chunk_id int64 1 8.2k | text stringlengths 1.34k 5.06k |
|---|---|
7,301 | with STEC recover from the infection without further complication. How ever, 510 of children with STEC hemorrhagic colitis go on within a few days to develop systemic complications such as hemolytic uremic syndrome (HUS), characterized by acute kidney failure, thrombocy topenia, and microangiopathic hemolytic anemia (see Chapter 560). Severe illnesses occur most often among children 6 months to 10 years old. Young children with STEC associated bloody diarrhea and neu trophilic leukocytosis in the early course of their diarrhea are at risk for HUS progression. Older individuals can also develop HUS or throm botic thrombocytopenic purpura. STEC transmits person to person (e.g., in families and daycare cen ters) and in contaminated food and water; a small inoculum can lead to infection. STEC food borne outbreaks have arisen from undercooked hamburger, apple cider, lettuce, spinach, mayonnaise, salami, dry fer mented sausage, and unpasteurized dairy products. STEC primarily affects the colon, where organisms adhere to intesti nal cells and produce attaching effacing lesions such as those seen with EPEC and contain related genes (e.g., intimin, Tir, EspA D). Unlike EPEC, STEC produces two major Shiga toxins (Stx1 and Stx2; previ ously called verotoxins and Shiga like). STEC may produce one or both toxins and their closely related variants. Stx1 is essentially identical to Shiga toxin, the protein synthesisinhibiting exotoxin of Shigella dys enteriae serotype 1. Stx2 and variants of Stx2 are more distantly related to Shiga toxin, although they share conserved sequences. STEC Shiga toxins are composed of a single A subunit noncovalently associated with a pentamer composed of identical B subunits. The B subunits bind to globotriaosylceramide (Gb3), a glycosphingolipid receptor on host cells. The A subunit is taken up by endocytosis. The toxin target is the 28S ribosomal RNA (rRNA), which is depurated by the toxin at a specific adenine residue, causing protein synthesis to cease and affected cells to die. These toxins are carried on bacteriophages that are normally inactive (lysogenic) in the bacterial chromosome; when the phages are induced to replicate (e.g., by the stress induced by many antibiotics), they cause lysis of the bacteria and release of large amounts of toxin. Toxin translocation across the intestinal epithelium into the systemic circulation can lead to damage of vascular endothelial cells, resulting in activation of the coagulation cascade, formation of microthrombi, intravascular hemolysis, and ischemia. The clinical outcome of an STEC infection depends on a strain specific combination of epithelial attachment and the toxin factors. The Stx2 toxins are associated with a higher risk of causing HUS. Strains producing only Stx1 often cause only watery diarrhea and, infre quently, HUS. The most common STEC serotypes are E. coli O157:H7, E. coli O111:NM, and E. coli O26:H11, although several hundred other STEC serotypes have also been described. E. coli O157:H7 is the most viru lent serotype and the serotype most frequently associated with HUS; however, other non O157 serotypes also cause this illness. ENTEROAGGREGATIVE HEMORRHAGIC ESCHERICHIA COLI In 2011, a massive outbreak of an unusual O104:H4 strain of diarrhea genic |
7,302 | E. coli began in Germany. Eventually, 4,000 individuals were sickened with hemorrhagic colitis; the outbreak involved primarily adults (100 children were reported affected). More than 800 people developed HUS, and 50 of these individuals died. Genomic analysis suggested the outbreak strain was most closely related to EAEC and had acquired a lambdoid bacteriophage with genes for Shiga toxin Stx2a. It was thus a hybrid pathogen with colonization mechanisms similar to a typical EAEC strain and toxin production typical of an STEC strain. This outbreak strain carries Pic on the chromosome and a pAA like plasmid encoding AAF, AggR, Pet, ShET1, and dispersin. A second virulence plasmid encodes multiple antibiotic resistances. The high morbidity and mortality associated with this strain may reflect the stronger adherence of EAEC compared with STEC, delivering more Stx to target cells. Alternative terminology for this strain includes enteroaggregative hemorrhagic E. coli and Shiga toxinproducing EAEC. Whether Shiga toxin production in an EAEC background mer its separate classification is unclear. Organisms with Shiga toxin genes in an atypical EPEC background were designated as a separate group (referred to as STEC, EHEC, or verotoxin producing E. coli) before the relative importance of the various genes was clear. EPEC strains are a heterogeneous group themselves. The important issue is not the nomenclature, but rather the concept that virulence genes can move between E. coli, resulting in new variants. DIFFUSELY ADHERENT ESCHERICHIA COLI Multiple studies in both developed and developing countries find DAEC associated with diarrhea, particularly in children after the first 1 2 years of life. DAEC strains isolated from children and adults seem to represent two different bacterial populations. Age dependent sus ceptibility or the use of inappropriate detection methods may explain discrepancies among epidemiologic studies. Data suggest that these organisms also cause travelers diarrhea in adults. DAEC produces pro longed watery diarrhea that is usually not dysenteric. DAEC strains produce diffuse adherence on intestinal epithelial cells using the AfaDr like surface fimbriae (designated F1845). The outer membrane protein AIDA I also associates with diffuse adher ence. DAEC secrete the serine protease autotransporters of Enterobac teriaceae (SPATE) cytotoxin Sat. Bacteria expressing AfaDr adhesins interact with membrane bound receptors, including decay accelerating factor (DAF). The structural and functional lesions induced by DAEC include loss of microvilli and a decrease in the expression and enzyme activities of functional brush borderassociated proteins. AfaDr DAEC isolates produce a secreted autotransporter toxin that induces marked fluid accumulation in the intestine. DAEC strains typically induce IL 8 production in vitro. DIAGNOSIS The features of suspected E. coli diarrheal illness are seldom distinc tive enough to allow confident diagnosis strictly on clinical observa tions and routine laboratory studies such as blood counts. Practical, nonDNA dependent methods for routine diagnosis of diarrheagenic E. coli have been developed primarily for STEC. Serotype O157:H7 is suggested by isolation of an E. coli that fails to ferment sorbitol on MacConkey sorbitol medium; latex agglutination confirms that the organism contains O157 LPS. Commercially available enzyme immunoassay or latex agglutination assays |
7,303 | detect Shiga toxins in the routine hospital laboratory, although their variable sensitivity may limit their value. Commercial assays such as the FilmArray Gastrointestinal Panel and Eurofins Diatherix Panel rapidly detect genetic markers for EPEC, EAEC, ETEC, STEC, and EIEC, among other pathogen genes, directly from a fecal sample in several hours and have been shown to reduce hospitalizations and treatment costs. Although some STEC (O157:H7 strains) can be detected in routine microbiology laboratories using selective media and appropriate antisera, the diagnosis of other diar rheagenic E. coli infection is traditionally made based on tissue culture assays (e.g., HEp 2 cells assay for EPEC, EAEC, and DAEC) or identi fication of specific virulence factors of the bacteria by phenotype (e.g., toxins) or genotype. Multiplex, real time, or conventional polymerase chain reaction (PCR) can be used for presumptive diagnosis of isolated E. coli colonies. The genes commonly used for diagnostic PCR are lt and st for ETEC; IpaH or iaL for EIEC; eae and bfpA for EPEC; eae, Stx1, and Stx2 for STEC; AggR or the AA plasmid for EAEC; and daaC or daaD for DAEC. Serotyping does not provide definitive identification of pathotypes (except for selected cases such as O157:H7) because each pathotype 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. 1784 Part XV u Infectious Diseases contains many serotypes and some serotypes can belong to more than one pathotype. Consequently, serotyping should not be used routinely for diarrheagenic E. coli identification in clinical laboratories (e.g., to diagnose EPEC in infantile diarrhea), except during an outbreak investigation. Other laboratory data are, at best, nonspecific indicators of etiology. Fecal leukocyte examination of the stool is often positive with EIEC or occasionally positive with other diarrheagenic E. coli. With EIEC and STEC there may be an elevated peripheral blood PMN count with a left shift. Determination of Stx2 blood levels in the early, post bloody diar rhea period may be useful to identify children at risk of HUS; however, a validated clinical test is not readily available. Fecal lactoferrin, IL 8, and IL 1 can be used as inflammatory markers. Electrolyte changes are nonspecific, reflecting only fluid loss. TREATMENT The cornerstone of management is appropriate fluid and electro lyte therapy (Fig. 246.1). In general, this therapy should include oral replacement and maintenance with rehydration solutions such as those specified by the World Health Organization (WHO). Early volume expansion during STEC infection may reduce renal injury and improve patient outcomes. Upon refeeding, continued supplementation with oral rehydration fluids is appropriate to prevent recurrence of dehydra tion. Early refeeding (within 6 8 hours of initiating rehydration) with breast milk or infant formula or solid foods should be encouraged. Pro longed withholding of feeding can lead to chronic diarrhea and malnu trition. If the child is malnourished, oral zinc should be given to speed recovery and decrease the risk of |
7,304 | future diarrheal episodes. In children, validated criteria for antimicrobial therapy of diarrheal disease do not exist. The routine use of antimicrobials to treat child hood diarrhea is not recommended by the WHO except in severe cases. Nonbloody diarrhea rarely requires antimicrobial therapy. Anti microbials should be reserved for dysenteric presentations, when host immunity is compromised by specific disorders, malnutrition, and chronic disease (Table 246.2). Antimicrobials should also be consid ered for severe travelers diarrhea and diarrhea accompanied by fever and bloody stools. In settings of good healthcare resources, rapid molecular testing for STEC should be performed before initiating anti biotics, which can increase the risk for HUS. Emerging antimicrobial resistance among diarrheal E. coli and other bacterial pathogens complicates treatment. Multiple studies in devel oping countries have found that diarrheagenic E. coli strains typically are resistant to antibiotics such as trimethoprim sulfamethoxazole (TMP SMX) and ampicillin (6070). Most data come from case series or clinical trials in adults with travelers diarrhea. ETEC responds to antimicrobial agents such as TMP SMX when the E. coli strains are susceptible. ETEC cases from travelers diarrhea trials respond to cipro floxacin, azithromycin, and rifaximin. However, other than for a child recently returning from travel in the developing world, empirical treat ment of severe watery diarrhea with antibiotics is seldom appropriate. In resource poor settings where rapid molecular panel tests are not available, EIEC infections may be treated before culture results are finalized because the clinician suspects shigellosis and has begun empirical therapy. If the organisms prove to be susceptible, TMP SMX is an appropriate choice. Although treatment of EPEC infection with TMP SMX intravenously or orally for 5 days may be effective in speed ing resolution, the lack of a rapid diagnostic test in the resource poor setting makes treatment decisions difficult. Ciprofloxacin or rifaximin is useful for EAEC travelers diarrhea, but pediatric data are sparse. Specific therapy for DAEC has not been defined. The STEC strains represent a particularly difficult therapeutic dilemma; many antibiotics can induce bacterial stress, toxin produc tion, and phage mediated bacterial lysis with toxin release. Antibiotics should not be given for STEC infection because they can increase the risk of HUS (see Chapter 560). In settings with rapid molecular diag nostics, a delay in providing antibiotics is rarely consequential and can allow the clinician to more confidently recommend or exclude antibi otics from the therapeutic plan. PREVENTION OF ILLNESS In the developing world, prevention of disease caused by pediatric diarrheagenic E. coli is probably best done by maintaining prolonged breastfeeding, paying careful attention to personal hygiene, and fol lowing proper food and water handling procedures. People traveling Watery diarrhea Bloody diarrhea Rehydration Oral fluids, if tolerated IV fluids if oral fluids are not tolerated Rehydration Oral fluids, if tolerated IV fluids if oral fluids are not tolerated or severe clinical presentation Antimotility agents Not recommended for presumed or possible STECEHEC Adults: Fluoroquinolones Ciprofloxacin: 750 mg once or 500 mg twice per day for 3 days Levofloxacin: 500 mg once |
7,305 | or 500 mg daily for 3 days Azithromycin: 1,000 mg once or 500 mg daily for 3 days Rifaximin: 400 mg twice per day or 200 mg three times per day for 3 days Children: Azithromycin: 10 mgkg on day 1 and then 5 mgkg on days 2 and 3 Hospitalize IV hydration (0.9 NaCl or Lactated Ringers) Avoid antibiotics and antimotility agents to reduce risk for HUS Avoid nonsteroidal antiinflammatory agents (NSAIDS) to reduce kidney injury Do not use blood or platelet transfusions unless hemodynamically unstable, severe thrombocytopenia, or bleeding due to increased risk of HUS STECEHEC identified and 12 yrs old? Yes Antimotility agents Loperamide Adults: 4 mg then 2 mg following each unformed stool (max 16 mg per day by prescription; 8 mg per day over the counter). Use for 2 days maximum Children: Not recommended Bismuth salicylate Adults: 524 mg every 30 min for up to 8 doses Children : Not recommended due to risk of Rye syndrome Antibiotics May not be necessary for mild illness Consider when 2 unformed stools per day Adults: Fluoroquinolones Ciprofloxacin: 750 mg once or 500 mg twice per day for 3 days Levofloxacin : 500 mg once or 500 mg daily for 3 days Azithromycin: 1,000 mg once or 500 mg daily for 3 days Rifaximin: 400 mg twice per day or 200 mg three times per day for 3 days Children: Azithromycin: 10 mgkg on day 1 and then 5 mgkg on days 2 and 3 Fig. 246.1 Algorithmic treatment summary for presumed and pos sible E. coli diarrheal illness. Table 246.2 Risk Factors Favoring Antibiotic Therapy in Children with Acute Diarrhea RISK FACTOR EVIDENCE CHILD FACTORS Age 3 mo Poor evidence in general; strong indication for neonates Severe clinical presentation Poor evidence but strong indications Malnutrition Strong evidence Chronic disease and immune deficiency Strong evidence (IBD and HIV); otherwise poor evidence; strong indications SETTING FACTORS Daycare centers, closed institutions, hospitals Strong evidence if bacteria spread is a potential Travelers diarrhea Evidence for adult is strong; poor evidence in children 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 247 u Cholera 1785 to these places can be best protected by handwashing and consuming only processed water, bottled beverages, breads, fruit juices, fruits that can be peeled, or foods that are served steaming hot. Prophylactic antibiotic therapy is effective in adult travelers but has not been studied in children and is not recommended. Public health measures, including sewage disposal and food handling practices, have made pathogens that require a large inoculum to produce illness rela tively uncommon in industrialized countries where food screening and public health measures are robust. Food borne outbreaks of STEC are a problem for which no adequate solution has been found. During the occasional hospital outbreak of EPEC disease, attention to enteric iso lation precautions and cohorting may be |
7,306 | critical. Protective immunity against diarrheagenic E. coli remains an active area of research, and no vaccines are available for clinical use in chil dren. Multiple vaccine candidates based on bacterial toxins and colo nization factors have shown promise for prevention of ETEC in adult travelers, but long term protection with these vaccines has not been optimal, particularly in children. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 247 Cholera James P. Nataro Cholera is a dehydrating diarrheal disease that rapidly leads to death in the absence of immediate initiation of appropriate treatment. World wide, 1.3 billion people are at risk for cholera, resulting in an estimated 1 4 million cases and 95,000 deaths annually. Cholera is highly prone to producing outbreaks, and the ongoing outbreaks in Yemen and Haiti emphasize how cholera and potentially other infectious diseases can easily reemerge in areas that have long been considered free of the dis ease after a natural disaster or war related conflicts. ETIOLOGY Cholera is caused by Vibrio cholerae, a gram negative, comma shaped bacillus, subdivided into serogroups by its somatic O antigen. Of the 200 serogroups, only serogroups O1 and O139 have been associated with epidemics, although some non O1, non O139 V. cholerae strains (e.g., O75, O141) are pathogenic and can cause small outbreaks. A fla gellar H antigen is present but is not used for species identification. The O1 serogroup is further divided into classical and El Tor biotypes based on its biochemical characteristics. Since the turn of the 21st century, only O1 El Tor has been reported; hybrids and variants of V. cholerae O1 El Tor possessing classical genes have been reported worldwide. These hybrid and variant strains have been associated with more severe disease. Each biotype of V. cholerae can be further subdivided into Inaba, Ogawa, and Hikojima serotypes based on the antigenic determinants on the O antigen. Inaba strains have A and C antigenic determinants, whereas Ogawa strains have A and B antigenic determinants. Hiko jima strains produce all three antigenic determinants but are unstable and rare. Recent studies reveal that serotype switching results from a selection process as yet unidentified. EPIDEMIOLOGY The first six cholera pandemics originated in the Indian subcontinent and were caused by classical O1 V. cholerae. The seventh pandemic is the most extensive of all and is caused by V. cholerae O1 El Tor. This pandemic began in 1961 in Sulawesi, Indonesia, and has spread to the Indian subcontinent, Southeast Asia, Africa, Oceania, South ern Europe, and the Americas. In 1991, V. cholerae O1 El Tor first appeared in Peru before rapidly spreading in the Americas. Cholera becomes endemic in areas after outbreaks when a large segment of the population develops immunity to the disease after recurrent exposure. Although the Ganges River valley is the historical home of cholera, it is estimated that 90 of global cases now occur in Africa, where the disease remains highly endemic. In 1992 the first non O1 V. cholerae that resulted in epidemics was identified in |
7,307 | India and Bangladesh and was designated V. cholerae O139. From 1992 to 1994, this organism replaced O1 as the predomi nant cause of cholera in South Asia but has since been an uncommon etiologic agent. The hybrid El Tor strains were first identified sporadically in Ban gladesh. In 2004, during routine surveillance in Mozambique, isolates of V. cholerae O1 El Tor carrying classical genes were identified. Since then, hybrid and variant El Tor strains have been reported in other parts of Asia and Africa and have caused outbreaks in India and Viet nam. Although the classical biotype has virtually disappeared, its genes remain within the El Tor biotype. The current circulating strain in Haiti is closely related to the South Asian strain. Humans are the only known hosts for V. cholerae, but free living and plankton associated V. cholerae exist in the marine environment. The organism thrives best in moderately salty water but can survive in riv ers and freshwater if nutrient levels are high, as occurs when there is organic pollution such as human feces. The formation of a biofilm on abiotic surfaces and the ability to enter a viable but nonculturable state have been hypothesized as factors that allow V. cholerae to persist in the environment during interepidemic periods. Surface sea temperature, pH, chlorophyll content, the presence of iron compounds and chitin, and climatic conditions such as amount of rainfall and sea level rise are all important environmental factors that influence the survival of V. cholerae in the environment. Consumption of contaminated water and ingestion of under cooked shellfish are the main modes of transmission, but additional food sources are becoming increasingly common. In cholera endemic areas, the incidence is highest among children 2 years old, probably driven by the lack of previous exposure in young children. However, during cholera epidemics, all age groups are usually affected, particu larly in areas with no previous V. cholerae transmission. Persons with blood group O, decreased gastric acidity, malnutrition, immunocom promised states, and absence of local intestinal immunity (i.e., prior exposure) are at increased risk for developing severe disease. House hold contacts of cholera infected patients are at high risk of infection, because the stools of infected patients contain high concentrations of the pathogen. Moreover, upon repeated cycles of passage through humans, the organism becomes more virulent, demonstrating an increased number of copies of the cholera toxin encoding genes. PATHOGENESIS Large inocula of bacteria (108 colony forming units CFUs) are required for severe cholera to occur; however, for persons whose gas tric barrier is disrupted, a much lower dose (105 CFUs) is required, and the infectious dose may be lower after serial propagation of the patho gen through humans. After ingestion of V. cholerae from the environ ment, several changes occur in the microorganisms as they traverse the human intestine: increased expression of genes required for nutrient acquisition, downregulation of chemotactic responses, and expression of motility factors. Freshly excreted organisms (5 24 hours after shed ding) are maximally infectious and may |
7,308 | represent the predominant pathway for person to person transmission during epidemics. The principal virulence factors of V. cholerae O1 are the cholera toxin and the toxin coregulated pilus, a colonization factor that con fers adherence to the epithelium of the small intestine (Fig. 247.1). The cholera toxin consists of five binding B subunits and one active A subunit. The B subunits are responsible for binding to the GM1 gan glioside receptors located in the small intestinal epithelial cells. After binding, the A subunit is translocated into the cell, where it catalyzes adenosine diphosphate (ADP) ribosylation of the alpha subunit of the Gs signaling protein, which becomes constitutively active. Gs stimu lates adenylate cyclase, leading to accumulation of cyclic adenosine 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. 1786 Part XV u Infectious Diseases monophosphate and subsequent hyperactivation of the cystic fibro sis transmembrane conductance regulator (CFTR) chloride channel. Increased chloride and bicarbonate secretion by CFTR is accompanied by sodium and water loss into the small bowel, greatly exceeding the ability of the colon to reabsorb the fluid. These events eventually lead to massive purging of electrolyte rich stool, potentially resulting in rapid dehydration and depletion of electrolytes, including sodium, chloride, bicarbonate, and potassium. Metabolic acidosis and hypokalemia then ensue. CLINICAL MANIFESTATIONS Most cases of cholera are mild or inapparent. Among symptomatic individuals, approximately 20 develop severe dehydration that can rapidly lead to death. After a typical incubation period of 1 2 days (range: several hours to 5 days), acute watery diarrhea and vomiting ensue. The onset may be sudden, with profuse watery diarrhea, but some patients have a prodrome of anorexia and abdominal discomfort and the stool may initially be brown. Diarrhea can progress to pain less purging of profuse rice water stools (suspended flecks of mucus) with a fishy smell, which is the hallmark of the disease (Figs. 247.2 and 247.3). Fever is infrequent and suggests a different diagnosis. Vomiting with clear watery fluid is usually present at the onset of the disease. Stool from cholera patients typically contains more sodium (along with potassium and bicarbonate) compared with stool from diarrhea caused by other pathogens; the high stool volume, coupled with the presence of electrolytes, challenges clinicians to avoid dehydration and electro lyte imbalance. Muscle cramping and weakness commonly occur as a result of potassium and calcium imbalance. The term cholera gravis refers to the most severe form of the dis ease, characterized by rice water stools and fecal purging at rates of up to 500 1,000 mLhr. This condition inevitably leads to dehydration, manifested by decreased urine output, a sunken fontanel (in infants), sunken eyes, absence of tears, dry oral mucosa, shriveled hands and feet (washerwomans hands), poor skin turgor, thready pulse, and tachycardia. If left untreated, hypotension and vascular collapse are inevitable (see Fig. 247.3). Patients with metabolic acidosis can pres |
