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7,201 | inform the optimal therapeutic regimen. Trimethoprim sulfamethoxazole (TMP SMX) is the sulfonamide formulation that is recommended, although sulfadiazine and sulfisoxazole have been used. Increasing recognition of resistance to TMP SMX across and within Nocardia spp. highlights the importance of speciation of Nocardia isolates and of performing sensitivity testing in a certi fied microbiology laboratory. TMP SMX resistance rates as high as 42 have been reported. Administration of TMP SMX as prophy laxis against Pneumocystis jirovecii pneumonia is not always pro tective against nocardiosis, and thus clinicians should not exclude this diagnosis from the differential in patients receiving TMP SMX prophylaxis. 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 237 u Neisseria meningitidis (Meningococcus) 1737 Other antibacterial agents with in vitro activity against Nocardia spp. include but are not limited to amikacin, amoxicillin clavulanate, ceftriaxone, ciprofloxacin, clarithromycin, imipenem, linezolid, and minocycline. A recent study profiling the antimicrobial suscepti bility pattern of a diverse range of Nocardia revealed that among 146 isolates, the susceptibilities were 100 to linezolid, 96 to amikacin, 94 to TMP SMX, and 76 to imipenem. A similar retrospective study conducted in the United States from 1995 to 2004 revealed that 42 of the isolates were resistant to TMP SMX. Therefore while await ing sensitivity testing in patients with Nocardia isolated from a clini cal specimen, it may be reasonable to administer linezolid empirically, taking into account local susceptibility data. Subsequent therapeutic decisions should be guided by final sensitivity results and consider ation of the site of infection and pharmacokinetics of the available agents. It is not clear whether parenteral administration is superior to enteral formulations. However, most experts support the use of par enteral therapy for more severe disease, including endocarditis and CNS disease. In vitro and in vivo animal models have suggested the benefit of combination regimens for the treatment of nocardiosis. There are no clinical data to confirm the need for combination therapy; however, based on the preclinical data, there is expert support for using com bination therapy in CNS nocardiosis, in disseminated disease, and in children with an underlying immunocompromising condition. A vari ety of combination therapies have been suggested, with many experts favoring TMP SMX, amikacin, and a carbapenem or third generation cephalosporin. Since data on combination therapy are limited, anti biotic choices should primarily be guided by sensitivity testing of the clinical Nocardia isolate. Surgical drainage of abscesses can be helpful in hastening reso lution of nocardiosis. However, no comparative data have docu mented improvement in overall outcomes with adjunctive surgical intervention, and success has been reported with medical manage ment alone in resolving deep seated abscesses, even in the CNS. A literature review showed that among patients with CNS nocar diosis, 1 year overall mortality was approximately 20, limited by cases lost to follow up. Among patients who were treated with a combination of antibiotics |
7,202 | and neurosurgical procedures, mortal ity was lower (7). Therefore the decision to intervene surgically needs to be balanced with the potential consequences of a surgi cal procedure to drain an abscess. Intraventricular antibiotics have been reported. The necessary duration of therapy for nocardiosis varies depend ing on the clinical presentation and the status of the patient. The opti mal duration is uncertain, but long term therapy is common because of the propensity for relapse. Historically, superficial cutaneous infec tion has been treated for 3 months, pulmonary or systemic nocar diosis has been treated for 6 12 months, and CNS infection has been treated for at least 12 months. These intervals should only be con sidered as a guide for expected therapeutic durations. The ultimate duration should be dictated by clinical and radiographic resolution of disease. PROGNOSIS Historically, nocardiosis has been associated with significant mortal ity. Fortunately, more recent reports have documented an improved rate of complete cure to approximately 80. Predictably, attributable case fatality rates vary by disease entity. There is no attributable case fatality associated with cutaneous disease, but 1020 attributable case fatality has been assigned to disseminated and visceral disease. CNS disease has the highest attributable case fatality rates, reaching 25. Importantly, much of the data on case fatality rates are informed by predominantly adult cohorts, and thus there may be fewer fatal outcomes in children. Nonetheless, early diagnosis and intervention are important to reduce the morbidity and mortality of nocardiosis, especially in immunocompromised patients at increased risk for dis seminated disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Section 5 GramNegative Bacterial Infections Chapter 237 Neisseria meningitidis (Meningococcus) Manish Sadarangani Neisseria meningitidis (the meningococcus) is a commensal of the human nasopharynx in approximately 10 of the population and, on rare occasions, enters the bloodstream to cause devastating invasive disease such as meningitis and meningococcal septicemia (meningo coccemia). Although a rare endemic disease in most countries, the epi demiology of meningococcal disease varies widely over time and in different geographic regions, with both hyperendemic and epidemic disease patterns occurring. Onset of disease in susceptible individu als may be very rapid, within hours, and the case fatality rate is high, especially among those presenting with septic shock, despite access to modern critical care. Individual susceptibility is known to involve a complex relationship among environmental, host, and bacterial fac tors, and prevention of meningococcal disease through behavior mod ification (e.g., avoiding tobacco smoke) and vaccination offers the best prospect for control. ETIOLOGY N. meningitidis is a gram negative, fastidious, encapsulated, oxidase positive, aerobic diplococcus. Differences in the chemistry of the poly saccharide capsule allow definition of 12 (previously thought to be 13) serologically distinct meningococcal capsular groups, of which 6, des ignated A, B, C, W (previously designated W135), X, and Y, are respon sible for almost all cases of disease. Meningococcal strains may be subclassified on the basis of antigenic variation in two porin proteins found in the outer membrane, PorB (serotype) and PorA (serosubtype), and lipopolysaccharide (immunotype), using |
7,203 | serology. Serologic typing is being replaced by molecular typing methods, which target genes under immune selection to provide antigen sequence typing (based on amino acid variation in various surface proteins, including PorA and FetA). Sequencing of antigen genes (e.g., porA, fHbp, nadA, nhba) is an important means of monitoring pressure on meningococ cal populations by protein based vaccines containing these antigens. Because meningococci readily exchange genetic material, typing based on a few antigens cannot provide an accurate picture of relatedness of strains, an important goal in monitoring epidemiology. Multilocus sequence typing, which types meningococci using variation in seven housekeeping genes, has been widely used to map the distribution of genetic lineages of meningococci (http:pubmlst.orgneisseria) and provides a clearer picture of the genetic and epidemiologic relatedness of strains. To provide still better definition of genetic variation, in some countries, including the United Kingdom, whole genome sequencing is used to type meningococci and appears set to replace both antigen and multilocus sequence typing as costs continue to fall. The applica tion of molecular approaches to epidemiology has established that (1) endemic meningococcal disease is caused by genetically heterogeneous strains, although only a small number of genetic lineages are associated with the majority of cases of invasive disease, and (2) outbreaks are usually clonal, caused by single strains. 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. 1738 Part XV u Infectious Diseases EPIDEMIOLOGY Meningococci are transmitted during close contact through aerosol drop lets or exposure to respiratory secretions, as by kissing. The organism does not survive for long periods in the environment. Enhanced rates of mucosal colonization and increased disease risk are associated with activi ties that increase the likelihood of exposure to a new strain or increase proximity to a carrier, thus facilitating transmission, including kissing, bar patronage, binge drinking, attendance at nightclubs, men having sex with men, and living in freshman college dormitories. Factors that damage the nasopharyngeal mucosa, such as smoking and respiratory viral infection (notably influenza), are also associated with increased rates of carriage and disease, perhaps by driving upregulation of host adhesion molecules that are receptors for meningococci. Carriage is unusual in early childhood and peaks during adolescence and young adulthood. Meningococcal disease is a global problem, but disease rates vary by a factor of 10 to 100 fold in different geographic locations at one point in time and in the same location at different times. Most cases of meningococcal disease are sporadic, but small outbreaks (usually in schools or colleges, representing 3 of U.S. cases), hyperendemic disease (increased rates of disease persisting for a decade or more as a result of a single clone), and epidemic disease are all recognized pat terns. However, over the past decade, rates of meningococcal disease have declined in most industrialized countries, partly through intro duction of immunization programs and possibly aided by widespread legislation against |
7,204 | smoking in public places. The arrival of hyperinva sive lineages and their eventual decline through development of natu ral immunity is recognized as a major driver of changes in disease rates over time. The U.S. disease rate was 1.1 cases per 100,000 population in 1999 but had fallen to 0.11 per 100,000 by 2019 (Fig. 237.1). By contrast, the rate of disease in Ireland in 1999 was 12 per 100,000, and rates of 1,000 per 100,000 have been described during epidemic disease in sub Saharan Africa. Disease caused by dominant hyperendemic clones has been recognized in the past 2 decades in Oregon, United States; Que bec, Canada; Normandy, France; and across New Zealand. Laboratory data underreport meningococcal disease incidence rates because up to 50 of cases are not culture confirmed, particularly where prehospital antibiotics are recommended for suspected cases. In the United King dom, polymerase chain reaction (PCR) methods are used routinely for diagnosis of suspected cases, doubling the number of confirmed cases. The highest rate of meningococcal disease occurs in infants 1 year old, probably as a result of immunologic inexperience (antibody that recognizes meningococcal antigens is naturally acquired during later childhood), immaturity of the alternative and lectin complement path ways, and perhaps the poor responses made by infants to bacterial poly saccharides. In the absence of immunization, incidence rates decline through childhood, except for a peak of disease among adolescents and young adults, which may be related to increased opportunity for expo sure from social activities. The incidence of meningococcal disease is increased among persons with HIV infection. In the United States, most cases of disease in the first 5 years of life are caused by capsular group B strains. After age 5 years, disease cases are mostly distributed among capsular groups C, W, and Y. In most other industrialized countries, capsular group B strains predominate at all ages, in part because of introduction of routine capsular group C menin gococcal conjugate vaccine among infants andor toddlers. For unclear reasons, disease in children caused by group Y strains was uncommon in the United States before the 1990s and then began to increase. Rates of disease caused by this capsular group have also increased in several other countries but are declining in the United States. Disease caused by capsular group W strains has increased in the United Kingdom and in other countries in Europe and Australia as a result of a hyperinvasive clone, which appears to have originated in Latin America. Large outbreaks of capsular group A meningococcal disease occurred during and immediately after the First World War and Second World War in both Europe and the United States, but since the 1990s, almost all cases caused by capsular group A strains have occurred in Eastern Europe, Russia, and developing countries. The highest incidence of cap sular group A disease has occurred in a band across sub Saharan Africa, the meningitis belt, with annual endemic rates of 10 25 per 100,000 population. For more than a century, this region |
7,205 | has experienced large capsular group A epidemics every 7 10 years, with annual rates as high as 1,000 per 100,000 population. The onset of cases in the sub Saharan region typically begins during the dry season, possibly related to dry ing and damage to the nasopharyngeal mucosa; subsides with the rainy season; and may reemerge the following dry season. Rates of capsular group A meningococcal disease are currently falling across this region as a result of a mass vaccine implementation targeting strains bearing the A polysaccharide. However, both endemic and epidemic meningococ cal disease in this region is also caused by capsular groups C, W, and X strains. Capsular group A and group X are infrequent causes of disease in other areas of the world, although both A and W strains have been associated with outbreaks among pilgrims returning from the Hajj. PATHOGENESIS AND PATHOPHYSIOLOGY Colonization of the nasopharynx by N. meningitidis is the first step in either carriage or invasive disease. Disease usually occurs 1 14 days after acquisition of the pathogen. Initial contact of meningococci with host epithelial cells is mediated by pili, which may interact with the host CD46 molecule or an integrin. Close adhesion is then medi ated by Opa and Opc binding to carcinoembryonic antigen (CEA) cell adhesion molecule receptors and integrins, respectively. Subse quent internalization of meningococci by epithelial cells is followed by transcytosis through to the basolateral tissues and dissemination into the bloodstream. Immunoglobulin A1 protease secreted by inva sive bacteria degrades secretory IgA on the mucosal surface, circum venting this first line host defense mechanism. Once in the bloodstream, meningococci multiply rapidly to high levels to cause septicemia (meningococcemia). Patients with a higher bacterial load have a more rapid clinical deterioration and longer period of hospitalization, as well as a higher risk of death and permanent sequelae. Resistance to complement mediated lysis and phagocytosis is largely mediated by the polysaccharide capsule and lipopolysaccha ride (LPS). Outer membrane vesicles released from the surface of the organism contain LPS, outer membrane proteins, periplasmic proteins, and phospholipid and play a major role in the inflammatory cascade that leads to severe disease. Much of the tissue damage is caused by host immune mechanisms activated by meningococcal components, in particular LPS. During inva sive disease LPS is bound to a circulating plasma protein known as LPS binding protein. The host receptor complex for LPS consists of toll like receptor (TLR) 4, CD14, and myeloid differentiation protein 2. Binding of LPS to TLR 4, which is upregulated on circulating leukocytes dur ing septicemia, results in activation of a number of different cell types. An intense inflammatory reaction results from secretion of proinflam matory cytokines such as tumor necrosis factor (TNF) , interleukin 1.6 20102000 2020 R at e pe r 10 0, 00 0 po pu la tio n Year 199019801970 1.2 1.4 1.0 0.8 0.4 0.6 0.2 0.0 Fig. 237.1 Rate of meningococcal disease, by yearUnited States, 19702020. (Modified from Cohn AC, MacNeil JR, Clark TA, et |
7,206 | al; Centers for Disease Control and Prevention. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2013;62RR 2:128, updated with data from the CDC meningococcal surveillance data ta bles: https:www.cdc.govmeningococcalsurveillancesurveillance data.htmlfigure01.) 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 237 u Neisseria meningitidis (Meningococcus) 1739 (IL) 1, IL 6, IL 8, and granulocyte macrophage colony stimulating factor, levels of which are closely associated with plasma levels of LPS. The major antiinflammatory cytokines IL 1R, IL 2, IL 4, and IL 12 and transforming growth factor are present at very low levels. Both high and low levels have been observed for IL 10 and interferon . The pathophysiologic events that occur during meningococcal sep ticemia are largely related to microvascular injury. This injury leads to increased vascular permeability and capillary leak syndrome, pathologic vasoconstriction and vasodilation, disseminated intravascular coagula tion (DIC), and profound myocardial dysfunction. Increased vascular permeability can lead to dramatic fluid loss and severe hypovolemia. Capillary leak syndrome with or without aggressive fluid resuscitation (which is essential in severe cases) leads to pulmonary edema and respi ratory failure. Initial vasoconstriction is a compensatory mechanism in response to hypovolemia and results in the clinical features of pallor and cold extremities. After resuscitation, some patients experience warm shock, that is, intense vasodilation with bounding pulses and warm extremities, despite persistent hypotension and metabolic acidosis. Vir tually all antithrombotic mechanisms appear to be dysfunctional during meningococcal sepsis, leading to a procoagulant state and DIC. All these factors contribute to depressed myocardial function, but there is also a direct negative cytokine effect on myocardial contractility, thought to be largely mediated by IL 6. Hypoxia, acidosis, hypoglycemia, hypokale mia, hypocalcemia, and hypophosphatemia are all common features in severe septicemia and further depress cardiac function. Some patients become unresponsive to the positive inotropic effects of catecholamines and require high levels of inotropic support during intensive care man agement. These processes result in impairment of microvascular blood flow throughout the body and ultimately lead to multiorgan failure, which is responsible for much of the mortality. After invasion of the circulation, meningococci may also penetrate the blood brain barrier and enter the cerebrospinal fluid (CSF), facili tated by pili and possibly Opc. Once there, bacteria continue to pro liferate, and LPS and other outer membrane products can stimulate a proinflammatory cascade similar to that observed in the blood. This leads to upregulation of specific adhesion molecules and recruitment of leukocytes into the CSF. Central nervous system damage occurs directly by meningeal inflammation and indirectly by circulatory col lapse and causes a high rate of neurologic sequelae in affected patients. Death can occur from cerebral edema, which leads to increased intra cranial pressure (ICP) and cerebral or cerebellar herniation. Immunity There is an inverse correlation between the incidence of disease and the prevalence |
7,207 | of complement dependent serum bactericidal anti body (SBA). The level of SBA is highest at birth and among adults and lowest in children between 6 months and 2 years of age, when the high est incidence of disease occurs. Such antibodies are naturally elicited by asymptomatic carriage of pathogenic and nonpathogenic Neisse ria, such as Neisseria lactamica, and other antigenically related gram negative bacteria. A similar relationship was described for capsular groups A, B, and C. Vaccine trials support these earlier findings. For the meningococcal capsular group C conjugate vaccine, an SBA titer 1:8 correlated strongly with postlicensure vaccine effectiveness. For capsular group B disease, the data are less certain, but the proportions of capsular group B vaccine recipients with more than fourfold rises in SBA after vaccination or SBA titers 1:4 have been correlated with clin ical effectiveness in studies of outer membrane vesicle vaccines. These cutoffs are therefore currently used for regulatory approval of new meningococcal vaccines. The strong association between disease risk and genetic variation in human complement factor H further supports the importance of complement mediated protection against disease. There is evidence that mechanisms other than complement dependent bactericidal antibodies may be important in determining protection against meningococcal disease. Disease in individuals with complement deficiency has a different age distribution, has less severe clinical fea tures, and often involves unusual capsular groups. In particular, comple ment deficiency does not appear strongly related to an increased risk of capsular group B disease. Alternative surrogate markers of protection include the opsonophagocytic assay and antibody avidity, but no studies have attempted to link these laboratory tests with vaccine efficacy or even population protection, as has been found with SBA. Host Factors Host susceptibility is strongly related to age, as previously described, indicating that immunologic responsiveness andor navet in infancy and early childhood are key determinants of risk. Complement is a key factor in protection against meningococcal disease. Individuals with inherited deficiencies of properdin, factor D, or terminal complement components have up to a 1,000 fold higher risk for development of meningococcal disease than complement sufficient people. The risk of meningococcal disease is also increased in patients with acquired com plement deficiencies associated with diseases such as nephrotic syn drome, systemic lupus erythematosus (SLE), and hepatic failure and in patients treated with eculizumab, a monoclonal antibody against complement protein C5. Among those with complement deficiencies, meningococcal disease is more prevalent during late childhood and adolescence, when carriage rates are higher than in children 10 years old; meningococcal infec tions in these patients may be recurrent. Although meningococcal dis ease can occasionally be overwhelming in patients with late complement component deficiency, cases are more typically described as being less severe than in complement sufficient persons (with properdin defi ciency being the exception), perhaps reflecting that these cases are often caused by unusual capsular groups. In one study, one third of individuals with meningococcal disease caused by capsular groups X, Y, and W had a complement deficiency. Although protective against early infection, |
7,208 | extensive complement activation and bacteriolysis may contribute to the pathogenesis of severe disease once bacterial invasion has occurred. The sibling risk ratio for meningococcal disease is similar to that for other diseases where susceptibility shows polygenic inheritance, and a number of host genetic factors have now been identified to affect either susceptibility to meningococcal disease or severity of disease. The molecules implicated include proteins on epithelial surfaces, the complement cascade, pattern recognition receptors, clotting factors, and inflammatory mediators. Deficiencies in the complement pathways are consistently associated with an increased risk of meningococcal disease, with specific polymorphisms in mannose binding lectin and factor H found to be associated with disease susceptibility. A genome wide association study of 7,522 individuals in Europe identified single nucleotide polymorphisms (SNPs) within the CFH and CFHR3 genes that were associated with host susceptibility to meningococcal disease. Complement mediated bacteriolysis is known to be extremely important in protection against meningococcal disease, giving these associations biologic plausibility. In particular, factor H attaches to various binding proteins expressed on the bacterial surface, downregulating complement activation and allowing the organism to evade host responses. In terms of disease severity, a meta analysis of data from smaller studies found that SNPs in genes encoding plasminogen activator inhibitor 1 (SERPINE1), IL 1 receptor antagonist (IL1RN), and IL 1 (IL1B) are associated with increased mortality from meningococcal disease, as reflected in pathophysiologic changes that occur during invasive disease. CLINICAL MANIFESTATIONS The most common form of meningococcal infection is asymptomatic carriage of the organism in the nasopharynx. In the rare cases where invasive disease occurs, the clinical spectrum of meningococcal dis ease varies widely, but the highest proportion of cases present with meningococcal meningitis (3050). Other recognized presentations include bacteremia without sepsis, meningococcal septicemia with or without meningitis, pneumonia, chronic meningococcemia, and occult bacteremia. Focal infections in various sites (e.g., myocardium, joints, pericardium, bone, eye, peritoneum, sinuses, middle ear) are well recognized, and all may progress to disseminated disease. Urethri tis, cervicitis, vulvovaginitis, orchitis, and proctitis may also occur. Acute meningococcal septicemia cannot be distinguished from other viral or bacterial infections early after onset of symptoms (Table 237.1). Typical nonspecific early symptoms include fever, irritability, lethargy, respiratory symptoms, refusal to drink, and vomiting. Less 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. 1740 Part XV u Infectious Diseases Table 237.1 Prevalence of Symptoms and Signs in Children and Young People with Meningococcal Septicemia, Meningococcal Disease, and Meningococcal Meningitis SYMPTOM OR SIGN PREVALENCE RANGE (NUMBER OF STUDIES) BACTERIAL MENINGITIS MENINGOCOCCAL DISEASE MENINGOCOCCAL SEPTICEMIA Fever 6697 (10) 5897 (7) 98 (1) Vomiting or nausea 1870 (10) 4476 (6) Rash 962 (6) 59100 (9) 70 (1) Headache 359 (7) 1649 (5) 40 (1) Lethargy 1387 (6) 3665 (3) 59 (1) Coughing NA (0) 1527 (2) 33 (1) Irritable or unsettled 2179 (8) 3667 (3) 32 (1) Runny nose NA (0) 24 |
7,209 | (1) 31 (1) Muscle ache or joint pain 23 (1) 765 (3) 30 (1) Refusing food or drink 2676 (4) 1360 (3) 27 (1) Altered mental state 2693 (6) 4581 (3) NA (0) Stiff neck 1374 (13) 571 (6) NA (0) Impaired consciousness 6087 (4) 1072 (2) NA (0) Unconsciousness 418 (4) NA (0) NA (0) Chills or shivering NA (0) 39 (1) NA (0) Photophobia 516 (2) 231 (5) NA (0) Respiratory symptoms 2549 (4) 1623 (2) NA (0) Breathing difficulty 1334 (4) 11 (1) NA (0) Cold hands or feet NA (0) 43 (1) NA (0) Shock 816 (2) 2729 (2) NA (0) Seizures 1438 (12) 717 (3) NA (0) Diarrhea 2129 (2) 79 (2) NA (0) Abdominal pain or distention 17 (1) 4 (1) NA (0) Leg pain NA (0) 1137 (2) NA (0) Thirst NA (0) 8 (1) NA (0) Sore throat, coryza, or throat infection 18 (1) 24 (1) NA (0) Ill appearance NA (0) 79 (1) NA (0) Capillary refill time 2 sec NA (0) 83 (1) NA (0) Hypotension NA (0) 28 (1) NA (0) Abnormal skin color NA (0) 19 (1) NA (0) Bulging fontanel 1345 (4) NA (0) NA (0) Ear infection or ear, nose, and throat infections 1849 (5) NA (0) NA (0) Chest infection 14 (1) NA (0) NA (0) Brudzinski sign 1166 (2) NA (0) NA (0) Kernig sign 1053 (3) NA (0) NA (0) Abnormal pupils 10 (1) NA (0) NA (0) Cranial nerve pair involvement 4 (1) NA (0) NA (0) 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 237 u Neisseria meningitidis (Meningococcus) 1741 frequently, diarrhea, sore throat, and chillsshivering are reported. A maculopapular rash, which is indistinguishable from rashes seen after viral infections, is evident in approximately 10 of cases early in the course of infection (Fig. 237.2). Limb pain, myalgia, or refusal to walk may occur as the primary complaint in 7 of otherwise clini cally unsuspected cases. As the disease progresses, cold hands or feet and abnormal skin color may be important signs, capillary refill time becomes prolonged, and a nonblanching or petechial rash will develop in 80 of cases. In fulminant meningococcal septicemia, the disease progresses rapidly over several hours from fever with nonspecific signs to septic shock characterized by prominent petechiae and purpura (purpura fulminans) with poor peripheral perfusion, tachycardia (to compensate for reduced blood volume resulting from capillary leak), increased respiratory rate (to compensate for pulmonary edema), hypotension (a late sign of shock in young children), confusion, and coma (resulting from decreased cerebral perfusion). Coagulopathy, electrolyte disturbance (especially hypokalemia), acidosis, adrenal hemorrhage, renal failure, and myocardial failure may all develop (Fig. 237.3). Meningitis may be present. Meningococcal meningitis is indistinguishable from meningitis caused by other bacteria. Nonspecific symptoms and signs (see Table 237.1), including fever and headache, predominate, especially in the young |
7,210 | and early in the illness. Children 5 years old rarely report head ache. More specific symptoms of photophobia, nuchal rigidity, bulging of the fontanel, and clinical signs of meningeal irritation may develop but are unusual in infants. Seizures and focal neurologic signs occur less frequently than in patients with meningitis caused by Streptococcus pneumoniae or Haemophilus influenzae. A meningoencephalitis like picture can occur, associated with rapidly progressive cerebral edema and death from increased ICP, which may be more common with cap sular group A infection. Occult meningococcal bacteremia manifests as fever with or without associated symptoms that suggest a minor viral infection. Resolution of bacteremia may occur without antibiotics, but sustained bacteremia leads to meningitis in approximately 60 of cases and to distant infection of other tissues. Table 237.1 Prevalence of Symptoms and Signs in Children and Young People with Meningococcal Septicemia, Meningococcal Disease, and Meningococcal Meningitiscontd SYMPTOM OR SIGN PREVALENCE RANGE (NUMBER OF STUDIES) BACTERIAL MENINGITIS MENINGOCOCCAL DISEASE MENINGOCOCCAL SEPTICEMIA Toxic or moribund state 349 (2) NA (0) NA (0) Back rigidity 46 (1) NA (0) NA (0) Paresis 6 (1) NA (0) NA (0) Focal neurologic deficit 647 (3) NA (0) NA (0) This includes confusion, delirium, and drowsiness. The age ranges in the four studies are 0 14 yr, 0 2 yr, 0 12 mo, and 0 13 wk. One study reported the number of children and young people with ear, nose, and throat infections; the four other studies reported the number of ear infections only. Classification of conditions presented in the table reflects the terminology used in the evidence. NA, Not applicable. Data from National Collaborating Center for Womens and Childrens Health (UK). Bacterial meningitis and meningococcal septicaemia: management of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care. NICE Clinical Guidelines, No 102. London: RCOG Press; 2010. Fig. 237.2 Meningococcemia. A maculopapular, nonhemorrhagic rash that subsequently became petechial. (From Habif TP, ed. Clinical Dermatology, 6th ed. Philadelphia: Mosby; 2016: Fig 9 59.) A B Fig. 237.3 A, Purpuric rash in 3 yr old child with meningococcemia. B, Purpura fulminans in 11 mo old child with meningococcemia. (From Thompson ED, Herzog KD. Fever and rash. In: Zaoutis L, Chiang V, eds. Comprehensive Pediatric Hospital Medicine. Philadelphia: Mosby; 2007: Figs. 62 6 and 62 7.) Fig. 237.4 Rash of chronic meningococcemia. (From Persa OD, Jaz mati N, Robinson N, et al. A pregnant woman with chronic meningo coccaemia from Neisseria meningitidis with lpxL1 mutations. Lancet. 2014;384:1900.) 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. 1742 Part XV u Infectious Diseases Chronic meningococcemia, which occurs rarely, is characterized by fever, nontoxic appearance, arthralgia, headache, splenomegaly, and a maculopapular or petechial rash (Fig. 237.4). Symptoms are intermit tent, with a mean duration of illness of 6 8 weeks. Blood culture results are usually |
7,211 | positive, but cultures may initially be sterile. Chronic menin gococcemia may spontaneously resolve, but meningitis may develop in untreated cases. Some cases have been associated with complement defi ciency and others with sulfonamide therapy. One report indicates that up to 47 of isolates from patients with chronic meningococcemia (vs 10 in acute cases) have a pathogenic variant in the lpxl1 gene, leading to a reduced inflammatory response and a milder course of infection. DIAGNOSIS The initial diagnosis of meningococcal disease should be made on clin ical assessment to avoid delay in implementation of appropriate therapy. Laboratory findings are variable but may include leukocytopenia or leukocytosis, often with increased percentages of neutrophils and band forms, and anemia, thrombocytopenia, proteinuria, and hematuria. Elevations of erythrocyte sedimentation rate (ESR) and C reactive pro tein (CRP) may occur, but in patients with rapid onset of disease, these values may be within normal limits at presentation. Increased CRP in the presence of fever and petechiae makes the diagnosis likely. Hypoal buminemia, hypocalcemia, hypokalemia, hypomagnesemia, hypophos phatemia, hypoglycemia, and metabolic acidosis, often with increased lactate levels, are common in patients with meningococcal septicemia. Patients with coagulopathy have decreased serum concentrations of pro thrombin and fibrinogen and prolonged coagulation times. A confirmed diagnosis of meningococcal disease is established by isolation of N. meningitidis from a normally sterile body fluid such as blood, CSF, or synovial fluid. Meningococci may be identified in a Gram stain preparation andor culture of petechial or purpuric skin lesions, although this procedure is rarely undertaken, and occasionally are seen on Gram stain of the buffy coat layer of a centrifuged blood sample. Although blood culture may be positive in more than two thirds of cases before antibiotic use, culture results often are negative if the patient has been treated with antibiotics before collection of the culture specimen; data suggest that 50 are culture positive. Isolation of the organism from the nasopharynx is not diagnostic of invasive disease because the organism is a common commensal. PCR using primers specific for meningococcal genes (e.g., ctrA) has high sensitivity and specificity for detection of meningococci using whole blood samples and has increased confirmation of suspected cases by 40 in the United Kingdom. Lumbar puncture should be undertaken to establish a diagnosis of meningococcal meningitis in patients without contraindications, includ ing presence of septic shock, coagulopathy, thrombocytopenia, respira tory distress, seizures, increased ICP, or local infection. In patients with meningococcal meningitis, the cellular and chemical characteristics of the CSF are those of acute bacterial meningitis, showing gram negative diplococci in up to 75 of cases. CSF culture results may be positive in patients with meningococcemia in the absence of CSF pleocytosis or clinical evidence of meningitis; conversely, positive CSF specimens that are gram positive are sometimes culture negative. Overdecolorized pneumococci in Gram stain preparations can be mistaken for menin gococci, and therefore empirical therapy should not be narrowed to N. meningitidis infection on the basis of Gram stain findings alone. Detection of capsular polysaccharide antigens using rapid |
7,212 | latex agglu tination tests on CSF can support the diagnosis in cases clinically con sistent with meningococcal disease, but the tests have not performed adequately in clinical practice (poor sensitivity and cross reactivity of capsular group B test with Escherichia coli K1 antigen) and have been replaced by molecular diagnostic methods. Urine antigen testing is insensitive and should not be used. PCR based assays for detection of meningococci in blood and CSF have been developed, and multiplex PCR assays that detect several bacterial species associated with meningi tis, including the meningococcus, are used in some laboratories. Differential Diagnosis Meningococcal disease can appear similar to sepsis or meningi tis caused by many other gram negative bacteria, S. pneumoniae, Staphylococcus aureus, or group A streptococcus; to Rocky Mountain spotted fever, ehrlichiosis, or epidemic typhus; and to bacterial endo carditis. Viral and other infectious etiologies of meningoencephalitis should be considered in some cases. Petechial rashes are common in viral infections (enteroviruses, influ enza and other respiratory viruses, measles virus, Epstein Barr virus, cytomegalovirus, parvovirus) and may be confused with meningococ cal disease. Petechial or purpuric rashes are also associated with pro tein C or protein S deficiency, platelet disorders (including idiopathic thrombocytopenic purpura), Henoch Schnlein purpura, connective tissue disorders, drug eruptions, and trauma, including nonaccidental injury. The nonpetechial, blanching maculopapular rash observed in some cases of meningococcal disease, especially early in the course, may initially be confused with a viral exanthem. TREATMENT Antibiotics Empirical antimicrobial therapy should be initiated immediately after the diagnosis of invasive meningococcal infection is suspected and cul tures are obtained, using a third generation cephalosporin to cover the most likely bacterial pathogens until the diagnosis is confirmed. In regions with a high rate of lactamresistant S. pneumoniae, empiri cal addition of intravenous (IV) vancomycin is recommended (see Chapter 643.1) while awaiting the outcome of bacterial identification and sensitivity, but this is unnecessary in other settings where ceph alosporin resistance of pneumococci is very rare (in these settings a risk assessment of each case should be made). Once the diagnosis of lactamsensitive meningococcal disease is confirmed in the laboratory, some authorities recommend a switch to penicillin. Even with no evi dence that survival outcomes are different, however, limited evidence from one study indicates that in meningococcal purpura, necrotic skin lesions are less common among children treated with ceftriaxone than with penicillin. Furthermore, it may be cost effective to use a once daily dose of ceftriaxone for therapy in younger children, and this is the recommended practice in the United Kingdom (Table 237.2). No adequate studies have investigated the optimal duration of therapy for children, but the course is generally continued for 5 7 days. Early treatment of meningococcal infections may prevent serious sequelae, but timely early diagnosis is often difficult in the absence of petechial or purpuric skin findings. Among children presenting with petechial rashes, 110 may have underlying meningococcal disease, and protocols have been established to ensure that these patients are identified without exposing the 90 of cases without |
