catheters (CVCs), which terminate in a central vein such as the superior or inferior vena cava, are widely used in both adult and pediatric patients and are responsible for the major ity of catheter related infections. These catheters are frequently used in patients with chronic illnesses such as oncologic, gastrointestinal, and cardiovascular diseases and in critically ill patients, including neonates, who have many other risk factors for nosocomial infec tion. Patients in an intensive care unit (ICU) with a CVC in place have a fivefold greater risk for developing a nosocomial bloodstream infection than those without. Other risk factors that have been associated with increased incidence of CLABSIs include prolonged hospital stay, total parenteral nutrition, use of multiple concur rent CVCs or a CVC with multiple lumens, and use of short term nontunneled CVC. The use of peripherally inserted central catheters, which are inserted into a peripheral vein and terminate in a central vein, has increased in pediatric patients. Infection rates seem to be similar to long term tunneled CVCs, ranging between 2.0 and 3.51 per 1,000 catheter days, but other complications such as fracture, dislodgment, and occlusion are more common. When prolonged intravenous (IV) access is required, a cuffed sili cone rubber (Silastic) or polyurethane catheter may be inserted into the superior vena cava through the subclavian, cephalic, or jugular vein. The extravascular segment of the catheter passes through a subcutane ous (SC) tunnel before exiting the skin, usually on the superior aspect of the chest (e.g., Broviac or Hickman catheter). A cuff around the catheter near the exit site induces a fibrotic reaction to seal the tunnel. Totally implanted devices comprise a tunneled central catheter attached to an SC reservoir or port with a self sealing silicone septum immediately under the skin that permits repeated percutaneous needle access. The incidence of local (exit site, tunnel, and pocket) infection with long term catheters is 0.2 2.81,000 catheter days. The incidence of external tunneled CRBSI is 0.5 11.01,000 catheter days. The inci dence of CRBSI in implantable devices is much lower at 0.3 1.81,000 catheter days; however, treatment with total parenteral nutrition (TPN) eliminates this risk reduction because of a much greater rela tive increase in infection rate in ports. The risk for CRBSI is increased among premature infants, young children, and TPN patients. Catheter Associated Skin and Soft Tissue Infection A number of local infections can occur in the presence of a CVC. The clin ical manifestations of local infection include erythema, tenderness, and purulent discharge at the exit site or along the SC tunnel tract of the cath eter. Exit site infection denotes infection localized to the exit site, with out significant tracking along the tunnel, often with purulent discharge. Tunnel tract infection indicates infection in the SC tissues tracking along a tunneled catheter, which may also include serous or serosanguineous discharge from a draining |
7,057 | sinus along the path. Pocket infection indi cates suppurative infection of an SC pocket containing a totally implanted device. Bloodstream infection may coexist with local infection. The diagnosis of local infection is established clinically, but a Gram stained smear and culture of any exit site drainage should be performed to identify the microbiologic cause. The source is usually contamina tion by skin or gastrointestinal flora, and the most common organisms are Staphylococcus aureus, coagulase negative staphylococci, Pseudo monas aeruginosa, Candida spp., and mycobacteria. Green discharge is strongly suggestive of mycobacterial infection, and appropriate stains and culture should be performed. Treatment of local infection related to a short term CVC should include device removal. Exit site infection may resolve with device removal alone, but systemic symptoms should initially be managed with antimicrobial therapy. In the case of long term CVCs, exit site infections usually respond to local care with topical or systemic anti biotics alone. However, tunnel or pocket infections require removal of the catheter and systemic antibiotic therapy in almost all cases. When a tunneled CVC is removed as a result of tunnel infection, the cuff should also be removed and sent for culture if possible. In cases of mycobacterial infection, wide surgical debridement of the tissues is usually required for cure. Catheter Related Bloodstream Infection CRBSI occurs when microorganisms attached to the CVC are shed into the bloodstream, leading to bacteremia. The term catheter related bloodstream infection is reserved for a bloodstream infection that is demonstrated by CVC tip culture or other techniques to have been caused by colonization of the device. In contrast, the more general term central lineassociated bloodstream infection (CLABSI) is typically Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1668 Part XV u Infectious Diseases used for surveillance and can refer to any bloodstream infection that occurs in a patient with a CVC, unless there is an identified alternative source. On the device, the organisms are embedded in biofilms as orga nized communities. Colonization may be present even in the absence of symptoms or positive cultures. Organisms may contaminate the external surface of the CVC dur ing insertion or the intraluminal surface through handling of the cath eter hub or contaminated infusate. Most cases of CRBSI appear to be caused by intraluminal colonization, but external colonization may play a greater role in infections related to recently inserted (30 days) catheters or in immunocompromised patients. In most populations, gram positive cocci predominate, with about half of infections caused by coagulase negative staphylococci. Gram negative enteric bacteria are isolated in approximately 2030 of episodes, and fungi account for 510 of episodes. Fever without an identifiable focus is the most common clinical pre sentation of CRBSI; local soft tissue symptoms and signs are usually absent. Onset of fever or rigors during or soon after flushing of a cath eter is highly suggestive |
7,058 | of CRBSI. Symptoms and signs of complicated infection, such as septic thrombophlebitis, endocarditis, and ecthyma gangrenosum, may also be present. Blood cultures collected before beginning antibiotic therapy are gen erally positive from both the CVC and the peripheral blood. It is impor tant not to collect cultures unless infection is suspected, as blood culture contamination may occur and can lead to inappropriate therapy. To help interpret positive cultures with common skin contaminants, blood cul tures should be collected from at least two sites, preferably including all lumens of a CVC, before initiation of antibiotic therapy. Tests to differentiate CRBSI from other sources of bacteremia in the presence of a CVC include culture of the catheter tip, quantitative blood cultures, and differential time to positivity of blood cultures drawn from different sites. Definitive diagnosis of CRBSI can be important to identify those patients who might benefit from catheter removal. Although CVC tip culture can identify CRBSI, it precludes salvage of the catheter. The most readily available technique to confirm CRBSI without catheter removal is calculation of differential time to positivity between blood cultures drawn through a catheter and from a periph eral vein or separate lumen. During CRBSI, blood obtained through the responsible lumen will usually indicate growth at least 2 3 hours before peripheral blood or uncolonized lumens because of a higher intraluminal microorganism burden. Identical volumes of blood must be collected simultaneously from each site, and a continuously moni tored blood culture system is required. Specificity of this test is good (94100), and sensitivity is good when a peripheral blood culture is available (approximately 90) but poorer when comparing two lumens of a CVC (64). Where available, quantitative blood culture showing at least a threefold higher number of organisms from central compared with peripheral blood is similarly diagnostic. Treatment of CRBSI related to long term vascular access devices (e.g., Hickman, Broviac, totally implantable devices) with systemic antibiotics is successful for many bacterial infections without removal of the device. Antibiotic therapy should be directed to the isolated pathogen and given for a total of 10 14 days from the date of blood cul ture clearance. Until pathogen identification and susceptibility testing are available, empirical therapy, based on local antimicrobial suscepti bility data and usually including vancomycin plus an antipseudomonal aminoglycoside (e.g., gentamicin), penicillin (e.g., piperacillin tazobactam), or cephalosporin (e.g., ceftazidime or cefepime), is gener ally indicated. An echinocandin or azole antifungal should be initiated if fungemia is suspected. Patients who have a recent history of CRBSI with a resistant organism treated without CVC removal who subse quently develop severe sepsis should generally receive initial empirical therapy directed against that organism, because relapse is common. Antibiotic lock or dwell therapy, with administration of solutions of high concentrations of antibiotics or ethanol that remain in the cath eter for up to 24 hours, has been proposed to improve outcomes when used as an adjuvant to systemic therapy. Antibiotic locks are recom mended in patients receiving dialysis who may not have antibiotics frequently |
7,059 | delivered through the CVC, but evidence does not suggest that routine use of lock therapy is beneficial in other patient popula tions, and it may cause harm. Ethanol lock therapy increases the risk of CVC occlusion, and lock therapy can result in delays to necessary CVC removal. If blood cultures remain positive after 72 hours of appropriate ther apy, or if a patient deteriorates clinically, the device should be removed. Failure of CRBSI salvage therapy is common and can be serious in infections caused by S. aureus (approximately 50), Candida spp. (70), and Mycobacterium spp. (70). Other indications for remov ing a long term catheter include severe sepsis, suppurative thrombo phlebitis, and endocarditis. Prolonged therapy (4 6 weeks) is indicated for persistent bacteremia or fungemia after catheter removal, because this may represent unrecognized infective endocarditis or thrombo phlebitis. The decision to attempt catheter salvage should weigh the risk and clinical impact of persistent or relapsed infection against the risk of surgical intervention. CRBSI may be complicated by other intravascular infections such as septic thrombophlebitis or endocarditis. The presence of these con ditions may be suggested by preexisting risk factors (e.g., congenital heart disease), signs and symptoms, or persistent bacteremia or funge mia 72 hours after device removal and appropriate therapy. Screening for these complications in otherwise low risk children, even those with S. aureus infection, is not recommended, because the overall frequency is low, and the tests can be difficult to interpret and may lead to inap propriate therapy. Prevention of Infection Consistent implementation of evidence based prevention bundles has been essential to reduce HAI CLABSI rates. Prevention of CLABSI starts with preinsertion planning for the type and number of CVC lumens and selection of the venous site for CVC insertion. Insertion bundle elements include meticulous hand hygiene, aseptic skin preparation using 2 chlorhexidine gluconate, and use of maximal sterile barrier precautions in an operating roomlike environment. Maintenance bundles guide the daily safe care of CVCs to prevent infections, including protecting the CVC from gross contamination with excretions or body fluids, evidence based techniques to access and scrub the CVC hub and connectors, and assessing and changing the CVC site dressing. Regular assessment of the need for the catheter should be part of the daily medical and nurs ing care team discussions. In general, children with external CVCs are discouraged from swimming because of concern of subsequent CRBSI. However, existing evidence regarding risk of CRBSI related to swimming is limited. It is important to educate patient caregivers about the poten tial risk and the importance of maintaining a secured CVC with water resistant dressing if patients choose to swim. Catheters should routinely be removed as soon as they are no longer needed. Although prevalence of infection increases with prolonged duration of catheter use, routine replacement of a required CVC, either at a new site or over a guide wire, results in significant morbidity and is not recommended. Other practices that have been associated with reduction in CLABSI rates include use |
7,060 | of a chlorhexidine impregnated sponge at the exit site and daily bathing of ICU patients with 2 chlorhexidine gluconate. Use of antibiotic, tauro lidine, or ethanol lock solutions; heparin with preservatives; and alcohol impregnated caps, as well as antimicrobial impregnatedcoated catheters may be appropriate in high risk populations. There is no evidence that routine replacement of short term peripheral catheters prevents phlebi tis or other complications in children, so they should only be replaced when clinically indicated (e.g., phlebitis, dysfunction, dislodgment). URINARY CATHETERS Urinary catheters are a frequent cause of HAIs, with approximately 14 infections per 1,000 admissions, resulting in increasing duration of hospitalization, cost of patient care, morbidity, and mortality. Rates of CAUTI are highest among ICU patients. As with other devices, microorganisms adhere to the urinary catheter surface and establish a biofilm that allows proliferation. The physical presence of the catheter reduces the normal host defenses by preventing complete emptying of the bladder, thus providing a medium for growth, distending the ure thra, and blocking periurethral glands. Almost all patients catheterized Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 224 u Infection Associated with Medical Devices 1669 for 30 days develop bacteriuria. The mechanism of the infection can be either from organisms colonizing the patients perineal or rectal area or from organisms contaminating the hands of healthcare providers or con taminating equipment such as a collection bag. The organism burden in CAUTI is typically 100,000 colony forming unitsmL. Lower thresholds may be used where there is a high index of suspicion, but these episodes usually represent colonization rather than infection. Urine culture should only be performed in catheterized patients when infection is suspected, because asymptomatic colonization is ubiquitous and may lead to over treatment and subsequent development of bacterial resistance. Gram negative bacilli and Enterococcus spp. are the predominant organisms isolated in CAUTI; coagulase negative staphylococci are implicated in approximately 15 of cases. Symptomatic UTIs should be treated with antibiotics and catheter removal. Catheter colonization with Candida spp. is common but rarely leads to invasive infection, and treatment does not have a long term impact on colonization. Treatment for asymptom atic candiduria or bacteriuria is not recommended, except in neonates, immunocompromised patients, and those with urinary tract obstruction. All urinary catheters introduce a risk for infection and thus should be used only when necessary and for the minimum required duration. Existing evidence supports the benefit of using alternatives to indwell ing urethral catheters to prevent CAUTI, including external catheters in male patients, intermittent catheterization, or suprapubic catheters in selected patients. Hand hygiene and aseptic technique are part of the insertion bundles of interventions aimed at preventing CAUTI. Evidence based urinary catheter maintenance practices are essential to prevent hospital acquired CAUTI, including perineal hygiene, a closed drainage system, maintenance of unobstructed urine flow, and keeping the collection bag below the level of |
7,061 | the bladder. Technologic advances have led to the development of silver or antibiotic impregnated uri nary catheters that are associated with lower rates of infection. Pro phylactic antibiotics do not significantly reduce the infection rates for long term catheters but clearly increase the risk for infection with antibiotic resistant organisms. MECHANICAL VENTILATORS Endotracheal intubation and mechanical ventilation are lifesaving technologies to support patients with respiratory failure and patients undergoing surgical procedures. However, VAP has contributed to prolonged hospital stay and increased costs in patients in medical and surgical ICUs. VAP is more frequently reported in adult than in pedi atric patients. The mechanism of VAP is through microaspiration of colonizing oropharyngeal organisms to the lower respiratory tract and its associated host inflammatory response. Common pathogens caus ing VAP include gram negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and P. aeruginosa) and gram positive cocci (e.g., S. aureus and Streptococcus spp.). Risk factors for VAP include medications that increase gastric pH (e.g., H2 blockers, antac ids, proton pump inhibitors), decreased level of consciousness, use of paralytics or muscle relaxant agents, and prolonged intubation. Pro gressive or acute onset respiratory deterioration requiring increased mechanical setting support in a patient who has been intubated for more than 2 days should raise the suspicion of VAP. Chest diagnostic imaging and cultures of lower respiratory specimens (e.g., endotra cheal aspiration or bronchoalveolar lavage) should be considered. Evidence based practices to prevent VAP include use of noninvasive ventilation (e.g., continuous positive airway pressure CPAP, bilevel positive airway pressure BiPAP) when possible to avoid endotracheal intubation and prevention of microaspiration by elevating the head of the bed, controlling cuff pressure, minimizing and early weaning of sedation, and maintaining closed ventilator circuits. Oral care with chlorhexidine gluconate for oropharyngeal decontamination has been included as an element in several VAP prevention bundles. Evidence regarding the efficacy and safety of other interventions such as use of probiotics or silver coated endotracheal tubes has been inconclusive. CEREBROSPINAL FLUID SHUNTS Cerebrospinal fluid (CSF) shunting is required for the treatment of many children with hydrocephalus. The usual procedure uses a silicone rubber device with a proximal portion inserted into the ven tricle, a unidirectional valve, and a distal segment that diverts the CSF from the ventricles to either the peritoneal cavity (ventriculoperito neal VP shunt) or right atrium (ventriculoatrial VA shunt). The incidence of shunt infection ranges from 1 to 20 (average, 10). The highest rates are reported in young infants, patients with prior shunt infections, and certain etiologies of hydrocephalus. Most infec tions result from intraoperative contamination of the surgical wound by skin flora. Accordingly, coagulase negative staphylococci are iso lated in more than half the cases. S. aureus is isolated in approximately 20 and gram negative bacilli in 15 of cases. Four distinct clinical syndromes have been described: colonization of the shunt, infection associated with wound infection, distal infection with peritonitis, and infection associated with meningitis. The most common type of infection is colonization of the shunt, with non |