7,309 | ent with typical Kussmaul breathing. Although patients may be initially thirsty and awake, they rapidly progress to obtundation and coma. If fluid losses are not rapidly corrected, death can occur within hours. Cholera sicca is an unusual manifestation of severe cholera in which very rapid fluid loss is confined to the intestinal lumen; such patients may succumb to dehydration without frank diarrhea. LABORATORY FINDINGS Findings associated with dehydration such as elevated urine specific gravity and hemoconcentration are evident. Hypoglycemia is a com mon finding that is caused by decreased food intake during the acute illness. Serum potassium may be initially normal or even high in the presence of metabolic acidosis; however, as the acidosis is corrected, hypokalemia may become evident. Metabolic acidosis caused by bicarbonate loss and tissue hypoperfusion is a prominent finding in severe cholera. Serum sodium and chloride levels may be normal or decreased, depending on the severity of the disease. Serum calcium may be elevated because of hemoconcentration. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS In children who have acute watery diarrhea with severe dehydration residing in a cholera endemic area or who have recently traveled to an area known to have cholera, the disease may be suspected pend ing laboratory confirmation. Cholera differs from other diarrheal dis eases in that it often occurs in large outbreaks affecting both adults and children. Treatment of dehydration should begin as soon as possible. Diarrhea caused by other etiologies (e.g., enterotoxigenic Escherichia coli or rotavirus) may be difficult to distinguish from cholera clinically. Microbiologic isolation of V. cholerae remains the gold standard for diagnosis. Although definitive diagnosis is not required for treatment to be initiated, laboratory confirmation is necessary for epidemiologic surveillance. V. cholerae may be isolated from stools, vomitus, or rec tal swabs. Specimens may be transported on Cary Blair media if they cannot be processed immediately. Selective media, such as thiosulfate citratebile salts sucrose (TCBS) agar, should be used; V. cholerae exhibits a distinctive morphology on this medium, with confirmation made by serotyping. Because most laboratories in industrialized coun tries do not routinely culture for V. cholerae, clinicians should request appropriate cultures for clinically suspected cases. Rapid diagnostic tests are currently available and show high sensi tivity and specificity. These tests may be especially useful in areas with limited laboratory capacity, allowing early identification of cases at the Fig. 247.1 Cholera pathogenesis and cholera toxin action. After ingestion, Vibrio cholerae colonize the small intestine and secrete cholera toxin, which has a doughnut like structure with a central enzymatic toxic active A (CTA 1 CTA 2) subunit associated with a pentameric B subunit (CTB). After binding to GM1 ganglioside receptors on small intestinal epithelial cells, which are mainly localized in lipid rafts on the cell surface, the cholera toxin is endocytosed and transported to the degradosome via the endoplasmic reticulum (ER) by a retrograde pathway, which, dependent on cell type, may or may not involve passage through the Golgi apparatus. In the ER, CTA dissociates from CTB, allowing CTA 1 to reach |
7,310 | the cytosol by being translocated through the degradosome pathway. In the cytosol, CTA 1 subunits rapidly refold and bind to the Gs subunit of adenylate cyclase (AC) in the cell membrane; on binding, CTA 1 adenosine diphosphate (ADP) ribosylates the Gs subunit, which stimulates AC activity, leading to an increase in intracellular concentration of cyclic adenosine monophosphate (cAMP), activation of protein kinase A (PKA), phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel, and extracellular secretion of chloride ions (Cl) and water. Cholera toxinin duced Cl (and bicarbonate ion) secretion is particularly pronounced in intestinal crypt cells, whereas the increased intracellular cAMP concentrations in villus cells mainly inhibit the uptake of sodium chloride (NaCl) and water. (Adapted from Clemens J, Shin S, Sur D, et al. New generation vaccines against cholera. Nat Rev Gastroenterol Hepatol. 2011;8:701710; by permission of Nature Publishing Group.) 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 247 u Cholera 1787 onset of an outbreak and facilitating a timely response. Molecular iden tification with the use of polymerase chain reaction and DNA probes is available but often not feasible in areas where cholera exists. Stool examination reveals few fecal leukocytes and erythrocytes because cholera does not cause inflammation. Dark field microscopy may be used for rapid identification of typical darting motility in wet mounts of rice water stools, a finding that disappears once specific antibodies against V. cholerae O1 or O139 are added. COMPLICATIONS When optimally treated, patients with cholera typically recover fully without complications. Most adverse outcomes occur as a result of delayed or inadequate rehydration therapy. Renal failure from pro longed hypotension can occur. Unless potassium supplementation is provided, hypokalemia can lead to nephropathy and focal myocardial necrosis. Hypoglycemia is common among children and can lead to seizures unless it is appropriately corrected. Pneumonia is a frequent complication in young children and may be the result of aspiration during vomiting. TREATMENT Rehydration is the mainstay of therapy (see Chapter 74). Appropriate case management substantially decreases case fatalities to 1. Appli cation of World Health Organization (WHO) recommendations for diarrheal rehydration is recommended for all patients with diarrhea, but particularly when cholera is in the differential diagnosis. Children with mild or moderate dehydration may be treated with oral rehydra tion solution (ORS) unless the patient is in shock, is obtunded, or has intestinal ileus. Careful monitoring should occur during ORS, with attention to progression to more severe dehydration. Vomiting is not a contraindication to ORS. Severely dehydrated patients (10 body weight) require intravenous fluid, ideally with lactated Ringer solution. When available, rice based ORS should be used when oral rehydration is attempted, because this fluid has been shown to be superior to stan dard ORS in children and adults with cholera. The aim of rehydration should be replacement of the entire fluid deficit within 4 |
7,311 | hours, if pos sible. Careful monitoring of ongoing losses is essential. If stool volumes cannot be measured, losses may be roughly estimated at 10 20 mLkg of body weight for each episode of diarrhea or vomiting. After initial rehydration, patients should be reassessed every 1 2 hours, or more frequently if profuse diarrhea is ongoing; diarrhea typically begins to remit after 24 hours. Feeding should not be withheld during diarrhea. Frequent, small feedings are better tolerated than less frequent, large feedings. Antibiotics should only be given in patients with moderately severe to severe dehydration. As soon as vomiting stops (usually within 4 6 hours after initiation of rehydration therapy), an antibi otic to which local V. cholerae strains are sensitive must be admin istered. Antibiotics shorten the duration of illness, decrease fecal excretion of Vibrio, decrease the volume of diarrhea, and reduce the fluid requirement during rehydration. Single dose antibiot ics increase compliance and are generally recommended; doxycy cline, ciprofloxacin, and azithromycin are effective against cholera. The most clinical evidence for efficacy exists for tetracycline anti biotics (especially a single 300 mg dose of doxycycline). However, there are increasing reports of resistance to tetracyclines and to trimethoprim sulfamethoxazole and other drugs. Because of these multidrug resistant strains, antibiotic treatment must be tailored based on available susceptibility results from the area. Recommen dations for single dose therapy for children include doxycycline 24 mgkg PO as a single dose up to 300 mg; 300 mg PO should be given to children 12 years of age and older. Alternative single dose regimens include azithromycin 20 mgkg (max 1 g) PO, or cipro floxacin 20 mgkg (max 1 g) PO. Children 12 years of age should receive the adult doses. Cephalosporins and aminoglycosides are not clinically effective against cholera and therefore should not be used, even if in vitro tests show strains to be sensitive. Zinc should be given as soon as vomiting stops. Zinc deficiency is common among children in many developing countries. Zinc supple mentation in children 5 years old shortens the duration of diarrhea and reduces subsequent diarrhea episodes when given daily for 14 days at the time of the illness. Children 6 months old should receive 10 mg of oral zinc daily for 2 weeks, and children 6 months should receive 20 mg of oral zinc daily for 2 weeks. PREVENTION Improved personal hygiene, access to clean water, and sanitation are the mainstays of cholera control. Travelers from developed countries often have no prior exposure to cholera and are therefore at risk of devel oping the disease. Children traveling to cholera affected areas should avoid drinking potentially contaminated water and eating high risk Fig. 247.2 Rice water stool in a patient with cholera. (Modified from Harris JB, LaRocque RC, Qadri F. Cholera. Lancet. 2012;379:2466 2474.) Fig. 247.3 A child lying on a cholera cot showing typical signs of severe dehydration from cholera. The patient has sunken eyes, lethar gic appearance, and poor skin turgor, but within 2 hours was sitting |
7,312 | up, alert, and eating normally. (From Sack DA, Sack RB, Nair GB, et al. Cholera. Lancet. 2004;363:223233.) 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. 1788 Part XV u Infectious Diseases foods such as raw or undercooked fish and shellfish. No country or territory requires vaccination against cholera as a condition for entry. Alarmed by the increasing prevalence of cholera, in 2011 the World Health Assembly recommended the use of oral cholera vaccines to complement existing water, sanitation, and hygiene initiatives for chol era control. In 2016, a live oral cholera vaccine, CVD 103HgR (Vax chora, PaxVax), was licensed in the United States for use in adults age 18 64 years traveling to cholera affected areas. Older generation parenteral cholera vaccines have not been recom mended by the WHO because of the limited protection they confer and their high reactogenicity. Oral cholera vaccines are safe, are pro tective for approximately 2 5 years and confer moderate herd protec tion. Three oral cholera vaccines are currently available internationally and recognized by the WHO (Table 247.1). An internationally licensed killed whole cell oral cholera vaccine with recombinant B subunit (Dukoral, Crucell) has been available in 60 countries, including the European Union, and provides protection against cholera in endemic areas as well as cross protection against certain strains of enterotoxi genic E. coli. The two other vaccines (Shanchol, Shantha Biotech; and Euvichol, Eubiologics) are variants of the first vaccine and contain the V. cholerae O1 and O139 antigens but do not contain the B subunit. Without the B subunit, these vaccines do not require buffer for admin istration, thereby reducing administration costs and resources, making them easier to deploy. Several countries are now using oral cholera vaccines in mass vac cination campaigns where cholera remains a substantial problem. A cholera vaccine stockpile, established by the WHO, is now available and can be accessed by countries at risk for cholera, supplementing efforts to lessen the impact of this ongoing cholera scourge. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 247.1 Available Oral Cholera Vaccines VACCINE TRADE NAME CONTENTS DOSING SCHEDULE Dukoral (Crucell) 1 mg of recombinant B subunit of cholera toxin plus 2.5 1010 colony forming units of the following strains of V. cholerae: Formalin killed El Tor Inaba (Phil 6973) Heat killed classical Inaba (Cairo 48) Heat killed classical Ogawa (Cairo 50) Formalin killed classical Ogawa (Cairo 50) Children 2 6 yr old: 3 doses, 1 6 wk apart Adults and children 6 yr old: 2 doses, 1 6 wk apart Shanchol (Shantha Biotech) Euvichol (Eubiologics) V. cholerae O1: 600 EU Formalin killed El Tor Inaba (Phil 6973) 300 EU Heat killed classical Inaba (Cairo 48) 300 EU Heat killed classical Ogawa (Cairo 50) 300 EU Formalin killed classical Ogawa (Cairo 50) V. cholerae O139 600 EU of formalin killed strain 4260B Adults and children 1 yr |
7,313 | old: 2 doses, 2 wk apart WHO prequalified vaccines. Chapter 248 Campylobacter Ericka V. Hayes Campylobacter, typically Campylobacter jejuni and Campylobacter coli, are found globally and are among the most common causes of human intestinal infections. Clinical presentation varies by age and underlying conditions. ETIOLOGY More than 20 species of Campylobacter are recognized. Most of these have been isolated from humans, and many are considered pathogenic. The most significant of these are C. jejuni and C. coli, which are believed to cause the majority of human enteritis. More than 100 serotypes of C. jejuni have been identified. C. jejuni has been subspeciated into C. jejuni subsp. jejuni and C. jejuni subsp. doylei. Although C. jejuni subsp. doylei has been isolated from humans, it is much less common, less hardy, and more difficult to isolate. Other species, including Campylobacter fetus, Campylobacter lari, and Campylobacter upsaliensis, have been isolated from patients with diarrhea, although much less frequently (Table 248.1). Emerging Campylobacter spp. have been implicated in acute gastroen teritis, inflammatory bowel disease, and peritonitis, including C. concisus and C. ureolyticus. Additional Campylobacter spp. have been isolated from clinical specimens, but their roles as pathogens have not been established. Campylobacter organisms are gram negative, curved, thin (0.2 0.8 m wide), nonspore forming rods (0.5 5 m long) that usually have tapered ends. They are smaller than most other enteric bacterial pathogens and have variable morphology, including short, comma shaped or S shaped organisms and long, multispiraled, filamentous, seagull shaped organisms. Individual organisms are usually motile with a flagellum at one or both poles depending on the species. Such morphology enables these bacteria to colonize the mucosal surfaces of both the gastrointestinal (GI) and respiratory tracts and move through them in a spiraling motion. Most Campylobacter organisms are micro aerophilic, occasionally partially anaerobic, and oxidase positive. Most can transform into coccoid forms under adverse conditions, especially oxidation. EPIDEMIOLOGY Worldwide, Campylobacter enteritis is a leading cause of acute diar rhea. Efforts to reduce Campylobacter contamination and use of safe handling practices have led to decreased incidence. Campylobacter infections can be both food borne and water borne and most fre quently result from ingestion of contaminated poultry (chicken, tur key) or raw milk. Less often, the bacteria come from drinking water, household pets (cats, dogs, hamsters), and farm animals. Infections are more common in resource limited settings, are prevalent year round in tropical areas, and can exhibit seasonal peaks in temperate regions (late spring with a peak midsummer in most of the United States, with a smaller secondary peak in late fall). In industrialized countries, Campylobacter infections peak in early childhood and again in young adulthood (15 44 years). This second peak is not seen with Salmonella and Shigella infections. In resourcelimited countries, repeated infec tions are common in childhood, leading to increased immunity and rare disease in adulthood. Each year in the United States, there are an estimated 1.5 million cases of Campylobacter infection; in 2022 the incidence of infections with Campylobacter was 19.2 infections |
7,314 | per 100,000 population. Of these, death is rare, with 50 150 reports annu ally. In The Netherlands, medical record review shows that, on aver age, each resident acquires asymptomatic Campylobacter colonization every 2 years, progressing to symptomatic infection in approximately 1 of colonized people. 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 248 u Campylobacter 1789 Table 248.1 Campylobacter Species Associated with Human Disease SPECIES DISEASES IN HUMANS COMMON SOURCES C. jejuni Gastroenteritis, bacteremia, Guillain Barr syndrome Poultry, raw milk, cats, dogs, cattle, swine, monkeys, water C. coli Gastroenteritis, bacteremia Poultry, raw milk, cats, dogs, cattle, swine, monkeys, oysters, water C. fetus Bacteremia, meningitis, endocarditis, mycotic aneurysm, diarrhea Sheep, cattle, birds, dogs C. hyointestinalis Diarrhea, bacteremia, proctitis Swine, cattle, deer, hamsters, raw milk, oysters C. lari Diarrhea, colitis, appendicitis, bacteremia, UTI Seagulls, water, poultry, cattle, dogs, cats, monkeys, oysters, mussels C. upsaliensis Diarrhea, bacteremia, abscesses, enteritis, colitis, hemolytic uremic syndrome Cats, dogs, other domestic pets C. concisus Diarrhea, gastritis, enteritis, periodontitis Human oral cavity, dogs C. sputorum Diarrhea, bedsores, abscesses, periodontitis Human oral cavity, cattle, swine, dogs C. rectus Periodontitis C. mucosalis Enteritis Swine, dogs C. jejuni subsp. doylei Diarrhea, colitis, appendicitis, bacteremia, UTI Swine C. curvus Gingivitis, alveolar abscess Poultry, raw milk, cats, dogs, cattle, swine, monkeys, water, human oral cavity C. gracilis Head and neck abscesses, abdominal abscesses, empyema Dogs C. cryaerophila Diarrhea Swine Food borne infection is most common and can be seen with the con sumption of raw or undercooked meat and by cross contamination of other foods. Although chickens are the classic source of Campylobacter, many animal sources of human food can also harbor Campylobacter, including seafood. C. coli has been linked to swine. Poultry is more likely to be heavily contaminated, whereas red meats often have fewer organisms. Unpasteurized milk products are also a documented source. Additionally, many pets can carry Campylobacter, and flies inhabiting contaminated environments can acquire the organism. Shedding from animals can contaminate water sources. Humans can acquire infection from water, although much less frequently than from contaminated food. Airborne (droplet) transmission of Campylobacter has occurred in poultry workers. Use of antimicrobials in animal foods may increase the prevalence of antibiotic resistant Campylobacter isolated from humans. Human infection can result from exposure to as few as 500 bacte ria, although a higher dose (9,000 bacteria) is often needed to cause illness reproducibly. Inoculum effectiveness is dependent on host fac tors, including immune status and stomach acidification. C. jejuni and C. coli spread person to person, perinatally, and at childcare centers where diapered toddlers are present. People infected with C. jejuni usu ally shed the organism for weeks, but some can shed for months, with children tending toward longer shedding. Handwashing is critical to preventing spread in these environments. PATHOGENESIS Most Campylobacter isolates are acid sensitive and should, in theory, be eradicated in the stomach. |
7,315 | Therefore models for the pathogenesis of C. jejuni enteritis include mechanisms to transit the stomach, adhere to intestinal mucosal cells, and initiate intestinal lumen fluid accumulation. Host conditions associated with reduced gastric acidity, such as proton pump inhibitor use, and foods capable of shielding organisms in transit through the stomach may help allow Campylobacter to reach the intes tine. Once there, Campylobacter is able to adhere to and invade intestinal mucosal cells through motility, including use of flagellae, and by the use of surface proteins (e.g., PEB1, CadF), large plasmids (e.g., pVir), surface adhesins (e.g., JIpA), and chemotactic factors. Lumen fluid accumulation is associated with direct damage to mucosal cells resulting from bacte rial invasion and potentially from an enterotoxin and other cytotoxins. Additionally, C. jejuni has mechanisms that enable transit away from the mucosal surface. The factors used depend on the species involved. Campylobacter spp. differ from other enteric bacterial pathogens in that they have both N and O linked glycosylation capacities. N linked glycosylation is associated with molecules expressed on the bacterial surface, and O linked glycosylation appears limited to flagel lae. Slipped strand mispairing in glycosylation loci results in modified, antigenically distinct surface structures. It is hypothesized that anti genic variation provides a mechanism for immune evasion. C. fetus possesses a high molecular weight S layer protein that medi ates high level resistance to serum mediated killing and phagocytosis and is therefore thought to be responsible for the propensity to pro duce bacteremia. C. jejuni and C. coli are generally sensitive to serum mediated killing, but serum resistant variants exist. Some suggest these serum resistant variants may be more capable of systemic dissemination. Campylobacter infections can be followed by Guillain Barr syn drome (GBS), reactive arthritis, and erythema nodosum. Such com plications are thought to be from molecular mimicry between nerve, joint, and dermal tissue and Campylobacter surface antigens. Most Campylobacter infections are not followed by immunoreactive com plications, indicating that host conditions along with other factors, in addition to molecular mimicry, are required for these complications. It is proposed that low grade inflammation caused by Campylobacter, below the threshold that can be detected by endoscopy, results in cross talk with gut nerves, leading to symptoms. CLINICAL MANIFESTATIONS There are a variety of clinical presentations of Campylobacter infec tions, depending on host factors such as age, immune competence, and underlying conditions. Infection presents most often as gastroenteritis, but also as bacteremia, neonatal infections, and, less often, extraintes tinal infections. 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. 1790 Part XV u Infectious Diseases Acute Gastroenteritis Acute gastroenteritis with diarrhea is usually caused by C. jejuni (9095) or C. coli and, rarely, by C. lari, C. hyointestinalis, or C. upsaliensis. Infections with C. jejuni and C. coli are indistinguish able by clinical presentation. The average incubation period is 3 days (range: 1 |
7,316 | 7 days). One third of symptomatic patients can have a prodrome with fever, headache, dizziness, and myalgias; 1 3 days later, they develop cramping abdominal pain and loose, watery stools or, less frequently, mucus containing bloody stools. In severe cases (approximately 15), blood appears in the stools 2 4 days after the onset of symptoms. In younger children, 50 may develop blood in their stools. Some patients do not develop diarrhea at all, most often children who are 6 15 years old. Fever may be the only mani festation initially and is most pronounced in patients 1 year old. A reported 6090 of older children also complain of abdominal pain. The abdominal pain is most frequently periumbilical and sometimes persists after the stools return to normal. The abdominal pain can mimic appendicitis, colitis, or intussusception. Nausea is common, with up to 25 of adults developing vomiting. Vomiting tends to be more common the younger the patient and is most frequent in infants. Infection with species other than C. jejuni and C. coli may have milder symptoms. Diarrhea lasts approximately 7 days and will resolve spontaneously. More mild disease can last 1 2 days; 2030 of patients will have symptoms for 2 weeks, and 510 are symptomatic for 2 weeks. Relapse can occur in 510 of patients. Persistent or recurrent Cam pylobacter gastroenteritis has been reported in immunocompetent patients, in patients with hypogammaglobulinemia (both congenital and acquired), and in patients with AIDS. Persistent infection can mimic chronic inflammatory bowel disease (IBD); therefore Campy lobacter infection should also be considered when evaluating for IBD. Some evidence supports that Campylobacter infection may also be the trigger for development of IBD. Fecal shedding of the organisms in untreated patients usually lasts for 2 3 weeks, with a range from a few days to several months. Shedding tends to occur longer in young children. Acute appendicitis, mesenteric lymphadenitis, and ileocolitis have been reported in patients who have had appendectomy during C. jejuni infection. Bacteremia Transient bacteremia has been shown in early acute infection in 0.1 1 of patients. With the exception of bacteremia caused by C. fetus, bacteremia with Campylobacter occurs most often among patients with chronic illnesses or immunodeficiency (e.g., HIV), severe mal nutrition, and in extremes of age. However, bacteremia is also well described in patients without underlying disease. The majority of cases of bacteremia are asymptomatic. C. fetus causes bacteremia in adults with or without identifiable focal infection, usually in the setting of underlying conditions such as malignancy, immunodefi ciency, or diabetes mellitus. When symptomatic, C. jejuni bactere mia is associated with fever, headache, malaise, and abdominal pain. Relapsing or intermittent fever is associated with night sweats, chills, and weight loss when the illness is prolonged. Lethargy and confusion can occur, but focal neurologic signs are unusual without cerebro vascular disease or meningitis. Moderate leukocytosis with left shift may be found. Variable presentations have been described, including transient asymptomatic bacteremia, rapidly fatal septicemia, and pro longed bacteremia of 8 13 weeks. Focal |