7,213 | meningococcal disease to unnecessary parenteral antibiotic therapy (Fig. 237.5). Isolates of N. meningitidis with decreased susceptibility to penicillin (minimal inhibitory concentration of penicillin of 0.1 1.0 mgmL) have been reported from Europe, Africa, Canada, and the United States (4 of isolates in 2006). Decreased susceptibility is caused at least in part by altered penicillin binding protein 2 and does not appear to adversely affect the response to therapy. Isolates with reduced susceptibility to third generation cephalosporins have been described in France, but the level of reduced susceptibility is not likely to affect therapeutic out comes where these agents are used for treatment. Supportive Care Most children with meningococcal disease can be managed with anti biotics and simple supportive care and will improve rapidly. However, with an overall 510 case fatality rate, the priority in initiating man agement of children presenting with meningococcal disease is identifica tion of the life threatening features of the disease: shock and increased ICP. Delayed initiation of supportive therapy is associated with poor outcome, and protocols have therefore been established to aid clinicians in a step by step approach (http:www.meningitis.org). In all children presenting with meningococcal disease, assessment of the airway should be performed, because the airway could be compromised as a result of a depressed level of consciousness (elevated ICP in meningitis or poor cerebral perfusion in shock). In patients with meningococcal septice mia, supplementary oxygen should be used to treat hypoxia, which is caused by pulmonary edema (from capillary leak), and some patients will require endotracheal intubation. Hypovolemia requires both volume 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 237 u Neisseria meningitidis (Meningococcus) 1743 replacement and inotropic support to maintain cardiac output. Because ongoing fluid resuscitation may lead to pulmonary edema, endotracheal intubation and ventilation should be initiated in a patient who remains in compensated shock after 40 mLkg of fluid resuscitation to improve oxygenation and reduce work of breathing. Aggressive fluid resuscita tion with unbuffered electrolyte solutions in febrile African children led to increased mortality; similar studies in industrialized settings are required. Metabolic and hematologic abnormalities are common in meningococcal septicemia, and protocols recommend anticipation, assessment, and correction of glucose, potassium, calcium, magnesium, phosphate, clotting factors, and anemia. Children with meningococcal meningitis should be cautiously man aged with maintenance fluids (fluid restriction is not recommended and may be harmful), and those with increased ICP should be managed with close attention to maneuvers to maintain normal cerebral perfusion. If there is shock in the presence of elevated ICP, the shock should be care fully corrected to ensure that cerebral perfusion pressure is maintained. Many adjunctive therapies have been attempted in patients with severe meningococcal septicemia, but few have been subjected to randomized controlled trials (RCTs). Data are insufficient to recom mend the use of anticoagulant or fibrinolytic agents, extracorporeal membrane oxygenation, plasmapheresis, or hyperbaric oxygen. In |
7,214 | well designed clinical trials, an antibody directed against endotoxin (HA1A) did not confer any benefit in children with meningococcal disease, and although initially promising in adult sepsis, activated protein C was not useful in pediatric sepsis and was associated with an increased risk of bleeding. Recombinant bactericidal permeability increasing protein was studied in an underpowered (survival end point) trial and showed some potentially beneficial effects against sec ondary end points (amputations, transfusions, functional outcome) and requires further investigation. Although the benefits of corticosteroids for adjunctive therapy in pediatric bacterial meningitis caused by H. influenzae type b (Hib) are accepted, no pediatric data specifically demonstrate benefit in menin gococcal meningitis. However, some authorities extrapolate from ani mal data, from experience with Hib, and from compelling data from adult meningitis and recommend corticosteroids as adjunctive therapy in pediatric meningococcal meningitis, given with or soon after the first dose of antibiotics. Therapeutic doses of corticosteroids should not be used routinely in meningococcal septicemia. Some intensiv ists recommend replacement doses of corticosteroids in patients with treatment refractory septic shock, because severe sepsis caused by meningococcus is associated with adrenal insufficiency resulting from adrenal necrosis or hemorrhage (Waterhouse Friderichsen syndrome). COMPLICATIONS Adrenal hemorrhage, endophthalmitis, arthritis, endocarditis, peri carditis, myocarditis, pneumonia, lung abscess, peritonitis, and renal infarcts can occur during acute infection. Renal insufficiency requiring dialysis may result from prerenal failure. Reactivation of latent herpes simplex virus infections is common during meningococcal infection. A self limiting immune complex vasculitis may occur, usually in the first 10 days after onset of the disease, resulting in various manifesta tions, including fever, rash, arthritis, and rarely, iritis, pericarditis, or carditis. The arthritis is monoarticular or oligoarticular, involves large joints, and is associated with sterile effusions that respond to nonsteroi dal antiinflammatory drugs. Because most patients with meningococ cal meningitis become afebrile by the seventh hospital day, persistence or recrudescence of fever after 5 days of antibiotics warrants evaluation for immune complexmediated complications. The most common complication of acute severe meningococcal sep ticemia is focal skin infarction, which typically affects the lower limbs and can lead to substantial scarring and require skin grafting. Distal tissue necrosis in purpura fulminans may require amputation (which should be delayed to allow demarcation) in approximately 2 of sur vivors. Avascular necrosis of epiphyses and epiphyseal metaphyseal defects can result from the generalized DIC and may lead to growth disturbance and late skeletal deformities. Deafness is the most frequent neurologic sequela of meningitis, occur ring in 510 of children. Cerebral arterial or venous thrombosis with resultant cerebral infarction can occur in severe cases. Meningococ cal meningitis is rarely complicated by subdural effusion or empyema or by brain abscess. Other rare neurologic sequelae include ataxia, sei zures, blindness, cranial nerve palsies, hemiparesis or quadriparesis, and obstructive hydrocephalus (manifests 3 4 weeks after the onset of illness). Behavioral and psychosocial complications of the disease are frequently reported. PROGNOSIS The case fatality rate for invasive meningococcal disease is 510, with clear differences related to age of the patient |
7,215 | and meningococcal genotype. Most deaths occur within 48 hours of hospitalization in chil dren with meningococcemia. Poor prognostic factors on presentation include hypothermia or extreme hyperpyrexia, hypotension or shock, purpura fulminans, seizures, leukopenia, thrombocytopenia (includ ing DIC), acidosis, and high circulating levels of endotoxin and TNF . The presence of petechiae for 12 hours before admission, absence of meningitis, and low or normal ESR indicate rapid, fulminant progres sion and a poorer prognosis. Table 237.2 Treatment of Neisseria meningitidis Invasive Infections Beyond the Newborn Period DRUG ROUTE DOSE DOSING INTERVAL (hr) MAXIMUM DAILY DOSE NOTES Penicillin G IM or IV 300,000 400,000 unitskgday 4 6 (4 hourly for meningitis) 12 24 million units Does not clear carriage, and prophylaxis is required at the end of treatment Ampicillin IM or IV 200 400 mgkgday 4 6 (4 hourly for meningitis) 8 g Does not clear carriage, and prophylaxis is required at the end of treatment Cefotaxime IM or IV 180 225 mgkgday 6 8 (6 hourly for meningitis) 8 12 g Recommended in the neonate Ceftriaxone IM or IV 75 100 mgkgday 12 24 2 4 g Preferred treatment as only once or twice daily, and may reduce skin complications ALTERNATIVE THERAPY IN THE FACE OF LIFE THREATENING LACTAM ALLERGY Chloramphenicol IV 50 100 mgkgday 6 2 4 g Adjust based on target serum concentrations (15 25 mgL) Meropenem IV 60 120 mgkgday 8 3 6 g Monitor blood levels to avoid toxicity. Rate of cross reactivity in penicillin allergic adults is 23. May not be available due to manufacturing issues. IM, Intramuscular; IV, intravenous. 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. 1744 Part XV u Infectious Diseases Because complement deficiency is rare in patients with capsular group B infection, screening is unlikely to be useful in detecting cases caused by this group, but some authorities recommend routine screen ing in these cases. However, with one third or more of cases of disease caused by groups X, Y, and W apparently associated with complement deficiency, it is clearly appropriate to screen after infection with non B capsular groups. PREVENTION Secondary Prevention Close contacts of patients with meningococcal disease are at increased risk of infection because such individuals are likely to be colonized with the index cases (hyperinvasive) strain. Antibiotic prophylaxis should be offered as soon as possible to individuals who have been exposed directly to a patients oral secretions, for whom the risk may be 1,000 times the background rate in the population. This includes household, kissing, and close family contacts of cases, as well as child care and recent preschool contacts in the United States. Up to 30 of cases occur in the first week, but the risk persists for up to 1 year after presentation of the index case. Although prophylaxis is effective in pre venting secondary cases, coprimary cases may occur |
7,216 | in the days after presentation of the index case, and contacts should be carefully evalu ated if they develop symptoms. Advice on management of nonclose contacts, such as those in daycare, nursery settings, or school and other institutions, varies in different countries because the risk of a second ary case in this situation is low and opinion on risk assessment var ies. Ceftriaxone, ciprofloxacin, and rifampin are 9095 effective in reducing nasopharyngeal carriage of N. meningitidis and are acceptable agents for prophylaxis, with ciprofloxacin the drug of choice in some countries (Table 237.3). Azithromycin should not be used as the first line choice for prophylaxis but is recommended in the rare instance of ciprofloxacin resistance. Prophylaxis is not routinely recommended for medical personnel except those with exposure to aerosols of respira tory secretions, such as through mouth to mouth resuscitation, intu bation, or suctioning before or in the 24 hours after antibiotic therapy is initiated in the index case. Neither penicillin nor ampicillin treatment eradicates nasopharyn geal carriage and should not be routinely used for prophylaxis. Patients with meningococcal infection treated solely with penicillin or ampicil lin are therefore at risk of relapse or transmission to a close contact and should receive antimicrobial prophylaxis with one of the agents listed in Table 237.3 before hospital discharge. The preference is to use cef triaxone for treatment of the index case, in which case further prophy laxis is not required. Droplet infection control precautions should be observed for hospitalized patients for 24 hours after initiation of effec tive therapy. All confirmed or probable cases of meningococcal infec tion must be reported to the local public health department according to national or regional regulations. Fig. 237.5 Treatment algorithm for petechial rash. See Medi cines and Healthcare Products Regulatory Agency Drug Safety Update, 2009;3(3). Available from www.mhra.gov.uk. CRP, C reactive protein; PCR, polymer ase chain reaction. (Data from National Collaborating Center for Womens and Childrens Health (UK). Bacterial meningitis and meningococcal septicaemia: management of bacterial men ingitis and meningococcal sep ticaemia in children and young people younger than 16 years in primary and secondary care. NICE Clinical Guidelines, No 102. Lon don: RCOG Press; 2010.) Child or young person has a petechial rash Give intravenous ceftriaxone if any of the following occur at any point during assessment, and go to bacterial meningitis or meningococcal disease pathway: If the child or young person has an unexplained petechial rash, carry out the following investigations: Petechiae start to spread A rash becomes purpuric There are signs of meningitis or septicemia The child or young person appears ill If petechiae are not spreading and the child or young person does not appear ill, consider: Other possible diagnoses Performing full blood count and coagulation screen Full blood count CRP Coagulation screen Blood culture Wholeblood PCR for N. meningitidis Blood glucose Blood gas Clinical diagnosis of meningitis or septicemia? Yes Yes Yes Yes No No No No Does the child or young person have a fever or history of fever? |
7,217 | Is CRP andor white blood cell count raised? Meningococcal disease less likely but not ruled out Treat with intravenous ceftriaxone immediately, or with cefotaxime if administering calcium containing infusions Admit to hospital and monitor vital signs closely Doubt remains about the childs or young persons condition? If the child or young person is at low risk of meningococcal disease and discharged after initial observation, advise parents to return to hospital if the child or young person appears ill Assess clinical progress (vital signs) and carry out observations at least hourly over the next 46 hours Manage for bacterial meningitis or meningococcal disease per localnational guidelines Examine for signs of underlying meningitis or septicemia (including shock) (use the lists of symptoms and signs in the prehospital management pathway) 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 237 u Neisseria meningitidis (Meningococcus) 1745 Close contacts of cases could also be immunized to further reduce the risk of secondary infection, as described later. Vaccination Meningococcal plain polysaccharide vaccines containing capsular polysac charides from capsular groups A C or capsular groups A, C, W, and Y have been available since the 1960s and used in the control of outbreaks and epidemics and for high risk groups. However, polysaccharide vaccines are poorly immunogenic in infants, do not induce immunologic mem ory, and are associated with immunologic hyporesponsiveness (reduced response to future doses of polysaccharide). Plain polysaccharide vaccines have been superseded by meningococcal protein polysaccharide conjugate vaccines, which are generally more immunogenic than plain polysaccha rides, are immunogenic from early infancy, induce immunologic memory, and are not associated with hyporesponsiveness. The conjugate vaccines contain meningococcal polysaccharides that are chemically conjugated to a carrier protein. Three carrier proteins are used in various meningococ cal conjugate vaccines: tetanus toxoid, diphtheria toxoid, and the mutant diphtheria toxin CRM197. However, although plain polysaccharide vac cines should be considered redundant in most industrialized countries where the new generation conjugates are available, they may still have a role in some regions where conjugates are not yet available. The first meningococcal conjugate vaccine used was a monovalent capsular group C meningococcal conjugate vaccine (MenC), introduced in the United Kingdom in 1999 and administered to all children and young people 19 years old in a mass catch up campaign before establish ment in the routine infant immunization schedule. The MenC vaccine has proved highly effective (95) in controlling disease through both direct protection of the vaccinated population and induction of herd immunity, protecting the wider population. Herd immunity is induced through the impact of conjugate vaccines on colonization, reducing carriage and block ing transmission of meningococci among adolescents and young adults. Monovalent MenC vaccines are used widely in the industrialized countries of Western Europe, Canada, and Australia, where disease caused by cap sular group C meningococci has virtually disappeared. However, serologic surveys show that antibody levels wane, |
7,218 | especially after infant immuni zation, and booster doses are now recommended during adolescence to sustain individual and population immunity. Quadrivalent meningococcal A, C, Y, and W conjugate vaccines (MenACWY) have been available since 2005 and are routinely used for U.S. adolescents and as a single adolescent booster dose in some coun tries that had established MenC infant programs more than a decade ago. MenACWY was initially introduced as a single dose at 11 years of age in the United States, but concerns about waning immunity led to the adop tion of a second dose. The initial reports on the effectiveness (80) of MenACWY in the U.S. program indicates that these vaccines are likely to provide control of disease caused by capsular groups C, W, and Y (capsular group A being unimportant currently), although the program has taken some time to become fully established. As the population of immunized adolescents and young adults in the United States grows, the effects of these vaccines on carriage of meningococci likely will reduce disease among other segments of the population through herd immu nity, assuming the transmission dynamics of Y and W meningococci are the same as for capsular group C. Although MenACWY vaccines are not currently recommended in the United States for routine use in younger age groups in view of the low rate of disease caused by these capsular groups in infancy, they may provide broader protection in countries that are already using MenC vaccines in infant programs. Other combination vaccines containing various conjugates, including Hib MenC (used in the United Kingdom as a 12 month booster) and Hib MenCY, may have a role in broadening protection beyond MenC in early life. Table 237.4 outlines the current U.S. programmatic recommendations. Individuals of any age at high risk of meningococcal disease, such as those with complement deficiency, and travelers to regions where there is a risk of epidemic meningococcal disease caused by A or W should receive MenACWY (see Table 237.4). The risk of disease among close contacts of cases of disease caused by vaccine capsular groups may be further reduced if they are offered MenACWY in addition to antimicro bial prophylaxis. A possible association between MenACWY diphtheria toxoid and Guillain Barr syndrome, which caused concern early after the vaccine was first used in the United States, has not been substantiated. A capsular group A meningococcal conjugate vaccine (MenA) has been developed for use in the sub Saharan African meningitis belt, and implementation in 2010 through mass vaccination appears to have interrupted disease caused by this capsular group. The majority of disease in infants and in most industrialized coun tries is caused by capsular group B polysaccharidebearing meningococci. This polysaccharide capsule has chemical identity with glycosylated protein antigens in the human fetus and, as a self antigen, is therefore not immunogenic in humans and leads to the theoretical risk of induc tion of autoimmunity. Vaccine development has therefore focused on subcapsular protein antigens. Several countries (e.g., Cuba, Norway, New Zealand) successfully controlled capsular |
7,219 | group B epidemics by immunizing with tailor made outer membrane vesicle vaccines Table 237.3 Antibiotic Prophylaxis to Prevent Neisseria meningitidis Infection AGE GROUP DOSE DURATION EFFICACY RIFAMPIN Infants 1 mo 5 mgkg PO every 12 hr 2 days (4 doses) Children 1 mo and adults 15 20 mgkg PO every 12 hr (max 600 mg) 2 days (4 doses) 9095 CEFTRIAXONE Children 15 yr 125 mg IM 1 dose 9095 Children 15 yr and adults 250 mg IM 1 dose 9095 CIPROFLOXACIN Children 1 mo and adults, 20 mgkg (max 500 mg) PO 1 dose 9095 AZITHROMYCIN (NOT RECOMMENDED ROUTINELY) All ages 10 mgkg (max 500 g) PO 1 dose 90 Recommended for household and kissing contacts. In the United States, chemoprophylaxis is recommended for: Household contact, especially children 2 yr old Childcare or preschool contact at any time during 7 days before onset of illness Direct exposure to index patients secretions through kissing, sharing toothbrushes, or eating utensils at any time during 7 days before onset of illness Mouth to mouth resuscitation, unprotected contact during endotracheal intubation during 7 days before onset of illness Frequently slept in same dwelling as index patient during 7 days before onset of illness Passengers seated directly next to the index case during airline flights lasting more than 8 hours (gate to gate), or passengers seated within one seat in any direction from an index case on a flight of any duration if the index case was coughing or vomiting during the flight Always check with current local public health guidance for full recommendations Not recommended for pregnant women (ceftriaxone is agent of choice in this setting). Use only if fluoroquinolone resistant strains of N. meningitidis have not been identified in the community. Discussion with an expert is recommended for treatment in infants age 1 mo. IM, Intramuscularly; PO, orally (by mouth). 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. 1746 Part XV u Infectious Diseases prepared from blebs of outer membrane harvested from the respective epidemic strains. The principal limitation of outer membrane vesicle vaccines is that the bactericidal antibody responses induced by immu nization are limited to the vaccine strain, because the response is largely directed against the homologous PorA (serosubtype) protein, and they are therefore not considered for use in endemic settings, including the United States or most other industrialized countries. Promising approaches for prevention of capsular group B disease have been developed over the past decade. One vaccine that was devel oped for adolescent immunization was licensed in the United States in 2014 and contains two variants of factor Hbinding protein (2FHbp; Pfizer vaccines); it appears highly immunogenic in the target popula tion, inducing bactericidal antibodies directed against a panel of strains bearing variants of fHbp. It is currently recommended for use in high risk groups and during outbreaks (see Table 237.4). Factor Hbinding |
7,220 | protein appears to be an important virulence determinant, aiding sur vival of meningococci in blood, and is expressed by virtually all strains. A four component meningococcal vaccine, 4CMenB (Bexsero, GSK Vaccines), is licensed in Europe and North America and avail able in various other regions. This vaccine contains outer membrane vesicles (derived from the New Zealand outbreak strain) and three recombinant proteins: a single variant of factor Hbinding protein (FHbp), neisserial adhesin A (NadA), and neisserial heparin binding antigen (NHBA). 4CMenB vaccine induced bactericidal antibodies against strains containing the vaccine antigens in infants, toddlers, and adolescents in clinical trials. The vaccine appears to have a generally favorable safety profile, although induction of fever in infants and pain at the injection site in other age groups are common. This vaccine has been used to control university outbreaks of capsular group B menin gococcal disease in the United States and Canada and hyperendemic disease in Quebec, Canada. Current recommendations for use in the United States are outlined in Table 237.4. It was recommended for rou tine use in the infant immunization program in the United Kingdom in 2014 and deployed from September 2015. Early data reported a 75 reduction in age groups that were fully eligible for vaccination, with a high coverage rate of 95 (a nonsignificant vaccine effectiveness of 53 after two doses and 59 after a booster dose at 1 year of age). A large cluster randomized trial in Australia found no effect of 4CMenB on carriage of disease causing meningococci, highlighting that the benefit of this vaccine is likely to be via direct protection. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 237.4 Recommendations for Meningococcal Vaccination (United States, 2021) GENERAL POPULATION 2 23 MO 2 10 YR 11 23 YR 24 YR Not routinely recommended Not routinely recommended A single dose of MenACWY conjugate vaccine at age 11 12 yr with a booster dose at age 16 yr Not routinely recommended MenB series may be offered at age 16 23 yr on basis of shared clinical decision making (2 doses of MenB FHbp or 4CMenB) SPECIAL POPULATIONS AT INCREASED RISK OF MENINGOCOCCAL DISEASE RISK FACTOR 2 23 MO 2 9 YR 10 YR Persistent complement deficiencies (including patients using a complement inhibitor), functional or anatomic asplenia 4 doses of MenACWY conjugate vaccine at 2, 4, 6, and 12 mo; if commencing at age 7 23 mo, 2 doses of MenACWY conjugate vaccine, with second dose administered at age 12 mo and 12 wk after first dose 2 doses of MenACWY conjugate vaccine at least 8 wk apart 2 doses of MenACWY conjugate vaccine at least 8 wk apart and MenB vaccine (2 doses of 4CMenB or 3 doses of MenB Hbp) At risk during a community outbreak with a vaccine capsular group covered by the relevant vaccine 4 doses of MenACWY conjugate vaccine at 2, 4, 6, and 12 mo; if commencing at age 7 23 mo, 2 doses of MenACWY conjugate vaccine, with second dose administered at |
7,221 | age 12 mo and 12 weeks after first dose 2 doses of MenACWY conjugate vaccine at least 8 wk apart 2 doses of MenACWY conjugate vaccine at least 8 wk apart or MenB vaccine (2 doses of 4CMenB or 3 doses of MenB FHbp) depending on the capsular group of the outbreak Travel to or resident of countries where meningococcal disease is hyperendemic or epidemic 4 doses of MenACWY conjugate vaccine at 2, 4, 6, and 12 mo; if commencing at age 7 23 mo, 2 doses of MenACWY conjugate vaccine, with second dose administered at age 12 mo and 12 weeks after first dose 2 doses of MenACWY conjugate vaccine at least 8 wk apart 2 doses of MenACWY conjugate vaccine at least 8 wk apart Persons with HIV infection 4 doses of MenACWY conjugate vaccine at 2, 4, 6, and 12 mo; if commencing at age 7 23 mo, 2 doses of MenACWY conjugate vaccine, with second dose administered at age 12 mo and 12 weeks after first dose 2 doses of MenACWY conjugate vaccine at least 8 wk apart 2 doses of MenACWY conjugate vaccine at least 8 wk apart Booster every 5 yr if ongoing risk (after 3 yr if 7 yr old). Boosters 1 yr after primary series and every 2 3 yr thereafter if remains at increased risk. For example, visitors to the meningitis belt of sub Saharan Africa. Vaccination also is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj. Note that different MenACWY conjugate vaccines are interchangeable, but different MenB vaccines (4CMenB and MenB FHbp) are not interchangeable Adapted from https:www.cdc.govvaccineshcpacip recsvacc specificmening.html 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 238 u Neisseria gonorrhoeae (Gonococcus) 1747 Neisseria gonorrhoeae is the causative agent of gonorrhea, an infection of the genitourinary tract mucous membranes and of the mucosa of the rectum, oropharynx, and conjunctiva. Among sexually transmissible infections, gonorrhea transmitted by sexual contact or perinatally is second only to chlamydial infections in the number of cases reported to the U.S. Centers for Disease Control and Prevention (CDC). This high prevalence and the development of antibiotic resistant strains have led to significant morbidity. ETIOLOGY N. gonorrhoeae is a nonmotile, aerobic, nonspore forming, gram negative diplococcus with flattened adjacent surfaces. Optimal growth occurs at 3537C (9598.6F) and at pH 7.2 7.6 in an atmosphere of 35 carbon dioxide. The specimen should be inoculated quickly onto fresh, moist, modified Thayer Martin or specialized transport media, because gonococci do not tolerate drying. Thayer Martin selective medium contains antimicrobial agents that inhibit the normal flora present in clinical specimens from mucosal sites that may otherwise overgrow gonococci. Presumptive identification may be based on col ony appearance, Gram stain, and production of cytochrome oxidase. Gonococci are differentiated from other Neisseria spp. by the fermenta tion |
7,222 | of glucose but not maltose, sucrose, or lactose. Gram negative dip lococci are seen in infected material, often within polymorphonuclear leukocytes (PMNs). As with all gram negative bacteria, N. gonorrhoeae possesses a cell envelope composed of an inner cytoplasmic membrane, a middle layer of peptidoglycan, and an outer membrane. The outer membrane contains lipooligosaccharide (LOS; also called endotoxin), phospho lipid, and a variety of proteins that contribute to cell adherence, tis sue invasion, and resistance to host defenses. Systems previously used to characterize gonococcal strains included auxotyping and serotyp ing. Auxotyping is based on genetically stable requirements of strains for specific nutrients or cofactors as defined by an isolates ability to grow on chemically defined media. Serotyping systems were based on specific monoclonal antibodies directed against a porin protein called PorB (formerly Protein I or PorI), a trimeric outer membrane protein that makes up a substantial part of the gonococcal envelope structure. Changes in the PorB protein present in a community are believed to result, at least in part, from selective immune pressure. DNA based typing methods have now supplanted auxotyping and serotyping. Older gel based DNA based typing methods that included restriction fragment length polymorphism (RFLP) analysis of genomic DNA or rRNA (ribotyping) or typing of genes encoding opacity protein (opa) were labor intensive and sometimes lacked the ability to accurately dis criminate among strains. Methods currently used include the N. gon orrhoeae multiantigen sequence typing (NG MAST), which examines the sequences of the variable internal fragments of two highly poly morphic N. gonorrhoeae genes (porB encoding PorB and tbpB encod ing subunit B of transferrin binding protein), multilocus sequence typing (MLST), which analyzes the sequences of seven chromosomal housekeeping genes, and whole genome sequencing. EPIDEMIOLOGY Since gonorrhea became a nationally notifiable disease in 1944, U.S. rates have ranged between a historic high of 467.7 cases per 100,000 population in 1975 and a historic low of 98.1 per 100,000 in 2009. However, rates of gonorrhea have increased almost every year since 2009 (with an overall increase of 118 between 2009 and 2021), with a total of 710,151 cases and a rate of 214.0100,000 reported in 2021. Rates of reported gonorrhea are also highest in the South (242.9100,000); among young adults age 20 24 (860.5 cases per 100,000); among males (249.7100,000 vs 177.9100,000 among females); and among Blacks (652.9100,000 vs 78.9100,000 among Whites). The higher case rate among men and the magnitude of recent increases suggest either increased transmission, increased case ascertainment (e.g., through increased extragenital screening among men who have sex with men MSM), or both. The con current increase in cases reported among women suggests parallel increases in heterosexual transmission, increased screening among women, or both. Molecular typing methods (e.g., NG MAST, MLST) are used to ana lyze the spread of individual strains of N. gonorrhoeae within a com munity. Maintenance and subsequent spread of gonococcal infections in a community are sustained through continued transmission by asymptomatically infected people and also by a hyperendemic, high risk core group |
7,223 | such as commercial sex workers, MSM, or adolescents with multiple sexual partners. This latter observation reflects that most persons who have symptomatic gonorrhea cease sexual activity and seek care, unless economic need or other factors (e.g., drug addiction) drive persistent sexual activity. Thus many core transmitters belong to a subset of infected persons who lack or ignore symptoms and continue to be sexually active, underscoring the importance of seeking out and treating the sexual contacts of infected persons who present for treat ment. Oral sex has a role in sustaining gonorrhea in MSM by provid ing a pool of untreated asymptomatic pharyngeal infections and may account for as much as one third of symptomatic gonococcal urethritis in MSM. Gonococcal infection of neonates usually results from peripar tum exposure to infected exudate from the cervix of the mother. An acute infection begins 2 5 days after birth. The incidence of neonatal infection depends on the prevalence of gonococcal infection among pregnant women, prenatal screening for gonorrhea, and neonatal oph thalmic prophylaxis. PATHOGENESIS AND PATHOLOGY N. gonorrhoeae infects primarily columnar epithelium because strati fied squamous epithelium is relatively resistant to invasion. Mucosal invasion by gonococci results in a local inflammatory response that produces a purulent exudate consisting of PMNs, serum, and desqua mated epithelium. The gonococcal LOS (endotoxin) exhibits direct cytotoxicity, causing ciliostasis and sloughing of ciliated epithelial cells. Tumor necrosis factor (TNF) and other cytokines are thought to medi ate the cytotoxicity of gonococcal infections. Complement activation also contributes to the acute inflammatory response. Gonococci may ascend the urogenital tract, causing urethritis or epididymitis in postpubertal males and acute endometritis, salpin gitis, and peritonitis (collectively termed acute pelvic inflammatory disease or PID) in postpubertal females. Dissemination from the fal lopian tubes through the peritoneum to the liver capsule results in perihepatitis (Fitz HughCurtis syndrome). Gonococci that invade the lymphatics and blood vessels may cause inguinal lymphadenopa thy; perineal, perianal, ischiorectal, and periprostatic abscesses; and disseminated gonococcal infection (DGI). A number of gonococcal virulence and host immune factors are involved in the penetration of the mucosal barrier and subsequent manifestations of local and systemic infection. Selective pressure from different mucosal environments probably leads to changes in the outer membrane of the organism, including expression of variants of pili, opacity (Opa) proteins (formerly called protein II), and LOS. These changes may enhance gonococcal attachment, invasion, replication, and evasion of the hosts immune response. For infection to occur, the gonococcus must first attach to host cells. Gonococci adhere to the microvilli of nonciliated epithelial cells by hairlike protein structures (pili) that extend from the cell wall. Pili undergo high frequency antigenic variation that may aid in Chapter 238 Neisseria gonorrhoeae (Gonococcus) Katherine Hsu, Sanjay Ram, and Toni Darville 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. 1748 Part XV u Infectious Diseases the organisms escape from the host |
7,224 | immune response and may pro vide specific ligands for different cell receptors. Opa proteins, most of which confer an opaque appearance to colonies, function as ligands for members of the carcinoembryonic antigenrelated cell adhesion molecule (CEACAM) family of proteins or heparin sulfate proteogly cans (HSPGs) to facilitate binding to human cells. Interactions between complement receptor 3 (CR3) on cervical epithelial cells and comple ment iC3b (deposited on bacteria), pili, and PorB on the gonococcal surface facilitate cellular entry of gonococci in women. In contrast, the interaction between LOS and asialoglycoprotein receptor (ASGP R) permits gonococcal entry into male urethral epithelial cells. Gonococci that express certain Opa proteins adhere to CEACAM3 and are phago cytosed by human neutrophils in the absence of serum. The interaction of Opa with CEACAM1 on CD4 T lymphocytes may suppress their activation and proliferation and contribute to the immunosuppression associated with gonorrhea. A gonococcal IgA protease inactivates IgA1 by cleaving the molecule in the hinge region and could contribute to colonization or invasion of host mucosal surfaces. Other phenotypic changes that occur in response to environmental stresses allow gonococci to establish infection. Examples include iron repressible proteins such as transferrin binding proteins (TbpA and TbpB) and lactoferrin binding proteins (LbpA and LbpB) for bind ing to and extracting iron from transferrin or lactoferrin, respectively, anaerobically expressed proteins, and proteins that are synthesized in response to contact with epithelial cells. Gonococci may grow in vivo under anaerobic conditions or in an environment with a relative lack of iron. Approximately 24 hours after attachment, the epithelial cell surface invaginates and surrounds the gonococcus in a phagocytic vacuole. This phenomenon is thought to be mediated by the insertion of the gonococcal PorB protein into the host cell, causing alterations in mem brane permeability. Subsequently, phagocytic vacuoles begin releasing gonococci into the subepithelial space by means of exocytosis. Viable organisms may then cause local disease (i.e., salpingitis) or disseminate through the bloodstream or lymphatics. Serum IgG and IgM directed against gonococcal proteins and LOS activate complement on gonococci. Gonococci have evolved several mechanisms to dampen complement activation. Scavenging cytidine monophospho N acetyl neuraminic acid (CMP Neu5Ac, the donor molecule for sialic acid) to sialylate its LOS is one such example, which reduces binding of bactericidal antibodies and simultaneously enhances binding of a complement inhibitor called factor H (FH). This property is often lost on subculturing gonococci on medium that lacks CMP Neu5Ac and is thus termed unstable serum resistance. In con trast, stable serum resistance (complement resistance independent of LOS sialylation) is often seen in gonococci that express particular porin proteins (most PorB.1As and select PorB.1Bs), which enables them to bind to complement inhibitors such as FH and C4b binding protein (C4BP). Such strains are often associated with disseminated disease. N. gonorrhoeae differentially subverts the effectiveness of complement and alters the inflammatory responses elicited in human infection. Stably serum resistant DGI isolates show less C3b deposition on their surface, inactivate C3b more rapidly, generate less C5a, and result in less |
7,225 | inflammation at local sites. PID isolates (grown in the absence of the donor molecule for sialic acid) are serum sensitive, deposit more C3b on their surface, generate more C5a, and result in more inflamma tion at local sites. IgG antibody directed against gonococcal reduction modifiable protein (Rmp) blocks complement mediated killing of N. gonorrhoeae. Anti Rmp blocking antibodies may harbor specificity for outer membrane protein (e.g., OmpA) sequences shared with other Neisseria spp. or Enterobacteriaceae, may be directed against a unique Rmp sequence upstream of the OmpA shared region that includes a cysteine loop, or both. Preexisting antibodies directed against Rmp facilitate transmission of gonococcal infection to exposed women; Rmp is highly conserved in N. gonorrhoeae, and the blocking of muco sal defenses may be one of its functions. Gonococcal adaptation also appears to be important in the evasion of killing by neutrophils. Exam ples include sialylation of LOS, increases in catalase production, and changes in the expression of surface proteins. Neutrophil phagosomes bearing gonococci show delayed fusion with primary granules, pro moting gonococcal survival within neutrophils. Other strategies gono cocci employ to evade killing by neutrophils include blocking lysozyme activity (mediated by the proteins SliC and adhesin complex protein ACP) and degrading neutrophil extracellular traps. Host factors may influence the incidence and manifestations of gonococcal infection. Prepubertal girls are susceptible to vulvovaginitis and rarely experience salpingitis. N. gonorrhoeae infects noncornified epithelium, and the thin noncornified vaginal epithelium and alkaline pH of the vaginal mucin predispose this age group to infection of the lower genital tract. Estrogen induced cornification of the vaginal epi thelium in neonates and mature females resists infection. Postpubertal females are more susceptible to salpingitis, especially during menses, when diminished bactericidal activity of the cervical mucus and reflux of blood from the uterine cavity into the fallopian tubes facilitate pas sage of gonococci into the upper reproductive tract. Populations at risk for DGI include asymptomatic carriers; neonates; menstruating, pregnant, and postpartum women; MSM; and individu als with congenital or acquired (for example, via pharmacologic inhibi tion) defects in complement. The asymptomatic carrier state implies failure of the host immune system to recognize the gonococcus as a pathogen, the capacity of the gonococcus to avoid being killed, or both. Pharyngeal colonization has been proposed as a risk factor for DGI. The high rate of asymptomatic infection in pharyngeal gonorrhea may account for this phenomenon. Women are at greater risk for develop ment of DGI during menstruation, pregnancy, and the postpartum period, presumably because of the maximal endocervical shedding and decreased peroxidase bactericidal activity of the cervical mucus during these periods. A lack of neonatal bactericidal IgM antibody is thought to account for the increased susceptibility of neonates to DGI. Persons with terminal complement component deficiencies (C5 C9) are at con siderable risk for development of recurrent episodes of DGI. CLINICAL MANIFESTATIONS Gonorrhea is manifested by a spectrum of clinical presentations from asymptomatic carriage, to the characteristic localized mucosal infec tions, to disseminated systemic infection (see Chapter 163). Asymptomatic |