7,062 | specific symptoms that reflect shunt malfunction as opposed to frank infection. Symptoms associated with colonized VP shunts include leth argy, headache, vomiting, a full fontanel, and abdominal pain. Fever is often absent or may be low grade (39C or 102.2F). Symptoms usually occur within months of the surgical procedure. Colonization of a VA shunt results in more severe systemic symptoms, and specific symptoms of shunt malfunction are often absent. Septic pulmonary emboli, pulmonary hypertension, and infective endocarditis are fre quently reported complications of VA shunt colonization. Chronic VA shunt colonization may cause hypocomplementemic glomerulo nephritis from antigen antibody complex deposition in the glomeruli, commonly called shunt nephritis; clinical findings include hyperten sion, microscopic hematuria, elevated blood urea nitrogen and serum creatinine levels, and anemia. Diagnosis is by Gram stain, microscopy, biochemistry, and culture of CSF. CSF should be obtained by direct aspiration of the shunt before administration of antibiotics, because CSF obtained from either lum bar or ventricular puncture is often sterile. It is unusual to observe signs of ventriculitis, and CSF findings can be only minimally abnor mal. Blood culture results are usually positive in VA shunt colonization but negative in cases of VP colonization. Wound infection presents with obvious erythema, swelling, dis charge, or dehiscence along the shunt tract and most often occurs within days to weeks of the surgical procedure. S. aureus is the most common isolate. In addition to the physical findings, fever is common, and signs of shunt malfunction eventually ensue in most cases. Distal infection of VP shunts with peritonitis presents with abdom inal symptoms, usually without evidence of shunt malfunction. The pathogenesis is likely related to perforation of the bowel at VP shunt placement or translocation of bacteria across the bowel wall. Thus gram negative isolates predominate, and mixed infection is common. The infecting organisms are often isolated from only the distal portion of the shunt. Common pathogens responsible for community acquired menin gitis, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b, cause bacterial meningitis in patients with shunts only rarely, and the clinical presentation is similar to that for acute bacterial meningitis in other children (see Chapter 643.1). Treatment of shunt colonization includes removal of the shunt and systemic antibiotic therapy directed against the isolated organisms. Treatment without removal of the shunt is rarely successful and should not be routinely attempted. After collection of appropriate samples for culture, empirical therapy is usually with vancomycin plus an antipseu domonal agent with relatively good CSF penetration, such as ceftazi dime or meropenem. Definitive therapy should be directed toward the isolate and should account for poor penetration of most antibiotics into the CSF across noninflamed meninges. Accordingly, intraventricular antibiotics may be indicated but are usually reserved unless there is evidence of treatment failure. If the isolate is susceptible, a parenteral antistaphylococcal penicillin with or without intraventricular vanco mycin is the treatment of choice. If the organism is resistant to peni cillins, systemic vancomycin and possibly intraventricular vancomycin are recommended. In gram negative infections, |
7,063 | a third generation cephalosporin with or without an intraventricular aminoglycoside is Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1670 Part XV u Infectious Diseases optimal. When using intraventricular antibiotics, monitoring CSF lev els is necessary to avoid toxicity. Removal of the colonized device is required for cure, and final replacement should be delayed until clearance of CSF cultures is docu mented. Many neurosurgeons immediately remove the shunt and place an external ventricular drain to relieve intracranial pressure (ICP), with a second stage shunt replacement once CSF sterilization has been con firmed. Others opt initially to exteriorize the distal end of the shunt and replace the shunt in a single stage procedure once CSF cultures remain sterile for 48 72 hours. Daily CSF cultures should be collected until clear ance has been documented on two to three consecutive specimens, and antibiotics should be continued for at least 10 days after documented sterilization of the CSF. Gram negative organisms may require a longer duration of therapy (up to 21 days). The CSF white cell count generally increases for the first 3 5 days of appropriate therapy, and that alone should not prompt concern for treatment failure. Distal shunt infection with peritonitis and wound infection are managed in a similar fashion. Treatment of bacterial meningitis with typical community acquired pathogens such as meningococcus or pneumococcus usually requires only systemic antibiotic therapy. Shunt replacement is not required in the absence of device malfunction, poor clinical response, persistent CSF culture positivity, or relapse of infection after antibiotic therapy. Prevention of Infection Prevention of shunt infection includes meticulous cutaneous prepara tion and surgical technique. Systemic and intraventricular antibiotics, antibiotic impregnated shunts, and soaking the shunt tubing in antibiot ics are used to reduce the incidence of infection, with varying success. Systemic prophylactic antibiotics given before and during shunt insertion can reduce the risk for infection and should be used routinely but should not be continued for more than 24 hours postoperatively. Antibiotic impregnated catheters also appear to reduce the risk of infection and may be used in high risk patients where the devices are available. PERITONEAL DIALYSIS CATHETERS During the first year of peritoneal dialysis for end stage renal disease, 65 of children will have one or more episodes of peritonitis. Bacterial entry comes from luminal or periluminal contamination of the catheter or by translocation across the intestinal wall. Hematogenous infection is rare. Infants and young children who are in diapers are at highest risk for peritoneal dialysis catheterassociated infections. Infections can be localized at the exit site or associated with peritonitis, or both. Organ isms responsible for peritonitis include coagulase negative staphylococci (3040), S. aureus (1020), streptococci (1015), E. coli (5 10), Pseudomonas spp. (510), other gram negative bacteria (515), Enterococcus spp. (36), and fungi (210). S. aureus is more common in localized exit site or tunnel tract |
7,064 | infections (42). Most infectious epi sodes are caused by a patients own flora, and carriers of S. aureus have increased rates of infection compared with noncarriers. The clinical manifestations of peritonitis may be subtle and include low grade fever with mild abdominal pain or tenderness. Cloudy peritoneal dialysis fluid may be the first and predominant sign. With peritonitis, the peritoneal fluid cell count is usually 100 white blood cellsL. When peritonitis is suspected, the effluent dialysate should be submitted for a cell count, Gram stain, and culture. The Gram stain is positive in up to 40 of cases of peritonitis. Patients with cloudy fluid and clinical symptoms should receive empirical therapy, preferably guided by results of a Gram stain. If no organisms are visualized, vancomycin and either an aminoglycoside or a third or fourth generation cephalosporin with antipseudomonal activity should be given by the intraperitoneal route. Blood levels should be measured for glycopeptides and aminoglycosides. Patients without cloudy fluid and with minimal symptoms may have therapy withheld pending culture results. Once the cause is identified by cul ture, changes in the therapeutic regimen may be needed. Oral rifampin may be added as adjunctive therapy for susceptible S. aureus isolates but should not be used as a standalone agent and must prompt con sideration of drug interactions. Candidal peritonitis should be treated with catheter removal and intraperitoneal or oral fluconazole or an IV echinocandin such as caspofungin or micafungin, depending on the Candida spp. ; catheter retention has been associated with almost inevi table relapse and higher risk of mortality in adult studies. The duration of therapy for peritonitis is a minimum of 14 days, with longer treat ment of 21 28 days for episodes of S. aureus, Pseudomonas spp., and resistant gram negative bacteria and 28 42 days for fungi. Repeat epi sodes of peritonitis with the same organism within 4 weeks of previous therapy should lead to consideration of catheter removal or attempt at salvage with administration of a fibrinolytic agent and a longer course of up to 6 weeks of antibiotic therapy. In all cases, if the infection fails to clear after appropriate therapy or if a patients condition is deteriorating, the catheter should be removed. Exit site and tunnel tract infections may occur independently of perito nitis or may precede it. Appropriate antibiotics should be administered on the basis of Gram stain and culture findings and are typically given systemically only, unless peritonitis is also present. Some experts rec ommend that the peritoneal catheter be removed if Pseudomonas spp. or fungal organisms are isolated. Prevention of Infection In addition to usual hygienic practices such as hand hygiene and aseptic care of the catheter exit site, regular application of mupirocin or gen tamicin cream to the catheter exit site reduces exit site infections and peritonitis. Some practitioners recommend against the use of genta micin cream because of the risk of infection with gentamicin resistant bacteria. Systemic antibiotic prophylaxis should be considered at cath eter insertion, if there is |
7,065 | accidental contamination, and at dental proce dures. Antifungal prophylaxis with oral nystatin or fluconazole should be considered during antibiotic therapy to prevent fungal infection. IMPLANTABLE ORTHOPEDIC DEVICES Implantable orthopedic devices are used infrequently in children. Orthopedic device infection most often follows introduction of microorganisms at surgery through airborne contamination or direct inoculation, hematogenous spread, breakdown of overlying skin, or contiguous spread from an adjacent infection. Early postoperative infection occurs within 2 4 weeks of surgery, with manifestations typi cally including fever, pain, and local symptoms of wound infection. Chronic infection presents 1 month after surgery and is often caused by organisms of low virulence that contaminated the implant at surgery or by failure of wound healing. Typical manifestations include pain and deterioration in function. Local symptoms such as erythema, swelling, or drainage may also occur. Acute hematogenous infections are most often observed 2 years after surgery and may be more common in children with immunocompromise. Options for treatment include conservative management with operative debridement and irrigation and retention of the prosthesis, followed by a 3 to 6 month course of antimicrobial therapy, or more radical intervention with removal and replacement of all hardwareas either a one or two stage exchange with a shorter course of antibiotic therapy (2 6 weeks). If the prosthe sis is retained, suppressive oral antibiotic therapy may be considered after an initial treatment course, especially in patients who are under going intensive time limited treatment such as chemotherapy. As with other long term implanted devices, the most common organisms are coagulase negative staphylococci and S. aureus. With prior antibiotic therapy, the prosthesis culture may be negative; in these situations, molecular techniques to identify the organism are available, but sensi tivity and specificity are poorly understood. Orthopedic hardware such as screws and plates are more commonly encountered in children than true implantable orthopedic devices. The management of infections associated with these kinds of hardware is similar to other orthopedic device infections, but because the hard ware is typically temporary, it should generally be removed as soon as feasible. Systemic antibiotic prophylaxis, antibiotic containing bone cement, and operating rooms fitted with laminar airflow have been proposed to reduce infection. To date, results from clinical studies are conflicting. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1671 Antibacterial therapy in infants and children presents many challenges. A daunting problem is the paucity of pediatric data regarding phar macokinetics and optimal dosages; as a consequence, pediatric recom mendations are frequently extrapolated from adult studies. A second challenge is the need for the clinician to consider important differences among pediatric age groups with respect to the pathogenic species most often responsible for bacterial infections. Age appropriate antibi otic dosing and toxicities must be considered, taking into account the developmental status and |
7,066 | physiology of infants and children. Finally, the style of how a pediatrician uses antibiotics in children, particularly young infants, has some important differences compared with how antibiotics are used in adult patients. Specific antibiotic therapy is optimally driven by a microbiologic diagnosis, predicated on isolation of the pathogenic organism from a sterile body site and supported by antimicrobial susceptibility test ing. However, given the inherent difficulties that can arise in collecting specimens from pediatric patients and given the high risk of mortality and disability associated with serious bacterial infections in very young infants, much of pediatric infectious diseases practice is based on clini cal diagnoses and empirical use of antibacterial agents, often admin istered before andor without identification of the specific pathogen. Although there is an ever increasing emphasis on antimicrobial stew ardship, driven by the importance of using empirical therapy sparingly (to avoid selecting for resistant organisms), there are some settings in which antimicrobials must be administered before the presence of a specific bacterial pathogen is proven. This is particularly relevant to the care of the febrile or ill appearing neonate or young infant under 30 days of age. Several key considerations influence decision making regarding the appropriate empirical use of antibacterial agents in infants and chil dren. It is important to know the age specific differential diagnosis with respect to likely pathogens. This information affects the choice of antimicrobial agent and also the dose, dosing interval, and route of administration (oral vs parenteral). A complete history and physical examination, combined with appropriate laboratory and radiographic studies, are necessary to identify specific diagnoses, information that in turn affects the choice, dosing, and degree of urgency of administration of antimicrobial agents. The vaccination history may confer reduced risk for some invasive infections (i.e., Haemophilus influenzae type b, Streptococcus pneumoniae, Neisseria meningitidis), but a history of vaccination does not necessarily eliminate risk. The threat of serious bacterial infection in pediatric practice is also affected by the childs immunologic status, which may be compromised by immaturity (neo nates), underlying disease, and immunosuppressive medications used to treat other disorders (see Chapter 223). Infections in immunocom promised children may result from bacteria that are not considered pathogenic in immunocompetent children. The presence of foreign bodies (medical devices) also increases the risk of bacterial infections (see Chapter 224). The likelihood of central nervous system (CNS) involvement must be considered in all pediatric patients with serious bacterial infections, because many bacteremic pathogens in childhood carry a significant risk of hematogenous spread to the CNS. The patterns of antimicrobial resistance in the community and for the potential causative pathogen being empirically covered must also be considered. Resistance to penicillin and cephalosporins is frequent among strains of S. pneumoniae, often necessitating the use of other classes of antibiotics. Similarly, the striking emergence of community acquired methicillin resistant Staphylococcus aureus (MRSA) infec tions has complicated antibiotic choices, both when this pathogen is isolated in culture and for empirical coverage of skin and soft tissue infections. Extended spectrum lactamase (ESBL)producing |