7,317 | Extraintestinal Infections Focal infections caused by C. jejuni are rare and occur mainly among neonates and immunocompromised patients. Multiple sites have been reported, including meningitis, pneumonia, thrombophlebitis, pan creatitis, cholecystitis, ileocecitis, urinary tract infection, arthritis, peritonitis, pericarditis, and endocarditis. C. fetus shows a predilec tion for vascular endothelium, leading to endocarditis, pericarditis, thrombophlebitis, and mycotic aneurysms. C. hyointestinalis has been associated with proctitis, C. upsaliensis with breast abscesses, and C. rectus with periodontitis. Perinatal Infections Perinatal infections are most often acquired at birth from a mother infected with or shedding Campylobacter. Maternal C. fetus and C. jejuni infections may be asymptomatic and can result in abortion, stillbirth, premature delivery, or neonatal infection with sepsis and meningitis. Severe perinatal infections are uncommon and are caused most often by C. fetus and, rarely, by C. jejuni. Neonatal infection with C. jejuni is associated with diarrhea that may be bloody. Nosocomial infections in nurseries have also been described. DIAGNOSIS The clinical presentation of Campylobacter enteritis can be similar to that of enteritis caused by other bacterial pathogens. The differen tial diagnosis includes Shigella, Salmonella, Escherichia coli, Yersinia enterocolitica, Aeromonas, Vibrio parahaemolyticus, and amebiasis. Fecal leukocytes are found in as many as 75 of cases, and fecal blood is present in 50 of cases (higher in pediatric patients). Campylo bacter should be considered in patients with bloody stools, fever, and abdominal pain. The diagnosis of Campylobacter enteritis is usually confirmed by identification of the organism in cultures of stool or rectal swabs. Isola tion is most likely from selective media such as CAMPY agar grown in microaerophilic conditions (510 oxygen), 110 carbon diox ide, with some hydrogen. Some C. jejuni grow best at 42C (107.6F). Growth on solid media results in small (0.5 1.0 mm), slightly raised, smooth colonies. Organisms can be identified from stool microscopi cally in approximately 50 of known Campylobacter cases. Gram stain is even less sensitive. Stool culture is 90 sensitive and is the standard method of diagnosis. Visible growth on stool culture is most often pres ent in 1 2 days. Visible growth in blood cultures is often not apparent until 5 14 days after inoculation. Routine culture may be adequate for isolation of C. jejuni because of the large numbers of bacteria that are often present. However, because Campylobacter organisms grow more slowly under routine conditions than do other enteric bacteria, routine culture can result in failure because of overgrowth of other enteric bacteria. Campylo bacter culture can be enhanced, when necessary, with selective media. However, selective culture media developed to enhance isolation of C. jejuni may inhibit the growth of other Campylobacter spp. Filtration methods are available and can preferentially enrich for Campylobacter by selecting for their small size. These methods allow subsequent cul ture of the enriched sample on antibiotic free media, enhancing rates of isolation of Campylobacter organisms inhibited by the antibiotics included in standard selective media. Isolation of Campylobacter from normally sterile sites does not require enhancement procedures. Clini cally, it is not necessary |
7,318 | to speciate Campylobacter because the disease is the same. Speciation can be done, when needed, and specialized lab oratories can perform strain typing when required for epidemiologic purposes. For rapid diagnosis of Campylobacter enteritis, direct carbolfuch sin stain of fecal smear, indirect fluorescence antibody test, dark field microscopy, or latex agglutination were used historically. Polymerase chain reaction testing is more specific and sensitive and has become more widely available for rapid testing, often grouped with testing for other bacterial, viral, and parasitic stool pathogens in a multi plex assay. At this time, the recommendation remains to confirm all positive rapid tests with culture, which also allows for susceptibil ity testing and epidemiologic investigations. Antigen tests are also available, although false positive results have been reported. Sero logic diagnosis is also possible and is most helpful in patients with late onset reactive arthritis or GBS, because these patients may have negative stool cultures by the time of presentation with these late complications. 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 248 u Campylobacter 1791 COMPLICATIONS Severe, prolonged C. jejuni infection can occur in patients with immu nodeficiencies, including hypogammaglobulinemia, malnutrition, and AIDS. In patients with AIDS, increased frequency and severity of C. jejuni infection occurs; severity correlates inversely with CD4 count. Complications can include acute complications, as described earlier, and late onset complications that may present after the acute infection has resolved. The most common late onset complications include reac tive arthritis and GBS. Reactive Arthritis Reactive arthritis can accompany Campylobacter enteritis in adoles cents and adults, especially in patients who are positive for HLA B27 (see Chapter 198). Reactive arthritis occurs in up to 3 of patients, although up to 13 may have joint symptoms. This manifestation usually appears 1 2 weeks after the onset of diarrhea (range 540 days). It involves mainly large joints and resolves without sequelae. The arthritis is typically migratory and occurs without fever. Syno vial fluid lacks bacteria. The arthritis responds well to nonsteroidal antiinflammatory drugs and typically resolves after 1 week, though cases are reported with symptoms lasting for several months. Reac tive arthritis with conjunctivitis, urethritis, and rash (including ery thema nodosum) also occurs but is less common. Guillain Barr Syndrome GBS is an acute demyelinating disease of the peripheral nervous sys tem characterized clinically by acute flaccid paralysis and is the most common cause of neuromuscular paralysis worldwide (see Chapter 656). GBS carries a mortality rate of approximately 2, and approximately 20 of patients develop major neurologic sequelae. C. jejuni has been identified as the trigger in up to 40 of patients with GBS and is most closely linked to the serotypes Penner O19 and O41. It has been reported 1 12 weeks after C. jejuni gastroen teritis in 1 of every 1,000 C. jejuni infections. Stool cultures obtained from patients with GBS at the |
7,319 | onset of neurologic symptoms have yielded C. jejuni in 25 of the cases. Serologic studies suggest that 2045 of patients with GBS have evidence of recent C. jejuni infection. Molecular mimicry between nerve tissue GM1 ganglioside and Campylobacter surface antigens may be the triggering factor in Campylobacter associated GBS. The Miller Fisher variant, which more often affects cranial nerves, is characterized by ataxia, areflexia, and ophthalmoplegia and is linked to cross reacting antibodies to the GQ1b ganglioside found in cranial nerve myelin; the most com mon serotype for this variant is Penner O2. When associated with Campylobacter, GBS is more likely to be the axonal form and has a worse prognosis with slower recovery and more neurologic disabil ity. The management of GBS includes supportive care, intravenous immunoglobulin, and plasma exchange. Other Complications Immunoglobulin A nephropathy and immune complex glomerulone phritis with C. jejuni antigens in the kidneys have been reported. Cam pylobacter infection has also been associated with hemolytic anemia and hemolytic uremic syndrome. Treatment Fluid replacement, correction of electrolyte imbalance, and sup portive care are the mainstays of treatment of children with Cam pylobacter gastroenteritis. Antimotility agents are contraindicated because they can cause prolonged or fatal disease. The need for anti biotic therapy in healthy patients with uncomplicated gastroenteri tis is controversial. Most healthy children do not require antibiotic therapy. Data suggest a shortened duration of symptoms (by an aver age of 1.3 days) and intestinal shedding of organisms if antibiotics are initiated early in the disease. Antibiotics are recommended for patients with bloody stools, high fever, or a severe course and for children who are immunosuppressed or have underlying diseases and individuals at high risk of developing severe disease (e.g., preg nancy). Extraintestinal infections (e.g., bacteremia) should also be treated with antibiotics. Most Campylobacter isolates are susceptible to macrolides, fluo roquinolones, aminoglycosides, chloramphenicol, tetracyclines, and clindamycin (though there is no clinical efficacy data for these last three agents, only in vitro data) and are resistant to cephalosporins, penicillins, and trimethoprim. Resistance to tetracyclines, mac rolides, and more often, fluoroquinolones has been increasingly reported. Antibiotic resistance among C. jejuni has become a seri ous worldwide problem. Macrolide resistance is increased in areas such as Thailand and Ireland, whereas fluoroquinolone resistance has been reported in Spain, Hungary, and multiple low and middle income countries in 50 of cultured Campylobacter. Fluoroqui nolone resistance continues to increase in the United States and is related to the use of quinolones in veterinary medicine and food products along with acquisition from travelers and antibiotic over use. Erythromycin resistant Campylobacter isolates are less common in the United States; therefore azithromycin is the drug of choice if therapy is required, particularly in pediatric patients. For treatment of gastroenteritis, the duration is 3 5 days. Drug sensitivities should be determined for patients who do not respond to therapy or any patient with invasive or extraintestinal infection. Sepsis is treated with parenteral antibiotics such as meropenem or imipenem, with or without an aminoglycoside. For extraintestinal infection caused |
7,320 | by C. fetus, prolonged therapy is advised. C. fetus isolates resistant to erythromycin and fluoroquinolones have been reported; therefore empirical therapy for serious C. fetus infection should avoid these agents pending susceptibilities. PROGNOSIS Although Campylobacter gastroenteritis is usually self limited, immu nosuppressed children (including children with AIDS) can experience a protracted or severe course. Septicemia in newborns and immuno compromised hosts has a poor prognosis, with an estimated mortal ity rate of 3040. Additional prognosis is based on the secondary sequelae that may develop. PREVENTION Most human Campylobacter infections are sporadic and are acquired from infected animals or contaminated foods or water. Interven tions to minimize transmission include good hand hygiene; cooking meats thoroughly; preventing recontamination after cooking by not using the same surfaces, utensils, or containers for both uncooked and cooked food; and avoiding unpasteurized dairy products. Also, it is important to ensure that water sources are not contaminated and that water is kept in clean containers. Persons infected with Cam pylobacter should avoid recreational water for at least 1 week after resolution of symptoms or as guided by local public health authori ties. Contact with infected animals should be avoided. No specific isolation is required; standard precautions are sufficient, although in a hospital or clinic setting with an incontinent child, contact precau tions are indicated. Outbreaks can occur in childcare settings. Infants and children should be excluded from childcare centers until stools are able to be contained in the diaper or for continent children when they no longer have fecal accidents and stool frequency is no more than two stools above that childs baseline (stools may remain loose). Breastfeeding appears to decrease symptomatic Campylobacter dis ease but does not reduce colonization. All cases of Campylopbacter should be reported to local health departments, as it is a nationally notifiable condition. Several approaches at immunization have been studied, including the use of live attenuated organisms, subunit vaccines, and killed whole cell vaccines. No vaccine is currently available. 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. 1792 Part XV u Infectious Diseases The genus Yersinia is a member of the order Enterobacterales, family Yersiniaceace and comprises more than 14 named species, 3 of which are established as human pathogens. Yersinia enterocolitica is by far the most common Yersinia species causing human disease and produces fever, abdominal pain that can mimic appendicitis, and diarrhea. Y. pseudotuberculosis is most often associated with mesenteric lymphade nitis. Y. pestis is the agent of plague and typically causes an acute febrile lymphadenitis (bubonic plague) and less often occurs as septicemic, pneumonic, pharyngeal, or meningeal plague. Other Yersinia species are uncommon causes of infections in humans, and their identification is often an indicator of immunodeficiency. Yersinia is enzootic and can colonize pets. Infections in humans are incidental and most often result from contact with |
7,321 | infected animals or their tissues; ingestion of contaminated water, milk, or meat; or for Y. pestis, the bite of infected fleas or inhalation of respiratory droplets (human, dog, cat). Association with human disease is less clear for Y. frederiksenii, Y. intermedia, Y. kristensenii, Y. aldovae, Y. bercovieri, Y. mollaretii, Y. rohdei, and Y. ruckeri. Some Yersinia isolates replicate at low temperatures (14C 33.839.2F) or survive at high tempera tures (5060C 122140F). Thus common food preparation and storage and common pasteurization methods might not limit the num ber of bacteria. Most are sensitive to oxidizing agents. 249.1 Yersinia enterocolitica Ericka V. Hayes ETIOLOGY Yersinia enterocolitica is a large, gram negative coccobacillus that exhibits little or no bipolarity when stained with methylene blue and carbolfuchsin. It ferments glucose and sucrose but not lactose, is oxi dase negative, and reduces nitrate to nitrite. These facultative anaerobes grow well on common culture media and are motile at 22C (71.6F) but not 37C (98.6F). Optimal growth temperature is 2528C (77 82.4F); however, the organism can grow at refrigerator temperature. Y. enterocolitica includes pathogenic and nonpathogenic members. It has six different biotypes (1A, 1B, and 2 5). Y. enterocolitica relies on other bacteria for iron uptake, and conditions associated with iron overload increase the risk of infection. EPIDEMIOLOGY Y. enterocolitica is transmitted to humans through food, water, animal contact, and contaminated blood products. Transmission can occur from mother to newborn. Y. enterocolitica appears to have a global distribution but is seldom a cause of tropical diarrhea. In 2022, the Centers for Disease Control and Prevention (CDC) Foodborne Dis eases Active Surveillance Network (FoodNet) reported an incidence of culture confirmed Y. enterocolitica infection in the United States of 1.97 per 100,000 population (635 increase compared to 2015, and an increase of 216 since 2020). Infection may be more common in Northern Europe. Most infections occur among children 5 years old (incidence: 1.6 1.9 per 100,000 population), with the majority among children 1 year old. It is estimated that Y. enterocolitica accounts for 5 of illnesses secondary to major bacterial enteric pathogens in chil dren 5 years old in the United States. Cases are more common in colder months and among males. Natural reservoirs of Y. enterocolitica include pigs, rodents, rabbits, sheep, cattle, horses, dogs, and cats, with pigs being the major animal reservoir. Direct or indirect contact with animals, including pets, other domesticated animals, and wild animals, may be responsible for 1 of cases of enteric illnesses caused by Y. enterocolitica. Culture and molecular techniques have found the organism in a variety of foods and beverages, including vegetable juice, pasteurized milk, carrots, and water. Consumption of contaminated water or food, particularly undercooked pork, is the most common form of transmission to humans. A source of sporadic Y. enterocolitica infections is chitterlings (pig intestines, chitlins), a traditional dish in the southeastern United States and in Latin America, often in celebration of winter holidays. The infection is often seen in young infants in the household because of contamination of |
7,322 | bottle and food preparation when chitterlings are prepared. In one study, 71 of human isolates were indistinguishable from the strains isolated from pigs. Y. enterocolitica is an occupational threat to butchers. In part because of its capacity to multiply at refrigerator tempera tures, Y. enterocolitica can be transmitted by intravenous injection of contaminated fluids, including blood products. Patients with conditions leading to iron overload are at higher risk of developing Yersinia infections. PATHOGENESIS The Yersinia organisms most often enter by the gastrointestinal tract and cause mucosal ulcerations in the ileum. Necrotic lesions of Peyer patches and mesenteric lymphadenitis occur. If septicemia develops, suppurative lesions can be found in infected organs. Infection can trig ger reactive arthritis and erythema nodosum, particularly in HLA B27positive individuals. Virulence traits of pathogenic biotypes (1B and 2 5) are encoded by chromosomal genes and a highly conserved 70 kb virulence plas mid (pYVpCD). The chromosomal genes control the production of heat stable enterotoxins, and the plasmid allows penetration through the intestinal wall. Adherence, invasion, and toxin production are the essential mechanisms of pathogenesis. The bacteria mainly invade the intestinal epithelium in the Peyer patches of the ileum. After invasion, plasmid encoded type III secretion of three antiphago cytic proteins protects Yersinia against the immunologic response of local macrophages. From Peyer patches, bacteria can disseminate to cause local or systemic disease. Motility appears to be required for Y. enterocolitica pathogenesis. Bioserotypes most associated with clini cal illness in humans are 1BO:8, 2O:5,27, 2O:9, 3O:3, and 4O:3, with bioserotype 4O:3 being the most common type in the United States. Yersinia does not produce siderophores and uses analogous siderophores from other bacteria or host chelated iron stores to thrive, placing patients with iron overload, as in hemochromatosis, thalassemia, and sickle cell disease, at higher risk for infection. CLINICAL MANIFESTATIONS Disease occurs most often as enterocolitis with diarrhea, fever, and abdominal pain. Acute enteritis is more common among younger children, and mesenteric lymphadenitis that can mimic appendicitis may be found in older children and adolescents. The incubation period is usually 4 6 days after exposure (range: 1 14 days). Stools may be watery and contain leukocytes and, less often, frank blood and mucus. Duration of diarrhea is often longer for Y. enterocolitica than for other causes of acute gastroenteritis, ranging from 12 to 22 days in several studies. Fever is common. Notably, prominent pharyngitis may be seen in 20 of patients at presentation, which may help distinguish it from other causes of gastroenteritis. Y. enterocolitica is excreted in stool for 1 4 weeks. Family contacts of a patient are often found to be asymptomatically colonized with Y. enterocolitica. Y. enterocolitica sep ticemia is less common and is most often found in very young children (3 months old) and immunocompromised persons. Systemic infec tion can be associated with splenic and hepatic abscesses, osteomyeli tis, septic arthritis, meningitis, endocarditis, and mycotic aneurysms. Exudative pharyngitis, pneumonia, empyema, lung abscess, and acute respiratory distress syndrome occur infrequently. Reactive complications include erythema nodosum, reactive |
7,323 | arthritis, and rarely uveitis. These manifestations may be more Chapter 249 Yersinia Ericka V. Hayes 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 249 u Yersinia 1793 common in select populations (Northern Europeans), in association with HLA B27, and in females. DIAGNOSIS Diagnosis is made typically through isolation of the organism, usu ally from the stool. Y. enterocolitica is easily cultured from normally sterile sites but requires special procedures for isolation from stool, where other bacteria can outgrow it. Yersinia should be cultured on selective agar (cefsulodin irgasan novobiocin CIN) at 2528C (7782.4F) to increase yield. If O:3 serogroup is suspected, Mac Conkey agar should be used at 2528C (7782.4F). Multiplex polymerase chain reaction (PCR) testing for Y. enterocolitica is also available, including on commercially available multiplex stool pan els. Many laboratories do not routinely perform the tests required to detect Y. enterocolitica; procedures targeted to this organism must be specifically requested. A history indicating contact with environ mental sources of Yersinia and detection of fecal leukocytes are help ful indicators of a need to test for Y. enterocolitica. The isolation of Yersinia from stool should be followed by tests to confirm that the isolate is a pathogen. Serodiagnosis is not readily available, and utility is limited by cross reactivity. Differential Diagnosis The clinical presentation is similar to other forms of bacterial entero colitis. The most common considerations include Shigella, Salmonella, Campylobacter, Clostridioides difficile, enteroinvasive Escherichia coli, Y. pseudotuberculosis, and occasionally Vibrio related diarrheal disease. Amebiasis, appendicitis, Crohn disease, ulcerative colitis, diverticulitis, and pseudomembranous colitis should also be considered. TREATMENT Enterocolitis in an immunocompetent patient is a self limited disease, and no benefit from antibiotic therapy is established. Patients with systemic infection and very young children (in whom septicemia is common) should be treated. Y. enterocolitica organisms are typically susceptible to trimethoprim sulfamethoxazole (TMP SMX), amino glycosides, third generation cephalosporins, and quinolones, although strains resistant to quinolones have been reported. Y. enterocolitica pro duces lactamases, which are responsible for resistance to penicillins and first generation cephalosporins. TMP SMX is the recommended empirical treatment for enterocolitis in children (generally a 5 day course) because it has activity against most strains and is well tol erated. In severe infections such as bacteremia, third generation cephalosporins, with or without aminoglycosides, are effective, and usually a 3 week course of therapy is administered, with possible transition to oral therapy. Patients on deferoxamine should discon tinue iron chelation therapy during treatment for Y. enterocolitica, especially if they have complicated gastrointestinal (GI) infection or extraintestinal infection. COMPLICATIONS Reactive arthritis, erythema nodosum, erythema multiforme, hemo lytic anemia, thrombocytopenia, and systemic dissemination of bac teria have been reported in association with Y. enterocolitica infection. Septicemia is more common in younger children, and reactive arthritis is more common in older patients. Arthritis appears to be mediated by immune complexes, which form as |
7,324 | a result of antigenic mimicry, and viable organisms are not present in involved joints. PREVENTION Prevention centers on reducing contact with environmental sources of Yersinia. Families should be warned of the high risk of chitterling preparation, especially with young infants and children in the house hold. The CDC has developed guidance for the public regarding safe practices for chitterling preparation found here: https:www.cdc.gov yersiniachitlins.html. Breaking the chain of transmission from animal reservoirs to humans holds the greatest potential to reduce infections, and the techniques applied must be tailored to the reservoirs in each geographic area. There is no licensed vaccine. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 249.2 Yersinia pseudotuberculosis Ericka V. Hayes Yersinia pseudotuberculosis has a worldwide distribution; Y. pseudo tuberculosis disease is less common than Y. enterocolitica disease. The most common form of disease is a mesenteric lymphadenitis that produces an appendicitis like syndrome. Y. pseudotuberculosis is asso ciated with a Kawasaki syndromelike illness in approximately 8 of cases. ETIOLOGY Y. pseudotuberculosis is a small, gram negative, aerobic, and facultative anaerobic coccobacillus. As with Y. enterocolitica, it ferments glucose and does not ferment lactose, is oxidase negative, catalase producing, urea splitting, and shares a number of morphologic and culture char acteristics. It is differentiated biochemically from Y. enterocolitica on the basis of ornithine decarboxylase activity; fermentation of sucrose, sorbitol, and cellobiose; and other tests, although some overlap between species occurs. Antisera to somatic O antigens and sensitiv ity to Yersinia phages can also be used to differentiate the two spe cies. Subspecies specific DNA sequences that allow direct probe and primer specific differentiation of Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica have been described. Y. pseudotuberculosis is more closely related phylogenetically to Y. pestis than to Y. enterocolitica. EPIDEMIOLOGY Y. pseudotuberculosis is zoonotic, with reservoirs in wild rodents, rab bits, deer, farm animals, various birds, and domestic animals, including cats and canaries. Transmission to humans is by consumption of or contact with contaminated animals or contact with an environmental source contaminated by animals, often water. Direct evidence of trans mission of Y. pseudotuberculosis to humans by consumption of lettuce and raw carrots has been reported. The organism has a worldwide dis tribution; however, infections are more commonly reported in Europe, in boys, and in the winter. During 19962014, FoodNet reported 224 cases of infections secondary to Y. pseudotuberculosis in the United States, with an annual average incidence of 0.03 per 100,000 persons. Compared with Y. enterocolitica infections, those caused by Y. pseudo tuberculosis are more likely to be invasive and occur in adolescents and adults. Iron overloading conditions, AIDS, other immunodeficiencies, and other debilitating diseases (including liver cirrhosis) may predis pose to invasive Y. pseudotuberculosis infection. PATHOGENESIS Ileal and colonic mucosal ulceration and mesenteric lymphadenitis are hallmarks of the infection. Necrotizing epithelioid granulomas may be seen in the mesenteric lymph nodes, but the appendix is often grossly and microscopically normal. The mesenteric nodes are often the only source of isolation of the organism. Y. pseudotuberculosis antigens bind directly |