7,226 | Gonorrhea The incidence of asymptomatic gonorrhea in children has not been ascertained. Gonococci have been isolated from the oropharynx of young children who have been abused sexually by male contacts; oro pharyngeal symptoms are usually absent. Most genital tract infections produce symptoms in children. However, as many as 80 of sexually mature females with urogenital gonorrhea infections are asymptomatic in settings in which most infections are detected through screening or other case finding efforts. This situation is in contrast to that in men, who are asymptomatic only 10 of the time. Asymptomatic rectal car riage of N. gonorrhoeae has been documented in 2668 of females with urogenital infection. Most persons with positive rectal culture results are asymptomatic. Most pharyngeal gonococcal infections are asymptomatic, although rarely acute tonsillopharyngitis or cervical lymphadenopathy can occur. Pharyngeal gonorrhea is easily acquired through fellatio and may account for a significant proportion of ure thral gonorrhea in MSM. Pharyngeal gonorrhea is increasingly preva lent, particularly among adolescents and young adults, associated with overall increasing prevalence of oral sex behaviors. Uncomplicated, Localized Gonorrhea Genital gonorrhea has an incubation period of 2 5 days in men and 5 10 days in women. Primary infection develops in the urethra of males, the vulva and vagina of prepubertal females, and the cervix of postpubertal females. Neonatal ophthalmitis (ophthalmia neonato rum) occurs in both genders. Urethritis is usually characterized by a purulent discharge and by dysuria without urgency or frequency. Untreated urethritis in males resolves spontaneously in several weeks or may be complicated by epi didymitis, penile edema, lymphangitis, prostatitis, or seminal vesiculi tis. Gram negative intracellular diplococci are found in the discharge. 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 238 u Neisseria gonorrhoeae (Gonococcus) 1749 In MSM, the rectal mucosa can become infected after receptive anal intercourse. Symptoms range from painless mucopurulent discharge and scant rectal bleeding to overt proctitis with associated rectal pain and tenesmus. In prepubertal females, vulvovaginitis is usually characterized by a purulent vaginal discharge with a swollen, erythematous, tender, and excoriated vulva. Dysuria may occur. Gonococcal infection should be considered in any girl with vaginal discharge, even when sexual abuse is not suspected; sexual abuse must be considered strongly when gonococcal infection is diagnosed in prepubertal children beyond the neonatal period. In postpubertal females, symptomatic gonococ cal cervicitis and urethritis are characterized by purulent discharge, suprapubic pain, dysuria, intermenstrual bleeding, and dyspareunia. The cervix may be inflamed and tender. In urogenital gonorrhea lim ited to the lower genital tract, pain is not enhanced by moving the cervix and the adnexa are not tender to palpation. Purulent material may be expressed from the urethra or ducts of the Bartholin gland. Rectal gonorrhea is often asymptomatic but may cause proctitis with symptoms of anal discharge, pruritus, bleeding, pain, tenesmus, and constipation. Asymptomatic rectal gonorrhea may not be from anal intercourse |
7,227 | but may represent translocation of infected secretions from cervicovaginal infection. Gonococcal ophthalmitis may be unilateral or bilateral and may occur in any age group after inoculation of the eye with infected secre tions. Ophthalmia neonatorum caused by N. gonorrhoeae usually appears from 2 5 days after birth (see Chapter 674). Ocular infection in older patients results from inoculation or autoinoculation from a genital site. The infection begins with mild inflammation and a sero sanguineous discharge. Within 24 hours, the discharge becomes thick and purulent and tense edema of the eyelids with marked chemosis occurs. If the disease is not treated promptly, corneal ulceration, rup ture, and blindness may follow. Disseminated Gonococcal Infection Hematogenous dissemination occurs in 13 of all gonococcal infec tions, more frequently after asymptomatic primary infections than symptomatic infections. Women previously accounted for the majority of cases, with symptoms beginning 7 30 days after infection and within 7 days of menstruation in about one half of cases, but more recent case series describe more male than female cases. The most common mani festations are asymmetric arthralgia, petechial or pustular acral skin lesions, tenosynovitis, suppurative arthritis, and rarely, carditis, men ingitis, and osteomyelitis. The most common initial symptom is acute onset of polyarthralgia with fever. Only 25 of patients complain of skin lesions. Most deny genitourinary symptoms; however, primary mucosal infection is documented by genitourinary cultures. Results of approximately 8090 of cervical cultures are positive in women with DGI. In males, urethral culture results are positive in 5060, pharyn geal culture results are positive in 1020, and rectal culture results are positive in 15 of cases. DGI is classified into two clinical syndromes that have some overlapping features. The more common tenosynovitis dermatitis syndrome is characterized by fever, chills, skin lesions, and poly arthralgia predominantly involving the wrists, hands, and fingers. Blood culture results are positive in approximately 3040 of cases, and results of synovial fluid cultures are almost uniformly nega tive. In suppurative arthritis syndrome, systemic symptoms and signs are less prominent and monoarticular arthritis is more com mon, often involving the knee. A polyarthralgia phase may precede the monoarticular infection. In cases of monoarticular involvement, synovial fluid culture results are positive in approximately 4555, and synovial fluid findings are consistent with septic arthritis. Blood culture results are usually negative. DGI in neonates usually occurs as a polyarticular suppurative arthritis. Dermatologic lesions usually begin as painful, discrete, 1 to 20 mm, pink or red macules that progress to maculopapular, vesicular, bullous, pustular, or petechial lesions. The typical necrotic pustule on an ery thematous base is distributed unevenly over the extremities, including the palmar and plantar surfaces, usually sparing the face and scalp. The lesions number between 5 and 40, and 2030 may contain gonococci. Although immune complexes may be present in DGI, complement lev els are normal, and the role of the immune complexes in pathogenesis is uncertain. Acute endocarditis is an uncommon (13) but often fatal mani festation of DGI that usually leads to rapid destruction of |
7,228 | the aortic valve. Acute pericarditis is a rarely described entity in patients with disseminated gonorrhea. Meningitis with N. gonorrhoeae has been documented, and signs and symptoms are similar to those of any acute bacterial meningitis. DIAGNOSIS Laboratory confirmation of gonococcal infection is essential, given the legal implications of potential sexual abuse in children and the need to refer sex partners of adolescents and adults for treatment. Given the advent of highly sensitive and specific nucleic acid amplification tests (NAATs), the use of less sensitive, nonamplified test technologies (nucleic acid hybridizationprobe tests, nucleic acid genetic transfor mation tests, or enzyme immunoassays) is no longer justified. Cul ture and susceptibility testing capability still need to be maintained, because culture is necessary to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treat ment regimens. Gram Stain and Culture Gram stains can be useful in the initial evaluation of patients with sus pected gonococcal infection. In males with symptomatic urethritis, a presumptive diagnosis of gonorrhea can be made by identification of gram negative intracellular diplococci (within PMNs) in the urethral discharge. A similar finding in females is not sufficient because Mima polymorpha and Moraxella, which are normal vaginal flora, have a sim ilar appearance. The sensitivity of the Gram stain for diagnosing gono coccal cervicitis and asymptomatic infections is also low. The presence of commensal Neisseria spp. in the oropharynx prevents the use of the Gram stain for diagnosis of pharyngeal gonorrhea. Culture can be performed of any site, including nongenital sites. Advantages of culture include the availability of an isolate for further studies, including antibiotic susceptibility testing. Disadvantages of culture include more stringent transport and growth requirements, lower sensitivity than NAATs, and a delay in availability of results. Material for cervical cultures is obtained as follows. After the exocervix is wiped, a swab is placed in the cervical os and rotated gently for sev eral seconds. Male urethral specimens are obtained by placement of a small swab 2 3 cm into the urethra. Rectal swabs are best obtained by passing a swab 2 4 cm into the anal canal; specimens that are heavily contaminated by feces should be discarded. For optimal culture results, specimens should be obtained with noncotton swabs, inoculated directly onto culture plates containing selective media (see later), and incubated immediately. The choice of anatomic sites to culture depends on the sites exposed and the clinical manifestations. If symptoms are present, samples from the urethra and rectum can be cultured for men, and samples from the endocervix and rectum can be cultured for all females, regardless of a history of anal intercourse. A pharyngeal cul ture specimen should be obtained from both men and women if symp toms of pharyngitis are present with a history of recent oral exposure or oral exposure to a person known to have genital gonorrhea. In a suspected case of child sexual abuse, culture or FDA approved NAAT are recommended methods of detection for N. gonorrhoeae in genital and extragenital |
7,229 | specimens. Culture of the endocervix should not be attempted until after puberty. Specimens from sites that are normally colonized by other organisms (e.g., cervix, rectum, pharynx) should be inoculated on a selective cul ture medium, such as modified Thayer Martin medium (fortified with vancomycin, colistin, nystatin, and trimethoprim to inhibit growth of indigenous flora). Specimens from sites that are normally sterile or minimally contaminated (i.e., synovial fluid, blood, cerebrospinal fluid) should be inoculated on a nonselective chocolate agar medium. If DGI is suspected, blood, pharynx, rectum, urethra, cervix, and syno vial fluid (if involved) should be cultured. Cultured specimens should 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. 1750 Part XV u Infectious Diseases be incubated promptly at 3537C (9598.6F) in 35 carbon diox ide. When specimens must be transported to a central laboratory for culture plating, a reduced, nonnutrient holding medium (i.e., Amies modified Stuart transport medium) preserves specimens with mini mal loss of viability for up to 6 hours. When transport may delay cul ture plating by 6 hours, it is preferable to inoculate the sample directly onto a culture medium and transport it at an ambient temperature in a CO2 enriched atmosphere. The Transgrow and John E. Martin Biologi cal Environmental Chamber (JEMBEC) systems of modified Thayer Martin medium are alternative transport systems. Nucleic Acid Amplification Tests The U.S. FDA has approved NAATs for use with genital (endocervi cal, vaginal, male urethral, and female and male first catch urine) and extragenital (pharyngeal and rectal) specimens. Advantages of using NAATs include less stringent transport conditions, more rapid turn around time, flexibility in sampling source (providing additional fea sibility of testing in settings where a physical exam is not done), and patient preference for less invasive sampling. However, NAATs can not provide antimicrobial susceptibility results, so in cases of persis tent gonococcal infection after treatment, clinicians should perform both culture and antimicrobial susceptibility testing. Although urine specimens are acceptable for women, the sensitivity for screening appears to be lower than with vaginal or endocervical swab samples. In contrast, the sensitivity and specificity of urine and urethral swab specimens from men are similar, so first catch urine is the recom mended sample type for urethral screening in men. Product inserts for each NAAT vendor must be carefully examined to assess current indications and allowable specimens. Some NAAT platforms are now FDA cleared for use with specimens from the rectum and pharynx, facilitating their use for clinical management of extragenital infec tions (gonorrhea screening of rectal and pharyngeal sites with NAATs is recommended quarterly for some sexually active MSM, e.g., those taking HIV prophylaxis). NAATs have not yet been FDA cleared for specimens from the conjunctiva, joint fluid, blood, or cerebrospinal fluid. Rapid NAATs with shortened turnaround times of 30 minutes and waivers allowing use in point of care settings such as physician offices, community |
7,230 | clinics, and other outpatient settings have now also been FDA cleared. Although data regarding NAAT for children are more limited and performance is test dependent, there is no evidence that performance of FDA approved NAAT for detection of N. gonorrhoeae among chil dren differs from that among adults. In a multicenter study of NAATs using strand displacement amplification or transcription mediated amplification in children being evaluated for sexual abuse, urine from prepubertal girls was a reliable alternative to vaginal culture for detec tion for N. gonorrhoeae. Consultation with an expert is necessary before using NAAT in this context, both to minimize the possibility of cross reaction with nongonococcal Neisseria species and other commensals (e.g., N. meningitidis, N. sicca, N. lactamica, N. cinerea, or Moraxella catarrhalis) and to ensure correct interpretation of results. Because of the implications of a diagnosis of N. gonorrhoeae infection in a child, only CLIA validated, FDA cleared NAATs should be used, and all posi tive specimens should be retained for additional confirmatory testing. TREATMENT All patients who are presumed or proven to have gonorrhea should be evaluated for concurrent syphilis, HIV, and Chlamydia trachomatis infection. The incidence of Chlamydia co infection is 1525 among males and 3550 among females. Patients beyond the neonatal period should be treated presumptively for C. trachomatis infection unless a negative chlamydial NAAT result is documented at the time treatment is initiated for gonorrhea. However, if chlamydial test results are not available or if a non NAAT result is negative for Chlamydia, patients should be treated for both gonorrhea and Chlamydia infec tion (see Chapter 272.2). Persons who receive a diagnosis of gonorrhea should be instructed to abstain from sexual activity for 7 days after treatment and until all sex partners are adequately treated (7 days after receiving treatment and resolution of symptoms, if present). Sexual partners exposed in the preceding 60 days should be examined, speci mens collected, and presumptive treatment started. N. gonorrhoeae has progressively developed resistance to the anti biotics used to treat it. Antimicrobial resistance in N. gonorrhoeae occurs as plasmid mediated resistance to penicillin and tetracycline and chromosomally mediated resistance to penicillins, tetracyclines, spectinomycin, fluoroquinolones, cephalosporins, and azithromycin. Emergence of cephalosporin resistance worldwide has prompted des ignation of N. gonorrhoeae as antibiotic resistance threat level Urgent by the CDC. Surveillance data from the CDC Gonococcal Isolate Sur veillance Project reveal concerning fluctuations in minimum inhibi tory concentration (MIC) for the oral cephalosporin cefixime and the injectable third generation cephalosporin ceftriaxone, leading the CDC to revise its U.S. gonorrhea treatment guidelines in 2012 to dual therapy (usually a combination of ceftriaxone and azithromycin) in an attempt to preserve the last commercially available effective treatment. However, the CDC revised its recommendations in 2020; ceftriaxone is now the only first line recommended treatment for gonorrhea at all sites. The change from dual therapy to monotherapy was based on (1) increasing concern for antimicrobial stewardship and the poten tial impact of dual therapy on commensal organisms and concurrent pathogens, (2) new |
7,231 | pharmacokinetic and pharmacodynamic data regarding optimal dosing for gonorrhea, and (3) increasing azithro mycin resistance (and therefore no optimal second drug to pair with a cephalosporin if dual therapy were the goal). Table 238.1 summarizes first line treatment regimens for neonate, child (weight 45 kg), adolescent, and adult gonococcal regimens. Mucosal, localized infections are treatable with single doses; dissemi nated infections are treated for a minimum of 1 week. Alternative regimens exist for adolescents and adults but are extremely limited. For patients with cephalosporin allergy, the combi nation of gentamicin (240 mg intramuscularly IM) plus azithromycin (2 g orally PO) cured 100 of uncomplicated urogenital cases in a trial of U.S. patients age 15 60 years; the combination of gemifloxacin (320 mg PO) (not licensed for use in those 18 years old) plus azithro mycin (2 g PO) cured 99 of uncomplicated urogenital cases in the same trial but was limited by 8 of patients vomiting within 1 hour of dual oral drug administration. For patients with azithromycin allergy, doxycycline (100 mg PO twice daily for 7 days) can be used in place of azithromycin as an alternative second antimicrobial. If ceftriaxone is not available, alternative cephalosporins include oral cefixime (800 mg PO), which has limited efficacy for pharyngeal gonorrhea, and other single dose injectable cephalosporin regimens, such as ceftizoxime (500 mg IM) or cefoxitin (2 g IM) with probenecid (1 g PO), neither of which offers any advantage over ceftriaxone for urogenital infection, and their efficacy against pharyngeal infection is less certain. Pregnant women with gonococcal infection should be treated with standard adult therapy. If allergy precludes standard treatment, con sultation with an infectious disease specialist is recommended. HIV co infected patients with gonococcal infection are treated the same as HIV negative patients. Follow up test of cure is not recommended for persons diagnosed with uncomplicated urogenital or rectal gonorrhea receiving recom mended or alternative regimens. However, any person with pharyngeal gonorrhea should return 7 14 days after treatment for a test of cure using culture, NAAT, or both, because pharyngeal gonorrhea is more difficult to eradicate. Symptoms persisting after treatment should be evaluated by culture for N. gonorrhoeae (with or without simultaneous NAAT), and any gonococci isolated should be tested for antimicrobial susceptibility. Treatment failure should be considered in (1) persons whose symptoms do not resolve within 3 5 days after appropriate treat ment and who report no sexual contact during posttreatment follow up and (2) persons with a positive test of cure (i.e., positive culture 72 hours or positive NAAT 7 days after receiving recommended treat ment) who report no sexual contact during posttreatment follow up. COMPLICATIONS Prompt diagnosis and correct therapy ensure complete recovery from uncomplicated gonococcal disease. Complications of gonorrhea result 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 238 u Neisseria gonorrhoeae (Gonococcus) 1751 from the spread |
7,232 | of gonococci from a local site of invasion. Complica tions and permanent sequelae may be associated with delayed treat ment, recurrent infection, metastatic sites of infection (meninges, aortic valve), and delayed or topical therapy of gonococcal ophthalmia. The interval between primary infection and development of a com plication is usually days to weeks. In postpubertal females, endometritis may occur, especially during menses, and may progress to salpingitis, tuboovarian abscess, and peritonitis (PID). Manifestations of PID include signs of lower genital tract infection (e.g., vaginal discharge, suprapubic pain, cervical tenderness) and upper genital tract infec tion (e.g., fever, leukocytosis, elevated erythrocyte sedimentation rate, and adnexal tenderness or mass). The differential diagnosis includes gynecologic diseases (ovarian cyst, ovarian tumor, ectopic pregnancy) and intraabdominal disorders (appendicitis, urinary tract infection, inflammatory bowel disease). Although N. gonorrhoeae and C. tracho matis are implicated in many cases of PID, this syndrome encompasses a spectrum of infectious diseases of the upper genital tract caused by N. gonorrhoeae, C. trachomatis, and endogenous flora (streptococci, anaerobes, gram negative bacilli). Treatment must therefore be broad. For women with more severe symptoms (inability to exclude surgical emergency, presence of tuboovarian abscess, severe illness, nausea, vomiting, or high fever), pregnancy, or lack of response to outpatient therapy within 72 hours, parenteral therapy should be initiated in the hospital. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women, because the clini cal response to outpatient treatment is similar among younger and older women. Recommended parenteral regimens are ceftriaxone (1 g intrave nously IV every 24 hours q24h) and metronidazole (500 mg PO or IV q12h); or cefotetan (2 g IV q12h); or cefoxitin (2 g IV q6h). Each of these regimens (ceftriaxone and metronidazole; cefotetan; or cefoxi tin) should be combined with doxycycline (100 mg PO or IV q12h). An alternative parenteral regimen is ampicillin sulbactam (3 g IV q6h) plus doxycycline (100 mg PO or IV q12h) or clindamycin (900 mg IV q8h) plus a loading dose of gentamicin (2 mgkg IV or IM) followed by maintenance gentamicin (1.5 mgkg q8h). Clinical experi ence should guide the transition to oral therapy, which usually can be initiated within 24 hours of improvement. Thereafter doxycycline (100 mg PO twice daily bid) to complete 14 days of total therapy, with oral clindamycin (450 mg PO 4 times daily qid) or metronidazole (500 mg PO bid) added for more effective anaerobic coverage, is provided. Parenteral therapy and IMPO therapy appear to be similar in terms of clinical efficacy for younger and older women with PID of mild to moderate severity. Recommended IMPO therapy regimens are as fol lows: a single dose of ceftriaxone (500 mg IM); single doses of cefoxitin (2 g IM) and probenecid (1 g PO) plus doxycycline (100 mg PO bid); or another parenteral third generation cephalosporin (e.g., ceftizoxime). Each of these regimens (ceftriaxone; cefoxitin and probenecid; other Table 238.1 Recommended Treatment of Gonococcal Infections AGE GROUP INFECTION TREATMENT REGIMEN LENGTH OF THERAPY |
7,233 | Neonates Ophthalmia neonatorum Ceftriaxone 25 50 mgkg IV or IM OR cefotaxime 100 mgkg IV or IM Once Disseminated infection Scalp abscess Septic arthritis Ceftriaxone 25 50 mgkg IV or IM every day OR cefotaxime 25 50 mgkg IV or IM q812h 7 days Meningitis Ceftriaxone 25 50 mgkg IV or IM every day OR cefotaxime 25 50 mgkg IV or IM q8 12h 10 14 days Endocarditis Ceftriaxone 25 50 mgkg IV or IM every day OR cefotaxime 25 50 mgkg IV or IM q8 12h Minimum 28 days Children 45 kg Pharyngeal infection Anorectal infection Urogenital infection Ceftriaxone 25 50 mgkg IV or IM (max 500 mg) Once Conjunctivitis Ceftriaxone 50 mgkg IM (max 1 g) plus consider lavage of infected eye with saline solution Once Disseminated infection Septic arthritis Ceftriaxone 50 mgkg IV or IM every day (max 1 g daily) 7 days Meningitis Ceftriaxone 50 mgkg IV or IM q12 24h (max 4 g daily) 10 14 days Endocarditis Ceftriaxone 50 mgkg IV or IM q12 24h (max 4 g daily) Minimum 28 days Adults, adolescents, and children 45 kg Pharyngeal infection Anorectal infection Urogenital infection Ceftriaxone 500 mg IM (or 1 g IM for persons 150 kg) Once Conjunctivitis Ceftriaxone 1 g IM plus consider lavage of infected eye with saline solution Once Disseminated infection Septic arthritis Ceftriaxone 1 g IV or IM every day 7 days Meningitis Ceftriaxone 1 2 g IV q12 24h 10 14 days Endocarditis Ceftriaxone 1 2 g IV q12 24h Minimum 28 days Ceftriaxone should be administered cautiously to neonates with hyperbilirubinemia, especially those born prematurely. Cefotaxime can be administered for those neonates unable to receive ceftriaxone because of simultaneous administration of IV calcium. Consult neonatal dosing references. Dose or dosing frequency changes after postnatal age 7 days of life: consult neonatal dosing references. IM, Intramuscularly; IV, intravenously; max, maximum; PO, orally. From Wangu Z, Hsu KK. Neisseria gonorrhoeae. In Long SS, Prober CG, Fischer M, Kimberlin D, eds. Principles and Practice of Pediatric Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2023: Table 126.1. 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. 1752 Part XV u Infectious Diseases parenteral third generation cephalosporin) should be combined with doxycycline (100 mg PO bid) and metronidazole (500 mg PO bid) for 14 days. Once inside the peritoneum, gonococci may seed the liver capsule, causing a perihepatitis with right upper quadrant pain (Fitz Hugh Curtis syndrome), with or without signs of salpingitis. Perihepatitis may also be caused by C. trachomatis. Progression to PID occurs in approximately 20 of cases of gonococcal cervicitis, and N. gonor rhoeae is isolated in approximately 40 of cases of PID in the United States. Untreated cases may lead to hydrosalpinx, pyosalpinx, tubo ovarian abscess, and eventual sterility. Even with adequate treatment of PID, the risk for sterility from bilateral tubal occlusion approaches 20 |
7,234 | after one episode of salpingitis and exceeds 60 after three or more episodes. The risk for ectopic pregnancy is increased approximately sevenfold after one or more episodes of salpingitis. Additional sequelae of PID include chronic pain, dyspareunia, and increased risk for recur rent PID. Urogenital gonococcal infection acquired during the first trimester of pregnancy carries a high risk for septic abortion. After 16 weeks of pregnancy, infection leads to chorioamnionitis, a major cause of pre mature rupture of the membranes and premature delivery. In males, without treatment, gonococcal urethritis usually resolves spontaneously over several weeks to months. Epididymitis and acute or chronic prostatitis are uncommon complications; most men with gonococcal epididymitis also have overt urethritis. Even more unusual complications include penile edema associated with penile dorsal lym phangitis or thrombophlebitis, periurethral abscess or fistulas, seminal vesiculitis, and balanitis in uncircumcised men. PREVENTION Efforts to develop gonococcal vaccines that confer broad cross protection have been unsuccessful thus far. A pilus vaccine elicited an antibody response and conferred protection against challenge with the homologous strain but did not protect against disease in a trial involv ing 3,250 volunteers. The high degree of interstrain and intrastrain antigenic variability of pili poses a formidable barrier to the develop ment of a single effective pilus vaccine. An outer membrane vaccine that was enriched in PorB also elicited an antibody response but failed to protect male volunteers against challenge with the homologous strain, likely because small amounts of Rmp present in the vaccine preparation elicited subversive antibodies. A formalin killed whole cell vaccine trial in 62 volunteers in an Inuvik population in Canada also failed to provide any protection. Gonococcal surface structures, such as the porin protein (isolated without contaminating Rmp), proteins expressed under various stress conditions that may be encountered in vivo and have been identified by proteomic and transcriptomic approaches, and lipooligosaccharides, may prove more promising as vaccine candidates. A retrospective epidemiologic analysis showed that a meningococ cal outer membrane vesicle vaccine (MeNZB) that was used to curb an epidemic of group B meningococcal disease in New Zealand was asso ciated with a clinical efficacy of 31 against gonorrhea, which lends optimism for development of a gonococcal vaccine. However, efficacy was only 14 in persons co infected with gonorrhea and chlamydia. Cross reactive antigens shared by N. gonorrhoeae and N. meningitidis may have contributed to the efficacy of the group B outer membrane vesicle vaccine against gonorrhea. In the absence of a vaccine, prevention of gonorrhea in adolescents and adults can be achieved through education, use of barrier protec tion (especially condoms), frequent screening of high risk popula tions as recommended by the U.S. Preventive Services Task Force (PSTF) and CDC (e.g., sexually active women 24 years old, MSM, individuals previously infected with gonorrhea), and early identifica tion and treatment of contactsall sex partners within the 60 days preceding symptom onset or gonorrhea diagnosis or, if none, the most recent sex partner should be examined and treated presumptively. For heterosexual patients, expedited partner therapy |
7,235 | (EPT) with cefixime (800 mg) can be delivered to partners by the patient, a public health worker, or a collaborating pharmacy, as permitted by law (https:w ww.cdc.govstdeptlegal). EPT has been shown to be safe and effec tive in the prevention of reinfection with gonorrhea and is endorsed by the American Academy of Pediatrics, American Academy of Fam ily Physicians, and Society of Adolescent Health and Medicine, along with other clinical organizations, for use when in person evaluation and treatment of the partner is impractical or unsuccessful. (Because of limited data regarding the effectiveness of EPT in reducing persistent or recurrent gonorrhea among MSM and the high risk for coexisting undiagnosed sexually transmitted infections such as HIV, shared clini cal decision making regarding EPT for MSM is recommended.) An infant born to a woman with cervical gonococcal infection has an approximately 30 risk of acquiring ophthalmic infection compared with a 5 risk if ocular prophylaxis is given. Gonococcal ophthal mia neonatorum can be prevented by instilling erythromycin (0.5) ophthalmic ointment into each eye in a single application at birth (see Chapter 674). If erythromycin ointment is unavailable, infants at risk for N. gonorrhoeae (especially those born to a mother with untreated gonococcal infection or with no prenatal care) can be administered cef triaxone 25 50 mgkg IV or IM, not to exceed 500 mg, in a single dose. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 239 Kingella kingae Pablo Yagupsky Kingella kingae is being increasingly recognized as the most common etiology of skeletal system infections in young children. ETIOLOGY K. kingae is a fastidious, facultative anaerobic, hemolytic member of the Neisseriaceae family that appears as pairs or short chains of gram negative coccobacilli with tapered ends (Fig. 239.1). EPIDEMIOLOGY K. kingae is asymptomatically carried in the posterior pharynx, and the colonized mucosa is the source of bloodstream invasion of the bacterium and its dissemination to the skeletal system or the endocardium, sites for which the organism has a particular tropism. Colonization usually starts after 6 months of age, suggesting that maternally derived immu nity, coupled with limited socialization, prevents the early acquisition of the bacterium. Colonization reaches a prevalence of 10 between 12 and 24 months and decreases in older children. Carried strains are replaced after weeks or months, suggesting that carriage induces a strain specific immune response that eradicates the colonizing strain but does not prevent the acquisition of an antigenically different organism. The vast majority of colonized children remain healthy, and the annual risk of a carrier to develop an invasive infection is 1. Pharyngeal colonization plays a crucial role in the transmission of the organism through intimate contact between siblings and play mates. Daycare attendance increases the risk for colonization and transmission, and clusters of invasive infection have been reported in childcare facilities. The species elaborates four different polysaccharide capsules (a d), which appear to represent important virulence factors. Whereas cap sules a and b characterize 95 of all invasive strains, capsules c and d are especially |
7,236 | found in mere pharyngeal colonizers. Colonizing K. kingae strains differ in their invasive potential. Whereas certain clones are commonly found as respiratory colonizers but are seldom isolated from disease sites, other clones are responsible for most of the morbid ity burden worldwide. Invasive K. kingae disease is most frequently diagnosed in otherwise healthy children between the ages 6 months and 4 years, coinciding 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 239 u Kingella kingae 1753 RBCs Kingella kingae organisms Fig. 239.1 Typical Gram stain of a positive blood culture vial from a child with K. kingae bacteremia showing pairs and short chains of plump gram negative coccobacilli. RBCs, Red blood cells. ?6 months 611 months 1.4 1.4 37.8 37.8 77 90 96.9 98.6 100 13 6.9 1.7 1.4 39.2P er ce nt 1217 months 1823 months Age interval 2429 months 3035 months ?36 months 100 Cumulative 90 80 70 60 50 40 30 20 10 0 Fig. 239.2 Age distribution of 291 previously healthy children with invasive K. kingae infection. (Data from Dubnov Raz G, Ephros M, Garty BZ, et al. Invasive pediatric Kingella kingae infections: a nationwide col laborative study. Pediatr Infect Dis J. 2010;29:639643.) with the peak prevalence of pharyngeal carriage (Fig. 239.2). In con trast, older children and adults with K. kingae infections often have underlying chronic diseases, immunosuppressing conditions, malig nancy, or cardiac valve pathology. Because of the highly fastidious nature of the organism, K. kingae is rarely recovered using traditional culture methods. An annual incidence of 9.4 per 100,000 culture proven invasive infections among Israeli children 5 years old has been calculated, but this figure can be considered only a minimal estimate because of the suboptimal culture detection of the organ ism. When sensitive species specific nucleic acid amplification test (NAAT) methods are consistently used, K. kingae appears as the most frequent etiology of skeletal system infections in children 6 months to 4 years old. In a Swiss study in which sensitive NAATs were routinely employed, the organisms caused 88 of all joint and bone infections in this age group. PATHOGENESIS The pathogenesis of K. kingae disease begins with adherence of the organism to the pharyngeal epithelium, mediated by pili and a non pilus adhesin. K. kingae secretes a potent repeats in toxin (RTX) toxin that is cytotoxic to respiratory epithelial cells, macrophages, and syn oviocytes, suggesting that it may play a role in disrupting the respira tory mucosa, promoting survival of the bacterium in the bloodstream, and facilitating invasion of skeletal system tissues. Children with K. kingae disease frequently present with symptoms of an upper respi ratory infection, hand foot and mouth disease, herpangina, herpetic stomatitis, or buccal aphthous ulcers, suggesting that viral induced damage to the colonized mucosal surface facilitates invasion of the bloodstream. CLINICAL DISEASE Septic arthritis is the most common invasive K. kingae |
7,237 | infection in children, followed by bacteremia, osteomyelitis, and endocarditis (Table 239.1). Except for patients with endocarditis, the presentation of invasive K. kingae infections is frequently mild, and a normal body temperature 38C (100.4F), a normal C reactive protein (CRP) level, and a normal white blood cell (WBC) count are common, requiring a high index of clinical suspicion. Mild to moderate thrombocytosis has been described in more than one third of patients. Septic Arthritis K. kingae septic arthritis primarily affects the large, weight bearing joints and the upper extremity joints. However, K. kingae infections of the small metacarpophalangeal, sternoclavicular, sacroiliac, and tarsal joints and the vertebral facets are also relatively common, in contrast to traditional bacterial pathogens associated with septic arthritis (see Chapter 726). The disease has an acute presentation, and children are brought to medical attention after a median of 3 days. The leukocyte count in the synovial fluid shows 50,000 WBCsL in almost 25 of the patients, and the Gram stain of synovial fluid is positive in only a small percentage of cases. Involvement of the hip joint resembles toxic synovitis, and the possibility of a K. kingae infec tion should always be suspected in children 4 years old presenting with hip pain or a limp. Osteomyelitis K. kingae osteomyelitis usually involves the long bones of the extremi ties (see Chapter 725). The calcaneus, talus, sternum, and clavicle are also frequently affected (and are rarely infected by other bacterial pathogens). In contrast to K. kingae arthritis, the onset of K. kingae bone infections is insidious, and the disease follows a subacute and indolent clinical course (Fig. 239.3). In 70 of patients K. kingae osteomyelitis is diagnosed after 1 week. MRI may show a distinct involvement of cartilages that are not yet ossified, which is only accom panied by a minor soft tissue reaction. Dissemination to the apophysis or epiphysis and contiguous joints is frequent. Despite the frequent diagnostic delay, chronic osteomyelitis and functional orthopedic dis abilities are unusual. SPONDYLODISCITIS In industrialized countries, K. kingae is the most common bacterium detected in children 4 years old with spondylodiscitis. The organism presumably penetrates the rich network of blood vessels that traverse the cartilaginous vertebral end plates and enters the annulus in young children during a bacteremic episode. K. kingae spondylodiscitis usu ally involves the lumbar intervertebral spaces and, with decreasing frequency, thoracolumbar, thoracic, lumbosacral, and cervical disks. Involvement of multiple disks is uncommon. Patients present with limping, lumbar pain, back stiffness, refusal to sit or walk, neurologic symptoms, or abdominal complaints. Radiography or MRI studies demonstrate narrowing of the intervertebral space. Patients respond well to appropriate antibiotic treatment and recover without complica tions, although residual thinning of the intervertebral space may occur. Drainage of paraspinal abscesses is necessary when signs of cord com pression appear. Tenosynovitis K. kingae is the etiology of most cases of hematogenous invasion of the tendon sheaths in children 4 years of age. The disease usually affects the extensor tendons of the hands and wrists and, more |
7,238 | rarely, the ankles and the feet. 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. 1754 Part XV u Infectious Diseases Occult Bacteremia Patients with K. kingae bacteremia and no focal infection (occult bac teremia) usually present with mild to moderate fever, symptoms sug gestive of a viral upper respiratory infection, a mean CRP level of 2.2 mgdL, and a mean WBC count of 12,700L. Children with K. kingae bacteremia respond favorably to a short course of antibiotics. Endocarditis In contrast to other K. kingae infections, K. kingae endocarditis is also diagnosed in school age children, adolescents, and adult patients. The disease may affect native and prosthetic valves. Predisposing factors include congenital cardiac malformations or rheumatic valvular dis ease, but some patients have previously normal hearts. Typically, the left side of the heart is involved, usually the mitral valve. Fever and acute phase reactants are elevated more in patients with endocardi tis than in those with uncomplicated bacteremia; no particular cutoff value accurately distinguishes between the two conditions. Despite the exquisite susceptibility of K. kingae to antibiotics, cardiac failure, sep tic shock, cerebrovascular accident (stroke), and other life threatening complications are common; the mortality rate is high (10); and many surviving patients later require valvular repair or replacement. Because of the potential severity of K. kingae endocarditis, routine echocardiographic evaluation of bacteremic children is recommended by some experts. DIAGNOSIS The diagnosis of K. kingae disease can be established by isolation of the bacterium from a normally sterile site such as blood, synovial fluid, or bone tissue. Although K. kingae grows on routine bacteriologic media, its recovery from exudates is frequently unsuccessful. Detec tion is enhanced by inoculating synovial fluid specimens into blood culture vials, suggesting that diluting samples in a large volume of nutrient broth reduces the concentration of detrimental factors. The bacteriologic diagnosis is significantly improved by the use of NAATs (polymerase chain reaction). The initial approach consisted of ampli fying the 16S ribosomal RNA (rRNA) gene, which is present in all bacteria followed by sequencing the species specific amplicon to iden tify the pathogen. The original molecular assays are being replaced by real time polymerase chain reaction tests that target K. kingaespecific genes that can be completed in a few hours. Routine use of these assays results in a fourfold improvement in the detection of the organism compared with the blood culture vial method and reduces the frac tion of culture negative septic arthritis in young children. The three K. kingaespecific genes that are targeted by the current tests are the rtx operon that encodes the RtxA toxin; the cpn60 (chaperonin 60 gene), also known as groEL; and the malate dehydrogenase (mdh) gene that combines excellent sensitivity and specificity and should be the pre ferred method. Because the bacterium frequently invades joints and bones that are small or difficult to reach or intervertebral |