7,067 | gram negative bacteria (Enterobacteriaceae) have reduced the effectiveness of penicillins and cephalosporins. Furthermore, carbapenem resistant Enterobacteriaceae (CRE) are an increasing problem among hospi talized patients, particularly in children with an epidemiologic con nection to regions of the world, such as India, where such strains are frequently encountered. Antimicrobial resistance occurs through many modifications of the bacterial genome (Tables 225.1 and 225.2). Mechanisms include enzyme inactivation of the antibiotic, decreased cell membrane per meability to intracellularly active antibiotics, efflux of antibiotics out of the bacteria, protection or alteration of the antibiotic target site, exces sive production of the target site, and bypassing the antimicrobial site of action. CRISPR (clustered regularly interspaced short palindromic repeats) elements in bacteria have also been shown to be related to emergence of antimicrobial resistance. CRISPRs are detectable in many bacterial genomes, protecting their genomes from attack by foreign DNA during transformation, phage invasion, or plasmid insertion. The mechanism of protection is mediated by insertion of small sequences of the invading DNA between palindromic repeats within the CRISPR element. Upon re exposure to similar DNA sequences from phage or invading bacteria, the existing sequence within the CRISPR is tran scribed into a small RNA that associates with CRISPR associated nucleases, blocking integration of the targeted foreign DNA. Dele tion of CRISPR elements in Enterococcus is inversely related to anti biotic resistance, and CRISPR deficient strains are selected for in the context of healthcare associated infections. CRISPR deficiency allows for evolution of significantly larger genomes, and the attendant inser tion of large sequences of DNA in turn enables expression of multiple antibiotic resistance genes. Antimicrobial resistance has reached crisis proportions, driven by the emergence of new resistance mechanisms (e.g., carbapen emases, including Klebsiella pneumoniaeassociated carbapen emases, or KPCs) and by overuse of antibiotics, both in healthcare and in other venues, such as agribusiness and animal husbandry. This increase in antibiotic resistance has rendered some bacterial infections encountered in clinical practice virtually untreatable. Accordingly, there is an urgent need to develop new antimicrobials and to rediscover some older antibiotics that have been out of use in recent decades but still retain activity against resistant organ isms. It is vital that practitioners use antibiotics only when truly indicated, with the narrowest feasible antimicrobial spectrum, to help thwart emergence of resistance. In addition, advocacy for vaccines, particularly conjugate pneumococcal vaccine, can also decrease the selective pressure that excessive antimicrobial use exerts on resistance. Effective antibiotic action requires achieving therapeutic levels of the drug at the site of infection. Other factors to consider include the impact of pH on antibiotic activity; for example, an antibiotic may pen etrate an abscess with adequate levels but may be inactive in the acidic milieu of the abscess cavity. Although measuring the level of antibi otic at the site of infection is not always possible, one may measure the serum level and use this level as a surrogate marker to achieve the desired effect at the tissue level. Various target serum levels are appro priate for |
7,068 | different antibiotic agents and are assessed by the peak and trough serum levels and the area under the therapeutic drug level curve (Fig. 225.1). These levels in turn are a reflection of the route of administration, drug absorption (IM, PO), volume of distribution, and drug elimination half life, as well as drug drug interactions that might Chapter 225 Principles of Antibacterial Therapy Mark R. Schleiss Section 3 Antibiotic Therapy Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1672 Part XV u Infectious Diseases enhance or impede enzymatic inactivation of an antibiotic or result in antimicrobial synergism or antagonism (Fig. 225.2). AGE AND RISK SPECIFIC USE OF ANTIBIOTICS IN CHILDREN Neonates The causative pathogens associated with neonatal infections are typi cally acquired around the time of delivery. Thus empirical antibiotic selection must take into account the importance of these organisms (see Chapter 148). Among the causes of neonatal sepsis in infants, group B Streptococcus (GBS) is the most common. Although intrapar tum antibiotic prophylaxis administered to women at increased risk for transmission of GBS to the infant has greatly decreased the incidence of this infection in neonates, particularly with respect to so called early onset disease, GBS infections are still frequently encountered in clinical practice (see Chapter 230). Gram negative enteric organisms acquired from the maternal birth canal, in particular Escherichia coli, are also common causes of neonatal sepsis. Although less common, Listeria monocytogenes is an important pathogen to consider, in par ticular because this organism is intrinsically resistant to cephalosporin antibiotics, which are often used as empirical therapy for serious bacte rial infections in young children. Salmonella bacteremia and meningi tis on a global basis is a well recognized infection in infants. All these organisms can be associated with meningitis in the neonate; therefore lumbar puncture should always be considered in the setting of bacte remic infections in this age group, and antibiotic management should include agents capable of crossing the blood brain barrier if meningitis cannot be excluded. Older Children Antibiotic choices in toddlers and young children were once driven by the high risk of this age group to invasive disease caused by H. influen zae type b (Hib; see Chapter 240). With the advent of conjugate vac cines against Hib, invasive disease has declined dramatically. However, outbreaks still occur and have been observed in the context of parental refusal of vaccines. Therefore the use of antimicrobials that are active against Hib remains important in many clinical settings, particularly if meningitis is a consideration. Other important pathogens to consider in this age group include E. coli, S. pneumoniae, N. meningitidis, and S. aureus. Strains of S. pneumoniae that are resistant to penicillin and cephalosporin antibiotics are frequently encountered in clinical prac tice. Similarly, MRSA is highly prevalent in children in the outpatient setting. Antibiotic resistance in S. pneumoniae and MRSA is a result |
7,069 | of mutations that confer alterations in penicillin binding proteins, the molecular targets of penicillin and cephalosporin activity (see Table 225.1). Depending on the specific clinical diagnosis, other pathogens encountered among older children include Moraxella catarrhalis, nontypeable (nonencapsulated) strains of H. influenzae, and Myco plasma pneumoniae, which cause upper respiratory tract infections and pneumonia; group A Streptococcus, which causes pharyngitis, skin and soft tissue infections, osteomyelitis, septic arthritis, and rarely, bacteremia with toxic shock syndrome; Kingella kingae, which causes bone and joint infections and bacteremia; viridians group streptococci and Enterococcus, which cause endocarditis; and Salmonella spp., which cause enteritis, bacteremia, osteomyelitis, and septic arthritis. Vector borne bacterial infections, including infections with Borrelia burgdorferi, Rickettsia rickettsii, and Anaplasma phagocytophilum, are increasingly recognized in certain regions, with an emerging increase in prevalence related to global climate change. Zoonotic exposures, pet ownership, and uncommon dietary intake may suggest less common pathogens such as Coxiella burnetii, Brucella abortus, Bartonella hense lae, Yersinia pestis, L. monocytogenes, and Francisella tularensis, all of which have unique antibiotic susceptibility profiles. These complexities Table 225.1 Mechanisms of Resistance to Lactam Antibiotics I. Alter target site (PBP) A. Decrease affinity of PBP for lactam antibiotic 1. Modify existing PBP a. Create mosaic PBP (1) Insert nucleotides obtained from neighboring bacteria (e.g., penicillin resistant Streptococcus pneumoniae) (2) Mutate structural gene of PBP(s) (e.g., ampicillin resistant lactamasenegative Haemophilus influenzae) 2. Import new PBP (e.g., mecA in methicillin resistant Staphylococcus aureus) II. Destroy lactam antibiotic A. Increase production of lactamases, carbapenemases 1. Acquire more efficient promoter a. Mutate existing promoter b. Import new promoter 2. Deregulate control of lactamase production a. Mutate regulator genes (e.g., ampD in stably derepressed Enterobacter cloacae) B. Modify structure of resident lactamase 1. Mutate structural gene (e.g., ESBLs in Klebsiella pneumoniae) C. Import new lactamase(s) with different spectrum of activity III. Decrease concentration of lactam antibiotic inside cell A. Restrict its entry (loss of porins) B. Pump it out (efflux mechanisms) ESBLs, Extended spectrum lactamases; PBP, penicillin binding protein. Adapted from Opal SM, Pop Vicas A. Molecular mechanisms of antibiotic resistance in bacteria. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Table 18 4. Table 225.2 Aminoglycoside Modifying Enzymes ENZYMES USUAL ANTIBIOTICS MODIFIED COMMON GENERA PHOSPHORYLATION APH(2) K, T, G SA, SR APH(3) I K E, PS, SA, SR APH(3) III K A E, PS, SA, SR ACETYLATION AAC(2) G PR AAC(3) I T, G E, PS AAC(3) III, IV, or V K, T, G E, PS AAC(6) K, T, A E, PS, SA ADENYLATION ANT(2) K, T, G E, PS ANT(4) K, T, A SA BIFUNCTIONAL ENZYMES AAC(6) APH(2) G, Ar SA, Ent AAC(6) lbcr G, K, T, FQ E Aminoglycoside modifying enzymes confer antibiotic resistance through three general reactions: N acetylation, O nucleotidylation, and O phosphorylation. For each of these general reactions, there are several different enzymes that attack a specific amino or hydroxyl group. The nomenclature for these enzymes lists the |
7,070 | molecular site where the modification occurs after the type of enzymatic activity. An aminoglycoside acetyltransferase (AAC) that acts at the 3 site is designated AAC(3).There may be more than one enzyme that catalyzes the same reaction, however, and Roman numerals may be necessary (e.g., AAC3 IV). A, Amikacin; AAC, aminoglycoside acetyltransferase; ANT, aminoglycoside nucleotidyltransferase; APH, aminoglycoside phosphotransferase; Ar, arbekacin, E, Enterobacteriaceae; Ent, enterococci, FQ, fluoroquinolone (acetylates the piperazine ring in some fluoroquinolones), G, gentamicin; K, kanamycin; PR, Providencia Proteus; PS, pseudomonads; SA, staphylococci; SR, streptococci; T, tobramycin. Adapted from Opal SM, Pop Vicas A. Molecular mechanisms of antibiotic resistance in bacteria. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Table 18 5. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1673 underscore the importance of formulation of a complete differen tial diagnosis in children with suspected severe bacterial infections, including an assessment of the severity of the infection in parallel with consideration of local epidemiologic disease trends. Knowledge of the antimicrobial susceptibility patterns in the community is also critically important in devising an antibiotic treatment strategy. Immunocompromised and Hospitalized Patients It is important to consider the risks associated with immunocompro mising conditions (malignancy, solid organ or hematopoietic stem cell transplantation, immunodeficiencies) and the risks conferred by con ditions leading to prolonged hospitalization (intensive care, trauma, burns). Influenza infection can also predispose to invasive bacterial infections, especially those caused by S. aureus. Measles infection is well known to predispose to serious bacterial infection, particularly with Mycobacteria. Infection with SARS CoV 2 can also be associated with bacterial and fungal opportunistic infections. Immunocompro mised children are predisposed to develop a wide range of bacterial, viral, fungal, or parasitic infections. Prolonged hospitalization can lead to nosocomial infections, often associated with indwelling catheters and caused by highly antibiotic resistant gram negative enteric organ isms. In addition to bacterial pathogens already discussed, Pseudomo nas aeruginosa and enteric organisms, including E. coli, K. pneumoniae, Enterobacter, and Serratia, are important opportunistic pathogens in these settings. The so called ESKAPE pathogens are a group of six highly virulent and antibiotic resistant organisms that are being increasingly recognized in hospitalized patients, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. Selection of appropriate antimicro bials is challenging because of the diverse causes and scope of antimi crobial resistance exhibited by these organisms. Many strains of enteric Fig. 225.1 Area under the curve (AUC; shaded area) for different an tibiotics. The AUC provides a meas ure of antibiotic exposure to bacterial pathogens. The greatest exposure comes with antibiotics that have a long serum half life and are adminis tered parenterally (upper left panel, antibiotic A). The lowest exposure occurs with oral administration (lower right panel, antibiotic C). |
7,071 | Dosing of antibiotic B once a day (upper right panel) provides far less exposure than dosing the same antibiotic every 6 hr (lower left panel). MIC, Mini mal inhibitory concentration. (From Pong AL, Bradley JS. Guidelines for the selection of antibacterial therapy in children. Pediatr Clin North Am. 2005;52:869894.) 2 4 6 8 10 12 14 16 18 20 22 24 100.0 10.0 1.0 0.1 A nt ib io tic c on ce nt ra tio n m g m L Time after administration (hrs) Antibiotic A, i.v. (half life ? 6 hrs) 2 4 6 8 10 12 14 16 18 20 22 24 100.0 10.0 1.0 0.1 A nt ib io tic c on ce nt ra tio n m g m L Time after administration (hrs) Antibiotic B, i.v. (half life ? 1 hr) 2 4 6 8 10 12 14 16 18 20 22 24 100.0 10.0 1.0 0.1 A nt ib io tic c on ce nt ra tio n m g m L Time after administration (hrs) Antibiotic B, i.v. (admin. every 6 hrs) 2 4 6 8 10 12 14 16 18 20 22 24 100.0 10.0 1.0 0.1 A nt ib io tic c on ce nt ra tio n m g m L Time after administration (hrs) Antibiotic C, p.o. (half life ? 1 hr) Resistant Streptococcus pneumoniae (MIC ? 2.0) Susceptible Streptococcus pneumoniae (MIC ? 0.1) Resistant Streptococcus pneumoniae (MIC ? 2.0) Susceptible Streptococcus pneumoniae (MIC ? 0.1) Resistant Streptococcus pneumoniae (MIC ? 2.0) Susceptible Streptococcus pneumoniae (MIC ? 0.1) Susceptible Streptococcus pneumoniae (MIC ? 0.1) Resistant Streptococcus pneumoniae (MIC ? 2.0) AUC for antibiotic C 8 9 0 4 8 12 16 20 24 Lo g (c ol on y fo rm in g un its m L) Time (hours) 0 1 2 3 4 5 6 7 8 9 0 4 8 12 16 20 24 Lo g (c ol on y fo rm in g un its m L) Time (hours) 0 1 2 3 4 5 6 7 8 9 0 4 8 12 16 20 24 Lo g (c ol on y fo rm in g un its m L) Time (hours) 0 1 2 3 4 5 6 7 Antibiotic 1 2Antibiotic 2 Antibiotic 1 No antibiotic (control) A B C Fig. 225.2 Antibacterial effects of antibiotic combinations. A, Combination of antibiotics 1 and 2 is indifferent; killing by antibiotic 2 is unchanged when antibiotic 1 is added. B, Combination of antibiotics 1 and 2 results in synergy; killing by antibiotic 2 is significantly enhanced when antibiotic 1 is added at a subinhibitory concentration. C, Combination of antibiotics 1 and 2 is antagonistic; killing by antibiotic 2 is diminished in the presence of antibiotic 1. (From Eliopoulos GM, Moellering RC Jr. Principles of anti infective therapy. In: Bennett JF, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Elsevier; 2015: Fig 17 1.) Downloaded for |
7,072 | mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1674 Part XV u Infectious Diseases organisms have resistance because of ESBLs (see Table 225.1). Class B metallo lactamases (also known as New Delhi metallo lactamases) that hydrolyze all lactam antibiotics except aztreonam and KPCs that confer resistance to carbapenems are increasingly being described. CRE are different from other multidrug resistant microorganisms in that they are susceptible to few (if any) antibacterial agents. Other modes of antimicrobial resistance exist that complicate management of common hospital acquired infections. P. aeruginosa encodes proteins that function as efflux pumps to eliminate multiple classes of antimicrobials from the cytoplasm or periplasmic space. In addition to these gram negative pathogens, infections caused by Enterococcus faecalis and E. faecium are inherently difficult to treat. Isolates of E. faecalis are typically susceptible to ampicillin, whereas most E. faecium are resistant to ampicillin, with resistance mediated by alterations in either the stoichiometry or sequence of a specific penicillin binding protein (PBP). These organisms may cause urinary tract infection (UTI) or infective endocarditis in immunocompe tent children and may be responsible for a variety of syndromes in immunocompromised patients, especially in the setting of prolonged intensive care. The emergence of infections caused by vancomycin resistant enterococcus (VRE) has further complicated antimicrobial selection in high risk patients and has necessitated the development of newer antimicrobials that target these highly resistant gram positive bacteria. Infections Associated with Medical Devices A special situation affecting antibiotic use is the presence of an indwelling medical device, such as a venous catheter, ventriculoperi toneal shunt, stent, or other catheter (see Chapter 224). In addition to S. aureus, coagulase negative staphylococci are a major consider ation. Coagulase negative staphylococci seldom cause serious disease in the absence of risk factors such as indwelling catheters. Empirical antibiotic regimens must take this risk into consideration. In addition to appropriate antibiotic therapy, removal or replacement of the colo nized prosthetic material is usually required for cure. ANTIBIOTICS, INCLUDING NEWER AGENTS AND THERAPIES COMMONLY USED IN PEDIATRIC PRACTICE Table 225.3 lists selected antibiotic medications, including recently licensed agents. Not all agents have formal pediatric indications, but dosage considerations for infants and children are provided, as available. Penicillins Although there has been ever increasing emergence of resistance to penicillins, these agents remain valuable and are commonly used for management of many pediatric infectious diseases. Penicillins remain the drugs of choice for pediatric infections caused by group A and group B streptococci, Treponema pallidum (syphilis), L. monocytogenes, and N. meningitidis. The semisynthetic penicil lins (nafcillin, cloxacillin, dicloxacillin) are useful for management of susceptible (non MRSA) staphylococcal infections. The aminope nicillins (ampicillin, amoxicillin) were developed to provide broad spectrum activity against gram negative organisms, including E. coli and H. influenzae, but the emergence of resistance (typically mediated by a lactamase) has limited their utility in many clinical settings. The carboxypenicillins (ticarcillin) and |