7,325 | to human leukocyte antigen (HLA) class II molecules and can function as superantigens, which might account for the clinical illness resembling Kawasaki syndrome. CLINICAL MANIFESTATIONS Pseudoappendicitis and mesenteric lymphadenitis with abdominal pain (often right lower quadrant tenderness), fever, and leukocytosis constitute the most common clinical presentation. Enterocolitis and extraintestinal spread are uncommon. Iron overload, diabetes mellitus, and chronic liver disease are often found concomitantly with extrain testinal Y. pseudotuberculosis infection. Renal involvement with tubu lointerstitial nephritis, azotemia, pyuria, and glucosuria can occur. Y. pseudotuberculosis can present as a Kawasaki syndromelike illness with fever of 1 6 days duration, strawberry tongue, pharyngeal ery thema, scarlatiniform rash, cracked, red, and swollen lips, conjuncti vitis, sterile pyuria, periungual desquamation, and thrombocytosis. 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. 1794 Part XV u Infectious Diseases Some of these children have had coronary changes. Other uncommon manifestations include septic arthritis, massive lower GI bleeding, post aneurysmal prosthetic vascular infection, and acute encephalopathy. DIAGNOSIS PCR of involved tissue can be used to identify Y. pseudotuberculo sis; isolation by culture can require an extended interval. Involved mesenteric lymph nodes removed at appendectomy can yield the organism by culture. Abdominal CT scan or ultrasound examination of children with unexplained fever and abdominal pain can reveal a characteristic picture of enlarged mesenteric lymph nodes and thickening of the terminal ileum with or without peritoneal findings, including appendiceal inflammation and periappendiceal fluid. Y. pseudotuberculosis is rarely recovered from stool. Serologic testing is available in specialized labs. Differential Diagnosis Appendicitis (most common), inflammatory bowel disease, and other intraabdominal infections should be considered. Kawasaki syndrome, staphylococcal or streptococcal disease, leptospirosis, Stevens Johnson syndrome, and collagen vascular diseases, including acute onset juve nile idiopathic arthritis, can mimic the syndrome with prolonged fever and rash. C. difficile colitis, meningitis, encephalitis, enteropathic arthropathies, acute pancreatitis, sarcoidosis, toxic shock syndrome, typhoid fever, and ulcerative colitis may also be considered. TREATMENT Uncomplicated mesenteric lymphadenitis caused by Y. pseudo tuberculosis is a self limited disease, and antimicrobial therapy is not required. Few data exist on optimal treatment and duration of therapy. Infections with Y. pseudotuberculosis can generally be man aged the same as those caused by Y. enterocolitica. Culture confirmed bacteremia should be treated with a third generation cephalosporin with or without an aminoglycoside, TMP SMX, fluoroquinolones, or chloramphenicol. COMPLICATIONS Erythema nodosum and reactive arthritis can follow infection. Coro nary aneurysm formation has been described with disease presenting as Kawasaki syndromelike illness. Rare local complications of GI dis ease include perforation, obstruction, and intussusception. PREVENTION Avoiding exposure to potentially infected animals and good food handling practices can prevent infection. The sporadic nature of the disease makes application of targeted prevention measures difficult. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 249.3 Plague (Yersinia pestis) Ericka V. Hayes ETIOLOGY Y. pestis is a gram negative, facultative anaerobe that is a pleomor phic, nonmotile, |
7,326 | nonspore forming coccobacillus and a potential agent of bioterrorism. It evolved from Y. pseudotuberculosis through acquisition of chromosomal changes and plasmid associated fac tors that are essential to its virulence and survival in mammalian hosts and fleas. Y. pestis shares bipolar staining appearance with Y. pseudotuberculosis and can be differentiated by biochemical reactions, serology, phage sensitivity, and molecular techniques. Y. pestis exists in four biovars: Antigua (Africa), Medievalis (Cen tral Asia), Orientalis (widespread), and Microtus (Asia). Of note, Microtus, while highly virulent in mice, does not cause disease in humans. EPIDEMIOLOGY Plague is endemic in at least 24 countries, with Democratic Republic of the Congo, Madagascar, and Peru accounting for the highest numbers of cases. Approximately 3,000 cases are reported worldwide per year, with 100 200 deaths. Plague is uncommon in the United States (0 40 reported casesyr); most of these cases occur west of a line from east Texas to east Montana, with 80 of cases in California, New Mexico, Arizona, and Colorado. In 2015, there was a cluster of 11 cases (with 3 deaths) in 4 months related to exposure at Yosemite National Park in Californias Sierra Nevada Mountains. The epidemic form of disease killed approximately 25 of the population of Europe in the Middle Ages in a series of several epidemics and pandemics. The epidemiology of epidemic plague involves extension of infection from the zoonotic reservoirs to urban rats, Rattus rattus and Rattus norvegicus, and from fleas of urban rats to humans. Epidemics are no longer seen. Selective pressure exerted by plague pandemics in medieval Europe is hypoth esized for enrichment of a pathogenic deletion variant in the gene encoding CCR5 (CCR5 32). The enhanced frequency of this muta tion in European populations endows approximately 10 of European descendants with relative resistance to acquiring HIV 1. The most common mode of transmission of Y. pestis to humans is through flea bites. Historically, most human infections are thought to have resulted from bites of fleas that acquired infection from feeding on infected urban rats. Less frequently, infection is caused by con tact with infectious body fluids or tissues or inhalation of respira tory secretions of infected animals. Currently, most cases of plague secondary to direct animal contact or inhalation of animal secretions are related to domestic cats or dogs. Direct transmission from human to human through droplet inhalation is possible but extremely rare. Laboratory transmission of Y. pestis has been described as well. Syl vatic plague can exist as a stable enzootic infection or as an epizootic disease with high host mortality. Ground squirrels, rock squirrels, prairie dogs, rats, mice, bobcats, cats, rabbits, and chipmunks may be infected. Transmission among animals is usually by flea bite or by ingestion of contaminated tissue. Xenopsylla cheopis is the flea usu ally associated with transmission to humans, but 30 species of fleas have been demonstrated as vector competent, and Pulex irritans, the human flea, can transmit plague and might have been an important vector in some historical epidemics. Both sexes are |
7,327 | similarly affected by plague, and transmission is more common in colder regions and seasons, possibly because of temperature effects on Y. pestis infections in vector fleas. PATHOGENESIS In the most common form of plague, infected fleas regurgitate organ isms into a patients skin during feeding. The bacteria translocate via lymphatics to regional lymph nodes, where Y. pestis replicates, result ing in bubonic plague. In the absence of rapidly implemented specific therapy, bacteremia can occur, resulting in purulent, necrotic, and hemorrhagic lesions in many organs. Both plasmid and chromosomal genes are required for full virulence. Pneumonic plague can be second ary to bacteremia or primary when infected material is inhaled. The organism is highly transmissible from persons with pneumonic plague and from domestic cats with pneumonic infection. This high transmis sibility and high morbidity and mortality have provided an impetus for attempts to use Y. pestis as a biologic weapon. CLINICAL MANIFESTATIONS Y. pestis infection can manifest as several clinical syndromes; infection can also be subclinical. The three principal clinical presentations of plague are bubonic plague, septicemic plague, and pneumonic plague. Bubonic plague is the most common form and accounts for 8090 of cases in the United States. From 2 to 8 days after a flea bite, lymphad enitis develops in lymph nodes closest to the inoculation site, including the inguinal (most common), axillary, or cervical regions. These buboes are very tender. Fever, chills, weakness, prostration, headache, and the development of septicemia are common. The skin might show insect bites or scratch marks. Purpura and gangrene of the extremities can 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 249 u Yersinia 1795 develop as a result of disseminated intravascular coagulation (DIC). These lesions may be the origin of the name Black Death. Untreated plague results in death in 50 of symptomatic patients. Death can occur within 2 4 days after onset of symptoms. Occasionally, Y. pestis establishes systemic infection and induces the systemic symptoms seen with bubonic plague without causing a bubo (primary septicemic plague). Because of the delay in diagnosis linked to the lack of the bubo, septicemic plague carries an even higher case fatality rate than bubonic plague. In some regions, bubo free septice mic plague accounts for 25 of cases. Pneumonic plague is the least common but most dangerous and lethal form of the disease. Incubation for primary pneumonic plague is 1 6 days. Pneumonic plague can result from hematogenous dissemi nation or, rarely, as primary pneumonic plague after inhalation of the organism from a human or animal with plague pneumonia or poten tially from a biologic attack. Signs of pneumonic plague include severe pneumonia with high fever, dyspnea, and hemoptysis. Meningitis, tonsillitis, and gastroenteritis can occur. Meningitis tends to be a late complication after inadequate treatment. Tonsillitis and gastroenteritis can occur with or without apparent bubo formation or lymphadenopathy. DIAGNOSIS |
7,328 | Plague should be suspected in patients with fever and history of expo sure to small animals in endemic areas. Bubonic plague should be suspected in a patient with a painful swollen lymph node, fever, and prostration who has been potentially exposed to fleas or rodents in the western United States. A history of camping or the presence of flea bites increases the index of suspicion. Y. pestis is readily transmitted to humans by some routine laboratory manipulations. Thus it is imperative to clearly notify a laboratory when submitting a sample suspected of containing Y. pestis. Labo ratory diagnosis is based on bacteriologic culture or direct visualiza tion using Gram, Giemsa, or Wayson stain of lymph node aspirates, blood, sputum, or exudates. Y. pestis grows slowly under routine cul ture conditions and best at temperatures that differ from those used for routine cultures in many clinical laboratories. Colonies are described as having a classic fried egg appearance and grow on sheep blood and chocolate agars, typically growing after 48 72 hours of incubation. Note some automated biochemical bacteria identification systems may misidentify Y. pestis. Suspected isolates of Y. pestis should be forwarded to a reference laboratory for confirmation. Special containment ship ping precautions are required. A rapid antigen test detecting Y. pes tis F1 antigen in sputum and serum samples exists. PCR testing and immunohistochemical staining for rapid identification are available in some reference and public health laboratories. Cases of plague should be reported to local and state health departments and the CDC. Sero logic testing is also available. A single positive serologic test confirms the diagnosis, but in early illness seroconversion may not yet have occurred; negative tests should be interpreted with caution, particu larly if there is high clinical suspicion for the diagnosis, and patients should continue to be treated. Differential Diagnosis The Gram stain of Y. pestis may be confused with Enterobacter agglomerans. Mild and subacute forms of bubonic plague may be confused with other disorders causing localized lymphadenitis and lymphadenopathy, including bacterial lymphadenitis, tularemia, and Bartonella henselae (cat scratch) lymphadenitis. Septicemic plague may be indistinguishable from other forms of overwhelming bacterial sepsis. Pulmonary manifestations of plague are similar to those of anthrax, Q fever, and tularemia, all agents with bioterrorism and biologic warfare potential. Thus the presentation of a suspected case, and espe cially any cluster of cases, requires immediate reporting. Additional information on this aspect of plague and procedures can be found at https:emergency.cdc.govagentplagueindex.asp. TREATMENT Patients with suspected plague should be placed on droplet isolation until pneumonia is ruled out, sputum cultures are negative, and anti biotic treatment has been administered for 48 hours. The treatment of choice for bubonic plague historically has been streptomycin (30 mgkgday, maximum 2 gday, divided every 12 hours intramuscularly IM for 10 days). Intramuscular streptomycin is inappropriate for sep ticemia because absorption may be erratic when perfusion is poor. The poor central nervous system penetration of streptomycin also makes this an inappropriate drug for meningitis. Furthermore, streptomycin might not be |
7,329 | widely and immediately available. Gentamicin (children, 7.5 mgkg IM or intravenously IV every 24 hours; adults, 5 mg kg IM or IV every 24 hours) has been shown to be as efficacious as streptomycin; in patients with abscesses, an additional agent may be needed in addition to an aminoglycoside because of poor abscess penetration (typically a fluoroquinolone). Dual therapy is recom mended for moderate to severe septicemic or pneumonic plague as well as bubonic plague with large buboes or any suspected case of bioterrorism related plague. Ciprofloxacin 10 mgkg every 8 or 12 hr IV or 15 mgkg every 8 or 12 hr PO (maximum 400 mgdose IV, 500 mgdose every 8 hr PO or 750 mgdose every 12 hr PO) and levo floxacin are also effective. Meningitis is usually treated with chloram phenicol or a fluoroquinolone. Resistance to these agents and relapses are rare. Y. pestis is susceptible in vitro to fluoroquinolones, which are effective in treating experimental plague in animals. Y. pestis is susceptible in vitro to penicillin, but penicillin is ineffective in treatment of human disease. Mild bubonic disease may be treated with oral chlorampheni col or doxycycline in children 8 years old. Clinical improvement is usually noted within 48 hours of initiating treatment. Recommended duration of therapy is 10 14 days, with a switch to oral therapy 2 days after defervescence and clinical improvement. Drainage of suppurative buboes may be needed; material is infectious, and appropriate precau tions should be taken intraoperatively. Postexposure prophylaxis should be given to close contacts of patients with pneumonic plague. Antimicrobial prophylaxis is rec ommended within 7 days of exposure for persons with direct, close contact with a patient with pneumonic plague or those exposed to an accidental or bioterrorist aerosol. Recommended regimens for postex posure prophylaxis for children regardless of age include doxycycline, ciprofloxacin, or levofloxacin for a 7 day course at the treatment doses. Contacts of cases of uncomplicated bubonic plague do not require pro phylaxis. Y. pestis is a potential agent of bioterrorism that can require mass casualty prophylaxis. PREVENTION Avoidance of exposure to infected animals and fleas is the best method of prevention of infection. In the United States, special care is required in environments inhabited by rodent reservoirs of Y. pestis and their ectoparasites. Patients with plague should be isolated if they have pul monary symptoms, and infected materials should be handled with extreme care. There is currently no available licensed vaccine for Y. pes tis in the United States. Several vaccine development trials are under way, and recombinant subunit vaccines based on rF1 and rV antigens seem to be the most promising. Using baits containing live vaccines for oral immunization of wild animals may be a helpful alternative for control of epidemics. 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. 1796 Part |
7,330 | XV u Infectious Diseases Aeromonas and Plesiomonas are gram negative bacilli that include spe cies capable of causing enteritis and, less frequently, skin and soft tissue infections and invasive disease. They are common in freshwater and brackish water and colonize animals and plants in these environments. 250.1 Aeromonas Ameneh Khatami and Adam J. Ratner ETIOLOGY Aeromonas is a member of the Aeromonadaceae family and includes two major groups of isolates: the nonmotile psychrophilic organisms that infect cold blooded animals, most often fish, and the motile meso philic organisms that infect humans and other warm blooded animals. Aeromonas species are oxidase and catalase positive, facultatively anaerobic, gram negative bacilli that ferment glucose. Aeromonas is a diverse genus with difficult taxonomy and species differentiation because of high nucleotide variability and has undergone multiple reclassifications of species and taxa in recent years. Sixteen species are recognized as clinically significant human pathogens, with Aeromonas hydrophila, Aeromonas veronii biotype sobria, and Aeromonas caviae most frequently associated with human infection. Aeromonas dhak ensis, which was first isolated from children with diarrhea in Dhaka, Bangladesh, and was initially classified as a subspecies of A. hydrophila, has been recognized as a distinct species and an important cause of human infection. EPIDEMIOLOGY Aeromonas organisms are found in fresh and brackish aquatic envi ronments, including rivers and streams, well water, both treated and bottled drinking water, and sewage. These organisms are most often detected in aquatic environments during warm weather months, when they reach greater population densities. Rates of human infection may also exhibit seasonality depending on local conditions. For example, Aeromonas is isolated with increased frequency from May to Octo ber in the Northern Hemisphere. Some species resist chlorination of water and exhibit tolerance to high salt concentrations. Aeromonas has been isolated from meats, milk, seafood, seaweed, and vegetables con sumed by humans. Asymptomatic colonization occurs in humans and is more common in inhabitants of tropical regions. Most human infec tions with Aeromonas are associated with exposure to contaminated water but may also be contracted via other routes, including ingestion of contaminated food. A systematic review of cases of travelers diar rhea worldwide implicated Aeromonas in 0.83.3 of infections, with highest frequencies in travelers to Southeast Asia and Africa. A study in Bangladesh of 56,000 stool samples from patients with diarrhea found that approximately 25 had a bacterial etiology detected, 13 of which were Aeromonas. Aeromonas infections have also been acquired at various sites of natural disasters. For example, after the 2004 Thai land tsunami, Aeromonas was the leading cause of skin and soft tissue infection among survivors. PATHOGENESIS Clinical and epidemiologic data seem to support that Aeromonas organisms are enteric pathogens, although this point is not universally accepted. Reasons for uncertainty include a lack of outbreaks with clonally distinct isolates, infrequent person to person transmis sion, absence of a robust animal model, and overlapping prevalence in symptomatic and asymptomatic individuals. In addition, there are conflicting data when comparing the human challenge model with characteristics of suspected outbreaks of |
7,331 | Aeromonas enteritis, further complicating interpretation. Aeromonas isolates possess a variety of potential virulence factors, including constitutive polar and inducible lateral flagella, fimbriae, outer membrane proteins, endotoxin (lipopolysaccharide), and cap sule. The mechanistic role of many of these factors in human patho genicity remains unclear. Polar flagella provide motility in liquid media, and lateral flagella may act as adhesins. There are numerous hemolysins, proteases, and heat labile and heat stable enterotoxins. Aeromonas cytotoxic enterotoxin (Actaerolysin) is secreted by a type II secretion system and is able to lyse erythrocytes, inhibit phagocy tosis, and induce cytotoxicity in eukaryotic cells. Aeromonas also has a type III secretion system with an effector protein that causes actin reorganization and eventual apoptosis in vitro. A type VI secretion sys tem has been described and functions analogously to a phage tail, with antimicrobial activity. Aeromonas sobria is the most enterotoxic among clinical isolates, and cytotoxic activity with cytopathic and intracellular effects is found in 89 of isolates. A few strains produce Shiga toxin. Some clinically important species have also been shown to harbor a cholera like toxin (Asao toxin). Aeromonas has serine proteases that can cause a cascade of inflammatory mediators, leading to vascular leakage, and in vitro studies show induction of apoptosis in murine macrophages by human isolates of Aeromonas. There are limited data on quorum sensing mole cules, which coordinate gene expression according to local density and may be involved in biofilm production or population control. CLINICAL MANIFESTATIONS Aeromonas may colonize humans asymptomatically or cause illness, including enteritis, focal invasive infections, and septicemia. Although apparently immunologically normal individuals may present with any of these manifestations, invasive disease is more common among immunocompromised persons. Enteritis The most common clinical manifestation of infection with Aeromo nas is enteritis, which occurs primarily among children 3 years old. Aeromonas is the third or fourth most common cause of childhood bacterial diarrhea and has been isolated from 2 to 10 of patients with diarrhea and 15 of asymptomatic controls. One study dem onstrated isolation from hospitalized neonates with diarrhea at rates of 019 depending on the season. Isolation from human feces also varies geographically based on food habits, level of sanitation, popula tion demographics, aquaculture and farming practices, and laboratory isolation methods used. Aeromonas diarrhea is often watery and self limited, although a dysentery like syndrome with blood and mucus in the stool has also been described. Fever, abdominal pain, and vomiting are common in children. Choleric diarrhea with rice water stools can also occur. Enteritis caused by A. hydrophila and A. sobria tends to be acute and self limited, whereas 30 of patients with A. caviae enteritis have chronic or intermittent diarrhea that may last 4 6 weeks. A. sobria and A. caviae are most frequently associated with travelers diarrhea. Complications of Aeromonas enteritis include intussusception, failure to thrive, hemolytic uremic syndrome, bacteremia, and postinfectious chronic colitis. Aeromonas infection may also present as acute segmen tal colitis, mimicking inflammatory bowel disease or ischemic colitis. Skin and Soft Tissue Infections |
7,332 | Skin and soft tissue infections are the second most common presenta tion of Aeromonas, most commonly associated with A. hydrophila, A. veronii, and A. schubertii. Predisposing factors include local trauma and exposure to contaminated fresh water. Aeromonas soft tissue infections have been reported after bites from a number of animal species, including alligators, tigers, bears, and snakes, and from tick Chapter 250 Aeromonas and Plesiomonas Ameneh Khatami and Adam J. Ratner 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 250 u Aeromonas and Plesiomonas 1797 bites. These infections have also been reported after sports injuries and medicinal leech therapy. Antibiotic prophylaxis is generally used in conjunction with leech therapy because of the presence of A. hydrophila in the gastrointestinal (GI) tract of leeches, where they aid in the breakdown of ingested red blood cells. However, emerg ing reports of ciprofloxacin resistant strains of Aeromonas isolated from leeches may affect this practice. The spectrum of skin and soft tissue infections is broad, ranging from a localized skin nodule to life threatening necrotizing fasciitis, myonecrosis, and gas gangrene. Soft tissue infections are most frequently found on the extremities, are often polymicrobial, and are 3 times more likely in men than in women. Aeromonas cellulitis, the most common skin manifesta tion, clinically presents similar to other forms of bacterial cellulitis but should be suspected in wounds after contact with a water source, especially during the summer. Septicemia Aeromonas septicemia, strongly associated with A. veronii biovar sobria and A. dhakensis infection, is the third most common presentation of infection and is associated with a mortality rate of 2773. Higher incidence occurs during summer months or during the wet season in the tropics. Patients present with the classic signs and symptoms of gram negative sepsis and may have GI symptoms, including abdomi nal pain, nausea, vomiting, and diarrhea. From 2 to 4 of patients may present with ecthyma gangrenosumlike lesions. Aeromonas may be the only organism isolated or may be part of a polymicrobial bac teremic illness. Most cases (approximately 80) occur in immuno compromised adults or those with hepatobiliary disease and in young children in whom the source of infection is probably Aeromonas in the GI tract. Less frequently, bacteremia can be secondary to trauma related myonecrosis or infected burns. In such patients, mortality is often higher than in those with primary bacteremia because of the underlying trauma. Rarely, Aeromonas bacteremia occurs in otherwise healthy adults exposed to fresh water. Other Infections Aeromonas is a rare cause of GI infections such as necrotizing gas troenteritis, peritonitis, cholecystitis, appendicitis, and liver and pancreas abscess formation; cardiovascular infections, including endocarditis and septic embolism; and pulmonary infections, includ ing tracheobronchitis, pneumonia, empyema, and lung abscess formation. Aeromonas is also associated with musculoskeletal infec tions, including osteomyelitis, pyogenic arthritis, pyomyositis, and necrotizing fasciitis, as well as ocular and ear, nose, and |