7,239 | disks, exudate samples or tissues are often unavailable for analysis. An alternative noninvasive diagnostic approach has been proposed consisting of obtaining an oro pharyngeal specimen and subjecting it to a sensitive K. kingaespecific NAAT. A compatible clinical picture, coupled with a positive test result, supports K. kingae as the probable cause of the disease. This strategy has the obvious limitation that the background carriage rate of the organ ism is around 10 in children of the relevant age and twice as high in those attending daycare centers, reducing the predictive value of a posi tive result. On the other hand, because the colonized oropharynx is the source of the bloodborne dissemination of the bacterium, the negative predictive value of the assay is high. For practical purposes, failure to detect K. kingae DNA sequences when using a sensitive molecular test virtually rules out the organism as the etiology of the infection. Novel commercially available plasma metagenomic next generation sequencing assays appear to be a promising tool for detecting the organism, especially in patients with endocarditis receiving antibiotics. TREATMENT K. kingae is usually highly susceptible to penicillin and cephalosporins but exhibits decreased susceptibility to oxacillin, precluding the use of isoxazolyl penicillins for confirmed K. kingae infections. Although lactamase production is frequently detected in colonizing K. kingae strains, its prevalence among invasive organisms is low and shows wide geographic variation. Testing for lactamase production should be rou tinely performed in all isolates derived from normally sterile body sites. Because of the lack of specific guidelines for treating K. kingae dis ease, patients have been administered a variety of antibiotic regimens according to protocols developed for infections caused by traditional bacterial pathogens. The first line therapy for skeletal infections in young children usually consists of intravenous (IV) administration of a second or third generation cephalosporin, pending culture or NAAT results. K. kingae is always resistant to glycopeptide antibiotics and clindamycin, a serious concern in areas where skeletal infections caused by community associated methicillin resistant Staphylococ cus aureus are common, and vancomycin or clindamycin are initially Fig. 239.3 K. kingae transphyseal osteomyelitis of the femur (arrow). This 3 yr old child limped for 3 weeks and was diagnosed with toxic synovitis. He was afebrile and had a leukocyte count of 9.8 109 cellsL, a C reactive protein level of 12 mgL, and an erythrocyte sedimentation rate of 42 mmhr. (Courtesy Prof. Dimitri Ceroni, Hpitaux Universitaires de Genve.) Table 239.1 Clinical Spectrum and Relative Frequency of K. kingae Infections CLINICAL DISEASE FREQUENCY Septic arthritis Osteomyelitis Spondylodiscitis Tenosynovitis Bursitis Bacteremia with no focus Endocarditis Pericarditis Laryngotracheobronchitis Pneumonia Pleural empyema Keratitis Corneal abscess Endophthalmitis Eyelid abscess , Very common; , common; , infrequent; , exceptional. 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 240 u Haemophilus influenzae 1755 administered to children with presumptive septic arthritis or osteomy elitis. The initial antibiotic |
7,240 | regimen is frequently changed to a cepha losporin (e.g., ceftriaxone) once K. kingae is identified or to ampicillin after lactamase production is excluded. A favorable clinical response and decreasing CRP levels to 20 gmL are used to guide switching to oral antibiotics and defining the duration of therapy. Antibiotic treat ment has ranged from 2 to 3 weeks for K. kingae arthritis, from 3 to 6 weeks for K. kingae osteomyelitis, and from 3 to 12 weeks for K. kingae spondylodiscitis. Although some children with septic arthritis have been managed with repeat joint aspirations and lavage, most patients respond promptly to conservative treatment with appropriate antibiot ics and do not require invasive surgical procedures. Children with K. kingae bacteremia without focal infection are initially treated with an IV lactam antibiotic and are subsequently switched to an oral drug once the clinical condition has improved. In most cases, therapy is administered for 1 2 weeks. Patients with K. kingae endocarditis are usually treated with an IV lactam antibiotic alone or in combination with an aminoglycoside for 4 7 weeks. Early surgical intervention is necessary for life threatening complications unresponsive to medical therapy. PREVENTION Because the risk of asymptomatic pharyngeal carriers for developing an invasive K. kingae infection is low, in the absence of clinical disease, there is no indication to eradicate the organism from the colonized mucosal surfaces. Nonetheless, in 25 reported outbreaks of K. kingae infections in child daycare centers, 68 of 402 (17) classmates developed a proven or presumptive infection, including fatal endocarditis, within 1 month, indicating that the causative strains combined unusual transmissibil ity and virulence. Under these circumstances, prophylactic antibiotic therapy to eradicate colonization in contacts and prevent further cases of the disease has been employed, consisting of either rifampin alone 10 mgkg or 20 mgkg twice daily for 2 days or rifampin in combination with amoxicillin (80 mgkgday) for 2 days or 4 days. The effectiveness of these regimens has ranged between 47 and 80, indicating that eradication of K. kingae from colonized mucosae is difficult to achieve. However, after antibiotic prophylaxis administration, no further cases of the disease have been detected, suggesting that reduction of the bacterial density by antibiotics, extinction of the precipitating viral infection, and or induction of an effective immune response by prolonged carriage is enough to decrease transmissibility and prevent additional cases. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 240 Haemophilus influenzae Nadia A. Kadry and Joseph W. St. Geme III Effective vaccines to prevent Haemophilus influenzae type b (Hib) disease, introduced in the United States and most other countries, have resulted in a dramatic decrease in the incidence of infections caused by this organism. However, mortality and morbidity from Hib infection remain a problem worldwide, primarily in resource poor countries. Occasional cases of invasive disease caused by nontype b strains con tinue to occur but are infrequent. Nontypeable isolates of H. influenzae are an important cause of otitis media, sinusitis, and chronic bronchitis. ETIOLOGY H. influenzae is a fastidious, |
7,241 | gram negative, pleomorphic coccobacil lus that requires factor X (hematin) and factor V (phosphopyridine nucleotide) for growth. Some H. influenzae isolates are surrounded by a polysaccharide capsule and can be segregated into one of six anti genically and biochemically distinct serotypes designated types a, b, c, d, e, and f. Isolates without a polysaccharide capsule are considered nontypeable. Isolates can also be categorized based on the production of indole and the presence of ornithine decarboxylase and urease and are sorted into biotypes I VIII. EPIDEMIOLOGY Before the advent of an effective Hib conjugate vaccine in 1988, Hib was a major cause of serious disease among children. There was a striking age distribution of cases, with 90 in children 5 years old and the majority in children 2 years old. The annual attack rate of invasive disease was 64 129 cases per 100,000 children 5 years old. Invasive disease caused by strains producing a nontype b capsule has been much less frequent but continues to occur. The incidence of invasive disease caused by type b and nontype b serotypes has been estimated at approximately 0.08 and 1.02 cases, respectively, per 100,000 children 5 years old per year in the United States. Nontypeable (nonencapsulated) H. influenzae strains also occasionally cause invasive disease, especially in neonates, immu nocompromised children, and children in resource poor countries. The estimated rate of invasive disease caused by nontypeable H. influenzae in the United States is 1.88 per 100,000 children 5 years old per year. Non typeable isolates are common etiologic agents in otitis media, sinusitis, and chronic bronchitis. More recent evidence also implicates nasopha ryngeal colonization with nontypeable H. influenzae in the development of asthma and allergic airway disease. Humans are the only natural hosts for H. influenzae, which is part of the normal respiratory flora in 6090 of healthy children. Most isolates are nontypeable. Before the advent of Hib conjugate vaccines, H. influenzae type b could be isolated from the pharynx of 25 of healthy preschool and school age children, with lower rates among infants and adults. Asymptomatic colonization with Hib occurs at a much lower rate in immunized populations. The continued circulation of type b strains despite current vaccine coverage levels suggests that elimination of Hib disease may be a for midable task. The few cases of Hib invasive disease in the United States now occur in both unvaccinated and fully vaccinated children. Approxi mately 50 of cases occur in infants who are too young to have received a complete primary vaccine series. Among the cases in patients who are old enough to have received a complete vaccine series, the major ity are underimmunized. To highlight this point, during a shortage of Hib vaccine, invasive disease developed in five children in Minnesota, all of whom were incompletely immunized. Continued efforts are neces sary to provide currently available Hib conjugate vaccines to children in resource poor countries, where affordability remains an important issue. In the prevaccine era, certain groups and individuals had an increased incidence of |
7,242 | invasive Hib disease, including Alaskan Natives, American Indians (Apache, Navajo), and African Americans. Per sons with certain chronic medical conditions were also known to be at increased risk for invasive disease, including individuals with sickle cell disease, asplenia, congenital and acquired immunodeficiencies, and malignancies. Unvaccinated infants with invasive Hib infection are also at increased risk for recurrence, reflecting that they typically do not develop a protective immune response to H. influenzae. Socioeconomic risk factors for invasive Hib disease include childcare outside the home, the presence of siblings of elementary school age or younger, short duration of breastfeeding, and parental smoking. A his tory of otitis media is associated with an increased risk for invasive dis ease. Much less is known about the epidemiology of invasive disease caused by nontype b strains, and it is not clear whether the epidemio logic features of Hib disease apply to disease caused by non Hib strains. Among age susceptible household contacts who have been exposed to a case of invasive Hib disease, there is increased risk for secondary cases of invasive disease in the first 30 days after exposure, especially in susceptible children 24 months old. Whether a similar increased risk exists for contacts of individuals with non Hib disease is unknown. The mode of transmission is usually direct contact or inhalation of respiratory tract droplets containing H. influenzae. The incubation period for invasive disease is variable, and the exact period of commu nicability is unknown. Most children with invasive Hib disease are col onized in the nasopharynx before initiation of antimicrobial therapy; 2540 may remain colonized during the first 24 hours of 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. 1756 Part XV u Infectious Diseases With the decline of disease caused by type b organisms, disease caused by other serotypes (a, c f) and by nontypeable strains has been recognized more clearly. There is no evidence that nontype b infec tions have increased in frequency. However, clusters of type a and, less often, type e and type f infections have occurred. Data from Israel sug gest that nontypeable H. influenzae is the most common cause of inva sive H. influenzae disease in that country. PATHOGENESIS The pathogenesis of Hib disease begins with adherence to respiratory epithelium and colonization of the nasopharynx, which is mediated by pilus and nonpilus adherence factors. The mechanism of entry into the intravascular compartment is unclear but appears to be influenced by cytotoxic factors. Once in the bloodstream, Hib, and perhaps other encapsulated strains, resist intravascular clearance mechanisms at least in part because of the polysaccharide capsule. In the case of Hib, the magnitude and duration of bacteremia influence the likelihood of dis semination of bacteria to sites such as the meninges and joints. Noninvasive H. influenzae infections such as otitis media, sinus itis, and bronchitis are usually caused by nontypeable |
7,243 | strains. These organisms gain access to sites such as the middle ear and sinus cavities by direct extension from the nasopharynx. Factors facilitating spread from the nasopharynx include eustachian tube dysfunction and ante cedent viral infections of the upper respiratory tract. Antibiotic Resistance Ampicillin resistance is increasingly common among H. influenzae iso lates. Resistance is typically driven by plasmid mediated production of a lactamase. lactamasenegative ampicillin resistant isolates have been identified and manifest resistance by production of a lactaminsensitive cell wall synthesis enzyme called penicillin binding protein 3 (PBP 3). Amoxicillin clavulanate is uniformly active against H. influenzae clinical isolates except for the rare lactamasenegative ampicillin resistant isolates. Among macrolides, azithromycin has in vitro activ ity against a high percentage of H. influenzae isolates; in contrast, the activity of erythromycin and clarithromycin against H. influenzae clinical isolates is poor. H. influenzae resistance to third generation cephalosporins has not been documented. Resistance to quinolones is rare, and resistance to trimethoprim sulfamethoxazole (TMP SMX) is present in approximately 10 of isolates. Immunity In the prevaccine era, the most important known element of host defense was antibody directed against the type b capsular polysac charide polyribosylribitol phosphate (PRP). Anti PRP antibody is acquired in an age related fashion and facilitates clearance of Hib from blood, in part related to opsonic activity. Antibodies directed against antigens such as outer membrane proteins or lipopolysaccharide (LPS) may also have a role in opsonization. Both the classical and alternative complement pathways are important in defense against Hib. Before the introduction of vaccination, protection from Hib infec tion was presumed to correlate with the concentration of circulating anti PRP antibody at the time of exposure. A serum antibody con centration of 0.15 gmL was considered protective against invasive infection. Unimmunized infants 6 months old and young children usually lacked an anti PRP antibody concentration of this magnitude and were susceptible to disease after encountering Hib. This lack of antibody in infants and young children may have reflected a matura tional delay in the immunologic response to thymus independent type 2 antigens such as unconjugated PRP, presumably explaining the high incidence of type b infections in infants and young children in the pre vaccine era. The conjugate vaccines act as thymus dependent antigens and elicit serum antibody responses in infants and young children (Table 240.1). These vaccines are believed to prime memory antibody responses on subsequent encounters with PRP. The concentration of circulating anti PRP antibody in a child primed by a conjugate vaccine may not correlate precisely with protection, presumably because a memory response may occur rapidly on exposure to PRP and provide pro tection. Conjugate vaccines have been shown to be highly effective against Hib disease and have been shown to reduce nasopharyngeal carriage rates. Much less is known about immunity to other H. influenzae serotypes or to nontypeable isolates. For nontypeable isolates, evidence suggests that antibodies directed against one or more outer membrane proteins are bactericidal and protect against experimental challenge. A vari ety of antigens |
7,244 | have been evaluated in an attempt to identify vaccine candidates for nontypeable H. influenzae, including outer membrane proteins (P1, P2, P4, P5, P6, D15, and Tbp AB), LPS, various adhesins (e.g., Hap, HMW1, and HMW2), and lipoprotein D. DIAGNOSIS Presumptive identification of H. influenzae is established by direct examination of a clinical specimen after staining with Gram reagents. Because of its small size, pleomorphism, and occasional poor uptake of stain, as well as the tendency for proteinaceous fluids to have a red background, H. influenzae is sometimes difficult to visualize. Further more, given that identification of H. influenzae by microscopy requires at least 105 bacteriamL in a clinical specimen (e.g., cerebrospinal fluid CSF), failure to visualize organisms does not preclude their presence. Culture of H. influenzae requires prompt transport and processing of specimens because the organism is fastidious. Specimens should not be exposed to drying or temperature extremes. Primary isolation of H. influenzae can be accomplished on chocolate agar. Serotyping of H. influenzae is accomplished by slide agglutination with type specific antisera or through polymerase chain reaction (PCR) amplification of the capsule locus (cap). Importantly, antigen based detection methods are prone to false positives because of antigen cross reactivity with other encapsulated organisms and are therefore not recommended as the primary diagnostic approach. Real time PCR and nucleic acid amplification tests (NAATs) can be used to specifically detect H. influenzae. Accurate serotyping is essential to monitor prog ress toward elimination of type b invasive disease. Timely reporting of cases to public health authorities should be ensured. CLINICAL MANIFESTATIONS AND TREATMENT The initial antibiotic therapy for invasive infections possibly caused by H. influenzae should be a parenterally administered antibiotic effective Table 240.1 Haemophilus influenzae Type b (Hib) Conjugate Vaccines Available in the United States VACCINE TRADE NAME COMPONENTS MANUFACTURER PRP T ActHib PRP conjugated to tetanus toxoid Sanofi PRP T Hibrix PRP conjugated to tetanus toxoid GlaxoSmithKline Biologicals PRP OMP PedvaxHIB PRP conjugated to OMP Merck PRP TDTaP IPV Pentacel PRP T DTaP IPV vaccines Sanofi Pasteur PRP OMPDTaP IPV HepB Vaxelis PRP OMP DTaP IPV HepB vaccines Merck DTaP, Diphtheria and tetanus toxoids and acellular pertussis vaccine; HepB, hepatitis B vaccine; IPV, trivalent inactivated polio vaccine; OMP, outer membrane protein complex from Neisseria meningitidis; PRP, polyribosylribitol phosphate. 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 240 u Haemophilus influenzae 1757 in sterilizing all foci of infection and effective against ampicillin resistant strains, usually an extended spectrum cephalosporin such as ceftriaxone. After the antimicrobial susceptibility of the isolate has been determined, an appropriate agent can be selected to complete the therapy. Ampicillin remains the drug of choice for the therapy of infec tions caused by susceptible isolates. If the isolate is resistant to ampicil lin, in selected circumstances ceftriaxone can be administered once daily for outpatient therapy. Oral antimicrobial agents are sometimes used to |
7,245 | complete a course of therapy initiated by the parenteral route and are typically initial therapy for noninvasive infections such as otitis media and sinusitis. If the organism is susceptible, amoxicillin is the drug of choice. An oral second or third generation cephalosporin or amoxicillin clavulanate may be used when the isolate is resistant to ampicillin. Meningitis In the prevaccine era, meningitis accounted for more than half of all cases of invasive H. influenzae disease. Clinically, meningitis caused by Hib cannot be differentiated from meningitis caused by Neisseria men ingitidis or Streptococcus pneumoniae (see Chapter 643.1). It may be complicated by other foci of infection such as the lungs, joints, bones, and pericardium. Antimicrobial therapy should be administered intravenously for 7 14 days for uncomplicated cases. Ceftriaxone and ampicillin cross the blood brain barrier during acute inflammation in concentrations ade quate to treat H. influenzae meningitis. Intramuscular therapy with cef triaxone may be an alternative in patients with normal organ perfusion. The prognosis of Hib meningitis depends on the age at presenta tion, duration of illness before appropriate antimicrobial therapy, CSF capsular polysaccharide concentration, and rapidity with which organisms are cleared from CSF, blood, and urine. Clinically mani fested inappropriate secretion of antidiuretic hormone and evidence of focal neurologic deficits at presentation are poor prognostic features. Approximately 6 of patients with Hib meningitis are left with some hearing impairment, probably because of inflammation of the cochlea and the labyrinth. Dexamethasone (0.6 mgkgday divided every 6 hours for 2 days), particularly when given shortly before or concurrent with the initiation of antimicrobial therapy, decreases the incidence of hearing loss. Major neurologic sequelae of Hib meningitis include behavior problems, language disorders, impaired vision, mental retar dation, motor abnormalities, ataxia, seizures, and hydrocephalus. Cellulitis Children with Hib cellulitis often have an antecedent upper respiratory tract infection. They usually have no prior history of trauma, and the infection is thought to represent seeding of the organism to the involved soft tissues during bacteremia. The head and neck, particularly the cheek and preseptal region of the eye, are the most common sites of involve ment. The involved region generally has indistinct margins and is tender and indurated. Buccal cellulitis is classically erythematous with a vio laceous hue, although this sign may be absent. H. influenzae may often be recovered directly from an aspirate of the leading edge, although this procedure is seldom performed. A blood culture may also reveal the causative organism. Other foci of infection may be present concomi tantly, particularly in children 18 months old. A diagnostic lumbar puncture should be considered at diagnosis in these children. Parenteral antimicrobial therapy is indicated until patients become afebrile, after which an appropriate oral antimicrobial agent may be substituted. A 7 to 10 day course is customary. Preseptal Cellulitis Infection involving the superficial tissue layers anterior to the orbital septum is termed preseptal cellulitis, which may be caused by H. influen zae. Uncomplicated preseptal cellulitis does not imply a risk for visual impairment or direct central nervous |
7,246 | system (CNS) extension. How ever, concurrent bacteremia may be associated with the development of meningitis. H. influenzae preseptal cellulitis is characterized by fever, edema, tenderness, warmth of the lid, and, occasionally, purple discol oration. Evidence of interruption of the integument is usually absent. Conjunctival drainage may be associated. S. pneumoniae, Staphylococ cus aureus, and group A Streptococcus cause clinically indistinguishable preseptal cellulitis. The latter two pathogens are more likely when fever is absent and the integument is interrupted (e.g., because of an insect bite or trauma). Children with preseptal cellulitis in whom H. influenzae and S. pneu moniae are etiologic considerations (young age, high fever, intact integ ument) should have a blood culture obtained. In addition, a diagnostic lumbar puncture should be considered. Parenteral antibiotics are indicated for preseptal cellulitis. Because methicillin susceptible and methicillin resistant S. aureus, S. pneumoniae, and group A hemolytic streptococci are other causes, empirical therapy should include agents active against these pathogens. Patients with pre septal cellulitis without concurrent meningitis should receive parenteral therapy for about 5 days, until fever and erythema have abated. In uncomplicated cases, antimicrobial therapy should be given for 10 days. Orbital Cellulitis Infections of the orbit are infrequent and usually develop as compli cations of acute ethmoid or sphenoid sinusitis. Orbital cellulitis may manifest as lid edema but is distinguished by the presence of proptosis, chemosis, impaired vision, limitation of the extraocular movements, decreased mobility of the globe, or pain on movement of the globe. The distinction between preseptal and orbital cellulitis may be difficult and is best determined by CT scan. Orbital infections are treated with parenteral therapy for at least 14 days. Underlying sinusitis or orbital abscess may require surgical drainage and more prolonged antimicrobial therapy. Supraglottitis or Acute Epiglottitis Supraglottitis is a cellulitis of the tissues of the laryngeal inlet (see Chapter 433). It has become exceedingly rare since the introduction of conjugate Hib vaccines. Direct bacterial invasion of the involved tis sues is probably the initiating pathophysiologic event. This dramatic, potentially lethal condition can occur at any age. Because of the risk of sudden, unpredictable airway obstruction, supraglottitis is a medical emergency. Other foci of infection, such as meningitis, are rare. Antimi crobial therapy directed against H. influenzae and other etiologic agents should be administered parenterally, but only after the airway is secured, and therapy should be continued until patients are able to take fluids by mouth. The duration of antimicrobial therapy is typically 7 days. Pneumonia The true incidence of H. influenzae pneumonia in children is unknown because invasive procedures required to obtain culture specimens are seldom performed (see Chapter 449). In the prevaccine era, type b strains were believed to be the usual cause. The signs and symptoms of pneumonia caused by H. influenzae cannot be differentiated from those of pneumonia caused by many other microorganisms. Other foci of infection may be present concomitantly. Children 12 months old in whom H. influenzae pneumonia is suspected should receive parenteral antimicrobial therapy initially because of their |
7,247 | increased risk for bacteremia and its complications. Older children who do not appear severely ill may be managed with an oral antimicrobial. Therapy is continued for 7 10 days. Uncomplicated pleural effusion associated with H. influenzae pneumonia requires no special intervention. However, if empyema develops, chest tube or sur gical drainage is generally indicated. Suppurative Arthritis Large joints, such as the knee, hip, ankle, and elbow, are affected most often (see Chapter 726). Other foci of infection may be present con comitantly. Although single joint involvement is the rule, multijoint involvement occurs in approximately 6 of cases. The signs and symp toms of septic arthritis caused by H. influenzae are indistinguishable from those in arthritis caused by other bacteria. Uncomplicated septic arthritis should generally be treated with an appropriate parenteral antimicrobial for at least a few days. If the clinical response is satisfactory, the remainder of the course of 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. 1758 Part XV u Infectious Diseases antimicrobial treatment may be given orally. Therapy is typically given for 3 weeks for uncomplicated septic arthritis, but may be continued beyond 3 weeks, until the C reactive protein concentration is normal and clinical symptoms are resolved. Pericarditis H. influenzae is a rare cause of pericarditis (see Chapter 489). Affected children often have had an antecedent upper respiratory tract infec tion. Fever, respiratory distress, and tachycardia are consistent find ings. Other foci of infection may be present concomitantly. The diagnosis may be established by recovery of the organism from blood or pericardial fluid. Gram stain or detection of PRP in pericardial fluid, blood, or urine (when type b organisms are the cause) may aid the diagnosis. Antimicrobials should be provided parenterally in a regimen similar to that used for meningitis (see Chapter 643.1). Pericardiectomy is useful for draining the purulent material effectively and preventing tamponade and constrictive pericarditis. Bacteremia Without an Associated Focus Bacteremia caused by H. influenzae may be associated with fever without any apparent focus of infection (see Chapter 220). In this situation, risk factors for occult bacteremia include the magnitude of fever (39C 102.2F) and the presence of leukocytosis (15,000 cellsL). In the prevaccine era, meningitis developed in approxi mately 25 of children with occult Hib bacteremia if left untreated. In the vaccine era, this H. influenzae infection has become exceed ingly rare. When it does occur, the child should be reevaluated for a focus of infection and a second blood culture should be performed. The child should be hospitalized and given parenteral antimicrobial therapy after a diagnostic lumbar puncture and chest radiograph are obtained. Miscellaneous Infections Rarely, H. influenzae causes urinary tract infection, epididymoorchitis, cervical adenitis, acute glossitis, infected thyroglossal duct cysts, uvu litis, endocarditis, endophthalmitis, primary peritonitis, osteomyelitis, and periappendiceal abscess. Invasive Disease in Neonates Neonates occasionally have invasive H. influenzae infection. In the infant with |
7,248 | illness within the first 24 hours of life, especially in asso ciation with maternal chorioamnionitis or prolonged rupture of mem branes, transmission of the organism to the infant is likely to have occurred through the maternal genital tract (which is colonized with nontypeable H. influenzae in 1 of pregnant women). Manifestations of neonatal invasive infection include bacteremia with sepsis, pneu monia, respiratory distress syndrome with shock, conjunctivitis, scalp abscess or cellulitis, and meningitis. Less frequently, mastoiditis, septic arthritis, and congenital vesicular eruption may occur. Otitis Media Acute otitis media is one of the most common infectious diseases of childhood (see Chapter 680). It results from the spread of bacteria from the nasopharynx through the eustachian tube into the middle ear cav ity. Usually, because of a preceding viral upper respiratory tract infec tion, the mucosa in the area becomes hyperemic and swollen, resulting in obstruction and an opportunity for bacterial multiplication in the middle ear. The most common bacterial pathogens are H. influenzae, S. pneu moniae, and Moraxella catarrhalis. Most H. influenzae isolates caus ing otitis media are nontypeable. Ipsilateral conjunctivitis may also be present. Amoxicillin (80 90 mgkgday) is a suitable first line oral antimicrobial agent, because the probability that the causative isolate is resistant to amoxicillin and the risk for invasive potential are sufficiently low to justify this approach. Alternatively, in certain cases, a single dose of ceftriaxone constitutes adequate therapy. In the case of treatment failure or if a lactamaseproducing isolate is obtained by tympanocentesis or from drainage fluid, amoxicillin clavulanate (Augmentin) is a suitable alternative. Conjunctivitis Acute infection of the conjunctivae is common in childhood (see Chapter 666). In neonates, H. influenzae is an infrequent cause. How ever, it is an important pathogen in older children. Most H. influenzae isolates associated with conjunctivitis are nontypeable, although type b isolates and other serotypes are occasionally found. Empirical treat ment of conjunctivitis beyond the neonatal period usually consists of topical antimicrobial therapy with sulfacetamide. Topical fluoroqui nolone therapy is to be avoided because of its broad spectrum, high cost, and high rate of emerging resistance among many bacterial spe cies. Ipsilateral otitis media caused by the same organism may be pres ent and requires oral antibiotic therapy. Sinusitis H. influenzae is an important cause of acute sinusitis in children, likely the most common etiology since implementation of routine vaccina tion against S. pneumoniae (see Chapter 429). Chronic sinusitis lasting 1 year or severe sinusitis requiring hospitalization is often caused by S. aureus or anaerobes such as Peptococcus, Peptostreptococcus, and Bacte roides. Nontypeable H. influenzae and viridans group streptococci are also frequently recovered. For uncomplicated sinusitis, amoxicillin is acceptable initial therapy. However, if clinical improvement does not occur, a broader spectrum agent, such as amoxicillin clavulanate, may be appropriate. A 10 day course is sufficient for uncomplicated sinusitis. Hospitalization for parenteral therapy is rarely required; the usual reason is suspicion of progression to orbital cellulitis. PREVENTION Immunization with a Hib conjugate vaccine is recommended for all infants. Prophylaxis is |
7,249 | indicated if close contacts of an index patient with type b disease are unvaccinated. The contagiousness of non Hib infections is not known, and prophylaxis is not recommended. Vaccine Several Hib conjugate vaccines are currently marketed in the United States, containing either PRPouter membrane protein (PRP OMP) or PRPtetanus toxoid (PRP T), which differ in the carrier protein used and the method of conjugating the polysaccharide to the protein (see Table 240.1 and Chapter 215). Available combination vaccines include Pentacel (Sanofi Pasteur), which consists of PRP T combined with DTaP vaccine (diphtheria and tetanus toxoids and acellular pertussis) and IPV vaccine (trivalent, inactivated polio vaccine), and Vaxelis (Merck), which consists of PRP OMP combined with DTaP, IPV, and hepatitis B vaccine. The Hib conjugate vaccines stimulate circulating anticapsular anti body and provide long term immunity through B cell memory. Prophylaxis Unvaccinated children 48 months old who are in close contact with an index case of invasive Hib infection are at increased risk for invasive infec tion. The risk for secondary disease for children 3 months old is inversely related to age. About half the secondary cases among susceptible house hold contacts occur in the first week after hospitalization of the index case. Because many children are now protected against Hib by prior immuni zation, the need for prophylaxis has greatly decreased. When prophylaxis is used, rifampin is indicated for all members of the household or close contact group, including the index patient, if the group includes one or more children 48 months old who are not fully immunized. Parents of children hospitalized for invasive Hib disease should be informed of the increased risk for secondary infection in other young children in the same household if they are not fully immunized. Parents of children exposed to a single case of invasive Hib disease in a childcare center or nursery school should be similarly informed, although there is disagreement about the need for rifampin prophylaxis for these children. For prophylaxis, children should be given rifampin orally (0 1 months old, 10 mgkgdose; 1 month old, 20 mgkgdose, not to exceed 600 mg dose) once daily for 4 consecutive days. The adult dose is 600 mg once daily. Rifampin prophylaxis is not recommended for pregnant women. 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 242 u Moraxella catarrhalis 1759 Chancroid is a sexually transmitted disease characterized by painful genital ulceration and inguinal lymphadenopathy. ETIOLOGY AND EPIDEMIOLOGY Chancroid is caused by Haemophilus ducreyi, a fastidious gram negative bacillus. It is most common in many low and middle income countries but also occurs sporadically in high income countries. Most cases in high income countries occur in returning travelers (90 are male) from endemic areas or occasionally in localized urban outbreaks associated with commercial sex workers. Chancroid is a risk factor for |
7,250 | transmission of HIV. Diagnosis of chancroid in infants and children is strong evidence of sexual abuse. Male circumcision lowers the risk for chancroid. The incidence of chancroid has declined significantly since 1981 and remains low in the United States. CLINICAL MANIFESTATIONS The incubation period is 4 7 days, with a small, inflammatory papule on the preputial orifice or frenulum in men and on the labia, four chette, or perineal region in women. The lesion becomes pustular, eroded, and ulcerative within 2 3 days. The ulcer edge is classically ragged and undermined. Without treatment, the ulcers may persist for weeks to months. Painful, tender inguinal lymphadenitis occurs in 50 of cases, more often among men. The lymphadenopathy can become fluctuant to form buboes, which can spontaneously rupture. DIAGNOSIS Diagnosis is usually established by the clinical presentation and the exclusion of both syphilis (Treponema pallidum) and herpes simplex virus infections. The ulcer of chancroid is accompanied by concurrent lymphadenopathy that is usually unilateral, unlike lymphogranu loma venereum (see Chapter 272.4). Genital herpes is characterized by vesicular lesions with a history of recurrence (see Chapter 299). Gram stain of ulcer secretions may show gram negative coccobacilli in parallel clusters (school of fish). Culture requires expensive, special media and has a sensitivity of only 80. There are currently no U.S. Food and Drug Administration (FDA)approved polymerase chain reaction (PCR) tests for H. ducreyi. PCR and indirect immunofluores cence using monoclonal antibodies are available as research tools and are performed by some clinical laboratories using their own in house Clinical Laboratory Improvement Amendments (CLIA)verified kits. TREATMENT Most H. ducreyi organisms are resistant to penicillin and ampicil lin because of plasmid mediated lactamase production. Spread of plasmid mediated resistance among H. ducreyi has resulted in lack of efficacy of previously useful drugs such as sulfonamides and tet racyclines. Chancroid is easy to treat if recognized early. The current treatment recommendation is for azithromycin (1 g as a single dose orally PO) or ceftriaxone (250 mg as a single dose intramuscularly) or ciprofloxacin (500 mg twice daily PO for 3 days) or erythromycin (500 mg 3 times daily PO for 7 days), the latter most often used in low and middle income countries, Fluctuant nodes may require drainage. Symptoms usually resolve within 3 7 days. Relapses can usually be treated successfully with the original treatment regimen. Patients with HIV infection may require a longer duration of treatment. Persistence of the ulcer and the organism after therapy should raise suspicion of resistance to the prescribed antibiotic. Chapter 241 Chancroid (Haemophilus ducreyi) H. Dele Davies and Shirley Delair Patients with chancroid should be evaluated for other sexually trans mitted infections, including syphilis, genital herpes, hepatitis B virus, HIV, chlamydia, and gonorrhea; an estimated 10 have concomitant syphilis or genital herpes. If initial HIV or syphilis testing is negative, patients should be tested again in 3 months because of the high rates of co infections. In low and middle income countries, patients with a compatible genital ulcer are treated for |