7,073 | ureidopenicillins (piperacil lin, mezlocillin, azlocillin) also have bactericidal activity against most strains of P. aeruginosa. Resistance to penicillin is mediated by a variety of mechanisms (see Table 225.1). The production of lactamase is a common mechanism exhibited by many organisms that may be overcome, with variable success, by including a lactamase inhibitor in the therapeutic for mulation with the penicillin. Such combination products (ampicillin sulbactam, amoxicillin clavulanate, ticarcillinclavulanic acid no longer available in the United States, piperacillin tazobactam) are potentially very useful for management of resistant isolates, but only if the resistance is lactamase mediated. Notably, MRSA and S. pneumoniae mediate resistance to penicillins through mechanisms other than lactamase production, rendering these combination agents of little value for the management of these infections. Cepha losporin (ceftazidimeavibactam, ceftolozanetazobactam) and car bapenem (meropenemvaborbactam, and imipenemrelebactam) antibiotics combined with lactamase inhibitors have also been recently licensed by the FDA (described later). In addition, the FDA has recently approved a novel lactamlactamase inhibitor com bination, sulbactamdurlobactam (SULDUR), designed specifically for the treatment of carbapenemresistant Acinetobacter baumannii infections, in particular, those associated with hospitalacquired and ventilatorassociated pneumonias. Table 225.4 lists adverse reactions to penicillins. Cephalosporins Cephalosporins differ structurally from penicillins insofar as the lactam ring exists as a six member ring, compared with the five member ring structure of the penicillins. These agents are widely used in pediatric practice, both in oral and parenteral formulations (Table 225.5). The first generation cephalosporins (e.g., cefazolin, a paren teral formulation, and cephalexin, an oral equivalent) are commonly used for management of skin and soft tissue infections caused by sus ceptible strains of S. aureus and group A streptococcus. The second generation cephalosporins (e.g., cefuroxime, cefoxitin) have better activity against gram negative bacterial infections than first generation cephalosporins and are used to treat respiratory tract infections, UTIs, and skin and soft tissue infections. A variety of orally administered second generation agents (cefaclor, cefprozil, loracarbef, cefpodoxime) are commonly used in the outpatient management of sinopulmonary infections and otitis media. The agents cefoxitin and cefotetan are also referred to as cephamycins, because they were originally isolated from actinomycetes (although synthetic versions also have been developed). The third generation cephalosporins (cefotaxime no longer avail able, ceftriaxone, and ceftazidime) are typically used for serious pedi atric infections, including meningitis and sepsis. Oral third generation cephalosporins have been developed, including cefixime, ceftibuten, cefdinir, cefpodoxime, and cefditoren. Ceftazidime is highly active against most strains of P. aeruginosa, making this a useful agent for febrile, neutropenic oncology patients. The FDA approved the combi nation of ceftazidime and the novel lactamase inhibitor avibactam in 2015. Current indications include complicated intraabdominal infec tions and UTIs. The combination may also be useful for the treatment of infection caused by KPCs. Pediatric experience is limited. Ceftriax one should not be mixed or reconstituted with a calcium containing product, such as Ringer or Hartmann solution or parenteral nutrition containing calcium, because particulate formation can result. Cases of fatal reactions with ceftriaxone calcium precipitates in the lungs and kidneys in neonates have |
7,074 | been reported. Cefepime is a fourth generation cephalosporin and has activity against P. aeruginosa along with good activity against methicillin susceptible S. aureus. Phase 3 studies of two new formulations of cefepime (one combined with a lactamase inhibitor, taniborbactam, and the other with a penicillanic acid sulfone lactamase inhibi tor, enmetazobactam) are ongoing. Cefpirome is a fourth generation cephalosporin with activity against P. aeruginosa and methicillin sensitive S. aureus (MSSA) and is licensed for complicated UTIs and ventilator associated pneumonia in adults, but no data on pediatric use are available. Ceftizoxime is a fourth generation cephalosporin that is no longer in use in the United States. Cefiderocol is a novel cephalosporin that is classified as a siderophore antibiotic and is used for treatment of resistant gram negative organisms, particularly P. aeruginosa, associated with complicated UTIs. It also recently received FDA approval for the treatment of hospital acquired bacterial pneu monia caused by resistant gram negative organisms. Its mechanism of action involves binding to iron, followed by active transport into bacterial cells. It was the first siderophore antibiotic to be approved by the FDA. It is approved for ages 18 and older, so pediatric experience is limited. Some classification schemes have classified it as a fourth generation cephalosporin. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1675 Table 225.3 Selected Antibacterial Medications (Antibiotics) DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Amikacin sulfate Amikin Injection: 50 mgmL, 250 mgmL Aminoglycoside antibiotic active against gram negative bacilli, especially Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, and Pseudomonas Neonates: Postnatal age 7 days, weight 1,200 2,000 g: 7.5 mg kg q12 18h IV or IM; weight 2,000 g: 10 mgkg q12h IV or IM; postnatal age 7 days, weight 1,200 2,000 g: 7.5 mgkg q8 12h IV or IM; weight 2,000 g: 10 mgkg q8h IV or IM Children: 15 25 mgkg24 hr divided q8 12h IV or IM Adults: 15 mgkg24 hr divided q8 12h IV or IM Cautions: Anaerobes, Streptococcus (including S. pneumoniae) are resistant. May cause ototoxicity and nephrotoxicity. Monitor renal function. Drug eliminated renally. Administered IV over 30 60 min. Drug interactions: May potentiate other ototoxic and nephrotoxic drugs. Target serum concentrations: Peak 25 40 mgL; trough 10 mgL. Amoxicillin Amoxil, Polymox Capsule: 250, 500 mg Tablet: chewable: 125, 250 mg Suspension: 125 mg5 mL, 250 mg5 mL Drops: 50 mgmL Penicillinase susceptible lactam: gram positive pathogens except Staphylococcus; susceptible gram negatives, including Salmonella, Shigella, Neisseria species, E. coli, and Proteus mirabilis Children: 20 50 mgkg24 hr divided q8 12h PO; higher dose of 8090 mgkg 24 hr PO for otitis media Adults: 250 500 mg q8 12h PO Cautions: Rash, diarrhea, abdominal cramping. Drug eliminated renally. Drug interaction: Probenecid. Amoxicillin clavulanate Augmentin Oral Tablet: 250, 500, 875 mg Tablet, chewable: 125, 200, 250, |
7,075 | 400 mg Suspension: 125 mg5 mL, 200 mg5 mL, 250 mg5 mL, 400 mg5 mL Lactam (amoxicillin) combined with lactamase inhibitor (clavulanate) enhances amoxicillin activity against penicillinase producing bacteria. S. aureus (not methicillin resistant organism), Streptococcus, Haemophilus influenzae, Moraxella catarrhalis, E. coli, Klebsiella, Bacteroides fragilis Neonates: 30 mgkg24 hr divided q12h PO Children: 20 45 mgkg 24 hr divided q8 12h PO; higher dose 80 90 mgkg24 hr PO for otitis media Cautions: Drug dosed on amoxicillin component. May cause diarrhea, rash. Drug eliminated renally. Drug interaction: Probenecid. Comment: Higher dose may be active against penicillin tolerantresistant S. pneumoniae. Ampicillin Polycillin, Omnipen Capsule: 250, 500 mg Suspension: 125 mg5 mL, 250 mg5 mL, 500 mg5 mL Injection Oral Lactam with same spectrum of antibacterial activity as amoxicillin Neonates: Postnatal age 7 days weight 2,000 g: 50 mgkg24 hr IV or IM q12h (meningitis: 100 mgkg24 hr divided q12h IV or IM); weight 2,000 g: 75 mgkg24 hr divided q8h IV or IM (meningitis: 150 mgkg24 hr divided q8h IV or IM). Postnatal age 7 days weight 1,200 g: 50 mgkg24 hr IV or IM q12h (meningitis: 100 mgkg24 hr divided q12h IV or IM); weight 1,200 2,000 g: 75 mgkg24 hr divided q8h IV or IM (meningitis: 150 mgkg24 hr divided q8hr IV or IM); weight 2,000 g: 100 mgkg24 hr divided q6h IV or IM (meningitis: 200 mgkg24 hr divided q6h IV or IM) Children: 100 200 mgkg24 hr divided q6h IV or IM (meningitis: 200 400 mgkg24 hr divided q4 6h IV or IM) Adults: 250 500 mg q4 8h IV or IM Cautions: Less bioavailable than amoxicillin, causing greater diarrhea. Drug interaction: Probenecid. Ampicillin sulbactam Unasyn Injection Lactam (ampicillin) and lactamase inhibitor (sulbactam) enhances ampicillin activity against penicillinase producing bacteria: S. aureus, H. influenzae, M. catarrhalis, E. coli, Klebsiella, B. fragilis Children: 100 200 mgkg24 hr divided q4 8h IV or IM Adults: 1 2 g q6 8h IV or IM (max daily dose: 8 g) Cautions: Drug dosed on ampicillin component. May cause diarrhea, rash. Drug eliminated renally. Note: Higher dose may be active against penicillin tolerantresistant S. pneumoniae. Drug interaction: Probenecid. Azithromycin Zithromax Tablet: 250 mg Suspension: 100 mg5 mL, 200 mg5 mL Azalide antibiotic with activity against S. aureus, Streptococcus, H. influenzae, Mycoplasma, Legionella, Chlamydia trachomatis, Babesia microti Children: 10 mgkg PO on day 1 (max dose: 500 mg) followed by 5 mgkg PO q24h for 4 days Group A streptococcus pharyngitis: 12 mgkg24 hr PO (max dose: 500 mg) for 5 days Adults: 500 mg PO on day 1, followed by 250 mg for 4 days Uncomplicated C. trachomatis infection: single 1 g dose PO Note: Very long half life permitting once daily dosing. No metabolic based drug interactions (unlike erythromycin and clarithromycin), limited GI distress. Shorter course regimens (e.g., 1 3 days) under investigation. For a 3 day course of therapy, use dose of (10 mgkg24 hr 3 days); single dose therapy, 30 mgkg (not for streptococcal pharyngitis). Aztreonam Azactam Injection Lactam |
7,076 | (monobactam) antibiotic with activity against gram negative aerobic bacteria, Enterobacteriaceae, and Pseudomonas aeruginosa Neonates: Postnatal age 7 days weight 2,000 g: 60 mgkg24 hr divided q12h IV or IM; weight 2,000 g: 90 mgkg24 hr divided q8h IV or IM; postnatal age 7 days weight 1,200 g: 60 mg kg24 hr divided q12h IV or IM; weight 1,200 2,000 g: 90 mg kg24 hr divided q8h IV or IM; weight 2,000 g: 120 mgkg24 hr divided q6 8h IV or IM Children: 90 120 mgkg24 hr divided q6 8h IV or IM. For cystic fibrosis, up to 200 mgkg24 hr IV Adults: 1 2 g IV or IM q8 12h (max dose: 8 g24 hr) Cautions: Rash, thrombophlebitis, eosinophilia. Renally eliminated. Drug interaction: Probenecid. Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1676 Part XV u Infectious Diseases Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Cefadroxil Generic Capsule: 500 mg Tablet: 1,000 mg Suspension: 125 mg5 mL, 250 mg5 mL, 500 mg5 mL First generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella, and Proteus Children: 30 mgkg24 hr divided q12h PO (max dose: 2 g) Adults: 250 500 mg q8 12h PO Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Long half life permits q12 24h dosing. Drug interaction: Probenecid. Cefazolin Ancef, Kefzol Injection First generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella, and Proteus Neonates: Postnatal age 7 days 40 mgkg24 hr divided q12h IV or IM; 7 days 40 60 mgkg24 hr divided q8h IV or IM Children: 50 100 mgkg24 hr divided q8h IV or IM Adults: 0.5 2g q8h IV or IM (max dose: 12 g24 hr) Caution: Lactam safety profile (rash, eosinophilia). Renally eliminated. Does not adequately penetrate CNS. Drug interaction: Probenecid. Cefdinir Omnicef Capsule: 300 mg Oral suspension: 125 mg5 mL Extended spectrum, semisynthetic cephalosporin Children 6 mo 12 yr: 14 mgkg24 hr in 1 or 2 doses PO (max dose: 600 mg24 hr) Adults: 600 mg q24h PO Cautions: Reduce dosage in renal insufficiency (creatinine clearance 60 mLmin). Avoid taking concurrently with iron containing products and antacids because absorption is markedly decreased; take at least 2 hr apart. Drug interaction: Probenecid. Cefepime Maxipime Injection Expanded spectrum, fourth generation cephalosporin active against many gram positive and gram negative pathogens, including P. aeruginosa and many multidrug resistant pathogens Children: 100 150 mgkg24 hr q8 12h IV or IM Adults: 2 4 g24 hr q12h IV or IM Adverse events: Diarrhea, nausea, vaginal candidiasis. Cautions: lactam safety profile (rash, eosinophilia). Renally eliminated. Drug interaction: Probenecid. Cefiderocol Fetroja Injection 1 g vials Expanded spectrum, classified in some classifications as a fourth generation cephalosporin; novel siderophore antibiotic; mechanism of action is mediated by binding to iron, followed by active transport into bacterial cells Indicated for treatment of |
7,077 | complicated urinary tract infections, including pyelonephritis, caused by susceptible gram negative microorganisms and for hospital acquired and ventilator associated pneumonia Adults: 2 g IV q8hr for 7 14 days Children: dose not established Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Not indicated for meningitis (in contrast with cefepime). Cefixime Suprax Oral Tablet: 200, 400 mg Suspension: 100 mg5 mL Third generation cephalosporin active against streptococci, H. influenzae, M. catarrhalis, Neisseria gonorrhoeae, Serratia marcescens, and Proteus vulgaris No antistaphylococcal or antipseudomonal activity Children: 8 mgkg24 hr divided q12 24h PO Adults: 400 mg24 hr divided q12 24h PO Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Does not adequately penetrate CNS. Drug interaction: Probenecid. Cefoperazone sodium Cefobid Injection Third generation cephalosporin active against many gram positive and gram negative pathogens Neonates: 100 mgkg24 hr divided q12h IV or IM Children: 100 150 mgkg24 hr divided q8 12h IV or IM Adults: 2 4 g24 hr divided q8 12h IV or IM (max dose: 12 g24 hr) Cautions: Highly protein bound cephalosporin with limited potency reflected by weak antipseudomonal activity. Variable gram positive activity. Primarily hepatically eliminated in bile. Drug interaction: Disulfiram like reaction with alcohol. Cefotaxime sodium Claforan Injection Third generation cephalosporin active against gram positive and gram negative pathogens. No antipseudomonal activity Neonates: 7 days: 100 mgkg24 hr divided q12h IV or IM; 7 days: weight 1,200 g 100 mgkg24 hr divided q12h IV or IM; weight 1,200 g: 150 mgkg24 hr divided q8h IV or IM Children: 150 mgkg24 hr divided q6 8h IV or IM (meningitis: 200 mgkg24 hr divided q6 8h IV) Adults: 1 2 g q8 12h IV or IM (max dose: 12 g24 hr) Cefotetan disodium Cefotan Injection Second generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, Klebsiella, Proteus, and Bacteroides. Inactive against Enterobacter Children: 40 80 mgkg24 hr divided q12h IV or IM Adults: 2 4 g24 hr divided q12h IV or IM (max dose: 6 g24 hr) Cautions: Highly protein bound cephalosporin, poor CNS penetration; lactam safety profile (rash, eosinophilia), disulfiram like reaction with alcohol. Renally eliminated (20 in bile). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1677 Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Cefoxitin sodium Mefoxin Injection Second generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, Klebsiella, Proteus, and Bacteroides. Inactive against Enterobacter Neonates: 70 100 mgkg24 hr divided q8 12h IV or IM Children: 80 160 mgkg24 hr divided q6 8h IV or IM Adults: 1 2 g q6 8h IV or IM (max dose: 12 g24 hr) Cautions: Poor CNS penetration; lactam safety profile (rash, eosinophilia). Renally eliminated. Painful given intramuscularly. Drug interaction: Probenecid. Cefpirome Cefrom Keiten Broact Cefir Fourth generation cephalosporin; indicated for complicated urinary tract infections, |
7,078 | including pyelonephritis, caused by susceptible gram negative microorganisms; indicated for hospital acquired and ventilator associated pneumonia Adults: 2 g IV q 8hr for 7 14 days Children: Dose not established Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Not indicated for meningitis (in contrast with cefepime). Cefpodoxime proxetil Vantin Tablet: 100 mg, 200 mg Suspension: 50 mg5 mL, 100 mg5 mL Third generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, M. catarrhalis, N. gonorrhoeae, E. coli, Klebsiella, and Proteus No antipseudomonal activity Children: 10 mgkg24 hr divided q12h PO Adults: 200 800 mg24 hr divided q12h PO (max dose: 800 mg24 hr) Uncomplicated gonorrhea: 200 mg PO as single dose therapy Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Does not adequately penetrate CNS. Increased bioavailability when taken with food. Drug interaction: Probenecid; antacids and H2 receptor antagonists may decrease absorption. Cefprozil Cefzil Tablet: 250, 500 mg Suspension: 125 mg5 mL, 250 mg5 mL Second generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, M. catarrhalis, Klebsiella, and Proteus spp. Children: 30 mgkg24 hr divided q8 12h PO Adults: 500 1,000 mg24 hr divided q12h PO (max dose: 1.5 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Good bioavailability; food does not affect bioavailability. Drug interaction: Probenecid. Ceftaroline fosamil Teflaro Injection 400 mgvial (20 mgmL reconstituted) 600 mgvial (30 mgmL reconstituted) Fifth generation cephalosporin active against S. aureus (including MRSA when used for skin and soft tissue infection), S. pyogenes, S. agalactiae, E. coli, K. pneumoniae, H. influenzae, and K. oxytoca Children: skinskin structure infections or community acquired pneumonia, 24 mgkg24 hr divided q8h IV (2 23 mo old) 5 14 days; 36 mgkg24 hr divided q8h IV (weight 33 kg) 5 14 days; 400 mg q8h IV (weight 33 kg) Adults: 600 mg q12h IV Caution: Lactam safety profile (rash, eosinophilia). Drug interaction: Probenecid. Ceftazidime Fortaz, Ceptaz, Tazicef, Tazidime Injection Third generation cephalosporin active against gram positive and gram negative pathogens, including P. aeruginosa Neonates: Postnatal age 7 days: 100 mgkg24 hr divided q12h IV or IM; 7 days weight 1,200 g: 100 mgkg24 hr divided q12h IV or IM; weight 1,200 g: 150 mgkg24 hr divided q8h IV or IM Children: 150 mgkg24 hr divided q8h IV or IM (meningitis: 150 mgkg24 hr IV divided q8h) Adults: 1 2 g q8 12h IV or IM (max dose: 8 12 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Increasing pathogen resistance developing with long term, widespread use. Drug interaction: Probenecid. Ceftazidimeavibactam Avycaz Injection (2 g0.5 g)vial: 2.5 g Equivalent to 2.635 g of ceftazidime and 0.551 g of avibactam sodium Third generation cephalosporin active against gram positive and gram negative pathogens, including P. aeruginosa; addition of lactamase; inhibits K. pneumoniae carbapenemases and AmpC type lactamases that are resistant to lactamases, tazobactam, and clavulanic acid Useful for complicated intraabdominal infections, urinary tract infections, and pneumonia Adults: 2.5 g (2 g0.5 g) IV q8h infused over 2 hr for 7 14 days Children: 3 |