7,333 | throat infec tions, including endophthalmitis, keratitis, orbital cellulitis, otitis media, and epiglottitis. Other rare infections include meningitis, urinary tract infection, pelvic inflammatory disease, lymphadeni tis, hot tub folliculitis, and surgical wound infections. Aeromonas is associated with tracheobronchitis and aspiration pneumonia after near drowning. DIAGNOSIS Diagnosis is established by isolation of Aeromonas in culture. The organism is generally grown on standard media when the source material is normally sterile. Often, Aeromonas is not identified by typical laboratory protocols for examining stool specimens. If Aeromonas is suspected, the yield may increase if the laboratory is notified before testing, because overnight enrichment in alkaline peptone water and culture on selective agars may be useful. Most strains (approximately 90) produce hemolysis on blood agar. Lactose fermenting strains of Aeromonas like A. caviae may not be identified if the clinical laboratory does not routinely perform oxidase tests on lactose fermenters isolated on MacConkey agar. Aeromonads are resistant to vibriostatic agent O129; however, dif ferentiation of Aeromonas from Vibrio spp. and identification of Aeromonas spp. and subspp. is not reliable using biochemical test ing. Similarly, classification of Aeromonas strains at the species and subspecies level is difficult to achieve by sequencing regions of the 16S rRNA gene. Sequencing of housekeeping genes, such as gyrB and rpoD, and multilocus sequence typing are accurate for species identification but are time , cost and labor intensive. Increasingly, laboratories use matrix assisted laser desorptionionization time of flight (MALDI TOF) mass spectrometry to rapidly identify organ isms because this method is accurate for Aeromonas as a genus and for many of the clinically important species. Because stool culture based diagnosis is time consuming, labor intensive, and costly on per positive culture basis, molecular tests for various enteric bacte rial pathogens, including multiplex polymerase chain reaction (PCR) assays that include targets for detection of Aeromonas, have been developed and are commercially available in some areas. TREATMENT Aeromonas enteritis is usually self limited, and antimicrobial therapy may not be indicated, although some studies suggest that antimi crobial therapy may shorten the course of the illness. Antimicrobial therapy is reasonable to consider in patients with protracted diarrhea, dysentery like illness, or underlying conditions such as hepatobiliary disease or an immunocompromised state. Antibiotic sensitivity var ies among species and also by geography; therefore it is important to perform susceptibility testing. Chromosomally mediated class B, C, and D lactamases are found in most species and can be difficult to identify because many are inducible. These include metallo and AmpC lactamases, which can lead to clinical failure if carbapen ems or third generation cephalosporins are used as monotherapy in high organism load infections. There is near uniform resistance to penicillins. Surgical intervention is the primary therapeutic modality in cases of necrotizing fasciitis, with most patients requiring more than one debridement in the first 48 hours. Septicemia can be treated with a fourth generation cephalosporin (e.g., cefepime) or cipro floxacin, with or without an aminoglycoside, although specific therapy should be guided by susceptibility data. Another option for less |
7,334 | severe infections includes trimethoprim sulfamethoxazole (TMP SMX). Evidence based recommendations for duration of treatment are lack ing, and thus treatment is typically guided by clinical response. In gen eral, diarrhea is treated for 3 days, wound infections for 7 10 days, and bacteremia for 14 21 days, depending on clinical response and host characteristics. PREVENTION Reducing contact with contaminated environmental fresh and brackish water and contaminated foods should reduce the risk for Aeromonas infections. Some Aeromonas outer membrane proteins are immunogenic and are candidate antigens for preclinical vaccine development. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 250.2 Plesiomonas shigelloides Ameneh Khatami and Adam J. Ratner ETIOLOGY Plesiomonas shigelloides is a facultatively anaerobic, gram negative, nonspore forming bacillus that ferments glucose. It is a catalase , oxidase , and indole positive motile organism with polar flagella. A high level of genetic diversity has been recognized among P. shigelloides strains, reflecting frequent homologous recombination. EPIDEMIOLOGY P. shigelloides is ubiquitous in freshwater and, because it can tolerate salinity of up to 4, can be found in estuarine or brackish water, as well as animal inhabitants of these ecosystems, including fish, shell fish, crustaceans, water mammals, amphibians, reptiles, and other ver tebrates. P. shigelloides has been recovered from healthy (colonized) 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. 1798 Part XV u Infectious Diseases and diseased animals, including cats. It can cause both sporadic infec tions and outbreaks in a range of animals. As a mesophile with opti mal growth temperature of 3539C (95102.2F), P. shigelloides has been found most often in tropical waters or during warmer months, although there are increasing reports of isolation from surface water in colder climates. Similarly, most cases of infection occur during the warmer months of the year. P. shigelloides is not a usual commensal organism in the human GI tract, and infection of humans is thought to be the result of consumption of contaminated water or raw seafood or possibly through contact with colonized animals. The frequency of isolation of P. shigelloides from diarrheal stools in these circumstances has been reported to range from 2 to 10. Mixed infection with Sal monella, Aeromonas, rotavirus, or other enteric pathogens may occur in almost one third of patients. The majority of symptomatic patients in North America have a known exposure to potentially contaminated water or seafood (notably oysters) or have traveled abroad. Plesiomonas has been reported to be associated with 1.35.4 of episodes of trav elers diarrhea, with the highest rates associated with travel to South and Southeast Asia. Other risk factors include immune compromise (in particular HIV infection), blood dyscrasias (including sickle cell disease), and young age. The highest rates of Plesiomonas enteritis occur in children 2 years old. Although P. shigelloides has a worldwide distribution, there is unexplained geographic variability in the inci dence of enteritis that may be related to |
7,335 | water temperatures and a lack of hygiene and sanitation. PATHOGENESIS Epidemiologic and microbiologic evidence in the form of a series of food borne outbreaks attributable to P. shigelloides indicates that this organism is an enteropathogen. However, the pathogenic capacity of P. shigelloides has not been confirmed through oral challenge stud ies, and these organisms have been isolated from the stools of healthy individuals at a low rate. The mechanism of enteritis is not known, but putative virulence factors have been described, including cholera like toxin, heat labile and heat stable enterotoxins, and lipopolysaccha ride. Most strains of P. shigelloides also secrete a hemolysin, which is thought to be a major virulence factor. In vitro studies show that iso lates of P. shigelloides can invade and induce apoptosis in cells of enteric origin, as well as exhibiting evidence of modulation of host defenses through inhibition of cathepsins involved in antigen processing and presentation. CLINICAL MANIFESTATIONS Clinical disease in humans generally begins 24 48 hours after expo sure to the organism, although incubation periods in excess of 4 days have been reported. Diarrhea can occur in all age groups, including neonates, is typically secretory, and less often presents as invasive dysentery. Secretory enteritis usually presents as a mild self limiting disease with watery diarrhea and abdominal pain, but in 13 of cases diarrhea can persist for 2 weeks. Dehydration, hypokalemia, and peritonitis are uncommon complications; however, there have been several reports of a cholera like presentation with severe secretory diarrhea. The frequency of secretory vs dysenteric presentation seems to cluster by individual outbreak, suggesting that either the human populations or the bacterial populations involved are associated with each particular presentation. Dysentery presents with macroscopic blood andor mucus in the stool, significant abdominal pain, and vomiting, with more severe cases also associated with fever. Fatal outcomes have been reported with severe cases of Plesiomonas dys entery, although in most of these cases the exact role of P. shigelloides is unclear. Extraintestinal infections, usually bacteremia, are rare and usually occur in patients with underlying immunodeficiency. About 90 of these cases are monomicrobial, and in almost half, P. shigelloides is also isolated from a site other than blood. Rarely, bacteremia accompanying enteritis has been documented in apparently otherwise normal chil dren. Septicemia also appears to result from ingestion of contaminated water or seafood and has a high mortality rate in adults. Other extrain testinal diseases include pneumonia, meningitis, osteomyelitis, septic arthritis, reactive arthritis, abscesses, and focal infections of the GI or reproductive tracts. Almost one third of all bacteremias occur in neo nates who present with early onset sepsis and meningitis, and although rare, these make up most of the reported cases of P. shigelloides men ingitis and have a very high mortality rate (80). In several cases of neonatal disease, Plesiomonas has also been isolated from maternal feces, suggesting intrapartum vertical transmission. Compared with Aeromonas and Vibrio spp., traumatic wounds sustained in aquatic environments less often contain P. shigelloides. DIAGNOSIS P. shigelloides is a |
7,336 | nonlactose fermenting organism and grows well on traditional enteric media with optimal growth at 30C (86F), although selective techniques may be required to isolate the organism from mixed cultures and to differentiate P. shigelloides from Shigella spp. If enrichment is necessary, alkaline peptone water or bile pep tone broth may be used. Colonies are nonhemolytic on 5 blood agar. Many strains cross react with Shigella on serologic testing but can be differentiated easily as oxidase positive organisms. P. shigelloides has a unique biochemical profile and can generally be identified using com mercial kits. Rapid identification systems, including MALDI TOF, can also be used to identify P. shigelloides. P. shigelloides is included in at least one U.S. Food and Drug Administration (FDA)approved com mercial panel that detects a range of enteropathogens directly from diarrheal stools (culture independent) by PCR. TREATMENT Enteritis caused by P. shigelloides is usually mild and self limited. In cases associated with dehydration or with a cholera like disease, patients usually respond favorably to oral rehydration solution. Consideration of antimicrobial therapy is reserved for patients with prolonged or bloody diarrhea, those who are immunocompromised, the elderly, and the very young. Data from uncontrolled studies sug gest that antimicrobial therapy may decrease the duration of symp toms, although no difference was found in an exclusively pediatric study. P. shigelloides produces a chromosomally encoded, noninducible lactamase, which generally renders strains resistant to the penicil lins, including broad spectrum penicillins. P. shigelloides is also usually resistant to aminoglycosides and tetracyclines. Most strains of P. shigel loides are susceptible to lactam lactamase inhibitor combinations and to TMP SMX, some cephalosporins, carbapenems, and fluoroqui nolones; however, therapy should be guided by antimicrobial suscep tibility testing because resistance to TMP SMX, fluoroquinolones, and other agents has been reported. Severe cases of P. shigelloides dysentery should be treated similarly to shigellosis (with empirical azithromycin or a third generation cepha losporin for children and ciprofloxacin or azithromycin for adults). Antibiotics are essential for therapy of extraintestinal disease. Empiri cal therapy with a third generation cephalosporin is often first line management, because most isolates are susceptible in vitro. Alterna tives include carbapenems, aztreonam, lactam lactamase inhibitor combinations, and quinolones. Definitive therapy should be guided by the susceptibility of the individual isolate. Duration of therapy ranges from 1 to 2 weeks but may be extended depending on underlying chronic conditions and clinical response. 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 251 u Pseudomonas, Burkholderia, and Stenotrophomonas 1799 251.1 Pseudomonas aeruginosa Thomas S. Murray and Ashley C. Howard ETIOLOGY Pseudomonas aeruginosa is an aerobic, gram negative rod. It can mul tiply in a great variety of environments that contain minimal amounts of organic compounds. Strains from clinical specimens do not fer ment lactose, are oxidase positive, and may produce hemolysis on blood agar. Many |
7,337 | strains produce pigments, including pyocyanin, pyoverdine, and pyorubrin, that diffuse into and color the surrounding medium. Strains of P. aeruginosa are differentiated for epidemiologic purposes by a variety of genotyping methods, including restriction fragment length polymorphisms using pulsed field gel electropho resis, multilocus sequence typing, and more recently, whole genome sequencing. EPIDEMIOLOGY P. aeruginosa is a classic opportunist. It rarely causes disease in people who do not have a predisposing risk factor. Compromised host defense mechanisms resulting from trauma, neutropenia, mucositis, immunosuppression, or impaired mucociliary trans port explain the predominant role of this organism in producing opportunistic infections. In pediatric settings, it is frequently seen in the respiratory secretions of children with cystic fibrosis (CF). In a pediatric review of 2,545 facilities from 2015 to 2017 by the National Healthcare Safety Network (NHSN), P. aeruginosa ranked among the top 10 organisms to cause central lineassociated bloodstream infections in all units: 2.8 neonatal intensive care unit (NICU), 5 pediatric intensive care unit (PICU), 5 pediatric oncology units, and 3.1 pediatric wards. P. aeruginosa was also the second most common cause of catheter associated urinary tract infections (UTIs) (18.4) and ventilator associated pneumonia (16.1) and the third most common cause of postoperative surgi cal site infections (8.3). In a multicenter U.S. prospective study of 33 sites from 2014 to 2018, P. aeruginosa was isolated in 2.7 of bacteremic episodes in children 1 year old and 3.7 in children 17 years of age. P. aeruginosa and other pseudomonads frequently enter the hospital environment on the clothes, skin, or shoes of patients or hospital per sonnel, with plants or vegetables brought into the hospital, and in the gastrointestinal (GI) tract of patients. Colonization of any moist or liq uid substance may ensue; the organisms may be found growing in any water reservoir, including distilled water, and in hospital kitchen sinks and laundries, some antiseptic solutions, and equipment used for respi ratory therapy and urinary procedures. Colonization of skin, throat, stool, and nasal mucosa of patients is low at admission to the hospital but increases to as high as 5070 with prolonged hospitalization and with the use of broad spectrum antibiotics, chemotherapy, mechanical ventilation, and urinary catheters. Patients intestinal microbial flora may be altered by the broad spectrum antibiotics, reducing resistance to colonization and permitting P. aeruginosa in the environment to populate the GI tract. Intestinal mucosal breakdown associated with medications, especially cytotoxic agents, and nosocomial enteritis may provide a pathway by which P. aeruginosa spreads to the lymphatics or bloodstream. PATHOLOGY The pathologic manifestations of P. aeruginosa infections depend on the site and type of infection. Because of its elaboration of toxins and invasive factors, the organism can often be seen invading blood ves sels and causing vascular necrosis. In some infections there is spread through tissues with necrosis and microabscess formation. In patients with CF, focal and diffuse bronchitisbronchiolitis leading to bronchi olitis obliterans has been reported. Pathogenesis Invasiveness of P. aeruginosa is mediated by a host of virulence fac tors. Bacterial attachment |
7,338 | is facilitated by pili that adhere to epithelium damaged by prior injury or infection. Extracellular proteins, proteases, elastases, and cytotoxins disrupt cell membranes, and in response, host produced cytokines cause capillary vascular permeability and induce an inflammatory response. Dissemination and bloodstream invasion follow extension of local tissue damage and are facilitated by the antiphagocytic properties of endotoxin, the exopolysaccharide, and protease cleavage of immunoglobulin G. P. aeruginosa also produces numerous exotoxins, including exotoxin A, which causes local necro sis and facilitates systemic bacterial invasion. P. aeruginosa possesses a type III secretion system composed of a needle structure that inserts into host cell membranes and allows secretion of exotoxins directly into host cells. The host responds to infection with a robust inflamma tory response, recruiting neutrophils to the infection site and produc ing antibodies to P. aeruginosa proteins. There is a lack of convincing data that these antibodies are protective against the establishment of infection. In addition to acute infection, P. aeruginosa is also capable of chronic persistence because of the formation of biofilms, organized commu nities of bacteria encased in an extracellular matrix. Biofilm forma tion requires attachment to a surface, proliferation of the organism, and production of exopolysaccharide as the main bacterial component of the extracellular matrix. A mature biofilm can persist despite an intense host immune response and is resistant to many antimicrobials. CLINICAL MANIFESTATIONS Most clinical patterns are related to opportunistic infections in immu nocompromised hosts (see Chapter 223) or are associated with shunts and indwelling catheters (see Chapter 224). P. aeruginosa may be intro duced into a minor wound of a healthy person as a secondary invader, and cellulitis and a localized abscess that exudes green or blue pus may follow. The characteristic skin lesions of P. aeruginosa, ecthyma gan grenosum, whether caused by direct inoculation or a metastatic focus secondary to septicemia, begin as pink macules and progress to hem orrhagic nodules and eventually to ulcers with ecchymotic and gan grenous centers with eschar formation, surrounded by an intense red areola (Table 251.1 and Fig. 251.1). Outbreaks of dermatitis and UTIs caused by P. aeruginosa have been reported in healthy persons after use of pools or hot tubs. Skin lesions of folliculitis develop several hours to 2 days after contact with these water sources. Skin lesions may be erythematous, macular, papular, or pustular. Illness may vary from a few scattered lesions to extensive truncal involvement. In some children, malaise, fever, vomiting, sore throat, conjunctivitis, rhinitis, and swollen breasts may be associated with dermal lesions. UTIs caused by P. aeruginosa are most often nos ocomial and are often associated with the presence of an indwelling urinary catheter, urinary tract malformations, and previous antibiotic use. UTIs may be minimized or prevented by prompt removal of the catheter and by early identification and corrective surgery of obstruc tive lesions when present. Burns and Wound Infection The surfaces of burns or wounds are frequently populated by P. aerugi nosa and other gram negative organisms; this initial colonization with a |
7,339 | low number of adherent organisms is a prerequisite to invasive disease. P. aeruginosa colonization of a burn site may develop into burn wound sepsis, which has a high mortality rate when the density of organisms reaches a critical concentration. Administration of antibiotics may Chapter 251 Pseudomonas, Burkholderia, and Stenotrophomonas 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. 1800 Part XV u Infectious Diseases diminish the susceptible microbiologic flora, permitting strains of rela tively resistant P. aeruginosa to flourish. Multiplication of organisms in devitalized tissues or associated with prolonged use of intravenous or urinary catheters increases the risk for septicemia with P. aeruginosa, a major problem in burned patients (see Chapter 89). Cystic Fibrosis P. aeruginosa is common in patients with CF, with increasing preva lence as children get older (see Chapter 454). Initial infection is caused by nonmucoid environmental strains of P. aeruginosa, but after a variable period, mucoid strains of P. aeruginosa that produce the antiphagocytic exopolysaccharide alginate, which are rarely encoun tered in other conditions, predominate. Repeated isolation of mucoid P. aeruginosa from the sputum is associated with increased morbidity and mortality. The infection begins insidiously or even asymptomati cally, and the progression has a highly variable pace. In children with CF, antibody does not eradicate the organism, and antibiotics are only partially effective; thus after infection becomes chronic, it cannot be completely eradicated. Repeated courses of antibiotics select for P. aeruginosa strains that are resistant to multiple antibiotics. Immunocompromised Persons Children with leukemia or other malignancies, particularly those who are receiving immunosuppressive therapy and who are neutropenic, typically with intravascular catheters, are extremely susceptible to sep ticemia caused by invasion of the bloodstream by P. aeruginosa that is colonizing the respiratory or GI tract. Signs of sepsis are often accom panied by a generalized vasculitis, and hemorrhagic necrotic lesions may be found in all organs, including the skin (ecthyma gangrenosum) (see Fig. 251.1). Hemorrhagic or gangrenous perirectal cellulitis or abscesses may occur, associated with ileus and profound hypotension. Nosocomial Pneumonia Although not a frequent cause of community acquired pneumonia in children, P. aeruginosa does cause nosocomial pneumonia, especially ventilator associated pneumonia, in patients of all ages. P. aeruginosa has historically been found to contaminate ventilators, tubing, and humidifiers. Such contamination is uncommon now because of dis infection practices and routine changing of equipment. Nevertheless, colonization of the upper respiratory tract and the GI tract may be fol lowed by aspiration of P. aeruginosacontaminated secretions, result ing in severe pneumonia. Prior use of broad spectrum antibiotics is a risk factor for colonization with antibiotic resistant strains of P. aerugi nosa. One of the most challenging situations is distinguishing between colonization and pneumonia in intubated patients. This distinction can Table 251.1 Pseudomonas aeruginosa Infections INFECTION COMMON CLINICAL CHARACTERISTICS Endocarditis Native right sided (tricuspid) valve disease with intravenous drug abuse Pneumonia Compromised local (lung) |
7,340 | or systemic host defense mechanisms; nosocomial (respiratory), bacteremic (malignancy), or abnormal mucociliary clearance (cystic fibrosis) may be pathogenetic; cystic fibrosis is associated with mucoid P. aeruginosa organisms producing capsular slime Central nervous system infection Meningitis, brain abscess; contiguous spread (mastoiditis, dermal sinus tracts, sinusitis); bacteremia or direct inoculation (trauma, surgery) External otitis Swimmers ear; humid warm climates, swimming pool contamination Malignant otitis externa Invasive, indolent, febrile, toxic, destructive, necrotizing lesion in young infants, immunosuppressed neutropenic patients, or diabetic patients; associated with seventh nerve palsy and mastoiditis Chronic mastoiditis Ear drainage, swelling, erythema; perforated tympanic membrane Keratitis Corneal ulceration; contact lens keratitis Endophthalmitis Penetrating trauma, surgery, penetrating corneal ulceration; fulminant progression Osteomyelitisseptic arthritis Puncture wounds of foot and osteochondritis; intravenous drug abuse; fibrocartilaginous joints, sternum, vertebrae, pelvis; open fracture osteomyelitis; indolent pyelonephritis and vertebral osteomyelitis Urinary tract infection Iatrogenic, nosocomial; recurrent UTIs in children, instrumented patients, and those with obstruction or stones Intestinal tract infection Immunocompromised, neutropenia, typhlitis, rectal abscess, ulceration, rarely diarrhea; peritonitis in peritoneal dialysis Ecthyma gangrenosum Metastatic dissemination; hemorrhage, necrosis, erythema, eschar, discrete lesions with bacterial invasion of blood vessels; also subcutaneous nodules, cellulitis, pustules, deep abscesses Primary and secondary skin infections Local infection; burns, trauma, decubitus ulcers, toe web infection, green nail (paronychia); whirlpool dermatitis; diffuse, pruritic folliculitis; vesiculopustular or maculopapular, erythematous lesions Fig. 251.1 Round, nontender skin lesion on 2 yr old females buttock. Note the black ulcerated center of the lesion and its red margin. (From Ghanaiem H, Engelhard D. A healthy 2 year old child with a round black skin lesion. J Pediatr. 2013;163:1225.) 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 251 u Pseudomonas, Burkholderia, and Stenotrophomonas 1801 often only be definitively resolved by using invasive culture techniques such as quantitative bronchoalveolar lavage. Infants P. aeruginosa is an occasional cause of nosocomial bacteremia in newborns and accounts for 25 of positive blood culture results in NICUs. A frequent focus preceding bacteremia is conjunctivitis. Older infants rarely present with community acquired sepsis caused by P. aeruginosa. In the few reports describing community acquired sepsis, preceding conditions included ecthyma like skin lesions, virus associated transient neutropenia, and prolonged contact with contami nated bath water or a hot tub. DIAGNOSIS P. aeruginosa infection is rarely clinically distinctive. Diagnosis depends on recovery of the organism from the blood, cerebrospinal fluid (CSF), urine, or needle aspirate of the lung or from purulent mate rial obtained by aspiration of subcutaneous abscesses or areas of celluli tis. In the appropriate clinical setting, recovery of P. aeruginosa from a coughed or suctioned sputum may represent infection; but it also may only represent colonization, and clinical judgment is required. Rarely, skin lesions that resemble P. aeruginosa infection may follow septice mia caused by Aeromonas hydrophila, other gram negative bacilli, and Aspergillus. When P. aeruginosa is recovered from nonsterile sites such as skin, mucous membranes, or |