7,251 | both chancroid and syphilis. All sexual contacts of patients with chancroid should be evaluated and treated. COMPLICATIONS Complications include phimosis in men and secondary bacterial infec tion. Bubo formation may occur in untreated cases. Genital ulceration as a syndrome increases the risk for transmission of HIV. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 242 Moraxella catarrhalis Timothy F. Murphy and Oscar G. Gmez Duarte Moraxella catarrhalis is an unencapsulated, gram negative diplococcus and is a human specific pathogen that colonizes the respiratory tract beginning in infancy. Patterns of colonization and infection with M. catarrhalis are changing in countries where pneumococcal conjugate vaccines are used widely. The most important clinical manifestation of M. catarrhalis infection in children is otitis media. ETIOLOGY M. catarrhalis has long been considered to be an upper respiratory tract commensal. Substantial genetic heterogeneity exists among strains of M. catarrhalis. Several outer membrane proteins demonstrate sequence differences among strains, particularly in regions of the proteins that are exposed on the bacterial surface. M. catarrhalis endotoxin lacks repeating polysaccharide side chains and is thus a lipooligosaccharide (LOS). In contrast to other gram negative respiratory pathogens, such as Haemophilus influenzae and Neisseria meningitidis, the LOS of M. catarrhalis is relatively conserved among strains; only three serotypes (A, B, and C), based on oligosaccharide structure, have been identi fied. Genetic and antigenic differences among strains account for the observation that resolving an infection by one strain does not induce protective immunity to other strains. M. catarrhalis causes recurrent infections, which generally represent reinfection by new strains. EPIDEMIOLOGY The ecologic niche of M. catarrhalis is the human respiratory tract. The bacterium has not been recovered from animals or environmen tal sources. Age is the most important determinant of the prevalence of upper respiratory tract colonization. Common throughout infancy, nasopharyngeal colonization is a dynamic process with active turn over as a result of acquisition and clearance of strains of M. catarrhalis. Some geographic variation in rates of colonization is observed. On the basis of monthly or bimonthly cultures, colonization during the first year of life may range from 33 to 100. Several factors likely account for this variability among studies, including living conditions, daycare attendance, hygiene, environmental factors (e.g., household smoking), and genetics of the population. The prevalence of colonization steadily decreases with age. Understanding nasopharyngeal colonization pat terns is important, because the pathogenesis of otitis media involves migration of the bacterium from the nasopharynx to the middle ear via the eustachian tube. 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. 1760 Part XV u Infectious Diseases The widespread use of pneumococcal polysaccharide vaccines in many countries has resulted in alteration of patterns of naso pharyngeal colonization in the population. A relative decrease in colonization by vaccine pneumococcal serotypes and M. catarrhalis has resulted in a decreased number of new upper respiratory infec tion episodes associated |
7,252 | with Streptococcus pneumoniae and M. catarrhalis. PATHOGENESIS OF INFECTION Strains of M. catarrhalis differ in their virulence properties. The spe cies is composed of complement resistant and complement sensitive genetic lineages, with the complement resistant strains being more strongly associated with virulence. Strains that cause infection in chil dren differ in several phenotypic characteristics from strains that cause infection in adults, in whom the most common clinical manifestation is lower respiratory tract infection in the setting of chronic obstructive pulmonary disease. The presence of several adhesin molecules with differing specifici ties for various host cell receptors reflects the importance of adherence to the human respiratory epithelial surface in the pathogenesis of infec tion. M. catarrhalis has long been viewed as an exclusively extracellular pathogen. However, the bacterium is now known to invade multiple cell types, including bronchial epithelial cells, small airway cells, and type 2 alveolar cells. In addition, M. catarrhalis resides intracellularly in lymphoid tissue, providing a reservoir for persistence in the human respiratory tract. As with many gram negative bacteria, M. catarrhalis sheds vesicles from its surface during growth. These vesicles are inter nalized by respiratory epithelial cells and mediate several virulence mechanisms, including B cell activation, induction of inflammation, and delivery of lactamases. Analysis of genomes reveals modest genetic heterogeneity among strains. M. catarrhalis forms biofilms in vitro and in the middle ears of chil dren with chronic and recurrent otitis media. It also promotes stable polymicrobial biofilms by enhancing the survival of other bacterial col onizing otopathogens. Biofilms are communities of bacteria encased in a matrix attached to a surface. Bacteria in biofilms are more resistant to antibiotics and to host immune responses than bacteria growing individually in planktonic form. CLINICAL MANIFESTATIONS M. catarrhalis causes predominantly mucosal infections in children. The mechanism of infection is migration of the infecting strains from the nasopharynx to the middle ear in the case of otitis media or to the sinuses in the case of sinusitis. The inciting event for both otitis media and sinusitis is often a preceding viral infection. Acute Otitis Media Approximately 80 of children have one or more episodes of otitis media by age 3 years. Otitis media is the most common reason that children receive antibiotics. On the basis of culture of middle ear fluid obtained by tympanocentesis, the predominant causes of acute otitis media are S. pneumoniae, H. influenzae, and M. catarrhalis. M. catarrhalis is cultured from the middle ear fluid in 1520 of patients with acute otitis media. When more sensitive methods (e.g., poly merase chain reaction PCR) are used, the number of middle ear fluid samples from children with otitis media in which M. catarrhalis is detected is substantially greater than by culture alone. The distribu tion of the causative agents of otitis media is changing as a result of widespread administration of pneumococcal conjugate vaccines, with M. catarrhalis and H. influenzae proportionally more common than S. pneumoniae. Acute otitis media caused by M. catarrhalis is clinically milder than otitis media caused |
7,253 | by H. influenzae or S. pneumoniae, with less fever and lower prevalence of a red, bulging tympanic membrane. However, substantial overlap in symptoms is seen, making it impossible to pre dict etiology in an individual child on the basis of clinical features. Tympanocentesis is required to make an etiologic diagnosis but is not performed routinely, and thus treatment of otitis media is generally empirical. Recurrent Otitis Media and Otitis Media with Effusion Otitis media with effusion refers to the presence of fluid in the middle ear in the absence of signs and symptoms of acute infection. Children who experience four or more episodes of acute otitis media in a year or who have at least 8 months of middle ear effusion in a year are defined as otitis prone. These children have conductive hearing loss, which places them at risk for speech delays and altered language develop ment. Analysis of middle ear fluid from children with otitis media with effusion using sensitive molecular techniques (e.g., PCR) indicates that bacterial DNA is present in up to 80 of samples from such children. Indeed, M. catarrhalis DNA is present, both alone and as a copatho gen, in a larger proportion of cases of otitis media with effusion than of acute otitis media. Biofilms may account for these observations, although definitive evidence is lacking. Sinusitis A small proportion of viral upper respiratory tract infections are com plicated by bacterial sinusitis. According to findings of studies that use sinus puncture, M. catarrhalis accounts for approximately 20 of cases of acute bacterial sinusitis in children and a smaller proportion in adults. Sinusitis caused by M. catarrhalis is clinically indistinguishable from that caused by S. pneumoniae or H. influenzae. Bacteremia M. catarrhalis rarely causes bacteremia or invasive infections in chil dren. When bacteremia occurs, the usual source is the respiratory tract. Some children have underlying immunocompromising conditions, but no particular immunodeficiency is associated with invasive M. catarrh alis infections. Pneumonia M. catarrhalis is an uncommon cause of community acquired pneu monia in children. Among older patients with chronic obstructive pul monary disease, M. catarrhalis is associated with acute exacerbations. DIAGNOSIS The clinical diagnosis of otitis media is made by demonstration of erythema and bulging of the tympanic membrane andor fluid in the middle ear by pneumatic otoscopy. A tympanocentesis is required to establish an etiologic diagnosis, but this procedure is not performed routinely. Thus the choice of antibiotic for otitis media is empirical and generally based on guidelines. Management of bacterial sinusitis is also empirical, because determining the etiology of sinusitis requires a sinus puncture, also a procedure that is not performed routinely. The key to making a microbiologic diagnosis is distinguishing M. catarrhalis from commensal Neisseria organisms that are part of the normal upper respiratory tract flora. Indeed, the difficulty in distin guishing colonies of M. catarrhalis from Neisseria spp. explains in part why M. catarrhalis has been overlooked in the past as a respiratory tract pathogen. M. catarrhalis produces round, opaque colonies that can |
7,254 | be slid across the agar surface without disruptionthe hockey puck sign. In addition, after 48 hours, M. catarrhalis colonies tend to be larger than Neisseria and take on a pink color. A variety of biochemi cal tests distinguish M. catarrhalis from Neisseria spp., and commer cially available kits based on these tests are available. Sensitive tests that employ PCR to detect respiratory tract bacterial pathogens in human respiratory tract secretions are in development. In addition, metagenomics next generation sequencing is a noninvasive option to make a diagnosis of upper or lower respiratory infections asso ciated with M. catarrhalis through evaluation of bacterial derived DNA in blood samples. Their application will likely contribute new informa tion about the epidemiology and disease patterns of M. catarrhalis. TREATMENT A high proportion of cases of M. catarrhalis otitis media resolve spon taneously. Treatment of otitis media is empirical, and clinicians are advised to follow guidelines of the American Academy of Pediatrics (see Chapter 680). 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 243 u Pertussis (Bordetella pertussis and Bordetella parapertussis) 1761 Strains of M. catarrhalis rapidly acquired lactamase worldwide in the 1970s and 1980s, rendering essentially all strains resistant to amoxi cillin. When M. catarrhalis is present as a copathogen in otitis media, its lactamase reduces the susceptibility of nontypeable H. influenzae and S. pneumoniae to amoxicillin. Antimicrobial susceptibility patterns have remained relatively stable for decades. However, strains of M. catarrhalis that are resistant to macrolides and fluoroquinolones have been isolated in several centers in Asia. Careful surveillance will be important to track the potential emergence of resistant strains more widely. Most strains of M. catarrhalis are susceptible to amoxicillinclavulanic acid, extended spectrum cephalosporins, macrolides (azithromycin, clarithromycin), trimethoprim sulfamethoxazole, and fluoroquinolones. PREVENTION Vaccines to prevent otitis media and other infections caused by M. catarrhalis are under development, but none is yet available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Pertussis is an acute respiratory tract infection; the term pertussis means intense cough and is preferable to whooping cough, because most infected individuals do not whoop. ETIOLOGY Bordetella pertussis is the cause of epidemic pertussis and the usual cause of sporadic pertussis. Bordetella parapertussis is an occasional cause of sporadic pertussis that contributes significantly to total cases of pertussis in Eastern and Western Europe and has been detected dur ing occasional regional pertussis outbreaks in the United States. B. per tussis and B. parapertussis are exclusive pathogens of humans and some primates. Bordetella holmesii, first identified as a cause of bacteremia in immunocompromised hosts without cough illness, is increasingly reported to cause pertussis like cough illness in small outbreaks in healthy persons. Bordetella bronchiseptica is a common animal patho gen. Occasional reports in humans describe a variety of body sites involved, and cases typically occur in immunocompromised persons or young children with intense exposure to animals. Bordetella petrii, |
7,255 | frequently found in soil, has been reported in cases of osteomyelitis, mastoiditis, and chronic respiratory infection in patients with cystic fibrosis. Bordetella hinzii has been isolated from the respiratory tract of poultry and rodents and has rarely been associated with human disease, including endocarditis, bacteremia, and urinary tract infec tion. Protracted coughing (which in some cases can be paroxysmal) is attributable sporadically to Mycoplasma, parainfluenza viruses, influenza viruses, enteroviruses, respiratory syncytial virus (RSV), or adenoviruses. EPIDEMIOLOGY A recent modeling study estimated that in 2014, 24.1 million cases of pertussis and 160,700 deaths caused by pertussis occurred world wide in children 5 years, reflecting significantly higher numbers than actual case counts. Before vaccination was available, pertussis was the leading cause of death from communicable disease among U.S. chil dren 14 years, with 10,000 deaths annually. Widespread use of whole cell pertussis vaccine (DTP) led to a 99 decline in cases. After the low U.S. number of 1,010 cases reported in 1976, there was an increase in annual pertussis incidence to 1.2 cases per 100,000 population from 1980 through 1989, with epidemic pertussis in many states in 1989 1990, 1993, and 1996. Since then, pertussis has become increasingly endemic, with shifting burden of disease to young infants, adolescents, and adults. By 2004, the incidence of reported pertussis in the United States was 8.9 cases per 100,000 in the general population and approxi mately 150 per 100,000 in infants 2 months, with 25,827 total cases reported, the highest since 1959. A total of 40 pertussis related deaths were reported in 2005, and 16 pertussis related deaths were reported in 2006; 90 of these cases occurred in infants. Prospective and serologic studies show that pertussis is underrec ognized, especially among adolescents and adults, in whom the actual number of U.S. cases is estimated to be 600,000 annually. A number of studies have documented pertussis in 1332 of adolescents and adults with cough illness for 7 days. Responding to these changes in epidemiology, vaccination containing tetanus toxoid, reduced content diphtheria toxoid, and acellular pertussis antigens (Tdap) was recom mended in 2006 for 11 to 12 year olds and was aimed to enhance con trol. With 70 uptake of Tdap in adolescents, the burden of disease in young adolescents fell commensurately, but without evidence of protec tion of the community (herd) of young infants, older adolescents, and adults. An epidemiologic shift has occurred as a result of substantial and rapid waning of protection after both DTaP and Tdap in the aging cohort of children and adolescents who were not primed with DTP (whole cell) vaccine, which was no longer used in the United States after 1997. The 42,000 cases of pertussis and 20 deaths reported in 2012 were the highest numbers in 50 years. A shift in disease burden was observed among 7 to 10 year olds in 2010, 13 to 14 year olds in 2012, and 14 to 16 year olds in 2014 as the cohort of solely DTaP vaccinated persons aged. Neither natural disease |
7,256 | nor vaccination provides complete or lifelong immunity against pertussis reinfection or disease. Subclinical reinfec tion undoubtedly contributed significantly to immunity against disease ascribed previously to both vaccine and prior infection. The resurgence of pertussis can be attributed to a variety of factors, including partial control of pertussis leading to less continuous exposure and increased awareness and improved diagnostics. Rapidly waning vaccine induced immunity and pathogen adaptation are the most important factors currently. Although the DTaP series is protective short term, vaccine effectiveness wanes rap idly, with estimates of only 10 protection 8.5 years after the fifth dose. Tdap protection also is short lived, with efficacy falling from 70 initially to 34 within 2 4 years. A retrospective cohort study of children born between 1999 and 2016 found that the risk of pertussis among immunized children was 5 times higher 3 years after vaccination compared with 1 year after vaccination. Divergence of circulating strains from vaccine strains began with the introduction of DTP, but with the exclusive use of acellular pertussis vaccines, pertactin deficient strains emerged and have become dominant in countries where these vaccines are used. Pertactin deficient B. pertussis was first reported in the United States from a Phila delphia infant case collection from 2008 to 2011. The Centers for Disease Control and Prevention (CDC) subsequently reported the earliest U.S. isolate from 1994 and rapid dominance of pertactin deficient strains in the United States since 2010. Despite the role of pertactin as a bacterial viru lence factor, illness severity in infants with pertactin deficient B. pertussis is similar to that of pertactin producing strains. Pending introduction of novel pertussis vaccine(s) that reduce colonization and transmission, per tussis will continue to be endemic, with cycling epidemics. PATHOGENESIS Bordetella organisms are small, fastidious, gram negative coccoba cilli that colonize only ciliated epithelium. The exact mechanism of disease symptomatology remains unknown. Bordetella species share a high degree of DNA homology among virulence genes. Only B. per tussis expresses pertussis toxin (PT), the major virulence protein. PT has numerous proven biologic activities (e.g., histamine sensitiv ity, insulin secretion, leukocyte dysfunction). Although injection of PT in experimental animals causes lymphocytosis immediately by rerouting lymphocytes to remain in the circulating blood pool, PT Chapter 243 Pertussis (Bordetella pertussis and Bordetella parapertussis) Emily E. Souder and Sarah S. Long 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. 1762 Part XV u Infectious Diseases does not cause cough. PT appears to have a central, but not a sin gular, role in pathogenesis. B. pertussis produces an array of other biologically active substances, many of which are postulated to have a role in disease and immunity. After aerosol acquisition, filamen tous hemagglutinin (FHA), some agglutinogens (especially fim briae Fim types 2 and 3), and the 69 kDa pertactin (Prn) protein are important for attachment to ciliated respiratory epithelial cells. Tracheal cytotoxin, adenylate |
7,257 | cyclase, and PT appear to inhibit clearance of organisms. Tracheal cytotoxin, dermonecrotic factor, and adenylate cyclase are postulated to be predominantly responsible for the local epithelial damage that produces respiratory symptoms and facilitates absorption of PT. Both antibody and cellular immune responses follow infection and immunization. Antibody to PT neu tralizes toxin, and antibody to Prn enhances opsonophagocytosis. Both disease and DTP appear to drive a mixed cellular and antibody (Th1) immunologic response, whereas both DTaP and Tdap drive a narrow, antibody dominant (Th2) response. Pertussis is extremely contagious, with attack rates as high as 100 in susceptible individuals exposed to aerosol droplets at close range. High airborne transmission rates were shown in a baboon model of pertussis despite vaccination with the acellular vaccine. B. pertussis does not survive for prolonged periods in the environment. Chronic carriage by humans is not documented. After intense exposure, as in households, the rate of subclinical infection is as high as 80 in fully immunized or previously infected individuals. When carefully sought, a symptomatic source case can be found for most patientsusually a sibling or related adult. CLINICAL MANIFESTATIONS Classically, pertussis is a prolonged disease, divided into catarrhal, paroxysmal, and convalescent stages. The catarrhal stage (1 2 weeks) begins insidiously after an incubation period ranging from 3 to 12 days with nondistinctive symptoms of congestion and rhinorrhea variably accompanied by low grade fever, sneezing, lacrimation, and conjunc tival suffusion. As initial symptoms wane, coughing marks the onset of the paroxysmal stage (2 6 weeks). The cough begins as a dry, inter mittent, irritative hack and evolves into the inexorable paroxysms that are the hallmark of pertussis. A well appearing, playful toddler with insignificant provocation suddenly expresses an anxious aura and may clutch a parent or comforting adult before beginning a machine gun burst of uninterrupted cough on a single exhalation, chin and chest held forward, tongue protruding maximally, eyes bulging and water ing, face purple, until coughing ceases and a loud whoop follows as inspired air traverses the still partially closed airway. Posttussive eme sis is common, and exhaustion is universal. The number and severity of paroxysms escalate over days to a week and remain at that plateau for days to weeks. At the peak of the paroxysmal stage, patients may have one or more episodes hourly. As the paroxysmal stage fades into the convalescent stage (2 weeks), the number, severity, and duration of episodes diminish. Infants 3 months old do not display the classic stages. The catarrhal phase lasts only a few days or is unnoticed, and then, after the most insignificant startle from a draft, light, sound, sucking, or stretching, a well appearing young infant begins to choke, gasp, gag, and flail the extremities, with face reddened. Cough may not be prominent, espe cially in the early phase, and whoop is infrequent. Apnea and cyanosis can follow a coughing paroxysm, or apnea can occur as the only symp tom (without cough). Both are more common with pertussis than with neonatal viral infections. |
7,258 | The paroxysmal and convalescent stages in young infants are lengthy. Paradoxically, in infants, cough and whoop ing may become louder and more classic in convalescence. Exacerba tions of paroxysmal coughing can occur throughout the first year of life with subsequent respiratory illnesses; these are not a result of recur rent infection or reactivation of B. pertussis. Adolescents and previously immunized children have foreshorten ing of all stages of pertussis. Adults have no distinct stages. Classically, adolescents and adults describe a sudden feeling of strangulation fol lowed by uninterrupted coughs, feeling of suffocation, bursting head ache, diminished awareness, and then a gasping breath, usually without a whoop. Posttussive emesis and intermittency of paroxysms separated by hours of well being are specific clues to the diagnosis. At least 30 of adolescents and adults with pertussis have nonspecific cough illness, distinguished only by duration, which usually is 21 days. Findings on physical examination generally are uninformative. Signs of lower respiratory tract disease are not expected unless complicating secondary bacterial pneumonia is present. Conjunctival hemorrhages and petechiae on the upper body are common. DIAGNOSIS Pertussis should be suspected in any individual who has a pure or pre dominant complaint of cough, especially if the following features are absent: fever, malaise or myalgia, exanthem or enanthem, sore throat, hoarseness, tachypnea, wheezes, and rales. For sporadic cases, a clinical case definition of cough of 14 days duration with at least one asso ciated symptom of paroxysms, whoop, or posttussive vomiting has a sensitivity of 81 and specificity of 58 for confirmation of pertus sis. Pertussis should be suspected in older children whose cough ill ness is escalating at 7 10 days and whose coughing is not continuous, but rather comes in bursts. Pertussis should be suspected in infants 3 months old with gagging, gasping, apnea, cyanosis, or a brief resolved unexplained event (BRUE). Sudden infant death occasionally is caused by B. pertussis. Adenoviral infections usually are distinguishable by associated fea tures, such as fever, sore throat, and conjunctivitis. Mycoplasma causes protracted episodic coughing, but patients usually have a history of fever, headache, and systemic symptoms at the onset of disease as well as more continuous cough and the frequent finding of rales on auscul tation of the chest. Epidemics of Mycoplasma and B. pertussis in young adults can be difficult to distinguish on clinical grounds. Although per tussis often is included in the differential diagnosis of young infants with afebrile pneumonia, B. pertussis is not associated with staccato cough (breath with every cough), purulent conjunctivitis, tachypnea, rales, or wheezes that typify infection by Chlamydia trachomatis or predominant lower respiratory tract signs that typify infection by RSV. Unless an infant with pertussis has secondary pneumonia and then appears ill, the findings on examination between paroxysms, including respiratory rate, are entirely normal. Foreign body aspiration should be considered in the differential diagnosis. Leukocytosis (15,000 100,000 cellsL) caused by absolute lym phocytosis is characteristic in the catarrhal stage. Lymphocytes are normal small cells, rather than the large, atypical lymphocytes |
7,259 | seen with viral infections. Adults, partially immune children, and occa sionally infants may have less impressive lymphocytosis. Absolute increase in neutrophils suggests a different diagnosis or secondary bacterial infection. Eosinophilia is not a manifestation of pertussis. A severe course and death are correlated with rapid rise and extreme leukocytosis (median peak white blood cell count in fatal vs nonfatal cases: 94,000 vs 18,000L, respectively) and thrombocytosis (median peak platelet count in fatal vs nonfatal cases: 782,000 vs 556,000L, respectively). Chest radiographic findings are only mildly abnormal in the majority of hospitalized infants, showing perihilar infiltrate or edema (sometimes with a butterfly appearance) and variable atelecta sis. Parenchymal consolidation suggests secondary bacterial infection. Pneumothorax, pneumomediastinum, and subcutaneous emphysema can be seen occasionally. Methods for confirmation of infection by B. pertussis (culture, polymerase chain reaction PCR, serology) have limitations in sensi tivity, specificity, or practicality, and the relative value of tests depends on the setting, phase of disease, and purpose of use (e.g., as clini cal diagnostic vs epidemiologic tools). PCR testing on nasopharyn geal wash specimens is the laboratory test of choice for B. pertussis identification. Both stand alone and multiplex assays are U.S. Food and Drug Administration (FDA) cleared and available commercially. PCR assays using only single primers (IS481) cannot differentiate between some Bordetella spp. and do not detect B. parapertussis. Mul tiplex assays using multiple targets can distinguish species. All assays detect pertactin deficient strains. For culture, a specimen is obtained by deep nasopharyngeal aspiration or with the use of a flexible swab 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 243 u Pertussis (Bordetella pertussis and Bordetella parapertussis) 1763 (Dacron or calcium alginatetipped) held in the posterior nasopharynx for 15 30 seconds (or until the cough occurs). A 1 casamino acid liquid is acceptable for holding a specimen up to 2 hours; Stainer Scholte broth or Regan Lowe semisolid transport medium is used for longer transport periods, up to 4 days. The preferred isolation media are Regan Lowe charcoal agar with 10 horse blood and 5 40 gmL cephalexin and Stainer Scholte media with cyclodextrin resins. Cultures are incubated at 3537C in a humid environment and examined daily for 7 days for slow growing, tiny, glistening colonies. Results of culture and PCR are expected to be positive in unimmunized, untreated children during the catarrhal and early paroxysmal stages of disease. However, less than 20 of culture or PCR tests have positive results in partially or remotely immu nized individuals tested in the paroxysmal stage. Serologic tests for detection of change in antibodies to B. pertussis antigens between acute and convalescent samples are the most sensi tive diagnostic tests in immunized individuals and are useful epide miologically. A single serum sample showing IgG antibody to PT 90 IUmL (2 standard deviations SD above the mean of the immunized population) indicates recent symptomatic |
7,260 | infection and usually is posi tive in the mid paroxysmal phase. Tests for IgA and IgM pertussis anti body, or antibody to antigens other than PT, are not reliable methods for serologic diagnosis of pertussis. TREATMENT Infants 3 months old with suspected pertussis usually are hospital ized, as are many 3 to 6 month old patients (i.e., unless witnessed paroxysms are not severe) and patients of any age if significant com plications occur. Prematurely born young infants have a high risk for severe, potentially fatal disease, and children with underlying cardiac, pulmonary, muscular, or neurologic disorders have increased risk of poor outcome beyond infancy. Table 243.1 lists caveats in the assess ment and care of infants with pertussis. The specific, limited goals of hospitalization are to (1) assess progression of disease and likelihood of life threatening events at peak of disease, (2) maximize nutrition, (3) prevent or treat complications, and (4) educate parents in the nat ural history of the disease and in care that will be given at home. Heart rate, respiratory rate, and pulse oximetry are monitored continuously with alarm settings so that paroxysms can be witnessed and recorded by healthcare personnel. Detailed cough records and documentation of feeding, vomiting, and weight change provide data to assess severity. Features of typical paroxysms that are not life threatening are duration 45 seconds; red, but not blue, color change; tachycardia or bradycardia (but not 60 beatsmin in infants); oxygen desaturation that spontane ously resolves rapidly at the end of the paroxysm; whooping or strength for brisk self rescue at the end of the paroxysm; self expectorated mucus plug; and posttussive exhaustion but not unresponsiveness. Assessing the need to provide oxygen, stimulation, or suctioning requires skilled personnel who can watchfully observe an infants ability for self rescue but who will intervene rapidly and expertly when necessary. The benefit of a quiet, dimly lighted, undisturbed, comforting environment can not be overestimated or forfeited in a desire to monitor and intervene. Feeding children with pertussis is challenging. The risk of precipitating cough by nipple feeding does not warrant nasogastric, nasojejunal, or parenteral alimentation in most infants. The composition or thickness of formula does not affect the quality of secretions, cough, or retention. Large volume feedings are avoided. Within 48 72 hours, the direction and severity of disease are obvi ous from an analysis of the recorded information. Hospital discharge is appropriate if, over 48 hours, disease severity is unchanged or dimin ished, intervention is not required during paroxysms, nutrition is adequate, no complication has occurred, and parents are adequately prepared for care at home. Apnea and seizures occur in the incremental phase of illness and in patients with complicated disease. Portable oxy gen, monitoring, or a suction apparatus should not be needed at home. Infants who have apnea, paroxysms that lead to life threatening events, or respiratory failure require escalating respiratory support and frequently require intubation and pharmaceutically induced paralysis. Antibiotics An antimicrobial agent always is given when pertussis is suspected or confirmed |
7,261 | to decrease contagiousness and to afford possible clinical benefit. Azithromycin is the drug of choice in all age groups, either for treatment or postexposure prophylaxis (Table 243.2). Macrolide resistance has been reported rarely in the United States, and recent isolates have retained susceptibility despite genetic strain adaptations. Infantile hyper trophic pyloric stenosis (IHPS) is associated with macrolide use in young infants, especially in those 14 days old, with higher risk in those receiv ing erythromycin vs azithromycin. The benefits of postexposure prophy laxis or treatment of infants far outweigh the risk of IHPS. Young infants should be managed expectantly if projectile vomiting occurs. The FDA also warns of the risk of fatal heart rhythms with the use of azithromy cin in patients already at risk for cardiovascular events, especially those with prolongation of the QT interval. Trimethoprim sulfamethoxazole (TMP SMX) is an alternative to azithromycin for infants 2 months old and children unable to receive azithromycin. Because of its limited effec tiveness, treatment of B. parapertussis is based on clinical judgment and is considered in high risk populations. Agents are the same as for B. per tussis. Treatment of infections caused by other Bordetella spp. should be undertaken with consultation of a subspecialist. Adjunct Therapies No rigorous clinical trial has demonstrated a beneficial effect of 2 adrenergic stimulants such as salbutamol and albuterol. Fussing asso ciated with aerosol treatment triggers paroxysms. No randomized, blinded clinical trial of sufficient size has been performed to evaluate the usefulness of corticosteroids in the management of pertussis; their clinical use is not warranted. A randomized, double blind, placebo controlled trial of pertussis immunoglobulin (IGIV) was halted pre maturely because of expirationlack of additional supply of the study product; there was no indication of clinical benefit. Standard immu noglobulin has not been studied and should not be used for treatment or prophylaxis. Isolation Patients with suspected pertussis are placed in isolation with droplet precautions to reduce close respiratory or mucous membrane contact with respiratory secretions. All healthcare personnel should wear a mask on entering the room. Screening for cough should be performed on entrance of patients to emergency departments, offices, and clin ics to begin isolation immediately and until 5 days after initiation of azithromycin therapy. Children and staff with pertussis in childcare facilities or schools should be excluded until therapy has been taken for 5 days. Care of Household and Other Close Contacts Azithromycin should be given promptly to all household contacts and other close contacts, such as those in daycare, regardless of age, history Table 243.1 Considerations in the Assessment and Care of Infants with Pertussis Infants with potentially fatal pertussis may appear well between episodes. A paroxysm must be witnessed before a decision is made between hospital and home care. Only analysis of carefully compiled cough record permits assessment of severity and progression of illness. Suctioning of the nose, oropharynx, or trachea should not be performed on a preventive schedule. Feeding in the period after a paroxysm may be more successful than |
7,262 | after napping. Family support begins at the time of hospitalization with empathy for the childs and familys experience to date, transfer of the burden of responsibility for the childs safety to the healthcare team, and delineation of assessments and treatments to be performed. Family education, recruitment as part of the team, and continued support after discharge are essential. 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. 1764 Part XV u Infectious Diseases of immunization, or symptoms (see Table 243.2). The same drugs and age related doses used for treatment are used for prophylaxis. Visita tion and movement of coughing family members in the hospital must be assiduously controlled until therapy has been taken for 5 days. In close contacts 7 years old who have received fewer than four doses of DTaP, DTaP should be given to complete the recommended series. Children 7 years old who received a third DTaP dose 6 months before exposure, or a fourth dose 3 years before exposure, should be given a booster dose. Individuals 9 years old should be given Tdap. Unmasked healthcare personnel exposed to untreated cases should be evaluated for postexposure prophylaxis and follow up. Coughing healthcare personnel with or without known exposure to pertussis should be evaluated promptly for pertussis. COMPLICATIONS Infants 2 months old have the highest reported rates of pertussis associated hospitalization (82), pneumonia (25), seizures (4), encephalopathy (1), and death (1). Infants 4 months old account for 90 of cases of fatal pertussis. Preterm birth and young maternal age are significantly associated with fatal pertussis. Neonates with pertussis have substantially longer hospitalizations, greater need for oxygen, and greater need for mechanical ventilation than neonates with viral respi ratory tract infection. The strategy of preventing pertussis in newborns through the vaccination of women with Tdap during pregnancy from 27 through 36 weeks of gestation is 8091 effective. One study found that among infants with pertussis, disease severity was reduced in those whose mothers were vaccinated during pregnancy, with maternal vac cination being 58 effective in preventing hospitalization. The principal complications of pertussis are apnea, secondary infec tions (e.g., otitis media, pneumonia), and physical sequelae of forceful coughing. Fever, tachypnea or respiratory distress between paroxysms, and absolute neutrophilia are clues to pneumonia. Expected pathogens include Staphylococcus aureus, Streptococcus pneumoniae, and bacte ria of oropharyngeal flora. Increased intrathoracic and intraabdominal pressure during coughing can result in conjunctival and scleral hem orrhage, petechiae on the upper body, epistaxis, pneumothorax and subcutaneous emphysema, umbilical or inguinal hernia, and rarely, hemorrhage in the central nervous system or retina. Laceration of the lingual frenulum occurs occasionally. The need for intensive care and mechanical ventilation usually is limited to infants 3 months old and children with underlying con ditions. Respiratory failure from apnea may mandate intubation and ventilation through the days when disease peaks; the prognosis is good. Progressive pulmonary hypertension |
7,263 | in very young infants and secondary bacterial pneumonia are severe complications of pertussis and are the usual causes of death. Pulmonary hyperten sion and cardiogenic shock with fatal outcome are associated with extreme elevation of lymphocyte and platelet counts. Autopsies in fatal cases show luminal aggregates of leukocytes in the pulmonary vasculature. Extracorporeal membrane oxygenation of infants with pertussis in whom mechanical ventilation failed has been associated with 80 fatality (questioning the advisability of this procedure). Exchange transfusion or leukapheresis is associated with marked reduction in lymphocyte and platelet counts. Although recovery has been reported in several cases, the benefit is unproven. Echocar diography should be performed in critically ill infants with pertussis to detect the presence of pulmonary hypertension and to intervene expeditiously. Acute neurologic events during pertussis almost always are the result of hypoxemia or hemorrhage associated with coughing or apnea in young infants. Apnea or bradycardia or both may result from apparent laryngospasm or vagal stimulation just before a coughing epi sode, from obstruction during an episode, or from hypoxemia after an episode. Seizures usually are a result of hypoxemia, but hyponatremia from excessive secretion of antidiuretic hormone during pneumonia can occur. The only neuropathology documented in pertussis is paren chymal hemorrhage and ischemic necrosis. Bronchiectasis has been reported rarely after pertussis. Children who have pertussis before age 2 years may have abnormal pulmonary function into adulthood. PREVENTION Universal immunization of children with pertussis vaccine, beginning in infancy with reinforcing dose(s) through adolescence and adult hood, is central to the control of pertussis. Prevention of pertussis mor tality in young infants depends on universal maternal immunization during each pregnancy and focused full immunization of contacts, both children and adults of all ages. Table 243.2 Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis AGE GROUP PRIMARY AGENTS ALTERNATIVE AGENT AZITHROMYCIN ERYTHROMYCIN CLARITHROMYCIN TMP SMX 1 mo Recommended agent 10 mgkgday in a single dose for 5 days Not preferred Erythromycin is substantially associated with infantile hypertrophic pyloric stenosis Use if azithromycin is unavailable; 40 50 mgkgday in 4 divided doses for 14 days Not recommended (safety data unavailable) Contraindicated for infants 2 mo of age (risk for kernicterus) 1 5 mo 10 mgkgday in a single dose for 5 days 40 50 mgkgday in 4 divided doses for 14 days 15 mgkgday in 2 divided doses for 7 days Contraindicated at age 2 mo For infants age 2 mo: TMP 8 mgkgday plus SMX 40 mg kgday in 2 divided doses for 14 days Infants age 6 mo and children 10 mgkg in a single dose on day 1 (max 500 mg), then 5 mgkg day (max 250 mg) on days 2 5 40 50 mgkgday (max 2 gday) in 4 divided doses for 14 days 15 mgkgday in 2 divided doses (max 1 gday) for 7 days TMP 8 mgkgday plus SMX 40 mgkgday in 2 divided doses (max TMP: 320 mg day) for 14 days Adults 500 mg in a single dose on day 1, then |