7,079 | mo to 2 yr: 62.5 mgkg (ceftazidime 50 mgkg and avibactam 12.5 mgkg) IV q8h for 5 14 days 2 yr to 18 yr: 62.5 mgkg (ceftazidime 50 mgkg and avibactam 12.5 mgkg) IV q8h for 5 14 days; not to exceed 2.5 g (ceftazidime 2 g and avibactam 0.5 g) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Increasing pathogen resistance developing with long term, widespread use. Drug interaction: Probenecid. Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1678 Part XV u Infectious Diseases Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Ceftolozanetazobactam Zerbaxa Injection Fifth generation cephalosporin (with lactamase inhibitor) indicated for complicated intraabdominal infections; acute pyelonephritis; complicated urinary tract infections; hospital acquired and ventilator associated bacterial pneumonia Adults: Community acquired pneumonia, skin and soft tissue infections 600 mg IV q12 h 5 7 days Children: Birth to 2 mo: 6 mgkg IV q8h 5 14 days 2 mo to 2 yr: 8 mgkg IV q8h 5 14 days 2 yr to 18 yr (33 kg): 12 mgkg IV q8h 5 14 days 2 yr to 18 yr (33 kg): 400 mg q8h OR 600 mg q12h IV 5 14 days Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Drug interaction: Probenecid. Ceftriaxone sodium Rocephin Injection Third generation cephalosporin widely active against gram positive and gram negative pathogens No antipseudomonal activity Neonates: 50 75 mgkg q24h IV or IM Children: 50 75 mgkg q24h IV or IM (meningitis: 75 mgkg dose once then 80 100 mgkg24 hr divided q12 24h IV or IM) Adults: 1 2 g q24h IV or IM (max dose: 4 g24 hr) Gonorrhea: 500 mg IM, single dose Cautions: Lactam safety profile (rash, eosinophilia). Eliminated via kidney (3365) and bile; can cause sludging. Long half life and dose dependent protein binding favors q24h rather than q12h dosing. Can add 1 lidocaine for IM injection. Drug interaction: Probenecid. In neonates, co administration with calcium containing products can result in severe precipitation and attendant embolic complications. Cefuroxime (cefuroxime axetil for oral administration) Ceftin, Kefurox, Zinacef Injection Suspension: 125 mg5 mL Tablet: 125, 250, 500 mg Second generation cephalosporin active against S. aureus, Streptococcus, H. influenzae, E. coli, M. catarrhalis, Klebsiella, and Proteus Neonates: 40 100 mgkg24 hr divided q12h IV or IM Children: 200 240 mgkg24 hr divided q8h IV or IM; PO administration: 20 30 mgkg24 hr divided q8 12h PO Adults: 750 1,500 mg q8h IV or IM (max dose: 6 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Food increases PO bioavailability. Drug interaction: Probenecid. Cephalexin Keflex, Keftab Capsule: 250, 500 mg Tablet: 500 mg, 1 g Suspension: 125 mg5 mL, 250 mg5 mL, 100 mgmL drops First generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella, and Proteus Children: 25 100 mgkg24 hr |
7,080 | divided q6 8h PO Adults: 250 500 mg q6h PO (max dose: 4 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Drug interaction: Probenecid. Cephradine Velosef Capsule: 250, 500 mg Suspension: 125 mg5 mL, 250 mg5 mL First generation cephalosporin active against S. aureus, Streptococcus, E. coli, Klebsiella, and Proteus Children: 50 100 mgkg24 hr divided q6 12h PO Adults: 250 500 mg q6 12h PO (max dose: 4 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Renally eliminated. Drug interaction: Probenecid. Ciprofloxacin Cipro Tablet: 100, 250, 500, 750 mg Injection Ophthalmic solution and ointment Otic suspension Oral suspension: 250 and 500 mg5 mL Quinolone antibiotic active against P. aeruginosa, Serratia, Enterobacter, Shigella, Salmonella, Campylobacter, N. gonorrhoeae, H. influenzae, M. catarrhalis, some S. aureus, and some Streptococcus Neonates: 10 mgkg q12h PO or IV Children: 15 30 mgkg24 hr divided q12h PO or IV; cystic fibrosis: 20 40 mgkg24 hr divided q8 12h PO or IV Adults: 250 750 mg q12h; 200 400 mg IV q12h PO (max dose: 1.5 g24 hr) Cautions: Concerns of joint destruction in juvenile animals but not seen in humans; tendonitis, superinfection, dizziness, confusion, crystalluria, some photosensitivity. Drug interactions: Theophylline; magnesium , aluminum , or calcium containing antacids; sucralfate; probenecid; warfarin; cyclosporine. Clarithromycin Biaxin Tablet: 250, 500 mg Suspension: 125 mg5 mL, 250 mg5 mL Macrolide antibiotic with activity against S. aureus, Streptococcus, H. influenzae, Legionella, Mycoplasma, and C. trachomatis Children: 15 mgkg24 hr divided q12h PO Adults: 250 500 mg q12h PO (max dose: 1 g24 hr) Cautions: Adverse events less than erythromycin; GI upset, dyspepsia, nausea, cramping. Drug interactions: Same as erythromycin: astemizole, carbamazepine, terfenadine, cyclosporine, theophylline, digoxin, tacrolimus. Clindamycin Cleocin Capsule: 75, 150, 300 mg Suspension: 75 mg5 mL Injection Topical solution, lotion, and gel Vaginal cream Protein synthesis inhibitor active against most gram positive aerobic and anaerobic cocci except Enterococcus Neonates: Postnatal age 7 days weight 2,000 g; 10 mgkg24 hr divided q12h IV or IM; weight 2,000 g: 15 mgkg24 hr divided q8h IV or IM; 7 days weight 1,200 g: 10 mgkg24 hr IV or IM divided q12h; weight 1,200 2,000 g: 15 mgkg24 hr divided q8h IV or IM; weight 2,000 g: 20 mgkg24 hr divided q8h IV or IM Children: 10 40 mgkg24 hr divided q6 8h IV, IM, or PO Adults: 150 600 mg q6 8h IV, IM, or PO (max dose: 5 g24 hr IV or IM or 2 g24 hr PO) Cautions: Diarrhea, nausea, Clostridium difficileassociated colitis, rash. Administer slow IV over 30 60 min. Topically active as an acne treatment. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1679 Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Cloxacillin sodium Tegopen Capsule: 250, 500 mg Suspension: 125 mg5 mL Penicillinase |
7,081 | resistant penicillin active against S. aureus and other gram positive cocci except Enterococcus and coagulase negative staphylococci Children: 50 100 mgkg24 hr divided q6h PO Adults: 250 500 mg q6h PO (max dose: 4 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia). Primarily hepatically eliminated; requires dose reduction in renal disease. Food decreases bioavailability. Drug interaction: Probenecid. Colistin (colistimethate sodium; polymyxin E) Injection Inhalation Treatment of multidrug resistant gram negative organisms (Enterobacteriaceae including extended spectrum lactamase and carbapenemase producing strains) Children: 2.5 5 mgkgday divided in 2 4 divided doses IV Adults: 300 mgday in 2 4 divided doses IV Cautions: Nephrotoxicity (3 in young children; higher rates in adolescents and adults); adjust dose for renal insufficiency; neurotoxicity (headaches, paresthesia, ataxia). Drug interactions: Should not be administered concomitantly with polymyxins or aminoglycosides. Co trimoxazole (trimethoprim sulfamethoxazole; TMP SMX) Bactrim, Cotrim, Septra, Sulfatrim Tablet: SMX 400 mg and TMP 80 mg Tablet DS: SMX 800 mg and TMP 160 mg Suspension: SMX 200 mg and TMP 40 mg5 mL Injection Antibiotic combination with sequential antagonism of bacterial folate synthesis with broad antibacterial activity: Shigella, Legionella, Nocardia, Chlamydia, Pneumocystis jiroveci Dosage based on TMP component Children: 6 20 mg TMPkg24 hr or IV divided q12h PO Pneumocystis carinii pneumonia: 15 20 mg TMPkg24 hr divided q12h PO or IV P. carinii prophylaxis: 5 mg TMPkg24 hr or 3 timeswk PO Adults: 160 mg TMP q12h PO Cautions: Drug dosed on TMP (trimethoprim) component. Sulfonamide skin reactions: rash, erythema multiforme, Stevens Johnson syndrome, nausea, leukopenia. Renal and hepatic elimination; reduce dose in renal failure. Drug interactions: Protein displacement with warfarin, possibly phenytoin, cyclosporine. Dalbavancin Dalvance 500 mgvial (20 mgmL after reconstitution) Injection Glycopeptide antibiotic; bacteriocidal; disrupts cell wall synthesis Indicated for acute bacterial skin and skin structure infections caused by susceptible gram positive bacteria; active against MRSA Adult dose: 1 dose regimen of 1,500 mg IV or 2 dose regimen of 1000 mg IV followed 1 wk later by 500 mg IV; infuse IV over 30 min Pediatric dose: Not approved for use in children Rapid IV infusion, as with other glycopeptide antibacterial agents, can cause reactions, including upper body flushing, urticaria, pruritus, back pain, and rash; stopping or slowing infusion may result in cessation of these reactions. Daptomycin Cubicin Injection Disrupts bacterial cell membrane function, causing depolarization leading to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death Active against enterococci (including glycopeptide resistant strains), staphylococci (including MRSA), streptococci, and corynebacteria. Approved for skin and soft tissue infections Acceptable for bacteremia and right sided endocarditis with susceptible strains Adults: In skin and soft tissue infections, 4 mgkg daptomycin IV once daily. For S. aureus bacteremia or right sided endocarditis, 6 mgkg IV once daily Children: For skinskin structure infections, 12 23 mo, 10 mgkg IV q24h; 2 6 yr, 9 mgkg IV q24h; 7 11 yr, 7 mgkg q24h; 12 17 yr, 5 mgkg q24h, all for up to 14 days. For staphylococcal bacteremia, 1 6 yr, 12 |
7,082 | mgkg q24h; 7 11 yr, 9 mgkg q24h; 12 17 yr, 7 mgkg q24h; all for up to 42 days. For staphylococcal endocarditis, 1 5 yr, 10 mgkg IV q24h for at least 6 wk; 6 yr, 6 mgkg IV q24h for at least 6 wk Cautions: Should not be used for pneumonia because drug inactivated by surfactants. Associated with rash, renal failure, anemia, and headache. Is reported to cause myopathy, rhabdomyolysis, and eosinophilic pneumonia. Drug interactions: Should not be administered with statins. Delafloxacin Baxdela Injection Oral Injection, lyophilized powder for reconstitution 300 mg vial (equivalent to 433 mg delafloxacin meglumine) Tablet, 450 mg (equivalent to 649 mg delafloxacin meglumine) Fluoroquinolone class of drugs; active against MSSA, MRSA, CoNS, and streptococci; retains activity against fluoroquinolone resistant S. aureus strains. Approved for skin and soft tissue infections and community acquired pneumonia. Adults: 300 mg IV q12h for 5 14 days OR 300 mg IV q12h, then switch to a 450 mg tablet PO q12h for 5 14 days OR 450 mg PO q12h for 5 14 days Children: No dosage established Similar to ciprofloxacin. Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1680 Part XV u Infectious Diseases Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Demeclocycline Declomycin Tablet: 150, 300 mg Capsule: 150 mg Tetracycline active against most gram positive cocci except Enterococcus, many gram negative bacilli, anaerobes, Borrelia burgdorferi (Lyme disease), Mycoplasma, and Chlamydia Children: 8 12 mgkg24 hr divided q6 12h PO Adults: 150 mg PO q6 8h Syndrome of inappropriate antidiuretic hormone secretion: 900 1,200 mg24 hr or 13 15 mgkg24 hr divided q6 8h PO with dose reduction based on response to 600 900 mg24 hr Cautions: Teeth staining, possibly permanent (if administered 8 yr old) with prolonged use; photosensitivity, diabetes insipidus, nausea, vomiting, diarrhea, superinfections. Drug interactions: Aluminum , calcium , magnesium , zinc and iron containing food, milk, dairy products may decrease absorption. Dicloxacillin Dynapen, Pathocil Capsule: 125, 250, 500 mg Suspension: 62.5 mg5 mL Penicillinase resistant penicillin active against S. aureus and other gram positive cocci except Enterococcus and coagulase negative staphylococci Children: 12.5 100 mgkg24 hr divided q6h PO Adults: 125 500 mg q6h PO Cautions: Lactam safety profile (rash, eosinophilia). Primarily renal (65) and biliary (30) elimination. Food may decrease bioavailability. Drug interaction: Probenecid. Doripenem Doribax Injection Carbapenem antibiotic with broad spectrum activity against gram positive cocci and gram negative bacilli, including P. aeruginosa and anaerobes Children: dose unknown Adults: 500 mg q8h IV Cautions: Lactam safety profile; does not undergo hepatic metabolism. Renal elimination (7075); dose adjustment for renal failure. Drug interactions: Valproic acid, probenecid. Doxycycline Vibramycin, Doxy Injection Capsule: 50, 100 mg Tablet: 50, 100 mg Suspension: 25 mg5 mL Syrup: 50 mg5 mL Tetracycline antibiotic active against most gram positive cocci except |
7,083 | Enterococcus, many gram negative bacilli, anaerobes, B. burgdorferi (Lyme disease), Mycoplasma, and Chlamydia Children: 2 5 mgkg24 hr divided q12 24h PO or IV (max dose: 200 mg24 hr) Adults: 100 200 mg24 hr divided q12 24h PO or IV Cautions: Teeth staining, possibly permanent (8 yr old) with prolonged use; photosensitivity, nausea, vomiting, diarrhea, superinfections. Drug interactions: Aluminum , calcium , magnesium , zinc , iron , kaolin , and pectin containing products, food, milk, dairy products may decrease absorption. Carbamazepine, rifampin, and barbiturates may decrease half life. Eravacycline Xerava 50 mg single dose vials Tetracycline class antibiotic (glycylcycline) active against Enterobacteriaceae, including extended spectrum lactamase producers; streptococci (including VRE); staphylococci (including MRSA); and CRE Indicated for treatment of complicated intraabdominal infections in adults Dose: 1 mgkg IV q12h 4 14 days; infuse IV over 60 min Contraindications similar to other tetracyclines, including photosensitivity; pseudotumor cerebri; concerns for discoloration of tooth enamel in children under 8 yr of age. Erythromycin E Mycin, Ery Tab, Eryc, Ilosone Estolate 125, 500 mg Tablet EES: 200 mg Tablet base: 250, 333, 500 mg Suspension: estolate 125 mg5 mL, 250 mg5 mL, EES 200 mg5 mL, 400 mg5 mL Estolate drops: 100 mgmL; EES drops: 100 mg2.5 mL Available in combination with sulfisoxazole (Pediazole), dosed on erythromycin content Bacteriostatic macrolide antibiotic most active against gram positive organisms, Corynebacterium diphtheriae, and Mycoplasma pneumoniae Neonates: Postnatal age 7 days: 20 mgkg24 hr divided q12h PO; 7 days weight 1,200 g: 20 mgkg24 hr divided q12h PO; weight 1,200 g: 30 mgkg24 hr divided q8h PO (give as 5 mg kgdose q6h to improve feeding intolerance) Children: Usual max dose: 2 g24 hr Base: 30 50 mgkg24 hr divided q6 8h PO Estolate: 30 50 mgkg24 hr divided q8 12h PO Stearate: 20 40 mgkg24 hr divided q6h PO Lactobionate: 20 40 mgkg24 hr divided q6 8h IV Gluceptate: 20 50 mgkg24 hr divided q6h IV; usual max dose: 4 g24 hr IV Adults: Base: 333 mg PO q8h; estolatestearatebase: 250 500 mg q6h PO Cautions: Motilin agonist leading to marked abdominal cramping, nausea, vomiting, and diarrhea. Associated with hypertrophic pyloric stenosis in young infants. Many different salts with questionable tempering of GI adverse events. Rare cardiac toxicity with IV use. Dose of salts differs. Topical formulation for treatment of acne. Drug interactions: Antagonizes hepatic CYP 3A4 activity: astemizole, carbamazepine, terfenadine, cyclosporine, theophylline, digoxin, tacrolimus. Gentamicin Garamycin Injection Ophthalmic solution, ointment, topical cream Aminoglycoside antibiotic active against gram negative bacilli, especially E. coli, Klebsiella, Proteus, Enterobacter, Serratia, and Pseudomonas Neonates: Postnatal age 7 days weight 1,200 2,000 g: 2.5 mg kg q12 18h IV or IM; weight 2,000 g: 2.5 mgkg q12h IV or IM; postnatal age 7 days weight 1,200 2,000 g: 2.5 mgkg q8 12h IV or IM; weight 2,000 g: 2.5 mgkg q8h IV or IM Children: 2.5 mgkg24 hr divided q8 12h IV or IM; alternatively, may administer 5 7.5 mgkg24 hr IV once daily Intrathecal: Preservative free preparation for intraventricular or |