7,341 | voided urine, quantitative cultures may be useful to differentiate colonization from invasive infection. In gen eral, 100,000 colony forming unitsmL of fluid or gram of tissue is evidence suggestive of invasive infection. Quantitative cultures of tis sue and skin are not routine and require consultation with the clinical microbiology laboratory. TREATMENT Systemic infections with P. aeruginosa should be treated promptly with an antibiotic to which the organism is susceptible in vitro. Response to treatment may be limited, and prolonged treatment may be necessary for systemic infection in immunocompromised hosts. Septicemia and other aggressive infections should be treated with either one or two bactericidal agents. Although the number of agents required is controversial, the evidence continues to suggest that the benefit of adding a second agent is questionable, even when studies have included immunosuppressed patients. Appropriate antibiotics for single agent therapy include ceftazidime, cefepime, ticarcillin clavulanate, and piperacillin tazobactam. Gentamicin or another aminoglycoside may be used concomitantly for synergistic effect. Ceftazidime has proved to be extremely effective in patients with CF, at 150 400 mgkgday divided every 6 8 hours intravenously (IV) to a maximum of 6 gday. Piperacillin or piperacillin tazobactam 240 400 mgkgday divided every 6 8 hours IV to a maximum of 12 gday also has proved to be effective therapy for susceptible strains of P. aeru ginosa. Continuous infusions of lactam antibiotics are more effective than the same daily dose given as pulse infusions. Additional effective antibiotics include imipenem cilastatin, meropenem, and aztreonam. Ciprofloxacin (20 30 mgkgday orally every 8 12 hours up to 500 mgdose) is the only available effective oral P. aeruginosa therapy, and although commonly used in children with CF, it is not approved in the United States for persons 18 years old, except for oral treatment of UTIs or when treating multidrug resistant (MDR) P. aeruginosa. Inhaled therapy with either tobramycin or aztre onam is also used for chronic pulmonary infection, with inhaled colis tin reserved for the treatment of resistant pseudomonads. Macrolide therapy decreases pulmonary exacerbations in patients with chronic lung disease and P. aeruginosa infection. The mechanism relates to altering the virulence properties of P. aeruginosa rather than direct bacterial killing. It is important to base continued treatment on antimicrobial suscep tibility tests because antibiotic resistance of P. aeruginosa is increasing. P. aeruginosa has many mechanisms for resistance to multiple classes of antibiotics, including but not limited to pathogenic variants, produc tion of lactamases, and drug efflux pumps. Throughout the United States there has been an alarming increase in MDR P. aeruginosa iso lates resistant to at least three antibiotic classes recovered from chil dren. NHSN data from 2015 to 2017 show 2.8 NICU, 12 PICU, 6 pediatric oncology, and 5.5 pediatric ward P. aeruginosa isolates were MDR, with increasing rates of carbapenem and piperacillintazobac tam resistance as well. Several newer agents demonstrate efficacy against MDR P. aerugi nosa. Ceftazidime avibactam and ceftolozane tazobactam combine cephalosporins with a lactamase inhibitor. Ceftolozane tazobactam inhibits AmpC and other extended spectrum lactamases but lacks |
7,342 | activity against carbapenemases. Ceftazidime avibactam inhibits class A carbapenemases but not metallo lactamases. Cefiderocol, a sider ophore cephalosporin, has enhanced stability to lactamases, includ ing metallo lactamases, Amp C, and carbapenemases. Meningitis can occur by spread from a contiguous focus, as a sec ondary focus when there is bacteremia, or after invasive procedures. P. aeruginosa meningitis is best treated with ceftazidime or meropenem in combination with an aminoglycoside such as gentamicin, both given IV. Concomitant intraventricular or intrathecal treatment with genta micin may be required when IV therapy fails but is not recommended for routine use. SUPPORTIVE CARE P. aeruginosa infections vary in severity from superficial to intense septic presentations. With severe infections there is often multisystem involvement and a systemic inflammatory response. Supportive care is similar to care for severe sepsis caused by other gram negative bacilli and requires support of blood pressure, oxygenation, and appropriate fluid management. PROGNOSIS The prognosis is dependent primarily on the nature of the underly ing factors that predisposed the patient to P. aeruginosa infection. In severely immunocompromised patients, the prognosis for patients with P. aeruginosa sepsis is poor unless susceptibility factors such as neutropenia or hypogammaglobulinemia can be reversed. The overall mortality rate was 12.3 in one series of 232 children with P. aerugi nosa bacteremia, with 3 dying within 48 hours of admission. Resis tance of the organism to first line antibiotics also decreases the chance of survival. The outcome may be improved when there is a urinary tract portal of entry, absence of neutropenia or recovery from neutro penia, and drainage of local sites of infection. P. aeruginosa is recovered from the lungs of most children who die of CF and adds to the slow deterioration of these patients. The prog nosis for normal development is poor in the few infants who survive P. aeruginosa meningitis. PREVENTION Prevention of infections is dependent on limiting contamination of the healthcare environment and preventing transmission to patients. Effective hospital infection control programs are necessary to identify and eradicate sources of the organism as quickly as possible. In hospi tals, infection can be transmitted to children by the hands of personnel, from washbasin surfaces, from catheters and other hospital equipment, and from solutions used to rinse suction catheters. Strict attention to hand hygiene before and between contacts with patients may prevent or interdict epidemic disease. Meticulous care and sterile procedures in the suctioning of endotracheal tubes, inser tion and maintenance of indwelling catheters, and removal of catheters as soon as medically reasonable greatly reduce the hazard of extrinsic contamination by P. aeruginosa and other gram negative organisms. Prevention of follicular dermatitis caused by P. aeruginosa contamina tion of whirlpools or hot tubs is possible by maintaining pool water at a pH of 7.2 7.8. Antimicrobial stewardship programs that promote the appropriate use of antibiotics in the hospital setting are critical for reducing the rates of MDR P. aeruginosa. Infections in burned patients may be minimized by protective iso lation, debridement of devitalized tissue, and topical |
7,343 | applications of bactericidal cream. Administration of intravenous immunoglobulin 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. 1802 Part XV u Infectious Diseases may be used. Approaches under investigation to prevent infection include development of a P. aeruginosa vaccine. No vaccine is currently licensed in the United States. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 251.2 Burkholderia cepacia Complex Ashley C. Howard and Thomas S. Murray Burkholderia cepacia is a filamentous gram negative rod now recog nized to be a group of related species or genomovars (B. cepacia, B. cenocepacia, B. multivorans). It is ubiquitous in the environment but may be difficult to isolate from respiratory specimens in the laboratory, requiring an enriched, selective media oxidation fermentation base supplemented with polymyxin Bbacitracin lactose agar (OFPBL) and as long as 3 days of incubation. B. cepacia is a classic opportunist that rarely infects normal tis sue but can be a pathogen for individuals with preexisting damage to respiratory epithelium, especially persons with CF or with immune dysfunction such as chronic granulomatous disease. B. cepacia has multiple virulence factors, including lipopolysaccharide, flagella, and a type III secretion system that promotes invasion of respiratory epi thelial cells. Resistance to many antibiotics and disinfectants appears to be a factor in the emergence of B. cepacia as a nosocomial patho gen. In critical care units it may colonize the tubing used to ventilate patients with respiratory failure. In some patients this colonization may lead to invasive pneumonia and septic shock. Although B. cepacia is found throughout the environment, human to human spread among CF patients occurs either directly by inhalation of aerosols or indirectly from contaminated equipment or surfaces, accounting for the strict infection control measures for children with CF who are colonized with B. cepacia. For example, CF patients colonized with B. cepacia are asked not to attend events where other persons with CF will be present. B. cepacia infections in persons with CF may represent chronic infection in some patients, but others, especially those with Burkholderia ceno cepacia, genomovar III, can develop an acute respiratory syndrome of fever, leukocytosis, and progressive respiratory failure, with more rapid decline in pulmonary function and lower survival rate. In 2016 2017, two healthcare associated B. cepacia outbreaks among non CF patients occurred as a result of contaminated liquid docusate that infected 63 persons from 12 states and prefilled saline flushes that infected 163 per sons with 7 deaths. In August 2021, a healthcare associated outbreak of B. stabilis was linked to ultrasound gel used in 59 persons in six states, with 48 cases of bloodstream infection. Treatment in hospitals should include standard precautions and avoidance of placing colonized and uncolonized patients in the same room. The use of antibiotics is guided by susceptibility studies of a patients isolates, because the susceptibility pattern of this species is quite vari able and resistant strains |
7,344 | are common. Trimethoprim sulfamethoxazole (TMP SMX) and doxycycline or minocycline are potential oral therapies for B. cepacia complex. For IV therapy without meningitis, meropenem (20 40 mgkgdose every 8 hours with a maximum dose of 6 gday) with a second agent such as TMP SMX, doxycycline, minocycline, ceftazidime, or amikacin is recommended. Extended infusions should be considered for difficult to treat infections. Even though there is primary resistance to aminoglycosides, these agents may be useful in combination with other antibiotics. Treatment with two or more agents may be necessary to con trol the infection and avoid the development of resistance. Cefiderocol, because of its increased stability against lactamases, has activity against some MDR B. cepacia complex. BURKHOLDERIA MALLEI (GLANDERS) Glanders is a severe infectious disease of horses and other domestic and farm animals that is caused by Burkholderia mallei, a nonmotile, gram negative bacillus that is occasionally transmitted to humans. It is acquired by inoculation into the skin, usually at the site of a previous abrasion, or by inhalation of aerosols. Laboratory workers may acquire it from clinical specimens. The disease is relatively common in Asia, Africa, and the Middle East. The clinical manifestations include septi cemia, acute or chronic pneumonitis, and hemorrhagic necrotic lesions of the skin, nasal mucous membranes, and lymph nodes. The diagnosis is usually made by recovery of the organism in cultures of affected tis sue. Glanders is treated with sulfadiazine, tetracyclines, or chloram phenicol and streptomycin over many months. The disease has been eliminated from the United States, but interest in this organism has increased because of the possibility of its use as a bioterrorism agent (see Chapter 763). Although standard precautions are appropriate when caring for hospitalized infected patients, biosafety level 3 pre cautions are required for laboratory staff working with B. mallei. No vaccine is available. BURKHOLDERIA PSEUDOMALLEI (MELIOIDOSIS) Melioidosis is an important disease of Southeast Asia and northern Australia and occurs in the United States mainly in persons returning from endemic areas. The causative agent is Burkholderia pseudomal lei, an inhabitant of soil and water in the tropics. It is ubiquitous in endemic areas, and infection follows inhalation of dust, ingestion, or direct contamination of abrasions or wounds. Human to human trans mission has only rarely been reported. Serologic surveys demonstrate that asymptomatic infection occurs in endemic areas. The disease may remain latent and appear when host resistance is reduced, sometimes years after the initial exposure. Diabetes mellitus is a risk factor for severe melioidosis. In 2021, four cases of melioidosis with two deaths occurred in Kansas, Minnesota, Texas, and Georgia in persons, includ ing children, with no known travel. The exposure is unknown but thought to be from a single source, such as a contaminated imported product or animal. Melioidosis may present as a primary skin lesion (vesicle, bulla, or urticaria) (Fig. 251.2). Pulmonary infection may be subacute and mimic tuberculosis or may present as an acute necrotizing pneumo nia. Occasionally, septicemia occurs and numerous abscesses are noted in various organs |
7,345 | of the body. Myocarditis, pericarditis, endocardi tis, intestinal abscess, cholecystitis, acute gastroenteritis, UTIs, septic arthritis, paraspinal abscess, osteomyelitis, mycotic aneurysm, and generalized lymphadenopathy all have been observed. Melioidosis may also present as an encephalitic illness with fever and seizures. It is also an agent of severe wound infections after contact with contaminated water after a tsunami. Diagnosis is based on visualization of charac teristic small, gram negative rods in exudates or growth on laboratory media such as eosinmethylene blue or MacConkey agar. Serologic Fig. 251.2 Thigh abscesses at the sites of mosquito bites in a 15 yr old Pennsylvania resident who had recently returned from Thai land, July 2016. Photo was taken 7 wk after onset. (From Mitchell PK, Campbell C, Montgomery MP, et al. Notes from the field: travelasso ciated melioidosis and resulting laboratory exposuresUnited States, 2016. MMWR. 2017;6637:10011002.) 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 252 u Tularemia (Francisella tularensis) 1803 tests are available, and diagnosis can be established by a fourfold or greater increase in antibody titer in an individual with an appropri ate syndrome. It is recognized as a possible agent of bioterrorism, and if suspected, the clinical microbiology laboratory should be notified immediately (see Chapter 763). B. pseudomallei is susceptible to many antimicrobial agents, and the U.S. Centers for Disease Control and Prevention (CDC) recommends meropenem or ceftazidime as IV therapies and TMP SMX or doxy cycline as oral therapy. Other choices include aminoglycosides, tetra cycline, chloramphenicol, and amoxicillin clavulanate. Therapy should be guided by antimicrobial susceptibility tests; two or three agents such as ceftazidime or meropenem plus TMP SMX, sulfisoxazole, or an aminoglycoside are usually chosen for severe or septicemic disease. For severe disease, prolonged treatment for 2 6 months is recommended to prevent relapses. Appropriate antibiotic therapy generally results in recovery. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 251.3 Stenotrophomonas Ashley C. Howard and Thomas S. Murray Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia or Pseudomonas maltophilia) is a short to medium sized, straight, gram negative bacillus. It is ubiquitous in nature and can be found in the hospital environment, especially in tap water or standing water, and may contaminate sinks and hospital equipment such as nebulizers. Strains isolated in the laboratory may be contaminants, may be a commensal from the colonized surface of a patient, or may represent an invasive pathogen. The species is an opportunist and is often recovered from immunosuppressed patients and patients with CF after multiple courses of antimicrobial therapy. Serious infec tions usually occur among those requiring intensive care, including neonatal intensive care, typically patients with ventilator associated pneumonia or catheter associated infections. Prolonged antibiotic exposure appears to be a frequent factor in nosocomial S. malto philia infections, probably because of its endogenous antibiotic resistance pattern. Common types of infection include pneumonia after airway colonization and aspiration, bacteremia, soft tissue infections, endocarditis, |
7,346 | and osteomyelitis. S. maltophilia bactere mia is a nosocomial infection associated with the presence of a central venous catheter. Strains vary as to antibiotic susceptibility, and the treatment of S. maltophilia can be difficult because of inherent antimicrobial resis tance. Data are lacking on whether there is clinical benefit to treat S. maltophilia recovered from the respiratory tract of a patient with CF. For invasive infections, TMP SMX (20 mgkgday TMP component every 6 8 hours) is the treatment of choice and is the only antimicrobial for which susceptibility is routinely reported. Minocycline monotherapy has recently been shown to be a viable alternative to TMP SMX and is reported for TMP SMX resistance strains with fewer adverse effects and similar clinical outcomes. Mean inhibitory concentration testing is available for other antibiotics, such as ticarcillin clavulanate, and also reserved for TMP SMXresistant isolates. For resistant organisms or for patients who cannot tolerate sulfa drugs, other options based on clinical outcome include ciprofloxacin and ceftazidime alone or in combination with other agents such as aminoglycosides. ACKNOWLEDGMENTS We would like to acknowledge Dr. Robert S. Baltimore for his contribu tion to this chapter and Dr. Michelle R. Rychalsky for antibiotic dosing regimens. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Tularemia is a zoonosis caused by the gram negative bacterium Fran cisella tularensis. Tularemia is primarily a disease of wild animals; human disease is incidental and usually results from tick or deer fly bites or from contact with infected live or dead wild animals. The ill ness caused by F. tularensis is manifest by multiple clinical syndromes, the most common consisting of an ulcerative lesion at the site of inocu lation with regional lymphadenopathy or lymphadenitis. F. tularensis is also a potential agent of bioterrorism (see Chapter 763). ETIOLOGY Francisella tularensis is a small, nonmotile, pleomorphic, catalase positive, gram negative coccobacillus. It can be classified into four main subspecies: F. tularensis subsp. tularensis (type A), F. tularensis subsp. hol arctica (type B), F. tularensis subsp. mediasiatica, and F. tularensis subsp. novicida. Type A can be further subdivided into four distinct genotypes designated A1a, A1b, A2a, and A2b, with A1b appearing to produce more serious disease in humans. Although all subspecies of F. tularensis can cause human infections, types A and B are most common, and type A is the most virulent. F. tularensis is an intracellular organism than can infect various host cell types, including macrophages, hepatocytes, and epithe lial cells. It is one of the most virulent bacterial pathogens known, with as few as 10 microorganisms causing infections in humans and animals. EPIDEMIOLOGY Tularemia is primarily found in the Northern Hemisphere. Type A is found predominantly in North America, whereas type B is found throughout North America, Europe, and Asia. Human infections with type B are usually milder and have lower mortality rates compared to infections with type A. F. tularensis subsp. mediasiatica appears to be restricted to Central Asia, whereas F. tularensis subsp. novicida has been isolated in North America, Australia, and |
7,347 | Southeast Asia. According to the Centers for Disease Control and Prevention (CDC), the number of annual reported cases of tularemia in the United States from 2010 to 2019 ranged from 124 to 314 per year. In 2015 the num ber of cases reported in the United States was the highest it had been over the previous 50 years. Tularemia occurs all over the Unites States, with the majority of cases reported from central states (Fig. 252.1). The U.S. incidence of tularemia from 2010 to 2019 was 0.10 per 100,000 residents; Arkansas (3.1100,000), South Dakota (1.9100,000), and Nebraska (0.9100,000) were the states with the highest incidence. Although cases of tularemia occur all year, most cases and outbreaks occur in warm summer months (May September). Tularemia is more common in males, although this is less true in children compared with adults. There is a bimodal distribution based on age with peaks in childhood (5 9 years) and later adulthood (50 69 years), potentially because of greater opportunities for environmental and animal expo sures at these ages (Fig. 252.2). PATHOGENESIS Of all the zoonotic diseases, tularemia is unusual because of the differ ent modes of transmission of disease. A large number of animals serve as a reservoir for this organism. In the United States, rabbits and ticks are the principal reservoirs. Dogs may be an intermediate vector. In the United States, Amblyomma americanum (lone star tick), Dermacentor variabilis (dog tick), and Dermacentor andersoni (wood tick) are the most common tick vectors. These ticks usually feed on infected small Chapter 252 Tularemia (Francisella tularensis) Kevin J. Downes 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. 1804 Part XV u Infectious Diseases rodents and later feed on humans. Deer flies (Chrysops spp.) can also transmit tularemia and are present in the western United States. F. tula rensis subsp. tularensis is carried by rabbits, ticks, and tabanid flies (e.g., deer flies), whereas subsp. holarctica is associated with aquatic habi tats and transmitted primarily by mosquitoes, but also aquatic rodents (beavers, muskrats), hares, voles, ticks, tabanid flies, and ingestion of contaminated water (e.g., ponds, rivers). The organism can penetrate both intact skin and mucous mem branes (eyes, mouth, gastrointestinal GI tract, or lungs), which are the most common portals of entry. Transmission can occur through the bite of infected ticks or other biting insects, by contact with infected animals or their carcasses, by consumption of contaminated foods or water, or through inhalation, as might occur in a labora tory setting or if a machine (e.g., lawn mower) runs over an infected animal carcass. Hunting or skinning infected wild rodents, such as rabbits or prairie dogs, has been the source of infection in numer ous reports. Domesticated animals such as cats and hamsters can also Fig. 252.1 Map of reported cases of tularemiaUnit ed States, 2020. (From Centers for Disease Control and |
7,348 | Prevention: TularemiaStatistics, https:www.cdc.gov tularemiastatisticsindex.html, Accessed: August 25, 2021.) One dot is placed randomly within county of residence for each reported case. 200 180 160 140 120 100 80 60 40 20 0 0 10 20 30 40 50 60 70 805 15 25 35 5 year age group C as es 45 55 65 75 85 90 Male Female Fig. 252.2 Incidence of reported cases of tularemia by age and sex United States, 20012020. (From Centers for Disease Control and Pre vention: TularemiaStatistics, https:www.cdc.govtularemiastatis ticsindex.html, Accessed: August 25, 2021.) transmit tularemia. Importantly, this organism is not transmitted from person to person. Usually 108 organisms are required to produce infection if F. tula rensis bacteria are ingested, but as few as 10 organisms may cause disease if they are inhaled or injected into the skin (i.e., via an insect bite). Infection with F. tularensis stimulates the host to produce anti bodies, which have been recognized as important in the immune response to this organism. The F. tularensis envelope is largely responsible for virulence and plays major roles in the ability of the organism to evade the immune system, attach to and invade cells, and cause severe disease. The body is most dependent on cell mediated immunity to contain and eradicate F. tularensis. Tularemia is usu ally followed by specific protection; chronic infection or reinfection is therefore unlikely. CLINICAL MANIFESTATIONS Symptoms of tularemia vary based on the mode of transmission. The average incubation period from infection until clinical symp toms is 3 days (range: 1 21 days). Early symptoms of infection are generally nonspecific: fever, chills, myalgias, arthralgias, headache, and fatigue. Bacteremia may be common in the early stages of infec tion. Acute infections often present with sudden onset of fever, and a pulse temperature dissociation may be present. Findings on phys ical examination may include lymphadenopathy, hepatospleno megaly, or skin lesions. Table 252.1 shows the frequency of various symptoms and examination findings. The clinical manifestations of tularemia have been divided into six major clinical syndromes (Table 252.2). Ulceroglandular and glandular disease are the two most common forms of tularemia in children. Infections after the bites of ticks or deer flies take these forms. Within 48 72 hours after inoculation of the skin, an ery thematous, tender, or pruritic papule may appear at the portal of entry. This papule may enlarge and form an ulcer with a black base. Ulcers are generally erythematous and painful with raised bor ders and may last several weeks, especially if untreated. Various other skin lesions have been described, including erythema mul tiforme and erythema nodosum. Approximately 20 of patients may develop a generalized maculopapular rash that occasionally becomes pustular. The unifying manifestation of glandular and ulceroglandular forms of tularemia is painful regional lymph adenopathy. Adenopathy may develop before, concurrent with, or 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. after |