7,264 | 250 mg day on days 2 5 2 gday in 4 divided doses for 14 days 1 gday in 2 divided doses for 7 days TMP 320 mgday to SMX 1600 mgday in 2 divided doses for 14 days Trimethoprim sulfamethoxazole (TMP SMX) can be used as an alternative agent to macrolides in patients 2 mo old who are allergic to macrolides, who cannot tolerate macrolides, or who are infected with a rare macrolide resistant strain of Bordetella pertussis. Adapted from Centers for Disease Control and Prevention (CDC). Recommended antimicrobial agents for treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR. 2005;54:116. 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 244 u Salmonella 1765 DTaP Vaccines Several diphtheria and tetanus toxoids combined with acellular pertussis vaccines (DTaP) or combination products currently are licensed in the United States for children 7 years old. Acellular pertussis vaccines all contain inactivated PT and two or more addi tional antigens (FHA, Prn, and Fim 2 and 3). Clinical effectiveness immediately at completion of the five dose series is approximately 80 for illness defined as paroxysmal cough for 21 days. Mild local and systemic adverse events are not uncommon, but more serious events (i.e., persistent crying for 3 hours or a hypotonic hyporesponsive episode) are rare after DTaP, are not specific to per tussis vaccine or associated with serious sequelae, and are not con traindications to subsequent doses. Four doses of DTaP should be administered during the first 2 years of life, generally at ages 2, 4, 6, and 15 18 months. In high risk settings, infants may be given DTaP as early as 6 weeks of age, with monthly doses through the third dose. The fourth dose may be administered as early as 12 months of age, provided that 6 months have elapsed since the third dose. When feasible, the same DTaP product is recommended for all doses of the primary vaccination series. The fifth dose of DTaP is recom mended for children at 4 6 years of age; a fifth dose is not necessary if the fourth dose in the series is administered on or after the fourth birthday. Local reactions increase modestly in rate and severity with succes sive doses of DTaP. Swelling of the entire thigh or upper arm, some times accompanied by pain, erythema, and fever, has been reported in 23 of vaccinees after the fourth or fifth dose of a variety of DTaP products. Limitation of activity is less than might be expected. Swell ing subsides spontaneously without sequelae. The pathogenesis is unknown. Extensive limb swelling after the fourth dose of DTaP usu ally is not associated with a similar reaction to the fifth dose and is not a contraindication to subsequent dose(s) of pertussis vaccines. Exempting children from pertussis immunization should be consid ered only within the narrow limits as |
7,265 | recommended. Exemptors have significantly increased the risk for pertussis and play a role in outbreaks of pertussis among immunized populations. Although well documented pertussis confers short term protection, the duration of protection is unknown; immunization should be completed on schedule in children diagnosed with pertussis. Pertussis vaccine (DTaP or Tdap) can be admin istered concurrently with any vaccine on the immunization schedule. Tdap Vaccines Two tetanus toxoid, reduced diphtheria toxoid, and acellular pertus sis antigen vaccine (Tdap) products were licensed in 2005 and rec ommended universally in 2006 for adolescents. The preferred age for Tdap vaccination is 11 12 years. All adolescents and adults of any age (including 65 years) who have not received Tdap should receive a single dose of Tdap promptly, regardless of interval since Td, or at least in place of one Td booster at the 10 year interval, or when indicated during wound management. Pregnant women should be given Tdap during every pregnancy to provide passive antibody protection to the infant until administration of DTaP. Although Tdap can be given at any time during pregnancy, optimal administration is early in the period between 27 through 36 weeks of gestation to maximize antibody concentration at birth. The safety of Tdap during pregnancy and effectiveness in reducing fatal pertussis in infants are proven. Special effort should be made to ensure that contacts of infants have received DTaP or Tdap as recommended. Clinical trials support the safety and immunogenicity of a second dose of Tdap; however, antipertussis antibodies decline rapidly after the first year. The CDC performed a decision analysis model of repeating Tdap at either a 5 or 10 year interval for the general population and concluded that booster(s) would have limited impact on pertussis disease burden. There is not a recommendation for a routine second dose of Tdap in the general population. A single dose of Tdap should be given to children 7 10 years of age who lack DTaP dose(s). Since 2019, the updated CDC recommendations allow use of either Tdap or Td when Td alone is indicated for catch up dose(s), or for decennial immunization, or for wound management in individuals who have received Tdap. Vaccines Under Development Several strategies are being tested to create pertussis vaccines that elicit a Th1 response, dampen the density of mucosal infection and trans mission, provide sustained protection against disease, and have toler able reactogenicity. These include use of live attenuated B. pertussis, a genetically (rather than a chemically) inactivated PT component, novel antigens, and adjuvants. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 244 Salmonella Jeffrey S. McKinney Salmonellosis is one of the most widely distributed and common food borne and fecal oral diseases in humans, and Salmonellae live in the intestinal tracts of multiple species. Salmonella infections are a major public health problem, with disproportionate morbidity and mortality among infants and children and in certain immunocompro mised individuals. Clinically, Salmonellae have been most broadly classified as being either nontyphoidal or typhoidal, with the latter causing typhoid (also |
7,266 | known as enteric) fever. The differences in the disease mani festations from these two groups of pathogens, one predominantly causing intestinal inflammation and the other leading to sys temic disease, are increasingly understood to be related to specific genes and pathogenicity islands in the genomes of the respective organisms. Most nontyphoidal serovars of Salmonella (widely distributed across multiple host species) are rarely able to overcome defense mechanisms in humans that limit bacterial dissemination from the intestine. Thus in immunocompetent humans, nontyphoidal serovars usually produce a self limiting gastroenteritis. By contrast, S. Typhi and S. Paratyphi (i.e., the typhoidal strains of Salmonella, notably host restricted to only humans) possess virulence traits that more readily allow them to over come mucosal barrier functions and then cause severe systemic illness, even in immunocompetent patients. However, a purely binary classification of Salmonellae as nontyphoi dal vs typhoidal can be a problematic oversimplification. For example, reports from Africa have identified strains of nontyphoidal Salmo nellae that are highly invasive and increasingly common. Like many gram negative bacteria, mobile or differentially expressed genetic elements can radically alter phenotypes in Salmonellae, sometimes in direct response to selective pressures like antimicrobial exposures given to individual patients andor in broader settings like agricultural antimicrobial use. Although DNA hybridization studies result in enough similarities for all Salmonellae to currently be classified in the single species Sal monella enterica, serologic studies can resolve more than 2,000 sero types. Serotype and DNA sequencing identification has helped clinical laboratories better trace disease outbreaks, and the Centers for Disease Control and Prevention (CDC) has published recent guidelines for a more consistent terminology to help both laboratory and clinical teams confront complex classification nomenclature. Host differences are also profoundly relevant to the outcomes of Salmonella exposures, infections, and disease. Infants and children, patients with certain immunologic vulnerabilities, and the extent to which a given Salmonella infection can evade host defenses andor antibacterial drugs can help predict, or at least better understand, the ultimate impact of Salmonella on both individual and public health. 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. 1766 Part XV u Infectious Diseases 244.1 Nontyphoidal Salmonellosis Jeffrey S. McKinney ETIOLOGY Salmonellae are motile, nonsporulating, gram negative rods that grow in aerobic and facultative anaerobic conditions. They remain viable at ambient or reduced temperatures for days and may survive for weeks in sewage, foods, pharmaceutical agents, and fecal material. They are resistant to many physical agents but can be killed by heat to 54.4C (130F) for 1 hour or 60C (140F) for 15 minutes. Most serotypes of nontyphoidal Salmonella have a broad host spec trum, including both warm blooded and cold blooded vertebrates, and even insects like flies and cockroaches. Some serotypes have more limited host ranges, such as S. dublin in cattle (recovered in human infections associated with unpasteurized milk) and S. choleraesuis in pigs. In |
7,267 | human infections, these two serotypes also have a notable propensity to cause more bacteremia and fewer gastrointestinal symp toms as compared with many other nontyphoidal Salmonellae. In sub Saharan Africa, nontyphoidal Salmonella has become a leading cause of bacteremia. Up to 95 of the serovars associated with invasive Sal monella disease among children in this geographic region are Salmo nella serovar Typhimurium (mostly of an unusual variant designated multilocus sequence type 313), a variant of sequence type 313 that does not express phase 2 flagella, or Salmonella serovar Enteritidis. This information represents a deviation from the historical assumption that nontyphoidal Salmonella is, by definition, relatively noninvasive. In the United States, nontyphoidal Salmonella infections still gener ally cause gastroenteritis that is localized and self limiting. In these uncomplicated cases, nontyphoidal Salmonella infection does not jus tify treatment with antibiotics. However, nontyphoidal infections can be severe in the young, the elderly, and patients with vulnerabilities in their immunity. EPIDEMIOLOGY Salmonellosis has a significant cost to society. Globally, estimates sug gest there are more than 90 million cases of Salmonella gastroenteritis annually, causing more than 150,000 deaths. In the United States, CDC estimates suggest an annual burden of more than 1.3 million Salmo nella infections, causing more than 26,000 hospitalizations, 420 deaths, and 400 million in direct medical costs, with approximately 30 people with unreported Salmonella illness for every one case confirmed by a laboratory test. Nearly half of culture proven nontyphoidal Salmonella infections occur in children, with the highest incidence among infants. With the burden of HIV infections and malnutrition in Africa, nonty phoidal Salmonella bacteremia has emerged as a major cause of mor bidity and mortality among both children and adults in Africa. Nontyphoidal Salmonella has a worldwide distribution, with the incidence influenced by local standards of hygiene, sanitation, and availability of safe water and food. Modern practices of mass food pro duction and distribution increase the potential for epidemics, which may be scattered so broadly as to only be fully appreciated via robust national monitoring systems, such as the CDCs FoodNet (https: www.cdc.govfoodnetfoodnet fast.html). FoodNet also helps build capacity for food borne disease surveillance through close collabora tions with PulseNet, EHS Net, Global SalmSurv, and other partners. Poultry meat and eggs are traditionally known to be a common source of salmonellosis, and even riding in a shopping cart next to poultry meat is a risk factor for infection of infants. However, con sumption of a wide variety of foods has now been associated with outbreaks, including fruits, vegetables, and multiple factory processed foods such as peanut butter, cookies, and infant formula. Salmonella infections in many parts of the world may be related to animal husbandry practices, including drug resistant strains that emerge in response to the widespread use of agricultural antimicrobi als. Subtherapeutic antimicrobials are often added to animal feeds to promote animal growth. There is now strong evidence linking resis tance to quinolones to the use of this group of antimicrobials in animal feeds. Resistance to ciprofloxacin approached 10 |
7,268 | of all nontyphoidal Salmonella isolates assessed by the CDC in 2017. In addition to the effect of antibiotic use in animal feeds, the rela tionship of Salmonella infections to prior antibiotic use in children in the month before the infection is well recognized. This association may be related to alterations in gut microbial ecology, which predisposes to colonization and infection with antibiotic resistant Salmonella isolates. The CDC reports that nontyphoidal Salmonella isolates during the period 20152017 continue to manifest increasing rates of resistance, with 16 of isolates being resistant to at least one essential antibiotic (including ciprofloxacin, azithromycin, ceftriaxone, ampicillin, and trimethoprim sulfamethoxazole). Variation in resistance among differ ent strains makes Salmonella culture and antibiotic susceptibility testing very important. It appears that some multidrug resistant (MDR) strains of Sal monella are also more virulent than susceptible strains. Poor clini cal outcomes with these infections do not relate solely to the initial empiric choice of ineffective antibiotics. Over the past 3 decades, S. Typhimurium phage type DT104 has emerged as a globally dissemi nated MDR strain. Typically resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline, DT104 also has the capacity to acquire resistance to other antibiotics. Many of the resis tance genes in DT104 are harbored on genomic islands. Integrons can also encode and disseminate virulence genes. Several risk factors are associated with outbreaks of Salmonella infection. Animals constitute the principal source of human dis ease from nontyphoidal Salmonella. High risk pets include reptiles, amphibians, poultry and other birds, rodents, and other small mam mals. The risk of Salmonella from turtles was so high that the U.S. Food and Drug Administration (FDA) banned the interstate sale and distri bution of turtles with shell length of less than 4 inches. Exposures can also occur from contact with cages or tanks with pets, from touching some pet foods and treats, and even at zoos without direct contact with an infected animal. Animals that carry Salmonella still appear healthy and clean and can readily transmit nontyphoidal Salmonella, including in childcare centers and schools. When nontyphoidal serovars are identified in a childcare attendee or staff member, adherence to hygiene practices is used to control infection. Return to school is allowed as long as stools are contained in a young childs diaper, toilet trained children do not have accidents using the toilet, and stool frequency becomes no more than two stools above the childs normal stooling frequency per day. In notable contrast to infections with typhoidal strains, demonstration of clearance of nontyphoidal Salmonella from stool cultures is neither sought nor required. Given the ubiquitous nature of the organism, nosocomial infec tions with nontyphoidal Salmonella strains can also occur via con taminated equipment and diagnostic or pharmacologic preparations. Patient to patient spread can also occur in hospital settings, par ticularly among vulnerable hosts like neonates. Nursery nosocomial infections from Salmonella can be very difficult to control, sometimes taking months to stop andor serving as a source for further spread through a hospital. PATHOGENESIS The estimated number of |
7,269 | bacteria that must be ingested to cause symp tomatic disease in healthy adults is 106 108 Salmonella organisms. Normal gastric acidity inhibits Salmonella multiplication, with most organisms rapidly killed at gastric pH 2.0. Achlorhydria, buffering medications, and rapid gastric emptying after gastroenterostomy allow more viable organisms to reach the small intestine and thus lower the infectious dose. Neonates and infants have hypochlorhydria and rapid gastric emptying, which contribute to their increased vulnerability to infection, even at lower inoculum exposures. The typical intestinal response to nontyphoidal Salmonella infec tion is enterocolitis, with diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses. Intestinal inflamma tion with neutrophils and macrophages usually involves the lamina propria. Underlying intestinal lymphoid tissue and mesenteric lymph 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 244 u Salmonella 1767 nodes enlarge and may demonstrate small areas of necrosis. Lymphoid hypertrophy may interfere with blood supply to the gut mucosa andor serve as a leading edge for intussusception. Hyperplasia of the reticu loendothelial system can also be found in the liver and spleen. If bac teremia develops, it may lead to localized infection and suppuration in almost any organ. Central to S. Typhimurium pathogenesis are two type III secre tion systems. These systems secrete and translocate bacterial proteins termed effectors into host cells. These effectors manipulate the host cell to allow bacterial invasion and assembly of an intracellular niche conducive to bacterial survival and replication. Two genomic pathoge nicity islands encode these type III systems. The Salmonella pathogenicity island 1 (SPI 1) is involved with epi thelial cell adherence and invasion (Fig. 244.1), which involves host cell membrane ruffling caused by organized actin rearrangement (Fig. 244.2). This adherent and invasive phenotype of Salmonella is activated under conditions like those found in the human small intestine (high osmolarity, low oxygen). The Salmonella pathogenicity island 2 (SPI 2) is involved with for mation of the Salmonella containing vacuole (Fig. 244.3), creating a replication permissive intracellular space (Fig. 244.4). Intracellular S. Typhimurium is found within special vacuoles that have diverged from the normal endocytic pathway. An ability to survive within monocytes macrophages is a key process for S. Typhimurium to establish a sys temic infection. Survival within host cells also shields Salmonella from antimicrobials. For example, gentamicin is not considered effective in vivo against Salmonella, even for strains found susceptible to this drug in vitro, because gentamicin does not effectively reach intracel lular bacteria. Bacteremia and systemic disease are possible with any Salmonella sero type, especially in individuals with reduced host defenses. Inflammatory bowel disease or gut ischemia can cause intestinal mucosal barrier defects. Malnutrition, corticosteroid therapy, interleukin (IL) 12interferon gamma axis defects, and posttransplant immunosuppressant agents can significantly compromise cell mediated immunity. The reticuloendothe lial system can be overloaded with hemoglobin or iron or have impaired function from lymphoma or leukemia. In addition, |
7,270 | other underlying sys temic conditions can predispose to serious Salmonella infections, includ ing sickle cell disease, collagen vascular diseases, HIVAIDS, defects in TH1 or TH17 immunity, and chronic granulomatous disease. As stated earlier, neonates and infants less than 3 months of age are also at higher risk of bacteremia from nontyphoidal Sal monella. This risk influences empiric treatment with appropri ate antibiotics, even in otherwise healthy patients in this young age group. Patients with sickle cell disease are at very high risk for Salmonella septicemia and osteomyelitis. This risk may be related to the presence of numerous infarcted areas in the gastrointestinal tract, bones, and reticuloendothelial organs, along with reduced phagocytic and opso nizing capacity of patients with sickle cell disease. CLINICAL MANIFESTATIONS Acute Enteritis The most common clinical presentation of salmonellosis is acute enteritis. After an incubation period of 6 72 hours (mean 24 hours), there is often abrupt onset nausea, vomiting, and crampy abdominal pain, located predominantly in the periumbilical area and the lower abdominal quadrants. These symptoms are usually followed by mild to severe watery diarrhea, sometimes containing blood, neutrophils, and mucus. Although fever is a classic feature, younger infants may exhibit a normal or subnormal temperature. Symptoms usually sub side within 2 7 days in otherwise healthy children. However, some children experience a septicemia like picture, with symptoms includ ing high fever, drowsiness, confusion, abdominal distention, menin gismus, andor seizures. Bacteremia After Salmonella gastroenteritis, it is estimated that 15 of oth erwise healthy children are thought to experience transient bacteremia after nontyphoidal Salmonella in U.S. settings. Bactere mia is usually accompanied by fever in older children but is often not associated with fever in infants. As described earlier, specific vulnerable hosts are far more likely to have systemic infection. Chil dren with HIV can have recurrent nontyphoidal Salmonella septice mia, despite antibiotic therapy, even without positive stool cultures or any clear nidus of infection. Some nontyphoidal strains are more likely to result in bacteremia, even without obvious gastrointestinal symptoms, including S. dublin and S. choleraesuis. In Africa, non typhoidal Salmonella is a much more common cause of pediatric bacteremia (see next). Nontyphoidal Salmonella Bacteremia as Emerging Disease in Africa In Africa, particularly sub Saharan Africa, nontyphoidal Salmonella has been increasingly recognized among the most common causes of all bacteremia in febrile children. Children age 6 36 months are at greatest risk, and case fatality rates can reach 25. Clinical features among children with invasive nontyphoidal Sal monella infections can be confusing, as diarrhea is often not a promi nent feature. Furthermore, 60 of these children have an apparent lower respiratory tract infection (perhaps from coinfection or comorbidity). Fever is present in 95 but may have no apparent focus. Figure 244.5 summarizes other clinical features. The lack of specificity of these features severely compromises the ability of cur rent clinical algorithms to identify invasive nontyphoidal Salmonella infections. Accordingly, blood culture and clinical microbiology systems for bacterial growth, isolation, speciation, and antibiotic susceptibility testing are required for diagnosis |
7,271 | and well informed treatment decision making. It remains unclear exactly why invasive infections by nontyphoidal Salmonella seem so much more frequent in Africa compared with the dominance of typhoid Salmonellae in Asia. HIV is one identified host risk factor for nontyphoidal Salmonella infection. Indeed, recurrent nontyphoidal Salmonella infection was part of early CDC case defini tions for AIDS. However, only 20 of African children with invasive nontyphoidal Salmonella disease are HIV positive. Other risks for invasive nontyphoidal Salmonella may include recent or severe malaria infections, anemia, and malnutrition. The epidemic patterns thus far appreciated for invasive infections by nontyphoidal Salmonella in Africa suggest that epidemics may occur over several years, peaking in the rainy season. However, it remains unclear how relevant human diarrheal disease or gastrointestinal car riage, or even food or zoonotic sources are, for invasive nontyphoidal Salmonella infection in this setting. Thus optimal strategies for inter rupting transmission are also not known. This is particularly prob lematic, given the emergence of extensive antibiotic resistance among nontyphoidal Salmonella isolates, including the lineage referred to as sequence type 313 (ST313). Recent studies have attempted to better understand the geographic spread and genetic features of ST313 lineage variants isolated inter nationally over time. Intriguingly, the antibiotic resistance patterns of these lineages seem to correlate with some large scale or sequential changes in empiric (e.g., chloramphenicol, third generation cephalo sporins, ciprofloxacin, and azithromycin) antibiotic use. ST313 lin eage genomic analysis also reveals the accumulation of pseudogenes, in what may be crucial loss of function genetic events involved in ST313 stepwise evolution, perhaps as part of adaptation to a more restricted (human) host range and from an intestinal to a systemic lifestyle. For invasive nontyphoidal Salmonella infections in Africa, evolv ing resistance patterns seem likely to force increasing reliance on more expensive treatment options. Local resistance patterns may help empirically, but given the rapid spread of various ST313 lin eages, susceptibility testing of individual patient isolates will be needed to ensure appropriate antibiotic choices. Targeted resistance gene sequencing, especially for gyrase mutations related to quino lone resistance, may also be warranted as that drug class becomes more widely used. 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. 1768 Part XV u Infectious Diseases Nontyphoidal Salmonella Bacteremia in Other Geographic Regions The emergence of invasive, high mortality nontyphoidal Salmonella infections in Africa underscores that the traditional binary division of Salmonella infections into typhoidal vs nontyphoidal may be a prob lematic oversimplification. However, in settings outside of Africa, nontyphoidal Salmonella infections still tend to be self limiting and noninvasive and are low mortality events for most children who are immunocompetent. Risk factors for systemic spread of nontyphoidal Salmonella include underlying sickle cell disease, HIVAIDS, intestinal mucosal barrier defects, malnutrition, IL 12interferon gamma axis defects, defects in TH1 or TH17 immunity, corticosteroid therapy or posttransplant immunosuppressants, reticuloendothelial system dysfunction (e.g., |
7,272 | from overload with hemoglobin or iron), lymphoma or leukemia, col lagen vascular diseases, and chronic granulomatous disease. Neonates and infants less than 3 months of age are also at higher risk of bactere mia from nontyphoidal Salmonella. Extraintestinal Focal Infection After bacteremia, Salmonellae have the propensity to cause focal sup purative infection of many organs. The most common focal infections involve the skeletal system, meninges, and intravascular sites. The peak incidence of Salmonella meningitis is in infancy, and the infection may be associated with a florid clinical course, high mortality, and neuro logic sequelae in survivors. Chronic Salmonella Carriage Although traditionally considered a complication among adults with Salmonella infection, chronic Salmonella carriage has important medi cal and epidemiologic implications and may occasionally occur in children. Colonization of the gallbladder by S. Typhi and persistent shedding from the gallbladder have long been appreciated. Reports sug gest some nontyphoidal Salmonellae (e.g., invasive nontyphoidal Salmo nella currently in Africa) can also establish long term carriage states. Antibiotic treatments of Salmonella infections are paradoxical in that the prospect of becoming a chronic carrier is believed to be increased by exposure to antibiotics. Yet clearance of established chronic carrier status requires prolonged medical treatment using antibiotics to which the Salmonella is susceptible and sometimes requires gallstone or gall bladder removal. DIAGNOSIS Few clinical features are specific enough to Salmonella to allow differ entiation from other infectious causes of gastroenteritis or diarrhea. Serologic tests also do not have diagnostic value. Definitive diagnosis requires identification of Salmonella via stool nucleic acid amplifica tion test (NAAT) or bacterial cultures. Stool cultures have higher yields Fig. 244.1 On contact with the epi thelial cell, Salmonellae assemble the Salmonella pathogenicity island 1en coded type III secretion system (TTSS 1) and translocate effectors (yellow spheres) into the eukaryotic cytoplasm. Effectors such as SopE, SopE2, and SopB then activate host Rho guano sine triphosphatase (GTPase), result ing in the rearrangement of the actin cytoskeleton into membrane ruffles, induction of mitogen activated protein kinase (MAPK) pathways, and destabi lization of tight junctions. Changes in the actin cytoskeleton, which are fur ther modulated by the actin binding proteins SipA and SipC, lead to bac terial uptake. MAPK signaling acti vates the transcription factors activator protein 1 (AP 1) and nuclear factor B (NF B), which turn on production of the proinflammatory polymorphonu clear leukocyte (PMN) chemokine in terleukin (IL) 8. SipB induces caspase 1 activation in macrophages, with the release of IL 1 and IL 18, augmenting the inflammatory response. In addi tion, SopB stimulates Cl secretion by its inositol phosphatase activity. The destabilization of tight junctions allows the transmigration of PMNs from the basolateral to the apical sur face, paracellular fluid leakage, and access of bacteria to the basolateral surface. However, the transmigration of PMNs also occurs in the absence of tight junction disruption and is further promoted by SopA. The actin cytoskel eton is restored, and MAPK signaling is turned off by the enzymatic activities of SptP. This also results in the |
7,273 | downmod ulation of inflammatory responses, to which SspH1 and AvrA also contribute by inhibiting activation of NF B. (From Haraga A, Ohlson MB, Miller SI. Salmo nellae interplay with host cells. Nat Rev Microbiol. 2008;6:5366.) Membrane ruffleTight junction Salmonella spp. Actin Epithelial cell SopE SopE2 SopB Rho GTPases SipA SipC MAPK MAPK SopB SopA Cl Cl NF?B AP1 NF?B IL8 PMN SipB Macrophage IL1? IL18 SspH1 AvrA Rho GTPases SptP 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 244 u Salmonella 1769 Fig. 244.3 Formation of the Salmonella containing vacuole (SCV) and induction of the Salmonella patho genicity island 2 (SPI 2) type III secretion system (TTSS) within the host cell. Shortly after internalization by macropinocytosis, Salmonellae are enclosed in a spa cious phagosome that is formed by membrane ruffles. Later, the phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium and is called the SCV. It contains the endocytic marker lysosomal associated membrane protein 1 (LAMP 1; purple). The Salmonella SPI 2 is induced within the SCV and translocates effector proteins (yellow spheres) across the phagosomal membrane several hours after phagocytosis. The SPI 2 effectors SifA and PipB2 contribute to formation of Salmonella induced filament along microtubules (green) and regulate mi crotubule motor (yellow star shape) accumulation on the Sif and the SCV. SseJ is a deacylase that is active on the phagosome membrane. SseF and SseG cause microtubule bundling adjacent to the SCV and direct Golgi derived vesicle traffic toward the SCV. Actin accumulates around the SCV in an SPI 2dependent manner, in which SspH2, SpvB, and SseI are thought to have a role. (From Haraga A, Ohlson MB, Miller SI. Sal monellae interplay with host cells. Nat Rev Microbiol. 2008;6:5366.) SifA PipB2 SCV Salmonella spp. Actin Epithelial cell Spacious phagosome Sif SseJ SseF SseG Nucleus Golgi Microtubules Secretory vesicles SspH2 SpvB Ssel Microtubule motors 1 m 10 m B A Fig. 244.2 Salmonella SPI 1mediated effects include host cell actin cytoskeletal rearrangements and host cell membrane ruffling as part of Salmonella invasion. A, HeLa cell infected with Salmonella fixed and stained for the actin cytoskeleton with phalloidin (green) and for Sal monella (yellow). B, Cos cell infected with Salmonella and prepared for scanning electron microscopy. Cell surface extensions in the process of enveloping the bacterium are pseudocolored green, and the microbe is in yellow. (From Rottner K, Stradal TEB, Wehland J. Bacteria host cell interactions at the plasma membrane: stories on actin cytoskeleton sub version. Dev Cell. 2005;9:317.) than rectal swabs. Blood cultures are suggested for patients at higher risk of bacteremia or endovascular focus and when enteric fever is a concern. Additionally, cultures of bone marrow (particularly valuable if antimicrobial agents have been administered or if stringent criteria are met for fever of unknown origin), duodenal fluid, and urine may be beneficial to detect enteric |
7,274 | fever. In patients with sites of local sup puration, aspirated specimens should be Gram stained and cultured. Salmonella organisms grow well on nonselective or enriched media, such as blood agar, chocolate agar, and nutrient broth, but stool speci mens containing mixed bacterial flora require a selective medium, such as McConkey, xylose lysine deoxycholate, bismuth sulfate, or Salmonella Shigella (SS) agar for isolation of Salmonella. Given Sal monella variation and evolution, it is important to pursue bacterial isolation, species identification, and antibiotic susceptibility testing to best inform the choice of effective therapeutic agents. State public health laboratories require Salmonella isolates as part of outbreak detection and investigation, increasingly via genomic characterization of strains. TREATMENT Appropriate therapy depends on the specific clinical presentation of Salmonella infection. In children with gastroenteritis, rapid clinical assessment, correction of dehydration and electrolyte disturbances, and supportive care are key. Antimotility drugs (e.g., loperamide) should not be given to children less than 18 years of age with acute diarrhea, but antiemetic drugs (e.g., ondansetron) can be given to facil itate oral rehydration in children older than 4 years. Antibiotics are generally not recommended for the treatment of iso lated uncomplicated Salmonella gastroenteritis because they can dis rupt normal intestinal flora and potentially prolong the fecal excretion of Salmonella. However, empiric antibiotics are started for young infants (3 months old) and for children with increased possibility of disseminated infec tion (e.g., children with HIV, malignancies, sickle cell disease, immuno deficiencies, or immunosuppression, as detailed earlier). In the United States, this empiric therapy includes a third generation cephalosporin, with a blood culture obtained just before the initial dose. If a patient does not appear ill and does not have any evidence of disseminated infection, oral azithromycin can be started, pending blood culture results. Ampicillin, trimethoprim sulfamethoxazole, or a fluoroquino lone may be considered as treatment options for susceptible strains. In cases of bacteremia, blood cultures need to be repeated to con firm clearance of infection. Transition from parenteral third generation 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. 1770 Part XV u Infectious Diseases cephalosporin to oral azithromycin or a fluoroquinolone can be con sidered after documented clearance of blood cultures and exclusion of secondary sites, for a total 7 to 10 day course. Disseminated disease needs to be rigorously excluded, as therapy is more prolonged for men ingitis (4 weeks) and osteomyelitis or other focal metastatic infections (4 6 weeks). Given the heterogeneity, evolution, and rapid geographic spread of Salmonella, it is important to maintain awareness of resistance trends as related to local and national community isolate patterns, any relevant interstate outbreaks, and global patterns of emerging Salmonella resis tance. Serially updated resources with this information include local microbiology laboratory data and open access reporting systems like the U.S. National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS). In NARMS reports from 2018, |
7,275 | the majority (81) of nontyphoidal Salmonella from humans were still not resistant to any of the antimicrobials tested. However, approximately 3, 10, and 0.3 of nontyphoidal Salmonella isolated from humans were intrinsically resistant to ceftriaxone, ciprofloxacin, and azithromycin, respectively. Some contemporary nontyphoidal Salmonellae are of particular interest, given their resistance to antimicrobials. S. Typhimurium DT104 spread globally in the 1990s, when it was resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. DT104 now sometimes also has reduced susceptibility to fluoroquinolones. Nontyphoidal Salmonella ST313 lineages (described earlier) continue A B C D E Fig. 244.4 Ultrastructural analysis of the distal small intestine with transmission electron microscopy. Distal small intestinal tissue was fixed with 1 glutaraldehyde. Short segments were cut open, post fixed with osmium tetroxide, contrasted with uranyl acetate, and dehydrated with a graded etha nol series before been embedded in epoxy resin. Thin sections were contrasted with lead citrate and analyzed in a JEM1400 transmission electron mi croscope (JEOL). Images were taken with TemCamF216 camera using EM MENU software (both TVIPS). A, Enterocytes in the distal intestine of healthy 5day old neonates exhibit large supranuclear vacuoles (SNV) in their apical cytoplasm; the nuclei are situated at the basolateral site (N). SNV contain internalized milk proteins. Asterisks indicate intercellular spaces between enterocytes. B, 4 days after infection of 1dayold mice with S. Typhimurium, the epithelium is infiltrated by polymorphonuclear cells (PMN). CE, Intraepithelial Salmonella microcolonies are observed. Some bacteria reside in spherical vacuoles, which contain electrondense material resembling the content of SNVs. Other bacteria appear to be localized in tight membrane bound vesicles with few visible connections between them, or with vesicles filled with electron dense material. (From Zhang K, Griffiths G, Repnik U, Hornef M. Seeing is understanding: Salmonellas way to penetrate the intestinal epithelium. Int J Med Microbiol. 2018 Jan;308:97106. Fig. 2.) Fever: 95 of cases, no apparent focus in 35 Blood tests: Severe anemia in 4050 of adults and 2540 of children, 95 of adults and 20 of children are HIV positive, CD4 count 200 cells per L in 80 of adults Splenomegaly: 3045 of cases Hepatomegaly: 1535 of cases Diarrhea: 2050 of cases, but often not a prominent feature Pneumonia: 60 of children and 30 of adults have an apparent lower respiratory tract infection focus, commonly due to coinfection Fig. 244.5 Clinical features of invasive nontyphoidal Salmonella (NTS) disease in adults and children in Africa. (From Feasey NA, Dougan G, Kingsley RA, et al. Invasive non typhoidal Salmonella disease: an emerging and neglected tropical disease in Africa. Lancet. 2012;379: 24892499.) 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 244 u Salmonella 1771 to show resistance pattern evolution in Africa. In the United States, S. Infantis has now supplanted other leading serotypes in poultry and not only exhibits deceased susceptibility to fluoroquinolones because of a gyrA pathogenic variant but also contains |