7,084 | intrathecal use: neonate: 1 mg24 hr; children: 1 2 mg24 hr intrathecal; adults: 4 8 mg24 hr Adults: 3 6 mgkg24 hr divided q8h IV or IM Cautions: Anaerobes, S. pneumoniae, and other Streptococcus are resistant. May cause ototoxicity and nephrotoxicity. Monitor renal function. Drug eliminated renally. Administered IV over 30 60 min. Drug interactions: May potentiate other ototoxic and nephrotoxic drugs. Target serum concentrations: Peak 6 12 mgL; trough 2 mgL with intermittent daily dose regimens only. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1681 Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Imipenem cilastatin Primaxin Injection Carbapenem antibiotic with broad spectrum activity against gram positive cocci and gram negative bacilli, including P. aeruginosa and anaerobes. No activity against Stenotrophomonas maltophilia Neonates: Postnatal age 7 days weight 1,200 g: 20 mgkg q18 24h IV or IM; weight 1,200 g: 40 mgkg divided q12h IV or IM; postnatal age 7 days weight 1,200 2,000 g: 40 mgkg q12h IV or IM; weight 2,000 g: 60 mgkg q8h IV or IM Children: 60 100 mgkg24 hr divided q6 8h IV or IM Adults: 2 4 g24 hr divided q6 8h IV or IM (max dose: 4 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia), nausea, seizures. Cilastatin possesses no antibacterial activity; reduces renal imipenem metabolism. Primarily renally eliminated. Drug interaction: Possibly ganciclovir. Imipenemrelebactam (imipenemcilastatin relebactam) Recarbrio 500 mg500 mg250 mg per vial (i.e., 1.25 gvial) Carbapenem antibiotic similar to imipenemcilastatin; addition of relebactam restores activity against K. pneumoniae isolates that encode KPCs; is indicated for treatment of complicated urinary tract infections and complicated intraabdominal infections and hospital acquiredventilator associated bacterial pneumonia in adults 18 yr of age and older Adults: 1.25 g IV q6h 4 14 days Children: No dosing information available Cautions: Lactam safety profile (rash, eosinophilia), nausea, seizures. Cilastatin possesses no antibacterial activity; reduces renal imipenem metabolism. Primarily renally eliminated. Linezolid Zyvox Tablet: 400, 600 mg Oral suspension: 100 mg5 mL Injection: 100 mg5 mL Oxazolidinone antibiotic active against gram positive cocci (especially drug resistant organisms), including Staphylococcus, Streptococcus, E. faecium, and Enterococcus faecalis. Interferes with protein synthesis by binding to 50S ribosome subunit Children: 10 mgkg q12h IV or PO Adults: Pneumonia: 600 mg q12h IV or PO; skin infections: 400 mg q12h IV or PO Adverse events: Myelosuppression, pseudomembranous colitis, nausea, diarrhea, headache, peripheral and optic neuropathy. Drug interaction: Probenecid. Loracarbef Lorabid Generic Capsule: 200 mg Suspension: 100 mg5 mL, 200 mg5 mL Carbacephem very closely related to cefaclor (second generation cephalosporin) active against S. aureus, Streptococcus, H. influenzae, M. catarrhalis, E. coli, Klebsiella, and Proteus Children: 30 mgkg24 hr divided q12h PO (max dose: 2 g) Adults: 200 400 mg q12h PO (max dose: 800 mg24 hr) Cautions: Lactam safety profile (rash, eosinophilia). |
7,085 | Renally eliminated. Drug interaction: Probenecid. Meropenem Merrem Injection Carbapenem antibiotic with broad spectrum activity against gram positive cocci and gram negative bacilli, including P. aeruginosa and anaerobes No activity against S. maltophilia Children: 60 mgkg24 hr divided q8h IV; meningitis: 120 mg kg24 hr (max dose: 6 g24 hr) q8h IV Adults: 1.5 3 g q8h IV Cautions: Lactam safety profile; appears to possess less CNS excitation than imipenem; 80 renal elimination. Drug interaction: Probenecid. Meropenemvaborbactam Vabomere 1 g1 g vials Carbapenem antibiotic with broad spectrum activity against gram positive cocci and gram negative bacilli, including P. aeruginosa and anaerobes Vaborbactam protects meropenem from degradation by certain serine lactamases including K. pneumoniae carbapenemases (KPCs); added to enhance activity for complicated urinary tract infections, including pyelonephritis caused by E. coli, K. pneumoniae, and E. cloacae species complex in adults 18 yr Adults: 4 g (meropenem 2 gvaborbactam 2 g) IV q8h for up to 14 days; infuse over 3 hr. Cautions: Lactam safety profile; appears to possess less CNS excitation than imipenem; 80 renal elimination. Drug interaction: Probenecid. Metronidazole Flagyl, Metro I.V., Topical gel, vaginal gel Injection Tablet: 250, 500 mg Highly effective in the treatment of infections caused by anaerobes. Oral therapy of C. difficile colitis Neonates: weight 1,200 g: 7.5 mgkg48 hr PO or IV; postnatal age 7 days weight 1,200 2,000 g: 7.5 mgkg24 hr q24h PO or IV; weight 2,000 g: 15 mgkg24 hr divided q12h PO or IV; postnatal age 7 days weight 1,200 2,000 g: 15 mgkg24 hr divided q12h PO or IV; weight 2,000 g: 30 mgkg24 hr divided q12 h PO or IV Children: 30 mgkg24 hr divided q6 8h PO or IV Adults: 30 mgkg24 hr divided q6h PO or IV (max dose: 4 g24 hr) Cautions: Dizziness, seizures, metallic taste, nausea, disulfiram like reaction with alcohol. Administer IV slow over 30 60 min. Adjust dose with hepatic impairment. Drug interactions: Carbamazepine, rifampin, phenobarbital may enhance metabolism; may increase levels of warfarin, phenytoin, lithium. Mezlocillin sodium Mezlin Infection Extended spectrum penicillin active against E. coli, Enterobacter, Serratia, and Bacteroides; limited antipseudomonal activity Neonates: Postnatal age 7 days: 150 mgkg24 hr divided q12h IV; 7 days: 225 mgkg divided q8h IV Children: 200 300 mgkg24 hr divided q4 6h IV; cystic fibrosis 300 450 mgkg24 hr IV Adults: 2 4 gdose q4 6h IV (max dose: 12 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains 1.8 mEq sodium. Interferes with platelet aggregation with high doses; increases noted in liver function test results. Renally eliminated. Inactivated by lactamase enzyme. Drug interaction: Probenecid. Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1682 Part XV u Infectious Diseases Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Mupirocin Bactroban Ointment Topical antibiotic active against Staphylococcus |
7,086 | and Streptococcus Topical application: Nasal (eliminate nasal carriage) and to the skin 2 4 times daily Caution: Minimal systemic absorption because drug metabolized within the skin. Nafcillin sodium Nafcil, Unipen Injection Capsule: 250 mg Tablet: 500 mg Penicillinase resistant penicillin active against S. aureus and other gram positive cocci, except Enterococcus and coagulase negative staphylococci Neonates: Postnatal age 7 days weight 1,200 2,000 g: 50 mg kg24 hr divided q12h IV or IM; weight 2,000 g: 75 mgkg24 hr divided q8h IV or IM; postnatal age 7 days weight 1,200 2,000 g: 75 mgkg24 hr divided q8h; weight 2,000 g: 100 mgkg24 hr divided q6 8h IV (meningitis: 200 mgkg24 hr divided q6h IV) Children: 100 200 mgkg24 hr divided q4 6h IV Adults: 4 12 g24 hr divided q4 6h IV (max dose: 12 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia), phlebitis; painful given intramuscularly; oral absorption highly variable and erratic (not recommended). Adverse effect: Neutropenia. Nalidixic acid NegGram Tablet: 250, 500, 1,000 mg Suspension: 250 mg5 mL First generation quinolone effective for short term treatment of lower UTIs caused by E. coli, Enterobacter, Klebsiella, and Proteus Children: 50 55 mgkg24 hr divided q6h PO; suppressive therapy: 25 33 mgkg24 hr divided q6 8h PO Adults: 1 g q6h PO; suppressive therapy: 500 mg q6h PO Cautions: Vertigo, dizziness, rash. Not for use in systemic infections. Drug interactions: Liquid antacids. Neomycin sulfate Mycifradin Tablet: 500 mg Topical cream, ointment Solution: 125 mg5 mL Aminoglycoside antibiotic used for topical application or orally before surgery to decrease GI flora (nonabsorbable) and hyperammonemia Infants: 50 mgkg24 hr divided q6h PO Children: 50 100 mgkg24 hr divided q6 8h PO Adults: 500 2,000 mgdose q6 8h PO Cautions: In patients with renal dysfunction because small amount absorbed may accumulate. Adverse events: Primarily related to topical application, abdominal cramps, diarrhea, rash. Like any aminoglycoside, ototoxicity and nephrotoxicity occur if absorbed. Nitrofurantoin Furadantin, Furan, Macrodantin Capsule: 50, 100 mg Extended release capsule: 100 mg Macrocrystal: 50, 100 mg Suspension: 25 mg5 mL Effective in treatment of lower UTIs caused by gram positive and gram negative pathogens Children: 5 7 mgkg24 hr divided q6h PO (max dose: 400 mg24 hr); suppressive therapy 1 2.5 mgkg24 hr divided q12 24h PO (max dose: 100 mg24 hr) Adults: 50 100 mg24 hr divided q6h PO Cautions: Vertigo, dizziness, rash, jaundice, interstitial pneumonitis. Do not use with moderate to severe renal dysfunction. Drug interactions: Liquid antacids. Ofloxacin Ocuflox 0.3 ophthalmic solution: 1, 5, 10 mL Floxin 0.3 otic solution: 5, 10 mL Quinolone antibiotic for treatment of conjunctivitis or corneal ulcers (ophthalmic solution) and otitis externa or chronic suppurative otitis media (otic solution) caused by susceptible gram positive, gram negative, anaerobic bacteria, or C. trachomatis Child 1 12 yr: Conjunctivitis: 1 2 drops in affected eye(s) q2 4h for 2 days, then 1 2 drops qid for 5 days Corneal ulcers: 1 2 drops q30min while awake and at 4 hr intervals at night for 2 days, then |
7,087 | 1 2 drops hourly for 5 days while awake, then 1 2 drops q6h for 2 days Otitis externa (otic solution): 5 drops into affected ear bid for 10 days Chronic suppurative otitis media: treat for 14 days Child 12 yr and adults: Ophthalmic solution doses same as for younger children. Otitis externa (otic solution): Use 10 drops bid for 10 or 14 days as for younger children Adverse events: Burning, stinging, eye redness (ophthalmic solution), dizziness with otic solution if not warmed. Omadacycline Nuzyra Injection 100 mgsingle dose vial Oral 150 mg tablet New subclass of tetracyclines; active against MSSA, MRSA CoNS, streptococci, including pneumococcus, and enterococci, including VRE Adults: 200 mg IV once OR 100 mg IV 2 doses OR 300 mg PO 2 doses Follow with maintenance dosing starting on day 2: Maintenance dose 100 mg IV qday OR 300 mg PO qday Treatment duration: 7 14 days Children: No dosing information available Omadacycline has comparable adverse events to other tetracyclines such as tooth discoloration, enamel hypoplasia, and inhibition of bone growth. However, no cases of photosensitivity were observed in phase 3 studies. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1683 Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Oxacillin sodium Prostaphlin Injection Capsule: 250, 500 mg Suspension: 250 mg5 mL Penicillinase resistant penicillin active against S. aureus and other gram positive cocci, except Enterococcus and coagulase negative staphylococci Neonates: Postnatal age 7 days weight 1,200 2,000 g: 50 mgkg24 hr divided q12h IV; weight 2,000 g: 75 mgkg24 hr IV divided q8h IV; postnatal age 7 days weight 1,200 g: 50 mgkg24 hr IV divided q12h IV; weight 1,200 2,000 g: 75 mgkg24 hr divided q8h IV; weight 2,000 g: 100 mgkg24 hr IV divided q6h IV Infants: 100 200 mgkg24 hr divided q4 6h IV Children: PO 50 100 mgkg24 hr divided q4 6h IV Adults: 2 12 g24 hr divided q4 6h IV (max dose: 12 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia) Moderate oral bioavailability (3565). Primarily renally eliminated Drug interaction: Probenecid Adverse effect: Neutropenia Penicillin G Injection Tablets Penicillin active against most gram positive cocci; S. pneumoniae (resistance is increasing), group A Streptococcus, and some gram negative bacteria (e.g., N. gonorrhoeae, N. meningitidis) Neonates: Postnatal age 7 days weight 1,200 2,000 g: 50,000 unitskg24 hr divided q12h IV or IM (meningitis: 100,000 U kg24 hr divided q12h IV or IM); weight 2,000 g: 75,000 U kg24 hr divided q8h IV or IM (meningitis: 150,000 Ukg24 hr divided q8h IV or IM); postnatal age 7 days weight 1,200 g: 50,000 Ukg24 hr divided q12h IV (meningitis: 100,000 Ukg24 hr divided q12h IV); weight 1,200 2,000 g: 75,000 Ukg24 hr q8h IV (meningitis: 225,000 Ukg24 hr divided q8h IV); weight |
7,088 | 2,000 g: 100,000 Ukg24 hr divided q6h IV (meningitis: 200,000 Ukg24 hr divided q6h IV) Children: 100,000 250,000 unitskg24 hr divided q4 6h IV or IM (max dose: 400,000 Ukg24 hr) Adults: 2 24 million units24 hr divided q4 6h IV or IM Cautions: Lactam safety profile (rash, eosinophilia), allergy, seizures with excessive doses particularly in patients with marked renal disease. Substantial pathogen resistance. Primarily renally eliminated Drug interaction: Probenecid Penicillin G, benzathine Bicillin Injection Long acting repository form of penicillin effective in treatment of infections responsive to persistent, low penicillin concentrations (1 4 wk) (e.g., group A Streptococcus pharyngitis, rheumatic fever prophylaxis) Neonates weighing 1,200 g: 50,000 unitskg IM once Children: 300,000 1.2 million unitskg q3 4wk IM (max dose: 1.2 2.4 million unitsdose) Adults: 1.2 million units IM q3 4wk Cautions: Lactam safety profile (rash, eosinophilia), allergy. Administer by IM injection only. Substantial pathogen resistance. Primarily renally eliminated. Drug interaction: Probenecid. Penicillin G, procaine Crysticillin Injection Repository form of penicillin providing low penicillin concentrations for 12 hr Neonates with weight 1,200 g: 50,000 unitskg24 hr IM Children: 25,000 50,000 unitskg24 hr IM for 10 days (max dose: 4.8 million unitsdose) Gonorrhea: 100,000 unitskg (max dose: 4.8 million units24 hr) IM once with probenecid 25 mgkg (max dose: 1 g) Adults: 0.6 4.8 million units q12 24h IM Cautions: Lactam safety profile (rash, eosinophilia) allergy. Administer by IM injection only. Substantial pathogen resistance. Primarily renally eliminated. Drug interaction: Probenecid. Penicillin V Pen VK, V Cillin K Tablet: 125, 250, 500 mg Suspension: 125 mg5 mL, 250 mg5 mL Preferred oral dosing form of penicillin, active against most gram positive cocci; S. pneumoniae (resistance is increasing), other streptococci, and some gram negative bacteria (e.g., N. gonorrhoeae, N. meningitidis) Children: 25 50 mgkg24 hr divided q4 8h PO Adults: 125 500 mg q6 8h PO (max dose: 3 g24 hr) Cautions: Lactam safety profile (rash, eosinophilia), allergy, seizures with excessive doses particularly in patients with renal disease. Substantial pathogen resistance. Primarily renally eliminated. Inactivated by penicillinase. Drug interaction: Probenecid. Piperacillin Pipracil Injection Extended spectrum penicillin active against E. coli, Enterobacter, Serratia, P. aeruginosa, and Bacteroides Neonates: Postnatal age 7 days 150 mgkg24 hr divided q8 12h IV; 7 days; 200 mgkg divided q6 8h IV Children: 200 300 mgkg24 hr divided q4 6h IV; cystic fibrosis: 350 500 mgkg24 hr IV Adults: 2 4 gdose q4 6h (max dose: 24 g24 hr) IV Cautions: Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains 1.9 mEq sodium. Interferes with platelet aggregationserum sicknesslike reaction with high doses; increases in liver function test results. Renally eliminated. Inactivated by penicillinase. Drug interaction: Probenecid. Piperacillin tazobactam Zosyn Injection Extended spectrum penicillin (piperacillin) combined with a lactamase inhibitor (tazobactam) active against S. aureus, H. influenzae, E. coli, Enterobacter, Serratia, Acinetobacter, P. aeruginosa, and Bacteroides Children: 300 400 mgkg24 hr divided q6 8h IV or IM Adults: 3.375 g q6 8h IV or IM Cautions: Lactam safety profile (rash, eosinophilia); painful given intramuscularly; each gram contains |
7,089 | 1.9 mEq sodium. Interferes with platelet aggregation, serum sicknesslike reaction with high doses, increases in liver function test results. Renally eliminated. Drug interaction: Probenecid. Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1684 Part XV u Infectious Diseases Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Plazomicin Zemdri 500 mg10 mL (50 mgmL) vials Each vial contains plazomicin sulfate equivalent to 500 mg plazomicin free base Aminoglycoside active against resistant Enterobacteriaceae, including CRE Adults: 15 mgkg IV q24hr infused over 30 min Duration of therapy should be guided by the severity of infection and the patients clinical status for up to 7 days; usual duration 4 7 days Children: no pediatric dose established May cause ototoxicity and nephrotoxicity. Monitor renal function. Drug eliminated renally. Drug interactions: May potentiate other ototoxic and nephrotoxic drugs. Quinupristindalfopristin Synercid IV injection: powder for reconstitution, 10 mL contains 150 mg quinupristin, 350 mg dalfopristin Streptogramin antibiotic (quinupristin) active against vancomycin resistant E. faecium (VRE) and methicillin resistant S. aureus (MRSA). Not active against E. faecalis Children and adults: VRE: 7.5 mgkg q8h IV for VRE; skin infections: 7.5 mgkg q12h IV Adverse events: Pain, edema, or phlebitis at injection site; nausea; diarrhea. Drug interactions: Synercid is a potent inhibitor of CYP 3A4. Sulfadiazine Tablet: 500 mg Sulfonamide antibiotic primarily indicated for treatment of lower UTIs caused by E. coli, P. mirabilis, and Klebsiella Toxoplasmosis: Neonates: 100 mgkg24 hr divided q12h PO with pyrimethamine 1 mgkg24 hr PO (with folinic acid) Children: 120 200 mgkg24 hr divided q6h PO with pyrimethamine 2 mgkg24 hr divided q12h PO 3 days, then 1 mgkg24 hr (max dose: 25 mg24 hr) with folinic acid Rheumatic fever prophylaxis: weight 30 kg: 500 mg24 hr q24h PO; weight 30 kg: 1 g24 hr q24h PO Cautions: Rash, Stevens Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic elimination; avoid use with renal disease. Half life: 10 hr. Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate. Sulfamethoxazole Gantanol Tablet: 500 mg Suspension: 500 mg5 mL Sulfonamide antibiotic used for treatment of otitis media, chronic bronchitis, and lower UTIs caused by susceptible bacteria Children: 50 60 mgkg24 hr divided q12h PO Adults: 1 gdose q12h PO (max dose: 3 g24 hr) Cautions: Rash, Stevens Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic elimination; avoid use with renal disease. Half life: 12 hr. Initial dose often a loading dose (doubled). Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate. Sulfisoxazole Gantrisin Tablet: 500 mg Suspension: 500 mg5 mL Ophthalmic solution, ointment Sulfonamide antibiotic used for treatment of otitis media, chronic bronchitis, and lower UTIs caused by susceptible bacteria. Also used for Nocardia Plasmodium falciparum resistant to chloroquine, toxoplasmosis in combination with pyrimethamine (sulfadiazine preferred). Children: 120 150 mgkg24 hr divided q4 6h PO (max dose: 6 g24 hr) Adults: 4 |