7,349 | skin ulceration in ulceroglandular disease. Cervical or poste rior auricular nodes are involved after bites on the head or neck, whereas enlarged axillary or epitrochlear nodes signal exposure on the arms. Nodes may vary in size from 0.5 to 10 cm and appear sin gly or in clusters. These affected nodes may become fluctuant and drain spontaneously and are often associated with overlying skin changes. Late suppuration of the involved nodes has been described in 2530 of patients despite effective therapy. Examination of this material from such lymph nodes usually reveals sterile necrotic material. Mortality with these forms of tularemia is rare, especially with implementation of effective treatment. Oropharyngeal tularemia results from consumption of poorly cooked meats or contaminated water. This syndrome is characterized by acute pharyngitis, with or without tonsillitis, and cervical lymph adenitis. Infected tonsils may become large and develop a yellowish white membrane that may resemble the membranes associated with diphtheria. GI disease may also occur and usually presents with mild, unexplained diarrhea or emesis but may progress to rapidly fulminant and fatal disease. GI bleeding can develop in more severe forms associ ated with intestinal ulcers. Oculoglandular disease is uncommon, but when it does occur, the portal of entry is the conjunctiva. Contact with contaminated fingers or debris is the most common mechanism of this form of tularemia. Disease is generally unilateral. The conjunctiva is pain ful and inflamed with yellowish nodules and pinpoint ulcerations. Purulent conjunctivitis with ipsilateral preauricular or submandib ular lymphadenopathy can develop and is referred to as Parinaud oculoglandular syndrome, although this term is not specific to tularemia. Corneal ulceration and perforation are uncommon but serious complications of this form of disease. The typhoidal form is usually associated with a large inocu lum of organisms and is a term used to describe nonlocaliz ing disease, regardless of the mode of transmission or portal of entry. Patients are often critically ill and bacteremic, and symp toms mimic those with other forms of sepsis: high fevers, con fusion, rigors, myalgias, vomiting, and diarrhea. Clinicians practicing in tularemia endemic regions must always consider this diagnosis in critically ill children. Complications of bactere mia with F. tularensis can include the development of meningitis, pericarditis, hepatitis, peritonitis, endocarditis, skinsoft tissue abscesses, and osteomyelitis. Because of its increased virulence, F. tularensis subsp. tularensis (type A disease) is more often associ ated with typhoidal tularemia. Patients with tularemia meningitis usually develop a marked cerebrospinal fluid (CSF) pleocytosis with a monocytic predominance. As with other causes of bacterial men ingitis, CSF glucose is low and protein is high. Pneumonia caused by F. tularensis (pneumonic form) can develop after inhalation (primary pulmonary infection) or second ary to hematogenous spread. Inhalation related infection has been described in laboratory workers who are working with the organism and results in a relatively high mortality rate. Aerosols from farm ing activities involving rodent contamination (haying, threshing) or animal carcass destruction with lawn mowers have been reported to cause pneumonia as well. Patients generally complain of |
7,350 | a nonpro ductive cough, dyspnea, or pleuritic chest pain. Chest radiographs of patients with pneumonic tularemia most often reveal diffuse, patchy infiltrates rather than focal areas of consolidation. Pleural effusions can also be present. In pulmonary infections, hilar or mediastinal adenopathy can develop, and in severe forms, necrotiz ing or hemorrhagic pneumonitis can occur. Mortality with pneu monic tularemia is high if untreated. DIAGNOSIS The diagnosis can be delayed because symptoms are often similar to other, more common infections. The history and physical examina tion of the patient may suggest the diagnosis, especially if the patient has a history of animal or tick exposure. Routine hematologic blood tests are nondiagnostic. Definitive diagnosis is made by growth of F. tularensis in culture. F. tularensis can be isolated in culture of lymph node biopsies or aspirates, blood, wounds, pharyngeal swabs, pleu ral fluid, or sputum specimens, although cultures are positive in only approximately 10 of cases. The organism can be identified on culture from skin lesions and lymph nodes for as long as a month after onset of disease. Polymerase chain reaction of tissue specimens may be more sensitive than culture but is currently used to make a presumptive diag nosis only. F. tularensis can be cultured in the microbiology laboratory on cysteineglucoseblood agar, but care should be taken to alert the personnel in the laboratory if this is attempted so that they can take the proper precautions to protect themselves from acquir ing infection; biosafety level 3 containment is necessary to avoid occupational exposure. Histopathologic findings of involved lymph nodes demonstrate granulomas with central necrosis (early) and caseation (late). Unfortunately, these findings cannot distinguish tularemia from other causes of granulomatous lymphadenitis, such as tuberculosis, catscratch disease (Bartonella henselae infection), or sarcoidosis. Chapter 252 u Tularemia (Francisella tularensis) 1805 Table 252.1 Common Clinical Manifestations of Tularemia in Children SIGN OR SYMPTOM APPROXIMATE FREQUENCY () Lymphadenopathy 90 Fever (38.3C 100.9F) 85 Ulcerescharpapule 45 Pharyngitis 40 Myalgiasarthralgias 40 Nauseavomiting 35 Hepatosplenomegaly 35 Table 252.2 Clinical Syndromes of Tularemia in Children CLINICAL SYNDROME CHARACTERISTICS OF SYNDROME Ulceroglandular Skin ulcereschar at site of inoculation; painful regional adenopathy Glandular Painful regional adenopathy without detectable skin ulceration Pneumonia Nonproductive cough, dyspnea, pleuritic chest pain; multilobar diffuse infiltrates lobar infiltrates on chest radiography Oropharyngeal Pharyngitis, mucosal ulcers, cervical adenopathy Oculoglandular Unilateral, painful, and often purulent conjunctivitis; chemosis; conjunctival ulcers; preauricular adenopathy Typhoidal Severe systemic disease (sepsis like syndrome): high fever, headaches, myalgias, arthralgias, neurologic symptoms 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. 1806 Part XV u Infectious Diseases The diagnosis of tularemia is most often established via serol ogy. In the standard tube agglutination (TA) test, a single titer of 1:160 in a patient with a compatible history and physical findings can establish the diagnosis. A microagglutination (MA) test is also available, and 1:128 is considered positive. Patients often do not produce |
7,351 | detectable antibodies until the second week of illness, so negative testing in the acute phase does not rule out infection. A fourfold increase in titer from paired serum samples collected 2 weeks apart (i.e., acute and convalescent titers) can also be consid ered diagnostic. False negative serologic responses can be obtained early in the infection or if paired sera are collected too close together. False positive serologic tests can also result from cross reactivity with other gram negative organisms, such as Brucella or Legionella species, particularly at low titers. Once infected, patients may have a positive agglutination test result (1:20 1:80) that persists for life. Other testing techniques available include enzyme linked immunosorbent assay (ELISA), analysis of urine for tularemia anti gen, indirect immunofluorescent assay, and immunohistochemical staining; these studies have less well established roles in the diag nosis of tularemia. Differential Diagnosis The differential diagnosis of ulceroglandular or glandular tula remia is broad and includes infection with pathogens that cause acute or subacute lymphadenitis: catscratch disease (B. henselae), infectious mononucleosis, typical bacterial pathogens (Staphylo coccus aureus, group A streptococcus), Mycobacterium tuberculo sis, nontuberculous mycobacteria, Toxoplasma gondii, Sporothrix schenckii, plague (Yersinia pestis), anthrax (Bacillus anthracis), melioidosis (Burkholderia pseudomallei), and rat bite fever (Strep tobacillus moniliformis, Spirillum minus). Noninfectious processes such as sarcoidosis and Kawasaki disease can also present simi larly. Oculoglandular disease may also occur with other infec tious agents, such as B. henselae, Treponema pallidum, Coccidioides immitis, herpes simplex virus (HSV), adenoviruses, and the bacte rial agents responsible for purulent conjunctivitis. Oropharyngeal tularemia must be differentiated from the same diseases that cause ulceroglandularglandular disease and from cytomegalovirus, HSV, adenovirus, and other viral or bacterial etiologies. Pneumonic tularemia must be differentiated from the other atypical pathogens that cause community acquired pneumonia, such as Mycoplasma and Chlamydophila, as well as mycobacteria, fungi, and rickettsiae. Inhalation plague, anthrax, and Q fever could also present similarly. Typhoidal tularemia must be differentiated from other forms of sepsis and from enteric fever (typhoid and paratyphoid fever) and brucellosis. TREATMENT Aminoglycosides are the mainstay of treatment of tularemia: gen tamicin is the drug of choice for the treatment of tularemia in children, and streptomycin is the drug of choice in adults. Table 252.3 displays therapeutic options for treatment of tularemia and for postexposure prophylaxis. Ciprofloxacin is often used for mild (localized) cases, especially those caused by subsp. holarctica, but is less commonly prescribed in children. Doxycycline has been used successfully, but the relapse rate is higher than with aminoglyco sides, and so it is not generally recommended. Ciprofloxacin and doxycycline are often used as adjunctive therapy for treatment of tularemia meningitis because of the poor penetration of aminogly cosides in the CSF. Ciprofloxacin can also be considered in cases of moderatesevere disease after initial treatment with an amino glycoside, if an IV to PO switch is warranted based on clinical improvement. lactam agents demonstrate poor activity against F. tularensis and should not be used. Therapy with aminoglycosides is typically continued for 7 10 days, but a |
7,352 | longer course is needed in more severe disease; 5 7 days may be sufficient for mild cases. Ciprofloxacin treatment is typically 10 14 days, although there is no FDA approved regimen for tularemia specifically. Treatment with doxycycline should be continued for 14 21 days because of an increased risk of relapse, likely because of its bacte riostatic nature. PROGNOSIS Poor outcomes are associated with a delay in appropriate treatment, but with rapid recognition and treatment, fatalities are exceedingly rare. The mortality rate for severe untreated disease (e.g., pneumo nia, typhoidal disease) can be as high as 30. Otherwise, the overall mortality rate is 1. Subspecies tularensis is associated with more aggressive disease and worse outcomes than subsp. holarctica. Relapses are uncommon if aminoglycoside therapy is used. Patients typically defervesce within 24 48 hours after starting therapy, although lymphadenopathy can take several weeks to resolve fully. Late suppuration of involved lymph nodes may occur despite adequate therapy. Patients who have not started on appro priate therapy early may respond more slowly to antimicrobial therapy. PREVENTION Prevention of tularemia is based on avoiding exposure. Children liv ing in tick endemic regions should be taught to avoid tick infested areas. Families should have a tick control plan for their immediate environment and for their pets. Protective clothing should be worn when entering a tick infested area. Insect repellents can be used safely Table 252.3 Recommended Treatment for Children with Tularemia INDICATION DRUG AND DOSAGE DURATION Moderate severe disease Gentamicin 5 7.5 mgkgday IV or IM divided every 8 12 hr or Streptomycin 3040 mgkgday IM divided every 12 hr (max 1 gdose) 10 days Mild disease Gentamicin 5 7.5 mgkgday IV or IM divided every 8 12 hr or Ciprofloxacin 20 40 mgkgday PO divided every 12 hr (max 500 mgdose) 5 7 days 10 14 days Meningitis Streptomycin or gentamicin (in doses given for moderate severe disease) PLUS Ciprofloxacin (20 40 mgkgday IV divided every 12 hr) or Doxycycline 4.4 mgkgday IV divided every 12 hr (max 100 mgdose) 10 days Postexposure prophylaxis Doxycycline 4.4 mgkgday PO divided twice daily (max 100 mgdose) or Ciprofloxacin 20 40 mgkgday PO divided twice daily (max 500 mgdose) 14 days Once daily dosing of gentamicin could be considered, although it has not specifically been studied for this indication. IM, Intramuscularly; IV, intravenously; PO, per os (i.e., 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. Chapter 253 u Brucella 1807 Human brucellosis is caused by organisms of the genus Brucella and continues to be a major public health problem worldwide. Humans are accidental hosts and acquire this zoonosis from direct contact with an infected animal (cattle, sheep, camels, goats, and swine) or consumption of products of an infected animal. Although brucellosis is widely recognized as an occupational risk among adults working with livestock, much of the brucellosis in |
7,353 | children is food borne and is associated with consumption of unpasteurized dairy products. Brucella spp. are also potential agents of bioterror ism (see Chapter 763). ETIOLOGY Brucella abortus (cattle), Brucella melitensis (goats and sheep), Bru cella suis (swine), and Brucella canis (dogs) are the most common organisms responsible for human disease. These organisms are small, aerobic, nonspore forming, nonmotile, gram negative coccobacil lary bacteria. Brucella spp. are fastidious in their growth but can be grown on various laboratory media, including blood and chocolate agars. EPIDEMIOLOGY Brucellosis is endemic in many parts of the world and is especially prevalent in the Mediterranean basin, Persian Gulf, Indian subcon tinent, and parts of Mexico and Central and South America. There are approximately 500,000 new cases annually worldwide, although accurate estimates of the prevalence of disease are lacking because of underreporting and underdiagnosis. Childhood brucellosis accounts for 1030 of cases. B. melitensis is the most prevalent species causing human brucel losis and is most often carried by sheep, goats, camels, and buffalo. Elk, caribou, bison, deer, moose, and swine can also be infected. Because of improved sanitation and animal vaccination, brucellosis has become rarer in countries with effective public health and domestic animal health programs, although recreational or occupational exposures continue to occur. Consumption of raw or unpasteurized dairy products in a child who has lived in or traveled to an endemic area is the key risk factor for pediatric brucellosis because most childhood Chapter 253 Brucella Kevin J. Downes in infants and children. Children should undergo frequent tick checks during and after their time in tick infested areas. If ticks are found on the child, forceps should be used to pull the tick straight out. The skin should be cleansed before and after this procedure. Children should also be taught to avoid sick and dead animals. Children should be encouraged to wear gloves, masks, and eye protection while cleaning wild game. Further, families should cook wild game thoroughly before eating. Prophylactic antimicrobial agents are generally not effective in pre venting tularemia and should not be used after exposure, with the exception of laboratory or bioterrorism exposures. No tularemia vac cine is currently available to the general public (one is available for high risk laboratory workers through the Department of Defense). Standard precautions are adequate for hospitalized children with tula remia because no cases of person to person transmission have been identified. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. cases are acquired via ingestion. In the United States in 2010, 50 of cases occurred in California, Arizona, Florida, and Texas. All age groups can be infected by Brucella, and infections are more common in males, likely because of more frequent occupational and recreational exposures. B. abortus cattle vaccine strain RB51 is a live, attenuated vaccine that has been used to vaccinate cattle in the United States since 1996. Very rare cases of human infection with this vaccine strain have been reported secondary to consumption of unpasteurized milk from vac cinated cows. These strains are |
7,354 | resistant to rifampin, a primary agent used in the treatment of brucellosis, so clinicians should consider RB51 in a patient with the correct exposure history. PATHOGENESIS Modes of transmission for these organisms include inoculation through cuts or abrasions in the skin, inoculation of the conjunc tiva, inhalation of infectious aerosols, or ingestion of contaminated meat or dairy products. Infected livestock are the most common source of human infection. In children the primary means of infec tion is through eating or drinking unpasteurized or raw dairy prod ucts. Individuals in endemic areas with occupational exposures to animals, such as farmers, veterinarians, and slaughterhouse work ers, are at highest risk; exposure to an infected animals abortion products or feces are notable risk factors in such occupations. Lab oratory workers are more often exposed to infected aerosols. The risk for infection depends on the nutritional and immune status of the host, the route of inoculation, and the species of Brucella. For reasons that remain unclear, it has been suggested that B. melitensis and B. suis are more virulent than B. abortus or B. canis. The major virulence factor for Brucella spp. appears to be its cell wall lipopolysaccharide (LPS). Strains containing smooth LPS have been demonstrated to have greater virulence and are more resis tant to killing by polymorphonuclear leukocytes. These organisms are facultative intracellular pathogens that can survive and repli cate within the mononuclear phagocytic cells (monocytes, mac rophages) of the reticuloendothelial system. Even though Brucella spp. are chemotactic for entry of leukocytes into the body, the leu kocytes are less efficient at killing these organisms than other bac teria despite the assistance of serum factors such as complement. Brucella spp. possess multiple strategies to evade immune responses and establish and maintain chronic infection. Specifically, dur ing chronic stages of infection, organisms persist within the liver, spleen, lymph nodes, and bone marrow and result in granuloma formation. Antibodies are produced against the LPS and other cell wall anti gens, providing a means of diagnosis and likely playing a role in long term immunity. The major factor in recovery from infection appears to be development of a cell mediated immune response, resulting in macrophage activation and enhanced intracellular killing. Specifically, sensitized T lymphocytes release cytokines (e.g., interferon , tumor necrosis factor ), which activate the macrophages and enhance their intracellular killing capacity. CLINICAL MANIFESTATIONS Brucellosis is a systemic illness that can be quite difficult to diag nose in children. Symptoms can be acute or insidious in nature and are usually nonspecific. The incubation period is generally 2 4 weeks but may be shorter with B. melitensis. Fever is present in 75 of cases, and the fever pattern can vary widely. The most common physical complaints are arthralgia, myalgia, and back pain. Systemic symptoms, such as fatigue, sweats, chills, anorexia, headache, weight loss, and malaise, are reported in the majority of adult cases but are less frequent in children. Other associated symp toms include abdominal pain, diarrhea, rash, vomiting, cough, and pharyngitis. The most |
7,355 | common physical manifestation of brucellosis is hepatic and splenic enlargement, which is present in approximately half of cases. Whereas arthralgia is common, arthritis occurs in a minority of cases. Arthritis is typically monoarticular and most Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1808 Part XV u Infectious Diseases often involves the knee or hip in children and the sacroiliac joint in adolescents and adults. Several types of skin lesions have been described with brucellosis, but there is no typical rash for this infec tion. Epididymo orchitis also can occur and is more common in adolescents and adults. In endemic countries, Brucella spp. are an important cause of occult bacteremia in young children. Because of the organisms ability to establish chronic infection, hepatic and splenic abscesses may develop. High grade fever and elevations in liver enzymes are common among children with primary bacteremia. Children with positive blood cultures typically have more acute presentations with increased markers of inflammation (leukocyte count, CRP, ferritin) compared with culture negative cases. Recurrent episodes of bac teremia can also occur (10 of cases), especially with inadequate primary treatment. These recurrent episodes are less often associ ated with fever (40 of cases), potentially indicating the indolent nature of chronic Brucella infections in children. Serious manifestations of brucellosis include endocarditis, men ingitis, osteomyelitis, and spondylitis. Although headache and malaise may be demonstrated in patients with uncomplicated brucellosis, invasion of the nervous system occurs in only 14 of cases. Death from brucellosis is rare, occurring in less than 1 of cases. Neonatal and congenital infections with these organisms have also been described, resulting from transplacental transmis sion, breast milk, and blood transfusions. The signs and symptoms associated with congenitalneonatal brucellosis are nonspecific. Hematologic abnormalities are common with brucellosis but occur in less than half of cases; leukopenia is the most common cytopenia to develop. Hemolytic complications can include micro angiopathic hemolytic anemia, thrombotic microangiopathy, and autoimmune hemolytic anemia. Secondary cases of hemophago cytic lymphohistiocytosis have also been described after brucellosis in children. Elevations of liver enzymes occur in approximately half of all cases of brucellosis and are more common when bacteremia is present. DIAGNOSIS A definitive diagnosis of brucellosis is established by isolating and identifying the organisms from cultures of the blood (most common), bone marrow, or other fluids and tissues. Unfortunately, cultures are insensitive and positive in only a minority of pediatric cases. In a study of 436 children with brucellosis in Israel from 2005 to 2014, 76 had positive blood cultures. However, the prevalence of bacteremia in this cohort, 64 of whom were hospitalized, was much higher than most prior reports, in which less than half of cases have had positive blood cultures. Isolation of the organism from a blood culture sample may require as long as 4 weeks unless the laboratory is using an automated culture system such as |
7,356 | the lysis centrifugation method, where the organism can be recovered in 5 7 days. Therefore it is prudent to alert the clinical microbiology laboratory that brucellosis is suspected, so that cultures can be held longer. Bone marrow cultures may be superior to blood cultures when evaluating patients who have received previous antimicrobial therapy. In addition to bacterial isolation, various serologic tests have been applied to the diagnosis of brucellosis. Microagglutination or serum (tube) agglutination tests are the most widely used and detect antibod ies against B. abortus, B. melitensis, and B. suis. These methods do not detect antibodies against B. canis or B. abortus vaccine strain RB51, which lack the smooth LPS; B. canisspecific antigen is required to diagnose this species. Antibodies can also be detected by other tests such as enzyme linked immunosorbent assay (ELISA). The Rose Ben gal plate test (RBT) is a rapid agglutination test that is used as a screen ing test in many endemic regions. It has good sensitivity (95) and low cost, but confirmation of RBT results with microbiologic or other serologic tests is advised. For a diagnosis to be made via serology alone, acute and conva lescent samples taken 2 4 weeks apart are recommended; a four fold or greater rise in titers is diagnostic of an acute infection. No single titer is ever diagnostic, but most patients with acute infec tions have titers of 1:160; lower titers may be present early in the disease course. Immunoglobulin M (IgM) antibodies can generally be detected within a week of illness onset, whereas IgG is detectable 2 4 weeks after infection. Because patients with active infection have both an IgM and an IgG response and the serum agglutination test measures the total quantity of agglutinating antibodies, the total quantity of IgG is measured by treatment of the serum with 2 mercaptoethanol. This fractionation is important in determining the significance of the antibody titer because low levels of IgM can remain in the serum for weeks to months after the infection has been treated. IgG titers decrease with effective therapy, and a negative 2 mercaptoethanol test after treatment indicates a favor able response. It is important to remember that all serologic results must be interpreted in light of a patients history and physical examina tion. False positive results from cross reacting antibodies to other gram negative organisms, such as Yersinia enterocolitica, Francisella tularensis, and Vibrio cholerae, can occur. In addition, the prozone effect can give false negative results in the presence of high titers of antibody. To avoid this issue, serum that is being tested should be diluted to 1:320. The enzyme immunoassay should only be used for suspected cases with negative serum agglutination tests or for the evaluation of patients in the following situations: (1) complicated cases, (2) suspected chronic brucellosis, or (3) reinfection. Polymerase chain reaction assays have been developed but are not available in most clinical laboratories. Differential Diagnosis Brucellosis should be considered in the differential diagnosis of fever of unknown origin in |