7,276 | an MDR plasmid that car ries up to 10 resistance genes, conferring resistance to cephalosporins, tetracycline, chloramphenicol, and sulfonamides. This MDR strain of serovar Infantis has been reported to account for up to 35 of the non typhoidal Salmonella infections in Israel. PROGNOSIS Most otherwise healthy children with Salmonella gastroenteritis recover fully without antimicrobial treatment. Malnourished children and those who do not receive adequate supportive care can be at risk for prolonged diarrhea and complications. Young infants and immu nocompromised patients often have systemic involvement, and chil dren with HIV can have a florid and recurring course. After infection, nontyphoidal Salmonella are excreted in feces for a median of 5 weeks, during which time the recovering patient can infect others via fecal oral routes or by contaminating foods. A prolonged carrier state is rare in children but is more common among those with biliary tract disease andor cholelithiasis. PREVENTION Control of transmission of Salmonella infections to humans requires control of the infection in animal reservoirs, judicious use of agri cultural antimicrobials, prevention of contamination of foodstuffs, and appropriate standards of food processing and inspection. Parents should be advised about the risk of various pets (especially reptiles, amphibians, and rodents). Large outbreaks are often related to mass food production, present ing among widely geographically distributed patients. In the United States, CDC outbreak investigations are reported, via this site: https: www.cdc.govSalmonellaoutbreaks.html, which includes maps and epidemiologic, traceback, and laboratory data, including outbreaks linked to specific foods, animals, and other sources. Awareness of these events can potentially blunt the extent of a given outbreak andor alert caregivers of vulnerable hosts. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 244.2 Enteric Fever (Typhoid and Paratyphoid Fever) Jeffrey S. McKinney Enteric fever (typhoid or paratyphoid fever) remains endemic in many developing countries. Given the ease of modern travel, cases regularly occur in developed countries as well, usually among returning travelers or from secondary transmission from an asymptomatic carrier. ETIOLOGY Typhoid fever is caused by S. enterica serovar Typhi (S. Typhi). A similar but often less severe disease is caused by Salmonella Paratyphi A, B, and C. All are classically referred to as typhoidal Salmonellae. Typhoidal Salmonellae share more than 90 of their genes with the classic nontyphoidal strain, S. Typhimurium, but several genetic clus ters known as pathogenicity islands and other genes have been acquired during evolution. The inactivation of single genes and the acquisition or loss of genes may have contributed to host adaptation and restriction of typhoidal strains. Importantly, whereas nontyphoidal Salmonella are found in many hosts and can be transmitted among them, typhoidal Salmonella only infects humans. In contrast to the diarrheal symptoms classically encountered in gastroenteritis caused by nontyphoidal Salmonellae, enteric fever caused by typhoid or paratyphoid Salmonellae may present as abdomi nal pain without diarrhea, a fever without focus, andor with extraint estinal foci of infection. Indeed, although enteric fever clearly starts in the gastrointestinal tract, the systemic nature of its presentation and symptomatology (and even its initial hard to detect |
7,277 | primary bactere mia) can delay diagnosis, in particular among patients returning from or living in endemic areas, where the differential diagnosis for fevers is broad. EPIDEMIOLOGY Recent large scale data and modeling efforts estimate that 14.3 million cases of typhoid and paratyphoid fevers occurred globally in 2017, a decline from 25.9 million cases in 1990. Incidence rates peak in the 5 to 9 year old age group, with roughly 13 of cases occurring in chil dren younger than 5 years and roughly 56 of cases among children younger than 15 years of age. South and Southeast Asia have notably high incidence rates, whereas moderate incidence rates are reported from Central and South America, Africa, Central and East Asia, and Oceania (Fig. 244.6). Typhoid fever is notable for the ongoing emergence of heterogeneous new patterns of drug resistance. After early outbreaks of chloramphenicol resistant S. Typhi infections, S. Typhi strains emerged that were multidrug resistant (MDR), fully resistant to all three of the tradi tional primary treatment antimicrobials: ampicillin, trimethoprim sulfamethoxazole, and chloramphenicol. There is also a considerable increase in fluoroquinolone resistant and even ceftriaxone resistant isolates of S. Typhi. In the United States, most travel associated cases of typhoid fever are now fluoroquinolone resistant. There are now S. Typhi strains that are extensively drug resistant (XDR) not only to ampicillin, trimethoprim sulfamethoxazole, and chloramphenicol but also to ceftriaxone and with full or intermedi ate resistance to ciprofloxacin. It appears that the new XDR S. Typhi strains came from a large outbreak in 2016 linked to contaminated water in Pakistans Sindh province. XDR Typhi infections were then reported globally among travelers to or from Pakistan. In 2019 U.S. res idents with no history of international travel were also diagnosed with XDR typhoid fever. The optimal therapy for these XDR isolates is still being determined, with preliminary recommendations suggesting the empiric use of a carbapenem (e.g., meropenem), azithromycin, or both. S. Typhi is highly adapted to infections of humans, and the discovery of a large number of pseudogenes in S. Typhi suggests that its genome may have undergone degeneration as part of a specialized association with the human host. S. Typhi has no apparent ability to cause trans missible disease in other animals. Thus direct or indirect contact with an infected human (either sick or a chronic carrier) is a prerequisite for infection. Ingestion of foods or water contaminated with human feces is the most common mode of transmission. So called street vendor foods outside the home are one risk factor noted in one case control study from Pakistan; such risks are included in practical guidance for travelers about food and water precautions from the CDC Yellow Book (Health Information for International Travel). However, more general water borne outbreaks related to poor sanitation or water system con tamination have also been described. Other causes of infection include consuming oysters and other shellfish cultivated in water contaminated by human sewage and the use of night soil as fertilizer. PATHOGENESIS Human volunteer experiments have |
7,278 | established an infecting dose of about 105109 organisms, with an incubation period ranging from 4 to 14 days. After ingestion, S. Typhi invades the gut mucosa of the terminal ileum via specialized antigen sampling cells known as M cells that overlie gut associated lymphatic tissues, through enterocytes, or via a paracellular route. In contrast to nontyphoi dal Salmonella, S. Typhi expresses factors that notably downregu late the pathogen receptormediated host inflammatory response. It assembles type III secretion systems to inject bacterial effectors that modulate host cell biology in elegant ways, including but not limited to rearrangements of host cell actin, facilitating invasion across the outer cell membrane and a host cell membrane ruffling process that forms a phagosome containing the bacteria. This phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium, forming the Salmonella containing vacuole (SCV). This intracellular niche offers Salmonella a physical barrier to some 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. 1772 Part XV u Infectious Diseases drugs (e.g., gentamicin, which has very poor intracellular penetra tion) and an intracellular replication site and means of host cell mediated systemic spread. After passing through the intestinal mucosa, S. Typhi organisms enter the mesenteric lymphoid system and then pass into the blood stream via the lymphatics. This primary bacteremia is usually asymp tomatic, and blood culture results are frequently negative at this early stage. The blood borne bacteria are disseminated through the body and are thought to colonize the organs of the reticuloendothelial system, where they replicate within macrophages. After a period of bacterial replication, S. Typhi organisms are shed back into the blood, causing a secondary bacteremia that coincides with the onset of clinical symp toms and marks the end of the incubation period (Fig. 244.7). During this secondary bacteremia, classically with fever, blood cultures are far more frequently positive, although culture of bone marrow can be even more sensitive. Both typhoidal and nontyphoidal Salmonellae are members of the same species and share substantive commonalities, including more than 90 of their DNA sequences. Yet a deeper appreciation of how and why typhoidal and nontyphoidal species differ offers insights at multiple levels, ranging from genetics and ecology, to pathobiology, to more nuanced clinical recognition and care. Despite typhoidal (and paratyphoidal, used interchangeably in this section, unless specified otherwise) fevers being synonymous with the clinical diagnosis of enteric fever, the initial enteric inflamma tion from S. Typhi is notably less than that caused from most non typhoidal Salmonellae. Clinically, presenting symptoms of typhoid tend to include less diarrhea and far less gut mucosal inflammation. In host cell cultures, S. Typhi induces lower levels of IL 8 neutrophil chemoattractant and less of a toll like receptor 5 (TLR5)driven pro inflammatory response than seen with nontyphoidal Salmonella. One potential implication of this is that nontyphoidal Salmonella may use inflammation derived luminal |
7,279 | substances such as electron acceptors like nitrate and tetrathionate, perhaps in competition with other fer menting gut microbes. Intriguingly, S. Typhi has genomic decay in a network of nontyphoidal Salmonella genes that are involved in anero bic metabolic pathways. This is not to say that S. Typhi never results in intestinal lesions. In advanced stages of typhoid fever, life threatening intestinal perforation can occur. However, the histopathology of typhoid perforation is dis tinct from the inflammation seen with nontyphoidal Salmonella gas troenteritis. With S. Typhi, inflammation that can finally penetrate the intestinal muscularis and serosa to cause perforation seems to originate from deeper sites, including underlying lymphoid tissue. In other tis sues, including liver, spleen, lymph nodes, and bone marrow, typhoid nodules composed of macrophage aggregates can also form. Gallbladder colonization is also a notable feature of S. Typhi and can result in years long Salmonella carriage and shedding, with pro found public health implications. The primary bacteremia of S. Typhi can seed the gallbladder, where exposure to bile upregulates S. Typhi (but seemingly not nontyphoidal Salmonella) type 3 secretion system genes that result in increased epithelial cell invasion. S. Typhi expresses a surface Vi (virulence) capsular polysaccha ride that is not present in nontyphoidal Salmonella or in S. Paratyphi A or B (which is relevant to the community level impact of current Vi based vaccines). Encoded as part of the S. Typhi pathogenicity island 7 (SPI 7), the Vi capsular polysaccharide interferes with the sur face exposure of S. Typhi lipopolysaccharide and flagellin in ways that dampen host TLR 4 and 5 mediated innate immune responses. Vi also blocks complement C3 binding to the S. Typhi surface, interfering with phagocytosis. Characterization of the typhoid toxin represents a major advance in understanding typhoid fever. Furthermore, in contrast to the Vi capsular polysaccharide, the typhoid toxin is expressed in both typhoi dal and paratyphoidal Salmonellae. This toxin may prove important for new therapeutic or diagnostic innovations based on antitoxin Incidence rate (per100000) 0 to 15 ATG VCT GrenadaDominica Barbados Comoros Marshall Isl Kiribati Solomon Isl FSM Vanuatu Samoa Fiji Tonga Maldives Mauritius TTOLCACaribbean TLS Persian Gulf Singapore Malta Eastern Mediterranean Balkan PeninsulaSeychelles West Africa 15 to 50 50 to 100 100 to 200 200 to 500 500 to 700 Fig. 244.6 Incidence rates (per 100,000) of typhoid and paratyphoid fevers, by country, in 2017. Inset maps detail smaller locations. ATG, Antigua and Barbuda; FSM, Federated States of Micronesia; Isl, Islands; LCA, Saint Lucia; TLS, Timor Leste; TTO, Trinidad and Tobago; VCT, Saint Vincent and the Grenadines. (From GBD 2017 Typhoid and Paratyphoid Collaborators. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;194:369381.) 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 244 u Salmonella 1773 approaches. Typhoid toxin has three subunits. |
7,280 | Subunit CdtB has DNAse Ilike nuclease activity that causes double stranded breaks in host cell DNA, leading to host G2M cell cycle arrest andor cell death. Subunit PltA is a pertussis like toxin with monoadenosine diphos phate (ADP)ribotransferase activity. Subunit PltB is a pertussis like toxin with receptor binding activity to glycans, especially sialoglycans, terminated in Neu5Ac. The functional typhoid toxin is composed of one CdtB and one PltA subunit, plus five PltB subunits. Typhoid toxin genes are expressed by intracellular S. Typhi in the SCV of host cells. The trafficking of the toxin uses an elegant mechanism, in which PltB binding to Neu5Ac is involved in both toxin export and toxin endocy tosis into target cells. The fact that Neu5Ac is the target for binding by PltB may help explain the cell tropism of typhoid toxin and also some of the human restriction of typhoidal infections and pathobiology at a molecular level. The presencegainsite specific expression of certain virulence factors by typhoidal Salmonellae may help explain disease nuances involved in typhoid fever. Acquisition and spread of resistance genes are also a clear and present danger. The overall quantity of pseudogenes in S. Typhi versus nontyphoi dal Salmonella genomes is also noteworthy. Whereas S. Typhis 200 pseudogenes account for roughly 4 of all its genes, the classic non typhoidal Salmonella exemplar S. Typhimurium genome includes less than 1 pseudogenes. One broad conceptual model for this is that S. Typhimurium remains more of a generalist, with a broad host range and more genes to facilitate survival in different hosts. By contrast, S. Typhi may have become a specialist, evolving to infect only humans. Furthermore, S. Typhi may infect humans in specific ways that bet ter evadesuppress early mucosal inflammatory events and cause more systemic spread, as well as sustained colonization and long term shed ding. This conceptual model may offer insights to understand the ongoing evolution or emergence of some new nontyphoidal Salmo nella strains that (akin to typhoidal strains) tend to cause more sys temic infections, as highlighted by the evolution of the nontyphoidal Salmonella ST313 strain in Africa. In addition to the virulence of infecting organisms, host factors also influence predisposition to infection. Patients with HIV are at significantly higher risk for infection with S. Typhi and S. Paratyphi. Patients with Helicobacter pylori infection also have an increased risk of acquiring typhoid fever. Compared to most nontyphoidal Salmonella infections that are often more severe and systemic in hosts with immune abnormalities, outbreaks of typhoid fever with systemic spread often affect many hosts who do not have significant underlying immunocompromise. CLINICAL MANIFESTATIONS The incubation period of typhoid fever is usually 7 14 days but depends on the infecting dose and ranges between 3 and 30 days. The presenta tion varies, from mild illness with low grade fever and malaise, to a severe clinical picture with profound abdominal discomfort and mul tiple complications. Severity and clinical outcome are influenced by many factors. These include duration of illness, age, previous exposure or |
7,281 | vacci nation history, virulence of the infecting strain, and quantity of the inoculum ingested. Given the profound changes in antimicrobial susceptibility patterns, choice of appropriate antimicrobial therapy is increasingly challenging, both empirically (given multiple various patterns of resistance) and after antimicrobial susceptivity results are secured (given the increasing inadequacy of many previously effec tive drugs). The presentation of typhoid fever may vary by patient age. Some reports from South Asia suggest typhoid fever may be more severe in children less than 5 years old in terms of rates of complications and hospitalization. In infancy, complications such as disseminated intra vascular coagulation seem more common, with higher case fatality rates. By contrast, neurologic complications and intestinal bleeding or perforation seem less common among children. Typhoid fever can start as a seemingly mild illness and then progress to a clinical picture that manifests as high grade fever. It can include a wide variety of associated features, such as anorexia, vomiting, hepatomegaly or splenomegaly, abdominal pain, andor headache (Table 244.1). In children, diarrhea may occur in earlier stages of the illness but may be followed by constipation, potentially interfering with ready access to stool for important microbial culture and susceptibility testing. In the absence of localizing signs, the early stages of the disease may be very difficult to differentiate from other endemic diseases, such as malaria and dengue fever. In some cases, a macular or maculopapular rash (rose spots) may be visible around the seventh to tenth day of the illness. These lesions may be difficult to see in dark skinned children and may occur in crops on the lower Fig. 244.7 Pathogenesis of typhoid fever, involving invasion of ileal enterocyte and Peyer patches and mesenteric lymph nodes, seeding the reticuloendothelial system (RES). Both primary and secondary bacteremia events can occur and relate to clinical stages of disease. (Adapted from Richens J. Typhoid fever. In: Cohen J, Powderly WG, Opal SM, eds. Infectious Diseases, 2nd ed. London: Mosby; 2004:15611566.) Salmonella typhi M cell Enterocytes lining terminal ileum Peyer patch and resident macrophage Mesenteric lymph nodes Primary bacteremia Seeding of RES: liver, spleen, gall bladder, bone marrow Secondary bacteremia Peyer patches reexposed to S. typhi via bile Widespread dissemination Pathogenesis of typhoid fever 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. 1774 Part XV u Infectious Diseases chest and abdomen, typically lasting 2 3 days (Fig. 244.8). Although so called pulse fever dissociation (relative bradycardia during fevers) has historically been invoked as a feature of typhoid fever, it has low positive predictive value, is nonspecific, and seems much less com mon in children than in adults. It is recognized that MDR S. Typhi infection is a more severe clini cal illness with higher rates of toxicity, complications, and case fatality rates. Depending on the specific infecting strain, this may be related to greater virulence and higher numbers of |
7,282 | circulating bacteria. If no complications occur, symptoms and physical findings gradu ally resolve within 2 4 weeks. However, illness may contribute to malnutrition. Although enteric fever caused by S. Paratyphi has tradi tionally been considered a more mild illness than that from S. Typhi, paratyphoid fever can also be severe, with significant drug resistance, morbidity, and complications. COMPLICATIONS Although altered liver function is found in many patients with enteric fever, clinically significant hepatitis, jaundice, and cholecystitis are relatively rare and may be associated with worse outcomes. Intestinal hemorrhage and perforation are infrequent among children. Intestinal perforation may be preceded by marked increase in abdominal pain (often in the right lower quadrant), tenderness, vomiting, and features of peritonitis. Peritoneal signs may be masked in patients receiving steroids. Rare complications include toxic myocarditis, which may mani fest as arrhythmias, sinoatrial block, or cardiogenic shock (Table 244.2). Neurologic complications are relatively uncommon among children; they include delirium, psychosis, increased intracranial pressure, acute cerebellar ataxia, chorea, deafness, and Guillain Barr syndrome. Although case fatality rates can be higher among patients with neurologic complications, recovery usually occurs without sequelae. Other reported complications include fatal bone marrow necrosis, disseminated intravascular coagulation, hemolytic uremic syndrome, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis. The propensity to become a carrier follows the epidemiology of gall bladder disease and cholelithiasis, generally increasing with patient age and antimicrobial resistance. DIAGNOSIS The mainstay of the diagnosis of typhoid fever is a positive culture of S. Typhi or S. Paratyphi from the blood or other anatomic site. Results of blood cultures are positive in 4060 of patients seen early in the course of disease, but serial high volume blood cultures may be required to identify Salmonella bacteremia. Stool and urine culture results may also become positive after the first week, and the stool cul ture may occasionally be positive even during the incubation period. NAATs for Salmonella can be part of diagnostic screening, but rec tal swab samples are less sensitive than stool samples. In this era of increasing antibiotic resistance (not only common but also heteroge neous patterns), species identification without culture to check anti biotic susceptibilities is suboptimal. Indeed, antibiotic susceptibility testing is now essential for determining optimal therapy. Bone marrow culture is highly sensitive (around 90) and remains positive in more than 50 of cases despite several days of antibiotic therapy. Bone mar row collection is relatively invasive, however, and tends to be employed as part of an extensive workup for patients meeting stringent criteria for a true fever of unknown origin. Punch biopsies from characteristic rose spots may be culture positive in up to 63 of cases, even with prior antibiotic treatment. Results of other laboratory investigations are largely nonspecific for the diagnosis of typhoid fever. The Widal test has common false negative and false positive results, and as a serologic test is highly dependent on geographic area and endemicity. Tests such as coagu lation studies, liver function studies, and abdominal imaging are examples of studies |
7,283 | that may be of use in assessing for complications of typhoid fever. Table 244.1 Common Clinical Features of Typhoid Fever in Children FEATURE RATE () High grade fever 95 Coated tongue 76 Anorexia 70 Vomiting 39 Hepatomegaly 37 Diarrhea 36 Toxicity 29 Abdominal pain 21 Pallor 20 Splenomegaly 17 Constipation 7 Headache 4 Jaundice 2 Obtundation 2 Ileus 1 Intestinal perforation 0.5 Data collected in Karachi, Pakistan, from 2,000 children. A B Fig. 244.8 A, Rose spot in volunteer with experimental typhoid fever. B, Small cluster of rose spots, usually located on lower abdo men. Lesions may be more difficult to identify in darker skinned people. (From Huang DB, DuPont HL. Problem pathogens: extra intestinal com plications of Salmonella enterica serotype Typhi infection. Lancet Infect Dis. 2005;5:341348.) 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 244 u Salmonella 1775 Table 244.2 Extraintestinal Infectious Complications of Typhoid Fever Caused by Salmonella enterica Serotype Typhi ORGAN SYSTEM PREVALENCE () RISK FACTORS COMPLICATIONS Central nervous system 335 Residence in endemic region, malignancy, endocarditis, congenital heart disease, paranasal sinus infections, pulmonary infections, meningitis, trauma, surgery, osteomyelitis of skull Encephalopathy, cerebral edema, subdural empyema, cerebral abscess, meningitis, ventriculitis, transient Parkinsonism, motor neuron disorders, ataxia, seizures, Guillain Barr syndrome, psychosis Cardiovascular system 15 Cardiac abnormalities (e.g., existing valvular abnormalities, rheumatic heart disease, congenital heart defects) Endocarditis, myocarditis, pericarditis, arteritis, congestive heart failure Pulmonary system 16 Residence in endemic region, past pulmonary infection, sickle cell anemia, alcohol abuse, diabetes, HIV infection Pneumonia, empyema, bronchopleural fistula Bone and joint 1 Sickle cell anemia, diabetes, systemic lupus erythematosus, lymphoma, liver disease, previous surgery or trauma, extremes of age, corticosteroid use Osteomyelitis, septic arthritis Hepatobiliary system 126 Residence in endemic region, pyogenic infections, intravenous drug use, splenic trauma, HIV, hemoglobinopathy Cholecystitis, hepatitis, hepatic abscesses, splenic abscess, peritonitis, paralytic ileus Genitourinary system 1 Urinary tract abnormalities, pelvic pathology, systemic abnormalities Urinary tract infection, renal abscess, pelvic infections, testicular abscess, prostatitis, epididymitis Soft tissue infections At least 17 cases reported in English language literature Diabetes Psoas abscess, gluteal abscess, cutaneous vasculitis Hematologic At least 5 cases reported in English language literature Hemophagocytosis syndrome From Huang DB, DuPont HL. Problem pathogens: extra intestinal complications of Salmonella enterica serotype Typhi infection. Lancet Infect Dis. 2005;5:341348. DIFFERENTIAL DIAGNOSIS Typhoid fever may mimic many febrile illnesses without localizing signs. In early stages, it can be confused with alternative conditions, such as gastroenteritis, bronchitis, and bronchopneumonia. As the disease pro gresses, the differential diagnosis may include bacterial sepsis, malaria, dengue fever, infectious mononucleosis, acute hepatitis, tuberculosis, brucellosis, tularemia, leptospirosis, amebiasis, Q fever, toxoplasmo sis, and rickettsial diseases. A classic cause of fevers among travelers returning from endemic areas, typhoid fever can also occur in those with direct, or even unappreciated, contact with other infected people. TREATMENT Antibiotic resistance among S. Typhi strains is now so heterogeneous and dynamic that the |
7,284 | importance of obtaining antibiotic susceptibility tests on clinical isolates cannot be overemphasized. Although empiric antibiotics still may be started, final decision making about optimal treatment should be based on antibiotic susceptibility results. Molecu lar testing of specific resistance genes can also help assess mechanisms and evolution of resistance. For years, third generation cephalosporins (e.g., ceftriaxone or cefo taxime) were a mainstay of empiric therapy. They were considered effective even for MDR S. Typhi andor for the increasing number of S. Typhi that were quinolone resistant. Yet now, with the recent emer gence of XDR S. Typhi, third generation cephalosporins may no lon ger be sufficient. In S. Typhi, MDR isolates are defined as resistant to all the first line of antibiotics previously suggested by the World Health Orga nization (WHO): ampicillin, trimethoprim sulfamethoxazole, and chloramphenicol. XDR S. Typhi is not only resistant to ampicil lin, trimethoprim sulfamethoxazole, and chloramphenicol but also resistant to third generation cephalosporins and quinolones. Gene sequencing, including one innovative study using clinical isolates from children with S. Typhi septicemia, found the phenotype of the XDR S. Typhi isolates matches with their genotypes, featured by the acquisi tions of the genes blaTEM1, dhfR7, sul1, catA1, qnrS, and blaCTX M 15 and a point mutation on gyrA. XDR S. Typhi cases were first noted by Pakistani health authorities in 2016, originating in Hyderabad, Sindh. By 2018, international trans mission of XDR S. Typhi cases had been noted. In 2019 and 2020, XDR S. Typhi was recovered from patients in the United States, both with and without a travel history. Patients without a travel history lived in six widely distributed states and did not appear to be linked or have a com mon source of infection. An unrelated cluster of ceftriaxone resistant Typhi infections linked to Iraq has also been reported in the United States and the United Kingdom. Taken together, this information led to an official CDC Health Advi sory in 2021 suggesting the need for empiric carbapenem, azithromy cin, or both for patients in the United States with suspected typhoid fever who traveled to Pakistan or Iraq, as well as those who had not trav eled from the United States. Patients with severe or complicated illness should receive a carbapenem, such as meropenem. Case reports have suggested that patients who do not improve on a carbapenem alone may benefit from the addition of a second antibiotic such as azithromycin. Patients with uncomplicated illness may be treated with oral azithromy cin alone. By contrast, for patients in the United States who traveled to countries other than Pakistan or Iraq, ceftriaxone may still be effective. In the United States, resistance to meropenem (a carbapenem) or azithromycin was not reported during 20172021. By contrast, roughly 80 of Typhi strains isolated in the United States now are resistant or have decreased susceptibility to quinolones, including ciprofloxacin. New MDR and XDR strains illustrate the profound importance of recognizing what antimicrobials will likely not work. Meanwhile, an encouraging relative reduction in the proportion |
7,285 | of MDR strains in some areas of Asia means some patients with susceptible S. Typhi infections can be treated with agents recently considered ineffective. Namely, in some highly endemic regions of South and Southeast Asia, 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. 1776 Part XV u Infectious Diseases strains susceptible to amoxicillin or trimethoprim sulfamethoxazole are increasingly common. The optimal duration of antimicrobial therapy is unclear, but most agents are suggested for at least 10 14 days, with longer courses for amoxicillin or trimethoprim sulfamethoxazole, 21 days for chloram phenicol, and as little as 7 days for azithromycin. Relapse rates can occur in almost 20 of patients within 4 weeks, especially in immuno compromised patients. In addition to antimicrobials, supportive treatment and main tenance of appropriate fluid and electrolyte balance are important. Although additional treatment with dexamethasone (3 mgkg initial dose, followed by 1 mgkg every 6 hours for 48 hours) is recommended by some for severely ill patients with shock, obtundation, stupor, or coma, corticosteroids should be administered only under strict super vision, because their use may mask signs of abdominal complications. PROGNOSIS The prognosis for a patient with enteric fever depends on the rapidity of diagnosis and institution of appropriate antibacterial therapy. Other factors are patient age, underlying health and nutrition, the causative Salmonella serotype, and the appearance of complications. Infants and children with underlying malnutrition and infections with resistant isolates are at higher risk of adverse outcomes. Despite appropriate therapy, 24 of infected children may expe rience relapse. Individuals who excrete S. Typhi more than 3 months after infection are regarded as chronic carriers. A chronic urinary car rier state can develop in children with schistosomiasis. PREVENTION Of the major risk factors for outbreaks of typhoid fever, contamination of water supplies with sewage is most important. Other risk factors are contact with another acutely infected individual or a chronic carrier and lack of water or sanitation services. During outbreaks, central chlo rination and domestic water purification are important. In endemic sit uations, consumption of street foods, especially ice cream and cut fruit, is recognized as an important risk factor. Human to human spread by chronic carriers is also important, and attempts should be made to tar get food handlers and high risk groups for S. Typhi carriage screening. Chronic carriers can be counseled as to the risk for disease transmis sion and the importance of handwashing. In the United States, two vaccines have been licensed by the FDA. Systematic review and meta analysis of randomized controlled clini cal trials estimate the cumulative efficacy of these two vaccines as only roughly 50. The Ty21a live attenuated vaccine can be used in people 6 years and older. It is administered orally, every other day, for a total of four doses to be completed at least 1 week before poten tial exposure; booster |
7,286 | frequency is every 5 years. The Ty21a vaccine induces both cell mediated and humoral immune responses against S. Typhi. It also may provide some protection against S. Paratyphi B. The unconjugated Vi capsular polysaccharide vaccine can be used in people 2 years and older. It is administered intramuscularly in a single dose to be administered at least 2 weeks before potential expo sure; booster frequency is every 2 years. This unconjugated vaccine induces a T cellindependent humoral immune response with lack of prolonged protection. Conjugated vaccines have been recommended, developed, and now deployed by the WHO. By covalently conjugating the Vi capsu lar polysaccharide to carrier proteins, conjugate vaccines can induce a T celldependent humoral immune response, even in young chil dren. Conjugated typhoid vaccines are under development, using a variety of carrier proteins, including tetanus toxoid, Exoprotein A from Pseudomonas, and diphtheria toxoid. The WHO has recommended the introduction of a single dose typhoid conjugate vaccine for infants and children age 6 months and older. A large study of the Typbar TCV conjugate vaccine in Hyderabad, Pakistan, found vaccine effectiveness was 55 against suspected typhoid fever and 95 against blood cul tureconfirmed S. Typhi. The vaccine was also 97 effective against XDR S. Typhi. In 2019, a historic milestone was successfully achieved in Pakistan with the vaccination in Sindh province of more than 9.4 million children age from 9 months to 15 years against typhoid fever, with a coverage rate of 95. Pakistan is the first country in the world to introduce the WHO recommended typhoid conjugate vaccine (TCV) into its routine immunization program. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 245 Shigella Patrick C. Seed Shigellosis, infection by Shigella species, is acute invasive enteric infec tion clinically manifested by diarrhea that is often bloody. The term dysentery describes a syndrome of bloody diarrhea with fever, abdom inal cramps, rectal pain, and mucoid stools. Bacillary dysentery is a term often used to distinguish dysentery caused by Shigella from ame bic dysentery caused by Entamoeba histolytica. ETIOLOGY Four species of Shigella cause the disease shigellosis: Shigella dysente riae (group A), Shigella flexneri (group B), Shigella boydii (group C), and Shigella sonnei (group D). Serotypes 15, 19, 19, and 1 in groups A D, respectively, further distinguish the species. Species and group distributions vary geographically and by antimicrobial susceptibility. EPIDEMIOLOGY The World Health Organization (WHO) estimates that 80 165 million cases of shigellosis occur each year worldwide, resulting in 600,000 deaths annually. Shigella spp. are endemic to temperate and tropical climates and are most common in countries and regions with inad equate public health sanitation and hygiene. In the U.S. Foodborne Disease Active Surveillance Network (FoodNet), Shigella remains the third most important pathogen. In 2020, the top three diarrheagenic pathogens, Campylobacter, Salmonella, and Shigella, had laboratory confirmed incidence rates (cases per 100,000 population) of 14.35, 13.33, and 3.05, respectively. Although infection can occur at any age, children younger than 10 years, identified as Black and of Hispanic ethnicity, have the |
7,287 | highest incidence rates. Males have an approxi mately 2.7 fold higher incidence than females. Upwards of 30 of children with shigellosis are hospitalized. Death resulting from shigel losis is rare among children (0.1). Infection in the first 6 months of life is rare. Breast milk from women living in endemic areas contains antibodies to both virulence plasmid encoded antigens and lipopoly saccharides, and breastfeeding might partially explain the age related incidence. Asymptomatic infection of children and adults occurs frequently in endemic areas. In cases of Shigella dysentery, up to 75 of family member contacts may have asymptomatic infection. Infection with Shigella occurs most often during the warm months in temperate cli mates and during the rainy season in tropical climates. In industrial ized societies, up to 50 of locally diagnosed cases are associated with international travel; the highest risk travel designation is Africa, fol lowed by Central America, South America, and parts of Asia. In recent years in the United States, travel to Haiti, the Dominican Republic, or India has been associated with acquisition of antibiotic resistant (fluo roquinolone) S. sonnei infections. Additional risk factors include men who have sex with men (MSM), including recent U.S. outbreaks of azithromycin resistant S. sonnei infections among affected individuals in the Midwest. In developed countries, S. sonnei is the most common cause and S. flexneri is the second most common cause of bacillary dysentery; in preindustrial societies, S. flexneri is most common and S. sonnei second 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 245 u Shigella 1777 in frequency. S. boydii is found primarily in India. S. dysenteriae sero type 1 tends to occur in massive epidemics but is also endemic in Asia and Africa, where it is associated with high mortality rates (515). The epidemiologic transition has favored the emergence of S. sonnei as the dominant serogroup in some countries, although the reason for this epidemiologic shift is not clear. Contaminated food (often a salad or other item requiring extensive handling of the ingredients) and water are important vectors. Expo sure to both contaminated freshwater and contaminated salt water is a risk factor for infection. Rapid spread within families, custodial institutions, and childcare centers demonstrates the ability of Shigella to be transmitted from one individual to the next and the requirement for ingestion of very few organisms to cause illness. Human challenge studies have demonstrated the high infectivity and low infectious dose for Shigella spp. Ten bacteria of the species S. sonnei and S. dysenteriae can cause dysentery. In contrast, ingestion of 108 1010 Vibrio cholerae is necessary to cause cholera. PATHOGENESIS Shigella has specialized mechanisms to survive the low gastric pH. Shi gella survives the acid environment in the stomach and moves through the gut to the colon, its target organ. Shigella spp. use a coordinated, temperature controlled program to hijack and invade |
7,288 | colonic epithe lial cells. A large (220 kb) plasmid encodes a group of polypeptides involved in cell invasion and killing, and loss of the plasmid attenuates virulence. Enteroinvasive Escherichia coli (EIEC) that harbor a closely related plasmid containing these invasion genes behave clinically simi lar to Shigellae (see Chapter 246). The virulence plasmid encodes a type III secretion system required to trigger entry into epithelial cells and apoptosis in macrophages. This secretion system translocates effector molecules from the bacterial cytoplasm to the membrane and cyto plasm of target host cells through a needle like appendage. The type III secretion system is composed of approximately 50 proteins, including the Mxi and Spa proteins involved in assembly and regulation of the type III secretion system, chaperones (IpgA, IpgC, IpgE, and Spa15), transcription activators (VirF, VirB, and MxiE), translocators (IpaB, IpaC, and IpaD), and approximately 30 effector proteins. In addition to the major plasmid encoded virulence traits, chromosomally encoded factors are required for full virulence. Shigellosis mostly affects the distal colon, although pancolitis can occur. Shigella spp. traverse the colonic epithelium through M cells in the follicle associated epithelium overlying the Peyer patches. Local ized or diffuse mucosal edema, ulcerations, friable mucosa, bleeding, and exudate may occur. Microscopically, ulcerations, pseudomem branes, epithelial cell death, infiltration extending from the mucosa to the muscularis mucosae by polymorphonuclear leukocytes (PMNs) and mononuclear cells, and submucosal edema occur. After Shigella transcytosis through M cells, it encounters resi dent macrophages and subverts macrophage killing by activating the inflammasome and inducing pyroptosis, apoptosis, and proinflamma tory signaling. Free bacteria invade the epithelial cells from the basolat eral side, move into the cytoplasm by actin polymerization, and spread to adjacent cells. Proinflammatory signaling by macrophages and epi thelial cells further activates the innate immune response involving natural killer cells and attracts PMNs. The influx of PMNs disintegrates the epithelial cell lining, which initially exacerbates the infection and tissue destruction by facilitating the invasion of more bacteria. Ulti mately, PMNs phagocytose and kill Shigella, thus contributing to the resolution of the infection. Some Shigella spp. produce toxins, including Shiga toxin and entero toxins. Shiga toxin is a potent exotoxin that inhibits protein synthesis. It is produced in significant amounts by S. dysenteriae serotype 1, by a subset of E. coli known as enterohemorrhagic E. coli (EHEC) or Shiga toxinproducing E. coli, and occasionally by other Shigella spp. Shiga toxin inhibits protein synthesis to injure vascular endothelial cells and trigger the severe complication of hemolytic uremic syndrome (see Chapter 246). Targeted deletion of the genes for other enterotoxins (ShET1 and ShET2) decreases the incidence of fever and dysentery in human challenge studies. Lipopolysaccharides are virulence factors for all Shigellae; other traits are important for only a few serotypes (e.g., Shiga toxin synthesis by S. dysenteriae serotype 1 and ShET1 by S. flex neri 2a). IMMUNITY In symptomatic infection, Shigella activates an intense innate immune response through triggering extracellular and intracellular pathogen recognition systems. The induction of acute inflammation with a mas sive |