7,090 | 8 g24 hr divided q4 6h PO Cautions: Rash, Stevens Johnson syndrome, nausea, leukopenia, crystalluria. Renal and hepatic elimination; avoid use with renal disease. Half life: 7 12 hr. Initial dose often a loading dose (doubled). Drug interactions: Protein displacement with warfarin, phenytoin, methotrexate. Tedizolid Sivextro 200 mg vial 200 mg tablet Oxazolidinone agent; indicated for skin and soft tissueskin structure infections caused by susceptible gram positive organisms; active against MSSA, MRSA, streptococci, enterococci Adults: 200 mg POIV qday for 6 days Children: Indicated for acute bacterial skin and skin structure infections in patients age 12 yr 12 yr: Safety and efficacy not established 12 18 yr: 200 mg POIV qday for 6 days Similar to linezolid. Adverse events may include myelosuppression, pseudomembranous colitis, nausea, diarrhea, headache, peripheral and optic neuropathy. Tigecycline Tygacil Injection Tetracycline class antibiotic (glycylcycline) active against Enterobacteriaceae, including extended spectrum lactamase producers; streptococci (including VRE); staphylococci (including MRSA); and anaerobes Children: unknown Adults: 100 mg loading dose followed by 50 mg q12h IV Cautions: Pregnancy; children 8 yr old; photosensitivity; hypersensitivity to tetracyclines; hepatic impairment (60 hepatic clearance). Drug interaction: Warfarin; mycophenolate mofetil. Tobramycin Nebcin, Tobrex Injection Ophthalmic solution, ointment Inhalation capsule (28 mg); inhalation solution (60 mg mL; 75 mgmL) Aminoglycoside antibiotic active against gram negative bacilli, especially E. coli, Klebsiella, Enterobacter, Serratia, Proteus, and Pseudomonas Can be administered by inhalational route Neonates: Postnatal age 7 days, weight 1,200 2,000 g: 2.5 mg kg q12 18h IV or IM; weight 2,000 g: 2.5 mgkg q12h IV or IM; postnatal age 7 days, weight 1,200 2,000 g: 2.5 mgkg q8 12h IV or IM; weight 2,000 g: 2.5 mgkg q8h IV or IM Children: 2.5 mgkg24 hr divided q8 12h IV or IM. Alternatively, may administer 5 7.5 mgkg24 hr IV. Preservative free preparation for intraventricular or intrathecal use: neonate, 1 mg24 hr; children, 1 2 mg24 hr; adults, 4 8 mg24 hr Adults: 3 6 mgkg24 hr divided q8h IV or IM Cautions: S. pneumoniae, other streptococcus, and anaerobes are resistant. May cause ototoxicity and nephrotoxicity. Monitor renal function. Drug eliminated renally. Administered IV over 30 60 min. Drug interactions: May potentiate other ototoxic and nephrotoxic drugs. Target serum concentrations: Peak 6 12 mgL; trough 2 mgL. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1685 Table 225.3 Selected Antibacterial Medications (Antibiotics)contd DRUG (TRADE NAMES, FORMULATIONS) INDICATIONS (MECHANISM OF ACTION) AND DOSING COMMENTS Trimethoprim Proloprim, Trimpex Tablet: 100, 200 mg Folic acid antagonist effective in prophylaxis and treatment of E. coli, Klebsiella, P. mirabilis, and Enterobacter UTIs; P. carinii pneumonia Children: For UTI: 4 6 mgkg24 hr divided q12h PO Children 12 yr and adults: 100 200 mg q12h PO. P. carinii pneumonia (with dapsone): 15 20 mgkg24 hr divided q6h for 21 days PO Cautions: Megaloblastic anemia, bone marrow suppression, nausea, |
7,091 | epigastric distress, rash. Drug interactions: Possible interactions with phenytoin, cyclosporine, rifampin, warfarin. Vancomycin Vancocin, Lyphocin Injection Capsule: 125 mg, 250 mg Suspension Glycopeptide antibiotic active against most gram positive pathogens including staphylococci (including MRSA and coagulase negative staphylococci), S. pneumoniae including penicillin resistant strains, Enterococcus (resistance is increasing), and C. difficileassociated colitis Neonates: Postnatal age 7 days, weight 1,200 g: 15 mgkg24 hr divided q24h IV; weight 1,200 2,000 g: 15 mgkg24 hr divided q12 18h IV; weight 2,000 g: 30 mgkg24 hr divided q12h IV; postnatal age 7 days, weight 1,200 g: 15 mgkg24 hr divided q24h IV; weight 1,200 2,000 g: 15 mgkg24 hr divided q8 12h IV; weight 2,000 g: 45 mgkg24 hr divided q8h IV Children: 45 60 mgkg24 hr divided q8 12h IV; C. difficile associated colitis; 40 50 mgkg24 hr divided q6 8h PO Cautions: Ototoxicity and nephrotoxicity, particularly when co administered with other ototoxic and nephrotoxic drugs. Infuse IV over 45 60 min. Cutaneous and systemic side effects can be observed with rapid IV infusions, fever, chills, phlebitis (central line is preferred for infusions). Renally eliminated. Target serum concentrations: Peak (1 hr after 1 hr infusion) 30 40 mgL; trough 5 10 mgL. In the Drug column, the generic drug name is in bold. In the Indications column, bold indicates major organisms targeted and mechanisms of action. CNS, Central nervous system; GI, gastrointestinal; IM, intramuscularly; IV, intravenously; PO, orally; UTIs, urinary tract infections. Table 225.4 Adverse Reactions to Penicillins TYPE OF REACTION FREQUENCY () OCCURS MOST FREQUENTLY WITH ALLERGIC Immunoglobulin E antibody 0.04 0.015 Penicillin G Anaphylaxis Early urticaria (72 hr) Cytotoxic antibody Rare Penicillin G Hemolytic anemia Antigen antibody complex disease Rare Penicillin G Serum sickness Delayed hypersensitivity 2 5 Ampicillin, amoxicillin Contact dermatitis IDIOPATHIC 2 5 Ampicillin Skin rash Fever Late onset urticaria GASTROINTESTINAL Diarrhea 3 11 Ampicillin Clostridioides difficile (formerly Clostridium difficile)associated colitis Rare Ampicillin HEMATOLOGIC Hemolytic anemia Rare Penicillin G Neutropenia 10 17 Penicillin G, nafcillin, oxacillin Platelet dysfunction 43 73 Piperacillin HEPATIC Elevated serum aspartate transaminase 0.01 22 Flucloxacillin, oxacillin Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1686 Part XV u Infectious Diseases A fifth generation cephalosporin called ceftaroline has been licensed. Ceftaroline is the active metabolite of the prodrug ceftaroline fosamil (which is the agent administered to the patient). Ceftaroline is a broad spectrum cephalosporin with bactericidal activity against resistant gram positive organisms, including MRSA, and common gram negative pathogens. It has FDA approval and is licensed for use in children. Ceftaroline is indicated for MRSA in the treatment of skin and soft tissue infections. It is also licensed for treatment of community acquired pneumonia but is not indicated for MRSA pneu monia. Ceftarolines activity is attributed to its ability to bind to PBP 2a with higher affinity than other lactams. Another fifth generation cephalosporin with a similar spectrum |
7,092 | of activity, ceftobiprole, has been approved for use in Canada and the European Union. A third fifth generation cephalosporin, ceftolozane, has been licensed. It is a derivative of ceftazidime with improved activity against Pseudomo nas spp. It is not stable against most ESBLs or carbapenemases. It is marketed in combination with the lactam inhibitor tazobactam to improve its activity against lactamaseproducing Enterobacteria ceae. Experience with children is limited. Table 225.6 lists adverse reactions to cephalosporins. Carbapenems The carbapenem group of antibiotics includes imipenem (formu lated in combination with cilastatin), meropenem, ertapenem, and doripenem. The basic structure of these agents is similar to that of lactam antibiotics, and these drugs have a similar mechanism of TYPE OF REACTION FREQUENCY () OCCURS MOST FREQUENTLY WITH ELECTROLYTE DISTURBANCE Hypokalemia Rare Nafcillin, oxacillin Hyperkalemia, acute Rare Penicillin G NEUROLOGIC Seizures Rare Penicillin G Bizarre sensations (Hoign syndrome) Rare Procaine penicillin RENAL Interstitial nephritis Variable Any penicillin Reaction can occur with any of the penicillins. With prolonged therapy. Adapted from Doi Y. Penicillins and lactamase inhibitors. In Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Table 20 7. Table 225.4 Adverse Reactions to Penicillinscontd Table 225.5 Classification of Parenteral and Oral Cephalosporins CEPHALOSPORINS FIRST GENERATION SECOND GENERATION CEPHAMYCINS THIRD GENERATION FOURTH GENERATION FIFTH GENERATION (MRSA ACTIVE) Parenteral Cefazolin (Ancef, Kefzol) Cefamandole (Mandol) Cefmetazole (Zefazone) Cefoperazone (Cefobid) Cefepime (Maxipime) Ceftaroline (Teflaro) Cephalothin (Keflin, Seffin) Cefonicid (Monocid) Cefotetan (Cefotan) Cefotaxime (Claforan) Cefpirome (Cefrom) Ceftobiprole (Zeftera) Cephapirin (Cefadyl) Cefuroxime (Kefurox, Zinacef) Cefoxitin (Mefoxin) Ceftazidime (Fortaz) Cefiderocol (Fetroja; Siderophore antibiotic) Ceftolozane (combined with tazobactam; Zerbaxa) Cephradine (Velosef) Ceftizoxime (Cefizox) Ceftriaxone (Rocephin) Moxalactam Ceftazidime avibactam (Avycaz) Oral Cefadroxil (Duricef, Ultracef) Cephalexin (Keflex, Biocef, Keftab) Cephradine (Velosef) Cefaclor (Ceclor) Cefprozil (Cefzil) Cefuroxime axetil (Ceftin) Loracarbef (Lorabid) Cefdinir (Omnicef) Cefditoren (Spectracef) Cefixime (Suprax) Cefpodoxime (Vantin) Ceftibuten (Cedax) Not currently available in the United States. Adapted from Lepak AJ, Andes DR. Cephalosporins. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Table 21 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1687 action. The carbapenems provide the broadest spectrum of anti bacterial activity of any licensed class of antibiotics and are active against gram positive, gram negative, and anaerobic organisms. Among the carbapenems, meropenem is the only agent licensed for treatment of pediatric meningitis. Importantly, MRSA and E. faecium are not susceptible to carbapenems. Carbapenems also tend to be poorly active against Stenotrophomonas maltophilia, ren dering their use for cystic fibrosis patients who are infected with this organism problematic. Ertapenem is poorly active against P. aeruginosa and Acinetobacter species and should be avoided when these pathogens are encountered. Although imipenem cilastatin is the first carbapenem approved for clinical use and the |
7,093 | carbape nem with the greatest clinical experience, this antibiotic unfortu nately has a propensity to cause seizures in children, particularly in the setting of intercurrent meningitis. Accordingly, merope nem is typically more suitable for pediatric use, where menin gitis is commonly a consideration. Carbapenems have also been combined with lactamase inhibitors. One example is merope nemvaborbactam, where the lactamase inhibitor vaborbac tam extends the spectrum of activity to include some ESBL and carbapenemase producing bacteria. No dosage recommendations exist as yet for pediatric use. Another example is imipenemrele bactam (imipenemcilastatinrelebactam), which is approved for complicated urinary tract and intraabdominal infections and for ventilator associated pneumonia. Other carbapenems in various stages of clinical trials include bena penum, panipenem, biapenem, razupenem, and tomopenem. Tebipe nem pivoxil is an orally available prodrug of tebipenem, a carbapenem with activity against multidrug resistant gram negative pathogens, including quinolone resistant and ESBL producing Enterobacteria ceae. Sulopenemsulopenem etzadroxilprobenecid is an oral carbape nem combination. Sulopenem etzadroxil is an oral prodrug form of sulopenem, a thiopenem with broad spectrum antibacterial activity against most gram positive and gram negative bacteria, not including P. aeruginosa. Probenecid is included to prolong half life. Panipenem is a combination agent coformulated with betamipron, which inhib its renal uptake of panipenem (analogous to imipenemcilastatin). Panipenem, biapenem, and tebipenempivoxil are licensed in Japan. There is minimal experience with pediatric dosing for all of these newer carbapenems. Table 225.6 Potential Adverse Effects of Cephalosporins TYPE SPECIFIC FREQUENCY Hypersensitivity Rash 13 Urticaria 1 Serum sickness 1 Anaphylaxis 0.01 Gastrointestinal Diarrhea 119 Nausea, vomiting 16 Transient transaminase elevation 17 Biliary sludge 2046 Hematologic Eosinophilia 110 Neutropenia 1 Thrombocytopenia 13 Hypoprothrombinemia 1 Impaired platelet aggregation 1 Hemolytic anemia 1 Renal Interstitial nephritis 15 Central nervous system Seizures 1 Encephalopathy 1 False positive laboratory Coombs positive 3 Glucosuria Rare Serum creatinine Rare Other Drug fever Rare Disulfiram like reaction Rare Superinfection Rare Phlebitis Rare Calcium antibiotic precipitation Unknown; can be associated with embolic events Ceftriaxone. Cephalosporins with thiomethyl tetrazole ring (MTT) side chain. Adapted from Craig WA, Andes DR. Cephalosporins. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Table 21 6. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1688 Part XV u Infectious Diseases Glycopeptides Glycopeptide antibiotics include vancomycin and teicoplanin, the less commonly available analog. These agents are bactericidal and act by inhibiting cell wall biosynthesis. The antimicrobial activity of the glycopeptides is limited to gram positive organisms, includ ing S. aureus, coagulase negative staphylococci, pneumococcus, enterococci, Bacillus, and Corynebacterium. Vancomycin is fre quently employed in pediatric practice and is of particular value for serious infections, including meningitis, caused by MRSA and penicillin and cephalosporin resistant S. pneumoniae. Vancomycin is also commonly used for infections in the setting of fever and neu tropenia in oncology patients, in |
7,094 | combination with other antibiot ics (see Chapter 223), and for infections associated with indwelling medical devices (see Chapter 224). Oral formulations of vancomy cin are occasionally used to treat pseudomembranous colitis caused by Clostridium difficile infections; intrathecal therapy may also be used for selected CNS infections. Vancomycin must be adminis tered with care because of its propensity to produce vancomycin infusion syndrome, which is a reversible adverse effect that is rare in young children and can typically be readily managed by slowing the rate of drug infusion. Newer FDA approved glycopeptide antibiotics include tela vancin, dalbavancin, and oritavancin; pediatric experience is lim ited. Telavancin is indicated for skin and skin structure infections caused by S. aureus (including MRSA), group A streptococcus, and E. faecalis (vancomycin susceptible isolates only). It is also approved for hospital acquired (including ventilator associated) pneumonia caused by S. aureus. The recommended adult dose for skin and soft tissue infections, and for nosocomial pneumo nia, is 10 mgkg intravenously (IV) every 24 hours for 7 21 days. Telavancin appears to be more nephrotoxic than vancomycin and has been associated with prolongation of the QT interval. Dalba vancins unique characteristic is its long half life, 150 250 hours. In adults with normal renal function, the dose is 1000 mg IV, fol lowed 1 week later by 500 mg IV. This agent can be considered when MRSA is confirmed or strongly suggested. Dalbavancin is not active against vancomycin resistant S. aureus. It is FDA approved for bac terial skin and soft tissue infections. Oritavancin is a vancomycin derivative with indications similar to those of dalbavancin. It has a half life of approximately 250 hours. The dosage for adults is a single 1200 mg dose administered IV over 3 hours. The FDA has approved dalbavancin and oritavancin for the treatment of acute bacterial skin and skin structure infections caused by gram positive bacteria, including MRSA. Cefilavancin is a unique agent spanning two antimicrobial classes in a single agent. It is a covalently linked glycopeptide cephalosporin heterodimer antibiotic that is highly active against gram positive bacteria and is in a phase 3 study. Aminoglycosides Aminoglycoside antibiotics include streptomycin, kanamycin, genta micin, tobramycin, netilmicin, and amikacin. The most commonly used aminoglycosides in pediatric practice are gentamicin and tobramycin. They exert their action by inhibiting bacterial protein synthesis. Although they are most often used to treat gram negative infections, the aminoglycosides are broad spectrum agents, with activity against S. aureus and synergistic activity against GBS, L. monocytogenes, viridans streptococci, Corynebacteria jeikeium, P. aeruginosa, coagulase negative staphylococci, and enterococci when co administered with a lactam agent. Aminoglycoside use has decreased with the development of alternatives, but they still play a key role in pediatric practice in the management of neonatal sepsis, UTIs, gram negative bacterial sepsis, and complicated intraabdomi nal infections; infections in cystic fibrosis patients (including both parenteral and aerosolized forms of therapy); and oncology patients with fever and neutropenia. Aminoglycosides, in particular strepto mycin, are also important in the management of Francisella |
7,095 | tularen sis, Mycobacterium tuberculosis, and nontuberculous mycobacterial infections. Toxicities of aminoglycoside therapy include nephrotoxicity and ototoxicity (cochlear andor vestibular), and serum levels as well as renal function and hearing should be monitored in patients on long term therapy. Toxicities of aminoglycosides may be reduced by the use of once daily dosing regimens with appropriate monitoring of serum levels. Hypokalemia, volume depletion, hypomagnesemia, and other nephrotoxic drugs may increase the renal toxicity of aminoglycosides. A rare complication of aminoglycosides is neuromuscular blockade, which may occur in the presence of other neuromuscular blocking agents and in the setting of infant botulism. A novel aminoglycoside, plazomicin, has recently been approved by the FDA for adult use. It was designed to evade all of the clinically rele vant aminoglycoside modifying enzymes (Table 225.2) responsible for aminoglycoside resistance. It is approved for complicated UTIs, includ ing pyelonephritis caused by E. coli, K. pneumoniae, Proteus mirabilis, and Enterobacter cloacae. FDA approval is pending for bloodstream infections caused by multidrug resistant Enterobacteriaceae, including CRE. Tetracyclines The tetracyclines (tetracycline hydrochloride, doxycycline, minocy cline, demeclocycline, eravacycline, omadacycline, and minocycline) are bacteriostatic antibiotics that exhibit their antimicrobial effect by binding to the bacterial 30S ribosomal subunit, inhibiting protein translation. These agents have a broad spectrum of antimicrobial activ ity against gram positive and gram negative bacteria, rickettsia, and some parasites. The oral bioavailability of these agents facilitates oral dosing for many infections, including Rocky Mountain spotted fever, anaplasmosis, ehrlichiosis, Lyme disease, and malaria. Tetracyclines must be prescribed judiciously to children 9 years old, because they can cause staining of teeth, hypoplasia of dental enamel, and abnormal bone growth in this age group. Tigecycline, a semisynthetic derivative of minocycline, is a paren teral agent of a new antibiotic class (glycylcyclines) and is licensed in the United States. It has a broader spectrum of activity (bacterio static) than traditional tetracyclines but retains the side effect profile of tetracyclines. Tigecycline is active against tetracycline resistant gram positive and gram negative pathogens, including MRSA and possibly VRE, but not Pseudomonas. Demeclocycline is an orally administered tetracycline with a similar antimicrobial spectrum as other agents in this class. A novel tetracycline derivative, eravacy cline (a fluorocycline), has recently been approved for treatment of complicated intraabdominal infections in adults and has the broad est spectrum of any tetracycline, including MRSA and CRE. Oma dacycline is another new tetracycline that is similar to that of other tetracyclines, functioning as an inhibitor of bacterial protein synthe sis, but has activity against bacterial strains expressing the two main forms of tetracycline resistance, specifically, antibiotic efflux and ribosomal protection. Complications of tetracyclines include eosinophilia, leukope nia and thrombocytopenia (tetracycline), pseudotumor cerebri, anorexia, emesis and nausea, hepatitis, photosensitivity, and a hypersensitivity reaction (urticaria, asthma exacerbation, facial edema, dermatitis) as well as a systemic lupus erythematosuslike syndrome (most common with minocycline). The FDA has issued a black box warning regarding tigecycline based on a meta analysis of 10 studies that showed increased mortality among patients receiv ing this drug. A salutary side |