7,289 | recruitment of PMNs produces intensive local tissue destruction. In rectal biopsies of infected patients, acute phase proinflammatory cytokines are induced, including interleukin (IL) 1, IL 6, IL 8, tumor necrosis factor (TNF) , and TNF . Concurrently, antiinflamma tory genes encoding IL 10 and transforming growth factor are also upregulated to mitigate uncontrolled inflammation. Furthermore, interferon expression is induced during human infection and is required to limit Shigella invasion in intestinal epithelial cells and mac rophages. Shigella specific immunity elicited upon natural infection is characterized by the induction of a humoral response. Local secretory immunoglobulin A (IgA) and serum IgG are produced against lipo polysaccharide and some protein effectors (Ipas). Protection is thought to be serotype specific. Natural protective immunity arises only after several episodes of infection, is of short duration, and seems to be effective in limiting reinfection, particularly in young children. How ever, children have delayed and reduced antigen specific antibody secreting cells with late and reduced mucosa IgA production against Shigella. Less effective adaptive immunity may put children at more risk for increased disease severity, mortality, and recurrences. CLINICAL MANIFESTATIONS AND COMPLICATIONS Shigella spp. produce intraintestinal and extraintestinal symptoms. Bacillary dysentery is clinically similar regardless of infecting serotype or species, but different species produce illnesses with different severity and risk for mortality, with S. dysenteriae type 1 most likely to pro duce any single manifestation and with greater severity. Ingestion of Shigellae is followed by an incubation period of 12 hours to several days before symptoms ensue. Severe abdominal pain, emesis, anorexia, generalized toxicity, urgency, and painful defecation characteristically occur (Table 245.1). The typically high fever with shigellosis distin guishes it from EHEC. The diarrhea may be watery and large volume initially, evolving into frequent, small volume, bloody, mucoid stools. Most children never progress to the stage of bloody diarrhea, but some have bloody stools from the outset. Significant dehydration is related to the fluid and electrolyte losses in stool and emesis. Untreated diarrhea can last 7 10 days; only approximately 10 of patients have diarrhea persisting for 10 days. Persistent diarrhea occurs in malnourished infants, children with AIDS, and occasionally previously normal chil dren. Even nondysenteric disease can be complicated by persistent ill ness. Physical examination initially shows abdominal distention and tenderness, hyperactive bowel sounds, and a tender rectum on digital examination. Rectal prolapse may be present, particularly in malnour ished children. Neurologic findings are among the most common extraintestinal manifestations of bacillary dysentery, occurring in as many as 40 of hospitalized children. EIEC can cause similar neurologic toxicity. Convulsions, headache, lethargy, confusion, nuchal rigidity, or hallu cinations may be present before or after the onset of diarrhea. Ani mal models suggest Shiga toxins activate brain endothelial cells and microglia and increase neurotransmitter levels. However, infections with Shiga toxinpositive and negative strains can lead to neurologic features. Seizures sometimes occur when little fever is present, sug gesting that simple febrile convulsions do not explain their appearance. Hypocalcemia or hyponatremia may be associated with seizures in a |
7,290 | small number of patients. Although symptoms often suggest central nervous system infection, and cerebrospinal fluid pleocytosis with minimally elevated protein levels can occur, meningitis caused by Shi gellae is rare. Based on animal studies, it has been suggested that pro inflammatory mediators, including TNF and IL 1, nitric oxide, and corticotropin releasing hormone, play a role in the enhanced suscepti bility to Shigella mediated seizures and encephalopathy. 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. 1778 Part XV u Infectious Diseases The most common complication of shigellosis is dehydration (Table 245.2). Inappropriate secretion of antidiuretic hormone with profound hyponatremia can complicate dysentery, particularly when S. dysen teriae is the etiologic agent. Hypoglycemia and protein losing enter opathy are common and are decreased by early appropriate antibiotic therapy. Severe protein losing enteropathy is associated with prolonged illness and linear growth shortfalls. Bacteremia is uncommon except in girls or women infected with HIV, malnourished children, young infants, and children with S. dysenteriae serotype 1 infection. When bacteremia occurs with dysentery (5), it is as likely to be caused by other enteric bacteria as by Shigella itself. The presence of E. coli, Kleb siella, and other enteric bacteria in blood cultures of children with shig ellosis may reflect the loss of the barrier function during severe colitis. The mortality rate is high (approximately 20) when sepsis occurs, with a greater likelihood of occurrence in HIV infected persons. Other major complications include disseminated intravascular coagulation (DIC), particularly in very young, malnourished children. Despite the extent to which the intestinal epithelial barrier is lost, bacteremia and DIC are uncommon. Neonatal shigellosis is rare, particularly among exclusively breastfed infants. Neonates may have only low grade fever with mild, nonbloody diarrhea. However, complications occur more often in neonates than in older children and include septicemia, meningitis, dehydration, colonic perforation, and toxic megacolon. Hemolysis, anemia, and hemolytic uremic syndrome (HUS) fre quently complicate S. dysenteriae serotype 1 infection. HUS is caused by Shiga toxinmediated vascular endothelial injury. Shiga toxinpro ducing non dysenteriae Shigella and E. coli that produce Shiga toxins (e.g., E. coli O157:H7, E. coli O111:NM, E. coli O26:H11, and less often, many other serotypes) also cause HUS (see Chapter 560.5). Rectal prolapse, toxic megacolon or pseudomembranous colitis (usually associated with S. dysenteriae), cholestatic hepatitis, conjunc tivitis, iritis, corneal ulcers, pneumonia, arthritis (usually 2 5 weeks after enteritis), reactive arthritis, cystitis, myocarditis, and vaginitis (typically with blood tinged discharge associated with S. flexneri) are uncommon events. Although rare, surgical complications of shigellosis can be severe; the most common are intestinal obstruction and appen dicitis with and without perforation. On average, the severity of illness and risk of death are least with disease caused by S. sonnei and greatest with infection by S. dysente riae type 1. Risk groups for severe illness and poor outcomes include infants; children who are not breastfed; |
7,291 | children with HIV; children recovering from measles; malnourished children and adults; adults 50 years old; and patients with dehydration, unconsciousness, hypo thermia or hyperthermia, hyponatremia, or lesser stool frequency who have a history of convulsions when first seen. Death is a rare outcome in well nourished older children. Multiple factors contribute to death in malnourished children with shigellosis, including illness in the first year of life, altered consciousness, dehydration, hypothermia, throm bocytopenia, anemia, hyponatremia, renal failure, hyperkalemia, hypoglycemia, bronchopneumonia, and bacteremia. The rare shigellosis associated Ekiri syndrome, or lethal toxic encephalopathy, constitutes severe toxicity, convulsions, extreme hyperpyrexia, and headache, followed by brain edema and a rapidly fatal outcome without sepsis or significant dehydration. DIFFERENTIAL DIAGNOSIS Although clinical features suggest shigellosis, they usually are insuf ficiently specific to allow confident diagnosis. Infection by Cam pylobacter jejuni, Salmonella spp., EIEC, Shiga toxinproducing E. coli (EHEC, e.g., E. coli O157:H7), Yersinia enterocolitica, Clostridi oides difficile, and Entamoeba histolytica, as well as inflammatory bowel disease, produce overlapping features and may challenge the clinician. DIAGNOSIS Presumptive data supporting a diagnosis of bacillary dysentery include the finding of fecal leukocytes (usually 50 or 100 PMNs per high power field, confirming the presence of colitis), fecal blood, and Table 245.1 Acute Clinical Manifestations of Shigellosis in Children 5 Years Old MANIFESTATION DYSENTERY (n 757) WATERY DIARRHEA (n 288) Fever 607 (80) 207 (72) Abdominal cramps 616 (81) 137 (48) Vomiting 136 (18) 89 (31) WHO defined dehydration 95 (13) 134 (47) Tenesmus 511 (68) 32 (11) Rectal prolapse 19 (3) 4 (1) From Kotloff KL, Riddle MS, Platts Mills JA, et al. Shigellosis. Lancet. 2018;391:801810. Table 245.2 Clinical Complications of Shigellosis INTESTINAL COMPLICATIONS Rectal prolapse Toxic megacolon Intestinal perforation Intestinal obstruction Appendicitis Persistent diarrhea EXTRAINTESTINAL COMPLICATIONS Dehydration Severe hyponatremia (serum sodium 126 mmolL) Hypoglycemia Focal infections (e.g., meningitis, osteomyelitis, arthritis, splenic abscesses, vaginitis) Sepsis, usually in malnourished or immunocompromised persons Seizure or encephalopathy Leukemoid reaction (peripheral leukocytes 40 000L) POSTINFECTIOUS MANIFESTATIONS Hemolytic uremic syndrome (HUS) Reactive arthritis Irritable bowel syndrome (IBS) Malnutrition Significantly more common in episodes with Shigella dysenteriae type 1 than with all other Shigella spp. among Bangladeshi children younger than 15 yr during the 1990s (rectal prolapse 52 vs 15, severe hyponatremia 58 vs 26, leukemoid reaction 22 vs 2, and HUS 8 vs 1). Typical acute symptoms include asymmetric oligoarthritis (usually lower limb), enthesitis, dactylitis, and back pain. Extraarticular manifestations include conjunctivitis and uveitis; urethritis and other genitourinary tract manifestations; oral, skin, and nail lesions; and rarely, cardiac abnormalities. IBS follows approximately 4 of Shigella episodes in studies from high resource settings. Adapted from Kotloff KL, Riddle MS, Platts Mills JA, et al. Shigellosis. Lancet. 2018;391:801810. 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 245 u Shigella 1779 demonstration in peripheral blood of leukocytosis with a dramatic left shift (often with more bands than mature segmented |
7,292 | neutrophils). The total peripheral white blood cell count is usually 5,000 15,000 cellsL, although leukopenia and leukemoid reactions occur. Culture of both stool and rectal swab specimens optimizes the chance of diagnosing Shigella infection. Culture media should include Mac Conkey agar and selective media such as xylose lysine deoxycholate and Salmonella Shigella agar. Transport media should be used if speci mens cannot be cultured promptly. Appropriate media should be used to exclude Campylobacter and Salmonella spp. and other agents. Stud ies of outbreaks and illness in volunteers show that the laboratory is often not able to confirm the clinical suspicion of shigellosis even when the pathogen is present. Multiple fecal cultures improve the yield of Shigella. Culture based diagnosis of Shigella infection, as with other enteric infections, is being displaced by molecular methods, often multiplexed, allowing testing for a panel of potential agents in a single rapid assay. Studies using molecular methods such as poly merase chain reaction (PCR) suggest that culture significantly underestimates the true frequency of infection. Quantitative PCR improves the ascertainment of Shigella burden in children with moderate to severe diarrhea in low income countries. The gener ally high negative predictive value (NPV) of many molecular tests for Shigella (generally 9597) make the tests useful for decisions regarding antibiotic use and discontinuation and the necessity to test for additional etiologies of diarrhea. Molecular testing provides no information about antibiotic susceptibility. Stool cultures should be considered where antibiotic resistant organisms are prevalent. In children who appear toxic, blood cultures should be obtained, especially in very young or malnourished infants, because of their increased risk of bacteremia. TREATMENT As with gastroenteritis from other causes, the first concern in a child with suspected shigellosis should be for fluid and electrolyte correc tion and maintenance (see Chapter 387). Drugs that impair intestinal motility (e.g., diphenoxylate hydrochloride with atropine Lomotil or loperamide Imodium) should not be used because of the risk of more severe and prolonged illness. Nutrition is a key concern in areas where malnutrition is common. A high protein and high caloric diet during convalescence enhances growth in 6 months after infection. Controlled studies show that cooked green bananas, a food rich in amylase resistant starches, sig nificantly improves outcome in severe disease. A single large dose of vitamin A (200,000 IU) lessens the severity of shigellosis in settings where vitamin A deficiency is common. Zinc supplementation (20 mg elemental zinc for 14 days) significantly decreases the duration of diarrhea, improves weight gain during recovery, enhances adaptive immunity to Shigellae, and decreases diarrheal disease in malnour ished children. The decision to use antibiotics remains challenging (Fig. 245.1). Many experts recommend withholding antibacterial therapy because of the self limited nature of the infection, the cost of drugs, the risk of emergence of resistant organisms, the risk of prolonging carriage (if Salmonella is present), or increasing the risk for HUS (EHEC). When a rapid multiplexed molecular stool pathogen detection test is available, waiting for a definitive diagnosis before administrating antibiotics should be |
7,293 | considered. However, a counter argument of empirical treatment for all children with suspected shigellosis has validity. Untreated illness can cause a child to have prolonged illness; chronic or recurrent diarrhea can ensue. Malnutrition can develop or worsen during prolonged illness, particularly in children in devel oping countries. The risk of continued excretion and subsequent infection of family contacts further argues against the strategy of withholding antibiotics. Shigella antimicrobial susceptibility varies by species and geography. In the United States, strains are frequently resistant to ampicillin (74) and trimethoprim sulfamethoxazole (TMP SMX) (36). In general, the proportion of antibiotic resistant isolates is lower in North Amer ica and Europe than in Asia or Africa. Previously, Shigella was widely regarded as susceptible in vitro to azithromycin, ceftriaxone, cefo taxime, cefixime, nalidixic acid, and quinolones. However, the Cen ters for Disease Control and Prevention (CDC) reports that 87 of S. sonneirelated U.S. cases are ciprofloxacin nonsusceptible, of which only approximately half followed international travel. Among MSM, clusters of shigellosis caused by S. sonnei and, to a lesser extent, S. flexneri were reported with up to 87 azithromycin resistance. Inter national travel increases the risk for antibiotic resistant infection. For example, Chinese isolates of S. sonnei are often resistant to TMP SMX (94.5), ampicillin (40.3), piperacillin (36.5), and ceftriaxone (12.8). Currently, in most developed and resourcepoor countries, Shigella strains are often resistant to ampicillin and TMP SMX. Therefore these drugs should not be used for empirical treatment of suspected shigellosis; they should be instituted only if the strain is known to be susceptible (e.g., in an outbreak caused by a defined strain). Empiri cal therapy in children with dysentery should be given based on considerations of regional infection cluster data and international travel history. Ceftriaxone (50 100 mgkg24 hr as a single daily dose intravenously or intramuscularly) can be used for empirical therapy, especially for small infants. The oral third generation cephalosporin cefixime (8 mgkg24 hr divided every 12 24 hours) may be consid ered, although treatment failures for S. sonnei infections have been reported in adults; oral first and second generation cephalosporins are inadequate as alternative drugs despite in vitro susceptibility. Azithromycin (12 mgkg24 hr orally for the first day, followed by 6 mgkg24 hr for the next 4 days) has proved to be an effective alterna tive drug for shigellosis. Ciprofloxacin (20 30 mgkg24 hr divided into two doses) is the drug of choice recommended by the WHO for all patients with bloody diarrhea, regardless of age. Note that since 2015, the CDC has tracked increasing resistance and reduced sus ceptibility to ciprofloxacin and azithromycin in the United States. Concurrent zinc supplementation is recommended with antibiotic therapy. Although quinolones are reported to cause arthropathy in imma ture animals and are associated with neuropathy, these risks are low in children and are outweighed by the value of these drugs for the treatment of this potentially life threatening disease. However, some experts recommend that the quinolones be reserved for seri ously ill children with bacillary |
7,294 | dysentery caused by an organism suspected or known to be resistant to other agents, because over use of quinolones promotes the development of resistance to these drugs. Treatment of patients in whom Shigella infection is suspected on clinical grounds should be initiated when these patients are first evaluated. Molecular stool testing or culture is obtained to exclude other pathogens and, in the case of culture, to assist in antibiotic changes should a child fail to respond to empirical therapy. A child who has typical dysentery and who responds to initial empirical anti biotic treatment should be continued on that drug for a full 5 day course even if the stool culture is negative, because of the methods low NPV. The logic of this recommendation is based on the proven difficulty of culturing Shigella from stools of ill patients during adult volunteer infection studies. In a child who fails to respond to therapy of a dysenteric syndrome in the presence of initially negative stool culture results, additional cultures should be obtained, or molecular testing, where available and cost permissive, should be performed, and the child should be reevaluated for other possible diagnoses. In the child with negative molecular stool testing for Shigellae, the high NPV makes the diagnosis less likely, and alternative diagnoses should be considered. PREVENTION Numerous measures have been recommended to decrease the risk of Shigella transmission to children. Mothers should be encouraged to prolong breastfeeding of infants. Families and daycare personnel 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. 1780 Part XV u Infectious Diseases should be educated in proper handwashing techniques and encouraged to wash hands after using the toilet, changing diapers, or engaging in preparation of foods. They should be taught how to manage poten tially contaminated materials such as raw vegetables, soiled diapers, and diaper changing areas. Children with diarrhea should be excluded from childcare facilities. Children should be supervised when hand washing after they use the toilet. Caretakers should be informed of the risk of transmission if they prepare food when they are ill with diar rhea. Families should be educated regarding the danger of swallowing contaminated water from ponds, lakes, or untreated pools. In develop ing countries, a safe water supply and appropriate sanitation systems are important measures for reducing the risk for shigellosis. There is not yet a vaccine that is effective for preventing infection by Shigella. Measles immunization can substantially reduce the incidence and severity of diarrheal diseases, including shigellosis. Every infant should be immunized against measles at the recommended age. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Firstline: Oral therapy Ciprofloxacin 15 mgkg twice daily for 3 days Parenteral therapy Ceftriaxone 50100 mg once daily for 3 days, intravenous or intramuscular PLUS Zinc 20 mg (10 mg for infants 6 months) for 1014 days, by mouth Adults Yes No Yes No Yes No Firstline: |
7,295 | Oral therapy Ciprofloxacin 500 mg once a day for 3 days Parenteral therapy Ceftriaxone 1 g every 24 h for 3 days, intravenous or intramuscular Secondline oral therapy: Azithromycin 12 mgkg once on day 1, then 6 mgkg once daily on days 24 (total course 4 days), oral Cefixime 8 mgkg once daily for 3 days, oral Trimethoprimsulfamethoxazole: 4 mgkg of trimethoprim and 20 mgkg sulfamethoxazole twice a day for 5 days Finish therapy Finish therapy Adjust therapy based on susceptibilities Choose different firstline or secondline therapy not used previously Consider if amebiasis is possible and give 5 days of oral metronidazole Children: 20 mgkg three times per day Adults: 500750 mg three times per day Known antibiotic susceptibilities? Improvement after 48 h of antibiotics? Improvement after an additional 48 h of antibiotics? Children Secondline oral therapy: Azithromycin 1 g for 1 day OR 500 mg every 12 h for 1 day, oral Cefixime 400 mg once daily for 3 days, oral Trimethoprimsulfamethoxazole: 160 mg of trimethoprim and 800 mg sulfamethoxazole twice a day for 5 days Fig. 245.1 Management algorithm: guidelines for treatment of shigellosis. Empirical therapy should be directed by hospital, clinical laboratory, or public health antibiograms whenever possible. Minimal inhibitory concentrations of 0.12 1.0 gmL for ciprofloxacin might be considered susceptible by laboratory standards but could harbor resist ance genes known to confer decreased susceptibility. Fluoroquinolo nes and azithromycin should be used with caution in patients taking the antimalarial artemether, because these drugs can prolong the QT inter val on the electrocardiogram and trigger arrhythmias. Trimethoprim sulfamethoxazole should be used if susceptibility is known or expected based on local data. Per WHO recommendations. Another acceptable regimen is a 7 to 10 day course of metronidazole followed by a luminal agent such as paromomycin or diiodohydroxyquinoline. (Data from The selection and use of essential medicines: report of the WHO Expert Committee, 2017. Geneva: World Health Organization; 2017. WHO technical report series; no. 1006.) Escherichia coli is an important cause of intraintestinal and extraint estinal infections. Intraintestinal infections present as diarrheal ill nesses. Extraintestinal infections include disease of the urinary tract (see Chapter 575), bloodstream (Chapters 148, 220, and 221), and cen tral nervous system (Chapter 643). E. coli causing extraintestinal and intraintestinal infections carry unique genetic attributes that encode different sets of virulence factors and genetic programs. Extraintestinal pathogenic E. coli increasingly harbor multidrug resistances, includ ing transferrable plasmids resulting in extended spectrum lactamase (ESBL) production and resistance to penicillins, cephalosporins, and aztreonam. Carbapenemase bearing E. coli have also emerged, often in combination with multiantibiotic class resistance, resulting in highly drug resistant strains. E. coli are members of the Enterobacteriaceae family and are fac ultative anaerobic, gram negative bacilli that usually ferment lactose. Most fecal E. coli organisms are commensal, are ubiquitous among the human gut microbiota starting in the first month of life, and do not cause diarrhea. Six major groups of diarrheagenic E. coli pathotypes have been characterized based on clinical, biochemical, and molecular genetic features: |
7,296 | enterotoxigenic E. coli (ETEC); enteroinvasive E. coli (EIEC); enteropathogenic E. coli (EPEC); Shiga toxinproducing E. coli (STEC), also known as enterohemorrhagic E. coli (EHEC) or verotoxin producing E. coli (VTEC); enteroaggregative E. coli (EAEC or EggEC); and diffusely adherent E. coli (DAEC). E. coli strains can also be categorized by their serogroup, where O refers to the lipopolysaccharide (LPS) O antigen or serotype and H refers to the flagellar antigen, for example, E. coli O157:H7. However, because each pathotype contains many serotypes (e.g., 117 ETEC sero types have been identified) and some serotypes can belong to more than one pathotype (e.g., O26:H11 can be either EPEC or EHEC depending on which specific virulence genes are present), serotyping usually does not provide definitive identification of pathotypes. Virulence characteristics and the association of those traits with ill ness define enteric E. coli pathogenicity (Table 246.1). The mechanism by which E. coli produces diarrhea typically involves specific adher ence to a glycoprotein or glycolipid receptor on a target intestinal cell, followed by production of a factor that injures or disturbs the func tion of intestinal cells. The genes for virulence properties and antibiotic resistance are often carried on transferable plasmids, pathogenicity islands, or bacteriophages. In the developing world, diarrheagenic E. coli cause frequent infec tions in the first years of life and are responsible for 3040 of all diar rhea cases in children worldwide. Cases peak during the warm months in temperate climates and during rainy season months in tropical cli mates. Most diarrheagenic E. coli strains (except STEC) require a large inoculum of organisms to induce disease, thus necessitating exposure to grossly contaminated ingestible materials. Infection is most likely when food handling or sewage disposal practices are suboptimal. The diarrheagenic E. coli pathotypes are also important in North America and Europe, although their epidemiology is less well defined in these areas than in the developing world. In North America, the various diar rheagenic E. coli strains may cause as much as 30 of infectious diar rhea in children 5 years old. A significant proportion of asymptomatic healthy children living in developing countries carry diarrheagenic E. coli pathotypes. Fecal contamination (human and animal), which is common in the low resource environments, facilitates the transmission of pathogens. Mod ern, highly sensitive microbiologic methods enhance the sensitivity Chapter 246 Escherichia coli Patrick C. Seed 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 246 u Escherichia coli 1781 of detection in stool samples, and small numbers of bacteria can be detected in stool samples. Therefore the prevalence of various entero pathogens in children with and without diarrhea must be considered. Excretion of enteropathogens by children without diarrhea may be explained by characteristics of the pathogens (virulence heterogene ity), the host (host susceptibility, age, nutritional status, breastfeeding, immunity), and environmental factors (inoculum size). ENTEROTOXIGENIC ESCHERICHIA COLI ETEC accounts for a |
7,297 | sizable fraction of dehydrating infantile diarrhea in the developing world (1030) and of travelers diarrhea (2060 of cases); ETEC is the most common cause of travelers diarrhea. The Global Enteric Multicenter Study (GEMS) found heat stable entero toxin (ST)expressing ETEC (with or without coexpression of heat labile enterotoxin LT) to be a leading cause of diarrhea and increased risk for death in young children in developing countries of Asia and Africa. The typical signs and symptoms include explosive watery, non mucoid, nonbloody diarrhea; abdominal pain; nausea; vomiting; and little or no fever. The illness is usually self limited and resolves in 3 5 days but occasionally lasts 1 week. Diarrhea follows ETEC colonization of the small intestine and elaboration of enterotoxin; however, ETEC causes few to no structural alterations in the gut mucosa. ETEC strains secrete one or two entero toxins. LT, a large molecule consisting of five receptor binding subunits Table 246.1 Clinical Characteristics, Pathogenesis, and Diagnosis of Diarrheagenic E. coli PATHOGEN POPULATIONS AT RISK CHARACTERISTICS OF DIARRHEA MAIN VIRULENCE FACTORS DIAGNOSISWATERY BLOODY DURATION ADHERENCE FACTORS TOXINS ETEC 1 yr old and travelers Acute Colonization factor antigens (CFs or CFAs); ECP Heat labile enterotoxin (LT) Heat stable enterotoxin (ST) Detection of enterotoxins (LT and ST) by enzyme immunoassays or PCR (lt, st) EIEC 1 yr old Acute Invasion plasmid antigen (IpaA D) Detection of invasion plasmid antigen of Shigella (ipaH) by PCR EPEC 2 yr old Acute, prolonged or persistent AE lesion, intiminTir, EspABD, Bfp EspF, Map, EAST1, SPATEs (EspC) Detection of intimin gene (eae) bundle forming pili (bfpA) by PCR and absence of Shiga toxins; HEp 2 cells adherence assay (LA, LLA) STEC (EHEC VTEC) 6 mo to 10 yr and elderly persons Acute AE lesion, intiminTir, EspABD Shiga toxins (Stx1, Stx2, and variants of Stx2) Detection of Shiga toxins by enzyme immunoassays or PCR (Stx1, Stx2); stool culture on MacConkey sorbitol media to detect E. coli O157. Simultaneous culture for O157 and nonculture assays to detect Shiga toxins EAEC 2 yr old, HIV infected patients, and travelers Acute, prolonged, or persistent Aggregative adherence fimbriae (AAF) SPATEs (Pic, Pet), ShET1, EAST1 Detection of AggR, AA plasmid, and other virulence genes: aap, aatA, astA, set1A by PCR; HEp 2 cells adherence assay (AA) DAEC 1 yr old and travelers Acute AfaDr, AIDA I SPATEs (Sat) Detection of Dr adhesins (daaC or daaD) and Dr associated genes by PCR; HEp 2 cells adherence assay (DA) , Not present; , present; , common; , very common; AE lesion, attaching and effacing lesion; AA, aggregative adherence; Bfp, bundle forming pili; DA, diffuse adherence; DAEC, diffusely adherent E. coli; EAEC, enteroaggregative E. coli; EAST1, enteroaggregative heat stable toxin; ECP, E. coli common pilus; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; EspABD, E. colisecreted proteins A, B, and D; ETEC, enterotoxigenic E. coli; LA, localized adherence; LLA, localized like adherence; PCR, polymerase chain reaction; ShET1, Shigella enterotoxin 1; SPATEs, serine protease autotransporter of Enterobacteriaceae; STEC, Shiga toxinproducing E. coli; |
7,298 | Tir, translocated intimin receptor; VTEC, verotoxin producing E. coli. 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. 1782 Part XV u Infectious Diseases and one enzymatically active subunit, is structurally, functionally, and neutralizing antibody cross reactive with cholera toxin produced by Vibrio cholerae. LT stimulates adenylate cyclase, resulting in increased cyclic adenosine monophosphate. ST is not related to cholera toxin and stimulates guanylate cyclase, resulting in increased cyclic guanosine monophosphate. Each toxin induces ion and water secretion into the intestinal lumen, resulting in profuse watery diarrhea. The toxin genes are carried on plasmids. Colonization of the intestine requires fimbria colonization factor antigens (CFAs), which promote adhesion to the intestinal epithelium. Over 25 CFA types exist and can be expressed alone or in combination. Roughly 3050 of ETEC isolates lack a characterized CFA. However, novel CFAs continue to be identified. CFAs are highly immunogenic, but their multiplicity and allelic variation elude vaccine development. Many strains produce a type IV pilus involved in colonization and shared among other gram negative bacterial pathogens. ETEC express type 1 pili (the common pilus), produced by commensal and pathogenic E. coli strains. TibA, a non fimbrial adherence factor, mediates potent bacterial attachment and invasion of cells. For many years, the O serogroup was used to distin guish pathogenic from commensal E. coli. Molecular classification of pathogenic E. coli based on specific virulence genes and whole genome phylogeny has largely replaced classic O serogroup typing. ENTEROINVASIVE ESCHERICHIA COLI EIEC infections produce watery diarrhea or dysentery with blood, mucus, and leukocytes in the stools, as well as fever, systemic toxicity, crampy abdominal pain, tenesmus, and urgency. The illness resembles bacillary dysentery because EIEC shares virulence genes with Shigella spp. Sequencing of multiple housekeeping genes indicates that EIEC is more related to Shigella than to noninvasive E. coli. EIEC diarrhea occurs mostly in outbreaks; however, endemic disease occurs in devel oping countries. In some areas of the developing world, as many as 5 of sporadic diarrhea episodes and 20 of bloody diarrhea cases are caused by EIEC (see Chapter 245). EIEC behave like Shigella in their capacity to invade gut epithelium and cause colonic lesions with ulcerations, hemorrhage, mucosal and submucosal edema, and infiltration by polymorphonuclear leuko cytes (PMNs). The invasive process involves initial entry into cells, intracellular multiplication, intracellular and intercellular spread, and host cell death. All bacterial genes necessary for entry into the host cell are clustered within a 30 kb region of a large virulence plasmid; these genes are closely related to those found on the invasion plasmid of Shigella spp. This region carries genes encoding the entry mediating proteins, including proteins that form a needle like injection appara tus called type III secretion, required for secreting the invasins (IpaA D and IpgD). The Ipas are the primary effector proteins of epithelial cell invasion. EIEC contact with host cells triggers |
7,299 | the syringe like type III secretion apparatus and injection of Ipas into the host cell cytoplasm. Like Shigella spp., EIEC are nonmotile (they lack H or flagellar anti gens) and are usually nonlactose fermenting. The serogroups of EIEC share LPS antigens related to Shigella LPS. ENTEROPATHOGENIC ESCHERICHIA COLI EPEC causes acute, prolonged, and persistent diarrhea, primarily in children 2 years old in resourcepoor countries, where the organ ism may account for 20 of infant diarrhea. In developed countries, EPEC causes occasional daycare center and pediatric ward outbreaks. Profuse watery, nonbloody diarrhea with mucus, vomiting, and low grade fever are common symptoms. Prolonged diarrhea (7 days) and persistent diarrhea (14 days) can lead to malnutrition, a potentially mortality associated outcome of EPEC infection in infants in the developing world. Studies show that breastfeeding is protective against diarrhea caused by EPEC. EPEC colonization causes blunting of intestinal villi, local inflam matory changes, and sloughing of superficial mucosal cells; EPEC induced lesions extend from the duodenum through the colon. EPEC induces a characteristic attaching and effacing histopathologic lesion, which is defined by the intimate attachment of bacteria to the epithelial surface and effacement of host cell microvilli. Factors responsible for the attaching and effacing lesion formation are encoded by the locus of enterocyte effacement (LEE), a pathogenicity island with genes for a type III secretion system, the translocated intimin receptor (Tir) and inti min, and multiple effector proteins such as the E. colisecreted proteins (EspA B D). Some strains adhere to the host intestinal epithelium in a pattern known as localized adherence, a trait that is mediated in part by the type IV bundle forming pilus (Bfp) encoded by a plasmid (the EAF plasmid). After initial contact, proteins are translocated through fila mentous appendages, forming a physical bridge between the bacteria and the host cell; bacterial effectors (EspB, EspD, Tir) are translocated through these conduits. Tir moves to the surface of host cells, where it is bound by a bacterial outer membrane protein intimin (encoded by the eae gene). Intimin Tir binding triggers polymerization of actin and other cytoskeletal components at the site of attachment. These cyto skeletal changes result in intimate bacterial attachment to the host cell, enterocyte effacement, and pedestal formation. Other LEE encoded effectors include Map, EspF, EspG, EspH, and SepZ. Various other effector proteins are encoded outside the LEE and secreted by the type III secretion system (the nonLEE encoded pro teins, or Nle). The contribution of these putative effectors (e.g., NleA EspI, NleB, NleC, NleD) to virulence is still under investigation. The presence and expression of virulence genes vary among EPEC strains. The eae (intimin) and bfpA genes serve as molecular markers of EPEC and genetically subdivide EPEC into typical and atypical strains. E. coli strains that are eaebfpA are classified as typical EPEC; most of these strains belong to common O:H serotypes. E. coli strains that are eaebfpA are classified as atypical EPEC. Current data sug gest that atypical EPEC are more prevalent than typical EPEC in |
7,300 | both developed and developing countries, even in persistent diarrhea cases. In the GEMS study, typical EPEC was most associated with increased risk of mortality, particularly in infants in Africa. ENTEROAGGREGATIVE ESCHERICHIA COLI EAEC infection produces (1) acute, prolonged, and persistent pedi atric diarrhea in developing countries, most prominently in children 2 years old and in malnourished children; (2) acute and persistent diarrhea in HIV infected adults and children; and (3) acute travelers diarrhea; EAEC is the second most common cause of travelers diar rhea after ETEC. Typical EAEC illness is manifested by watery, mucoid, secretory diarrhea with low grade fever and little or no vomiting. The watery diarrhea can persist for 14 days. Patients with EAEC may have grossly bloody stools, and EAEC cannot be excluded on stool charac teristics. EAEC colonization and infection lead to growth retardation and malnutrition in infants in the developing world. EAEC organisms form a characteristic biofilm on the intestinal mucosa and induce shortening of the villi, hemorrhagic necrosis, and inflammatory responses. The proposed model of pathogenesis of EAEC infection involves three phases: adherence to the intestinal mucosa by way of the aggregative adherence fimbriae or related adhesins, stimula tion of enhanced mucus production, and toxin mediated inflammation that results in damage to the mucosa and intestinal secretion. Diarrhea caused by EAEC is predominantly secretory. The intestinal inflamma tory response (elevated fecal lactoferrin, interleukin IL 8 and IL 1) may be related to growth impairment and malnutrition. EAEC strains adhere in an aggregative, stacked brick pattern, called aggregative adherence (AA), mediated by the AA fimbriae (AAF I, II, and III). Some strains produce toxins, including the plasmid encoded enterotoxin EAST1 (encoded by astA), a homolog of the ETEC ST; an autotransporter toxin called Pet; other STATE toxins; and the chromo somally encoded enterotoxin ShET1 (encoded by setA and setB). Other virulence factors include outer membrane and secreted proteins, such as dispersin (aap), and the dispersin transport complex (aatPABCD). EAEC is a heterogeneous group of E. coli. A transcriptional activator called AggR controls the expression of plasmid borne and chromo somal virulence factors. Identification of AggR appears to reliably identify illness associated pathogenic EAEC strains (typical EAEC). EAEC aggR positive strains carrying one to three of the genes aap, astA, and set1A are significantly associated with diarrhea compared 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 246 u Escherichia coli 1783 with EAEC isolates lacking these genes. Other than the AAF and AggR factors, EAEC strains are genetically diverse, display variable virulence, and belong to multiple serogroups. SHIGA TOXINPRODUCING ESCHERICHIA COLI The STEC, which include EHEC, produce a range of clinical syndromes from asymptomatic colonization, to mild diarrhea, to severe hemor rhagic colitis. Watery diarrhea that becomes bloody over several days characterizes STEC illness. STEC infrequently causes fever, a distin guishing difference with shigellosis or EIEC disease. Most people |
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