7,096 | effect of demeclocycline has been identified; it is occasionally used as an off label treatment of hyponatremia resulting from the syndrome of inappropriate antidiuretic hormone (ADH). The mechanism of action appears to be inhibition of adenylyl cyclase acti vation after ADH binds to renal vasopressin receptors. Sulfonamides Trimethoprim and the sulfonamides are bacteriostatic agents that inhibit the bacterial folate synthesis pathway, in the process impair ing both nucleic acid and protein synthesis. Sulfonamides interfere Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 225 u Principles of Antibacterial Therapy 1689 with the synthesis of dihydropteroic acid from paraaminobenzoic acid, whereas trimethoprim acts at a site further downstream, interfer ing with synthesis of tetrahydrofolic acid from dihydrofolic acid. The sulfonamides are available in both parenteral and oral formulations. Although there have historically been a large number of sulfonamide antibiotics developed for clinical use, relatively few remain available for pediatric practice. The most important agent is the combination of trimethoprim sulfamethoxazole (TMP SMX), used for treatment of UTIs. TMP SMX has also emerged as a commonly prescribed agent for staphylococcal skin and soft tissue infections, because this antibiotic generally retains activity against MRSA. TMP SMX also plays a unique role in immunocompromised patients, as a prophylactic and therapeu tic agent for Pneumocystis jiroveci infection. Other common sulfon amides include sulfisoxazole, which is useful in the management of UTIs, and sulfadiazine, which is a drug of choice in the treatment of toxoplasmosis. Recently, a novel sulfonamide, iclaprim, demonstrated noninferior ity to vancomycin in the treatment of complicated skin and soft tissue infections. Iclaprim is a diaminopyrimidine with a 20 fold higher affin ity for the target molecule for sulfonamides, dihydrofolate reductase, than trimethoprim. It was granted orphan drug status by the FDA for treatment of S. aureus infection in patients with cystic fibrosis but has not been formally approved for general use. Macrolides The macrolide antibiotics most often used in pediatric practice include erythromycin, clarithromycin, and azithromycin. This class of anti microbials exerts its antibiotic effect through binding to the 50S subunit of the bacterial ribosome, producing a block in elongation of bacterial polypeptides. Clarithromycin is metabolized to 14 hydroxy clarithro mycin, and this active metabolite also has potent antimicrobial activ ity. The spectrum of antibiotic activity includes many gram positive bacteria. Unfortunately, resistance to these agents among S. aureus and group A streptococcus is fairly widespread, limiting the usefulness of macrolides for many skin and soft tissue infections and for streptococ cal pharyngitis. Azithromycin and clarithromycin have demonstrated efficacy for otitis media. All macrolide members have an important role in the management of pediatric respiratory infections, including atypical pneumonia caused by M. pneumoniae, Chlamydophila pneu moniae, and Legionella pneumophila, as well as infections caused by Bordetella pertussis. Telithromycin, a ketolide antibiotic derived from erythromycin, was initially FDA approved for the treatment in adults of mild to |
7,097 | mod erate community acquired pneumonia, acute exacerbations of chronic bronchitis, and acute sinusitis, having good activity against the agents causing these infections (S. pneumoniae, M. pneumoniae, C. pneu moniae, and L. pneumophila for community acquired pneumonia; M. catarrhalis and H. influenzae for sinusitis). Reports of liver failure and myasthenia gravis from telithromycin prompted the withdrawal of the drug from the market. Solithromycin is a related next generation oral and IV fluoroketolide in phase 3 clinical development for the treatment of community acquired pneumonia. Drug interactions are common with erythromycin and to a lesser extent with clarithromycin. These agents can inhibit the CYP 3A4 enzyme system, resulting in increased levels of certain drugs, such as astemizole, cisapride, statins, pimozide, and theophylline. Itra conazole may increase macrolide levels, whereas rifampin, carba mazepine, and phenytoin may decrease macrolide levels. There are few reported adverse drug interactions with azithromycin. Cross resistance may develop between a macrolide and the subsequent use of clindamycin. Lincosamides The prototype of the lincosamide class of antibiotics is clindamycin, which acts at the ribosomal level to exert its antimicrobial effect. The 50S subunit of the bacterial ribosome is the molecular target of this agent. Its spectrum of activity includes gram positive aer obes and anaerobes. Clindamycin has no significant activity against gram negative organisms. An important role for clindamycin has emerged in the management of MRSA infections. Because of its out standing penetration into body fluids (excluding the CNS) and tissues and bone, clindamycin can be used for therapy of serious infections caused by MRSA. Clindamycin is also useful in the management of invasive group A streptococcus infections and in the management of many anaerobic infections, often in combination with a lactam. A form of inducible clindamycin resistance is exhibited by some strains of MRSA; therefore consultation with the clinical microbiol ogy laboratory is necessary before treating a serious MRSA infection with clindamycin. Pseudomembranous colitis, a common complica tion of clindamycin therapy in adults, is seldom observed in pediatric patients. Clindamycin also plays an important role in the treatment of malaria and babesiosis (when co administered with quinine), P. jiroveci pneumonia (when co administered with primaquine), and toxoplasmosis. Quinolones The fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, besifloxacin ophthalmic suspension, ofloxacin, and delafloxacin) are antimicrobials that inhibit bacterial DNA replica tion by binding to the topoisomerases of the target pathogen, inhibit ing the bacterial enzyme DNA gyrase. This class has broad spectrum activity against both gram positive and gram negative organisms. Some fluoroquinolones exhibit activity against penicillin resistant S. pneumoniae as well as MRSA. These agents uniformly show excellent activity against gram negative pathogens, including the Enterobac teriaceae and respiratory tract pathogens such as M. catarrhalis and H. influenzae. Quinolones are also highly active against pathogens associated with atypical pneumonia, particularly M. pneumoniae and L. pneumophila. Although these agents are not approved for use in children, there is a reasonable body of evidence that the fluoroquinolones are generally safe, well tolerated, and effective against a variety of bacterial infections frequently encountered in |
7,098 | pediatric practice. Parenteral quinolones are appropriate for critically ill patients with gram negative infections. The use of oral quinolones in stable outpatients may also be reasonable for treatment of infections that would otherwise require parenteral anti biotics (e.g., P. aeruginosa soft tissue infections such as osteochondri tis) or selected genitourinary tract infections. However, these agents should be reserved for situations when no other oral antibiotic alter native is feasible. In 2013 the FDA changed the warning labels for the fluoroquinolones to better describe the associated risk of permanent peripheral neuropathy. Additional risks include tendonitis, arrhyth mias, and retinal detachment. Moreover, in situations of overuse (e.g., typhoid fever, gonococcal infection), organisms have been demon strated to rapidly develop resistance. The FDA has advised against the use of quinolones for uncomplicated infections such as sinusitis and bronchitis. Thus use of fluoroquinolones in pediatric practice should still be approached with continued caution, and consultation with an expert is recommended. Streptogramins and Oxazolidinones The emergence of highly resistant gram positive organisms, in particular VRE, has necessitated development of new classes of antibiotics. One such class especially useful for resistant gram positive infections is the streptogramins. The currently licensed agent in this category is dalfopristin quinupristin, which is avail able in a parenteral formulation. It is appropriate for treatment of MRSA, coagulase negative staphylococci, penicillin susceptible and penicillin resistant S. pneumoniae, and vancomycin resistant E. faecium but not E. faecalis. Another licensed class of antibiotics for highly resistant gram positive infections is the oxazolidinone class. The prototype in this group is linezolid, available in both oral and parenteral formulations and approved for use in pediatric patients. Its mechanism of action involves inhibition of ribosomal protein synthesis. It is indicated for MRSA, VRE, coagulase negative staphylococci, and penicillin resistant Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1690 Part XV u Infectious Diseases S. pneumoniae. A related drug, tedizolid phosphate, is also FDA approved for acute bacterial skin and skin structure infections. It is more potent in vitro than linezolid against MRSA and may be asso ciated with less myelosuppression. It is available in both IV and oral formulations. There is little information on streptogramins and oxazolidinones in the treatment of CNS infections, and neither class is approved for pedi atric meningitis. Linezolid can cause significant anemia and thrombo cytopenia and is a monoamine oxidase inhibitor. A novel oxazolidinone, contezolid acefosamil (MRX 4), was recently approved for use in China. It is an orally active prodrug of the active anti microbial metabolite, contezolid (MRX I), an oxazolidinone that shows potent in vitro activity against various multidrug resistant gram positive bacteria, including MRSA. It also has activity against M. tuberculosis. Daptomycin Daptomycin is a novel member of the cyclic lipopeptide class of anti biotics. Its spectrum of activity includes virtually all gram positive organisms, including E. faecalis and E. faecium (including |
7,099 | VRE) and S. aureus (including MRSA). The structure of daptomycin is a 13 member amino acid peptide linked to a 10 carbon lipophilic tail, which results in a novel mechanism of action of disruption of the bacterial mem brane through the formation of transmembrane channels. These chan nels cause leakage of intracellular ions, leading to depolarization of the cellular membrane and inhibition of macromolecular synthesis. A theoretical advantage of daptomycin for serious infections is its bacte ricidal activity against MRSA and enterococci. It is administered intra venously; experience in children is limited. Myopathy and elevations in creatine phosphokinase have been described. An FDA warning has been issued linking some cases of eosinophilic pneumonitis to the use of daptomycin. Daptomycin is inactivated by surfactant and should not be used to treat pneumonia. Miscellaneous Agents Metronidazole, which functions by disruption of DNA synthesis, has a unique role as an antianaerobic agent and also possesses antiparasitic and anthelmintic activity. In 2017 a related drug, benznidazole, was approved through the FDAs orphan drug Accelerated Approval Path way. This antiprotozoal agent inhibits the synthesis of DNA, RNA, and proteins within Trypanosoma cruzi and is approved for adult and pedi atric use for Chagas disease. Rifampin is a rifamycin antibiotic that inhibits bacterial RNA polymerase and has a major role in the manage ment of tuberculosis. It is also of value in the management of other bacterial infections in pediatric patients, usually used as a second (syn ergistic) agent in the treatment of S. aureus infections or to eliminate nasopharyngeal colonization of Hib or N. meningitidis. Rifabutin is a related drug that has an off label indication for treatment of tuberculo sis, an orphan drug indication for Crohn disease, and an indication for prevention or treatment of disseminated Mycobacterium avium com plex disease in patients with HIV or immune deficiency. Rifaximin is a nonabsorbed rifamycin that has been used as an adjunct agent to treat patients with multiple recurrences of C. difficile infection. Fidaxomi cin is a first in class member of a new category of narrow spectrum macrocyclic antibiotic drugs. It is an RNA polymerase inhibitor with activity against C. difficile infection. The emerging crisis in antimicrobial resistance has also necessitated the rediscovery of antimicrobial agents seldom used in clinical practice in recent decades, such as colistin (colistimethate sodium), a mem ber of the polymyxin family of antibiotics (polymyxin E). The general structure of polymyxins consists of a cyclic peptide with hydropho bic tails. After binding to lipopolysaccharide in the outer membrane of gram negative bacteria, polymyxins disrupt both outer and inner membranes, leading to cell death. Colistin is broadly active against the Enterobacteriaceae family, including P. aeruginosa. It is also active against ESBL and carbapenemase producing strains. Toxicities are chiefly renal and neurologic. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Antibiotics are the most common class of medications prescribed to pediatric outpatients, and over 50 of pediatric inpatients receive anti biotics during their hospitalization. It is estimated that between 25 and 50 of antibiotic |
7,100 | prescriptions are inappropriate in drug choice, dose, or duration or are unnecessary altogether. THE NEED FOR ANTIMICROBIAL STEWARDSHIP: HARMS FROM OVERUSE There are many negative consequences of antibiotic overuse, including contributing to the dramatic rise in antibiotic resistance observed over the past 30 years, which has led to antibiotic resis tance being named by the World Health Organization (WHO) as one of the top 10 threats to human health. Antibiotics also carry with them a risk of individual patient level harm, including devel opment of Clostridioides difficile infection and antibiotic adverse events. For example, 21 of antibiotic courses among pediatric inpatients are complicated by an adverse event, and each additional day of antibiotic therapy is associated with 7 greater odds of expe riencing an adverse event. Among pediatric outpatients receiving broad versus narrow spectrum antibiotics for acute respiratory tract infections, adverse events are significantly more common in patients treated with broad spectrum therapy. Finally, an emerg ing area of research is the deleterious impact of antibiotics on the developing microbiome and its potential influence on future dis ease states, including childhood obesity, asthma, and other aller gic diseases. Collectively, these data highlight the importance of judicious antibiotic prescribing, both on a societal and individual patient level. DEFINING ANTIMICROBIAL STEWARDSHIP AND AN ANTIMICROBIAL STEWARDSHIP PROGRAM Antimicrobial stewardship is defined as coordinated interventions designed to improve the use of antimicrobial agents, such that dose, duration of therapy, and route of administration are optimized. The goal of these actions is to achieve the best clinical outcome for the patient, while minimizing the development of antimicrobial resis tance and risk of adverse events. It is paramount to recognize that simply reducing antimicrobial use is not a primary goal of anti microbial stewardship. However, because inappropriate antibiotic use is so common, optimization often results in de escalation from a broader to a narrower spectrum of therapy or discontinuing antibiot ics altogether. Antimicrobial stewardship programs (ASPs) are multidisciplinary teams designed to improve the safety and quality of patient care by deploying these coordinated interventions. ASPs are often led or co led by infectious diseases trained physicians and clinical pharmacists and work in collaboration with the infection prevention and control department, the clinical microbiology laboratory, and numerous stake holder groups, including hospital leadership, clinicians, nurses, and pharmacy. Multiple studies have demonstrated reductions in antibi otic use, decreasing rates of C. difficile infections, and cost avoidance after the implementation of ASPs, with variable impact on local anti biotic resistance rates. With this growing evidence base and the crisis of antimicrobial resistance, ASPs are now a Standard from The Joint Commission and a Centers for Medicare and Medicaid Services (CMS) Condition of Participation. Several guidelines provide evidence based recommendations for implementation of an ASP, includ ing the joint Infectious Diseases Society of America (IDSA) and Chapter 226 Antimicrobial Stewardship Kathleen Chiotos and Jeffrey S. Gerber Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other |
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