7,357 | endemic areas. It may present similar to other infections such as tularemia, cat scratch disease, malaria, typhoid fever, histoplasmosis, blastomycosis, and coccidioidomy cosis. Infections caused by Mycobacterium tuberculosis, atypical mycobacteria, rickettsiae, and Yersinia can also present similar to brucellosis. TREATMENT Many antimicrobial agents are active in vitro against Brucella spp., but clinical effectiveness does not always correlate with these results. Agents that provide good intracellular killing are required for elimina tion of Brucella infections. Because of the risk of relapse with mono therapy, combination therapy is generally recommended. Additionally, prolonged therapy (6 weeks or longer) is necessary to ensure an ade quate and sustained response. For uncomplicated infections in children 8 years of age or older, 6 weeks of doxycycline in combination with rifampin is recom mended (Table 253.1). For children younger than age 8 years, trimethoprim sulfamethoxazole (TMP SMX) plus rifampin is advised because of concerns about prolonged tetracycline use in young children. Although data support that the combination of doxycycline plus an aminoglycoside (streptomycin, gentamicin) is superior to the other oral combination therapies, with fewer treat ment failures and relapses, the inconvenience of parenteral therapy may limit this approach in uncomplicated cases, particularly in resource limited settings. Fluoroquinolones may be a viable alter native to doxycycline or TMP SMX but have not been studied in children. In more serious infections (e.g., endocarditis, meningitis, osteoar ticular infections), three drug therapy is advised. An aminoglycoside (streptomycin, gentamicin) should be administered for the first 7 14 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 253 u Brucella 1809 Table 253.1 Recommended Therapy for Treatment of Brucellosis AGECONDITION TREATMENT REGIMEN DURATION 8 yr, uncomplicated infection Doxycycline (PO; 4.4 mgkgday, max 200 mgday) in 2 divided doses plus Rifampin (PO; 15 20 mgkgday, max 600 900 mgday) in 1 2 divided doses Alternative: Doxycycline (PO; 4.4 mgkgday, max 200 mgday) in 2 divided doses plus Streptomycin (IMIV; 20 40 mgkgday, max 1 gday) in 2 4 divided doses or Gentamicin (IMIV; 5 7.5 mgkgday) once daily 6 wk 6 wk 6 wk 2 3 wk 1 2 wk 8 yr, uncomplicated infection Trimethoprim sulfamethoxazole (PO; trimethoprim: 10 mgkg day, max 480 mgday; sulfamethoxazole: 50 mgkgday, max 2.4 gday) in 2 divided doses plus Rifampin (PO; 15 20 mgkgday, max 600 900 mgday) in 1 2 divided doses 6 wk 6 wk Complicated infection (meningitis, endocarditis, osteomyelitis, spondylitis) Streptomycin (IMIV; 20 40 mgkgday, max 1 gday) in 2 4 divided doses or Gentamicin (IMIV; 5 7.5 mgkgday) once daily plus Doxycycline (IVPO; 4.4 mgkgday, max 200 mgday) in 2 divided doses (Trimethoprim sulfamethoxazole should be used for children 8 yr of age) plus Rifampin (IVPO; 15 20 mgkgday, max 600 900 mgday) in 1 2 divided doses 1 2 wk 1 2 wk 6 wk 6 wk Gentamicin can be given in divided doses if indicated based |
7,358 | on age. 46 mo for meningitis or endocarditis. Note: Because of resistance of B. abortus strain RB51 to rifampin, treatment with doxycycline plus trimethoprim sulfamethoxazole should be used if this isolate is identified. days of therapy, along with doxycycline (or TMP SMX) plus rifampin, which are continued for at least 6 weeks. For meningitis and endocar ditis, therapy is often continued for 4 6 months. Surgical interven tion should be pursued when appropriate, such as when deep tissue abscesses have developed. If B. abortus RB51 (cattle vaccine strain) is identified (or sus pected) as the cause of infection, the use of rifampin should be avoided. This is because the strain was derived by selection in rifampin enriched media and is thus inherently resistant to rifampin. As a result, a combination of doxycycline and TMP SMX should be used as treatment. Although relapse occurs in approximately 515 of cases, antimi crobial resistance is rare. Relapse is confirmed by isolation of Brucella within weeks to months after therapy has ended. Prolonged treatment is the key to preventing disease relapse, and steps should be taken to assure compliance with the long courses of therapy needed to achieve eradication. PROGNOSIS The primary indication of clinical response is resolution of symp toms, which may be slow; the average time to defervescence is 4 5 days. The prognosis after therapy is excellent if patients are compli ant with the prolonged therapy. Patients should be followed clini cally and serologically for 1 2 years. Before the use of antimicrobial agents, the course of brucellosis was often prolonged and associated with death. Since the institution of specific therapy, most deaths are a result of specific organ system involvement (e.g., endocarditis) in complicated cases. Initiation of antimicrobial therapy may precipitate a Jarisch Herxheimerlike reaction, presumably because of a large antigen load, but these reactions are rarely associated with serious complications. PREVENTION Prevention of brucellosis depends on effective eradication of the organism from livestock. Pasteurization of milk and dairy products for human consumption remains an important aspect of prevention. It should be noted that certification of raw milk does not eliminate the risk of brucellosis acquisition. No vaccine currently exists for use in children, and therefore education of the public continues to have a prominent role in the prevention of brucellosis. 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. 1810 Part XV u Infectious Diseases Legionellosis comprises Legionnaires disease (Legionella pneumo nia), other invasive extrapulmonary Legionella infections, and an acute flulike illness known as Pontiac fever. In contrast to the syndromes associated with invasive disease, Pontiac fever is a self limited illness that develops after aerosol exposure and may represent a toxic or hypersensitivity response to Legionella. ETIOLOGY Legionellaceae are aerobic, nonspore forming, nonencapsulated, gram negative bacilli that stain poorly with Gram stain when per formed on |
7,359 | smears from clinical specimens. Stained smears of Legio nella pneumophila taken from colonial growth resemble Pseudomonas. Unlike other Legionella species, Legionella micdadei stains acid fast. Although more than 60 species of the genus have now been identified, the majority (90) of clinical infections are caused by L. pneumophila, and most of the remainder are caused by L. micdadei, L. bozemanii, L. dumoffii, and L. longbeachae. The organisms are fastidious and require l cysteine, ferric ion, and keto acids for growth. Colonies develop within 3 5 days on buffered charcoal yeast extract agar, which may contain selected antibiotics to inhibit overgrowth by other microorganisms; Legionella rarely grows on routine laboratory media. EPIDEMIOLOGY The environmental reservoir of Legionella in nature is freshwater (lakes, streams, thermally polluted waters, potable water), and invasive pneumonia (Legionnaires disease) is related to exposure to human made water systems (plumbing, showerheads, cooling towers, certain medical devices, decorative fountains, hot tubs) via aerosols containing the bacteria. Growth of Legionella occurs more readily in warm water, and exposure to warm water sources is an important risk factor for disease. Epidemic and sporadic cases (most common) of community acquired Legionnaires disease can be attributed to potable water in the local environment of the patient. Risk factors for acquisition of spo radic community acquired pneumonia include exposure to cooling towers, nonmunicipal water supply, residential plumbing repairs, and lower water heater temperatures, which facilitate growth of bacteria or lead to release of a bolus of biofilm containing Legionella into potable water. The mode of transmission may be by inhalation of aerosols or by microaspiration. Outbreaks of Legionnaires disease have been associ ated with protozoa in the implicated water source; replication within these eukaryotic cells presumably amplifies and maintains Legionella within the potable water distribution system or in cooling towers. Outbreaks of community acquired pneumonia and some nosocomial outbreaks have been linked to common sources, including hot water heaters, evaporative condensers, cooling towers, whirlpool baths, water births, humidifiers, and nebulizers. Travel associated Legionnaires disease and Pontiac fever are increasingly recognized in major out breaks. Although person to person transmission has been reported, if it does occur, it is extremely rare. Hospital acquired infections are most often linked to potable water. Exposure may occur through three general mechanisms: (1) inhalation of contaminated water vapor through artificial ventilation; (2) aspira tion of ingested microorganisms, including those in gastric feedings that are mixed with contaminated tap water; and (3) inhalation of aerosols from showers, sinks, and fountains. Extrapulmonary legionel losis may occur through topical application of contaminated tap water into surgical or traumatic wounds. In contrast to Legionnaires disease, Pontiac fever outbreaks have occurred through exposure to aerosols from whirlpool baths and ventilation systems. The incidence of legionellosis in the United States continues to rise, and nearly 10,000 cases were reported to the Centers for Disease Con trol and Prevention (CDC) through the National Notifiable Disease Surveillance System in 2018. Because this is a passive reporting sys tem, these are likely underestimates of the incidence of disease, |
7,360 | which is estimated to occur at least twice as often as reported. An active laboratory based and population based surveillance system for track ing Legionella infections was recently launched by CDC, which will help to better assess its true incidence and epidemiology. (For up to date information, see https:www.cdc.govlegionella.) Legionellosis demonstrates geographic differences, and the vast majority of cases are classified as Legionnaires disease (99.5), with a small fraction as Pontiac fever (0.5). Legionella infections are reported most frequently in fall and summer, and recent studies show an association with total monthly rainfall and humidity. Approximately 0.55.0 of those exposed to a common source develop pneumonia, whereas the attack rate in Pontiac fever outbreaks is very high (85 100). Although Legionella is associated with 0.510 of pneumonia cases in adults, it is a rare cause of pneumonia in children, account ing for 1 of cases; however, infrequent testing for Legionella might underestimate its prevalence. Acquisition of antibodies to L. pneu mophila in healthy children occurs progressively over time, although these antibodies presumably reflect subclinical infection, mild respira tory disease, or antibodies that cross react with other bacterial species. Community acquired Legionnaires disease in children is increasingly reported (1.7 of reported cases), and most cases occur in children 15 19 years old, followed by infants. The incidence in infants is reported to be 0.11 per 100,000. Legionnaires disease is particularly severe in neonates. The epidemiology of hospital acquired Legionnaires disease in children is derived almost exclusively from case reports, so the true incidence of this entity is unknown. PATHOGENESIS Although Legionella can be grown on artificial media, the intracellular environment of eukaryotic cells provides the definitive site of growth. Legionella organisms are facultative intracellular parasites of eukary otic cells. In nature, Legionella replicate within protozoa found in freshwater. In humans, the main target cell for Legionella is the alveo lar macrophage, although other cell types may also be invaded. After entry, virulent strains of L. pneumophila stimulate the formation of a special phagosome that permits bacterial replication to proceed. The phagosome consists of components of the endoplasmic reticulum and escapes the degradative lysosomal pathway. Growth in macrophages occurs to the point of cell death, followed by reinfection of new cells, until these cells are activated and can subsequently kill intracellular microorganisms. Acute, severe infection of the lung provokes an acute inflammatory response and necrosis. Early on, more bacteria are found in extracellular spaces as a result of intracellular replication, lysis, and release of bacteria. Subsequently, macrophage activation and other immune responses produce intense infiltration of tissue by macro phages that contain intracellular bacteria, ultimately leading to control of bacterial replication and killing. Corticosteroid therapy poses a high risk for infection by interfering with T cell and macrophage function. Although community acquired Legionnaires disease may occur in healthy, immunocompetent patients without other comorbid conditions, those who have defects in cellular mediated immunity are at higher risk for infection. As in other diseases caused by facultative intracellular microorganisms, the out come is critically |
7,361 | dependent on the specific and nonspecific immune responses of the host, particularly macrophage and T cell responses. Risk factors for Legionnaires disease in adults include chronic dis eases of the lung (smoking, bronchitis), older age, diabetes, renal failure, immunosuppression associated with organ transplantation, cortico steroid therapy, and episodes of aspiration. In surveys of community acquired infection, a significant number of adults have no identified risk factors. The number of reported cases of community acquired Legionnaires disease in children is small. Among these cases, immu nocompromised status, especially corticosteroid treatment, coupled with exposure to contaminated potable water, is the major risk factor. Chapter 254 Legionella Jeffrey S. Gerber Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 254 u Legionella 1811 Infection in a few children with chronic pulmonary disease without immune deficiency has also been reported, but infection in children lacking any risk factors is uncommon. The modes of transmission of community acquired disease in children include exposure to mists, freshwater, water coolers, and other aerosol generating apparatuses. Nosocomial Legionella infection has been reported more frequently than community acquired disease in children and usually occurs in those who are immunocompromised (e.g., stem cell transplants, solid organ transplants), those with structural lung disease, or neonates receiving mechanical ventilation. The modes of acquisition include microaspira tion, frequently associated with nasogastric tubes, and aerosol inhala tion. Bronchopulmonary Legionella infections are reported in patients with cystic fibrosis and have been associated with aerosol therapy or mist tents. Legionnaires disease is also reported in children with asthma and tracheal stenosis. Chronic corticosteroid therapy for asthma is a reported risk factor for Legionella infections in children. CLINICAL MANIFESTATIONS Legionnaires disease was originally believed to cause atypical pneu monia associated with extrapulmonary symptoms and laboratory abnormalities, including diarrhea, confusion, hyponatremia, hypo phosphatemia, abnormal liver function studies, and evidence of renal dysfunction. Although a subset of patients may exhibit these classic manifestations, Legionella infection typically causes pneumonia that is indistinguishable from pneumonia produced by other infectious agents. The incubation period for Legionnaires disease is typically between 2 and 10 days, though it occasionally can be 3 4 weeks. Fever, cough, and chest pain are common presenting symptoms; the cough may be productive of purulent sputum or may be nonproductive. Although the classic chest radiographic appearance demonstrates rapidly progressive alveolar filling infiltrates, the chest radiographic appearance is widely variable, with tumor like shadows, evidence of nodular infiltrates, unilateral or bilateral infiltrates, or cavitation, although cavitation is rarely seen in immunocompetent patients. This picture overlaps sub stantially with disease caused by Streptococcus pneumoniae. Although pleural effusion is less often associated with Legionnaires disease, its frequency varies so widely that neither the presence nor absence of effusion is helpful in the differential diagnosis. Most reports of nosocomial Legionella pneumonia in children dem onstrate the following clinical features: rapid onset, temperature 38.5C (101.3F), cough, pleuritic chest |
7,362 | pain, tachypnea, and dyspnea. Abdomi nal pain, headache, and diarrhea are also common. Chest radiographs reveal lobar consolidations or diffuse bilateral infiltrates, and pleural effusions may be noted. Usually there is no clinical response to broad spectrum lactam (penicillins and cephalosporins) or aminoglycoside antibiotics. Concomitant infection with other pathogens, including Mycoplasma pneumoniae and Chlamydia pneumoniae, occurs in 510 of cases of Legionnaires disease; therefore, detection of another potential pulmonary pathogen does not preclude the diagnosis of legionellosis. Pontiac Fever Pontiac fever in adults and children is characterized by a shorter incu bation period (1 3 days) followed by high fever, myalgia, headache, and extreme debilitation, lasting for 3 5 days. Cough, breathlessness, diar rhea, confusion, and chest pain may occur, but there is no evidence for invasive infection. The disease is self limited without sequelae. Virtu ally all exposed individuals seroconvert to Legionella antigens. A very large outbreak in Scotland that affected 35 children was attributed to L. micdadei, which was isolated from a whirlpool spa. The onset of illness was 1 7 days (median: 3 days), and all exposed children developed sig nificant titers of specific antibodies to L. micdadei. The pathogenesis of Pontiac fever is not known. In the absence of evidence of true infection, the most likely hypothesis is that this syndrome is caused by a toxic or hypersensitivity reaction to microbial antigens. DIAGNOSIS Culture of Legionella from sputum, other respiratory tract specimens, blood, or tissue is the gold standard against which indirect methods of detection should be compared. If present, pleural fluid should be obtained for culture. Specimens obtained from the respiratory tract that are contaminated with oral flora must be treated and processed to reduce contaminants and plated onto selective media. Because these are costly and time consuming methods, many laboratories do not process specimens for culture. The urinary antigen assay that detects L. pneumophila serogroup I has revolutionized the diagnosis of Legionella infection and has 80 sensitivity and 99 specificity. The assay is a useful method in the prompt diagnosis of Legionnaires disease caused by this serogroup, which accounts for the majority of symptomatic infections. In the United States, this test is frequently used because it is widely available in reference laboratories. Where available, polymerase chain reaction (PCR) is used to identify L. pneumophila from bronchoscopic lavage and other clinical specimens to the exclusion of other respiratory pathogens. Other methods, including direct immunofluorescence, have low sensitivity and are generally not employed. Serological testing is of little clinical utility, as seroconversion may not occur for several weeks after the onset of infection, the available serologic assays do not detect all strains of L. pneumophila or all species, and cross reactivity occurs with several other gram negative organisms. In view of the low sensitivity of direct detection and the slow growth of the microorganism in culture, multiple diagnostics (culture, urine antigen, PCR if available) should be sent simultaneously and empiric antibiotic therapy considered when there is suggestive clinical evi dence, including the lack of response to |
7,363 | usual antibiotics. TREATMENT In community acquired pneumonia in adults who are hospitalized, guidelines recommend empiric treatment with a lactam plus a mac rolide or quinolone for treatment of atypical microorganisms (Legio nella, C. pneumoniae, M. pneumoniae). Evidence based guidelines for management of community acquired pneumonia in children typically do not include Legionella in the differential diagnosis or empiric treat ment recommendations. Effective treatment of Legionnaires disease is based in part on the intracellular concentration of antibiotics. Azithro mycin or the quinolones (ciprofloxacin and levofloxacin) have generally replaced erythromycin as therapy for patients with diagnosed Legionella infection. Doxycycline is an acceptable alternative. In serious infections or in high risk patients, parenteral therapy is recommended initially, although oral conversion is favored when tolerated, particularly because of the generally high bioavailability of oral macrolides, quinolones, and tetracyclines. The duration of antibiotic therapy for Legionnaires disease in adults is typically for a minimum of 5 days, although therapy may be continued for 10 14 days in more seriously ill or immunocompromised patients. Treatment of extrapulmonary infections, including prosthetic valve endocarditis and sternal wound infections, may require prolonged therapy. In vitro data and case reports suggest that trimethoprim sulfamethoxazole may also be effective. A large, retrospective study of hospitalized adults with Legionella pneumonia found no difference in mortality between those treated with azithromycin and with quinolones. The role of combination therapy is unknown. Antibiotic treatment for Pontiac fever is not recommended. PROGNOSIS The mortality rate for community acquired Legionnaires disease in adults who are hospitalized is approximately 15 but may exceed 50 in immunocompromised patients, although reporting bias might inflate these estimates. Precise estimates for children are unknown. The prognosis depends on underlying host factors and possibly on the duration of illness before initiation of appropriate therapy. Despite appropriate antibiotic therapy, patients may succumb to respiratory complications, such as acute respiratory distress syndrome. A high mortality rate is noted in case reports of premature infants and chil dren, virtually all of whom have been immunocompromised. Delay in diagnosis is also associated with increased mortality. Consequently, Legionella should be considered in the differential diagnosis of both community acquired and nosocomial pneumonia in children, espe cially in cases refractory to empirical therapy or with epidemiologic risk factors for legionellosis. 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. 1812 Part XV u Infectious Diseases The spectrum of disease resulting from human infection with Barton ella species includes the association of bacillary angiomatosis and cat scratch disease with Bartonella henselae. There are more than 30 vali dated species of Bartonella, but six major species are responsible for most human disease: B. henselae, B. quintana, B. bacilliformis, B. elizabethae, B. vinsonii, and B. clarridgeiae (Table 255.1). The remaining Bartonella spp. have been found primarily in animals, particularly rodents and moles. However, zoonotic infections from animal associated strains |
7,364 | of Bartonella spp. have been reported. In 2013 a novel Bartonella agent with the proposed name Candidatus Bartonella ancashi (Bartonella ancashensis) was described as a cause of verruga peruana. Members of the genus Bartonella are gram negative, oxidase negative, fastidious, aerobic rods that ferment no carbohydrates. B. bacilliformis is the only species that is motile, achieving motility by means of polar flagella. Optimal growth is obtained on fresh media containing 5 sheep or horse blood in the presence of 5 carbon dioxide. The use of lysis centrifugation for specimens from blood followed by cultivation on chocolate agar for extended periods (2 6 weeks) enhances recovery. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 255.1 Cat Scratch Disease (Bartonella henselae) Rachel C. Orscheln The most common presentation of Bartonella infection is cat scratch disease (CSD), which is a subacute, regional lymphadenitis caused most frequently by B. henselae. CSD is the most common cause of chronic lymphadenitis that persists for 3 weeks. ETIOLOGY B. henselae can be cultured from the blood of healthy cats. B. henselae organisms are the small, pleomorphic, gram negative bacilli visual ized with Warthin Starry stain in affected lymph nodes from patients with CSD. Development of serologic tests that showed prevalence of antibodies in 84100 of cases of CSD, culturing of B. henselae from CSD nodes, and detection of B. henselae by polymerase chain reaction (PCR) in the majority of lymph node samples and pus from patients with CSD confirmed the organism as the cause. Occasional cases of CSD may be caused by other organisms, including B. clarridgeiae, B. grahamii, B. alsatica, and B. quintana. EPIDEMIOLOGY CSD is common, with 24,000 estimated cases per year in the United States. B. henselae is transmitted most frequently by cutaneous inocu lation through the bite or scratch of a cat. However, transmission may occur through other routes, such as flea bites. Most patients (8799) with CSD have had contact with cats, many of which are kittens 6 months old, and 50 of patients have a definite history of a cat scratch or bite. Cats have high level bacteremia with Bartonella spp. for months without any clinical symptoms; kittens are more frequently bacteremic than adult cats. Transmission between cats occurs through the cat flea, Ctenocephalides felis. In temperate zones, most cases occur between September and March, perhaps in relation to the seasonal breeding of domestic cats or to the close proximity of family pets in the fall and winter. In tropical zones, there is no seasonal prevalence. Distribution is worldwide, and infection occurs in all races. Cat scratches appear to be more common among children, and males are affected more often than females. CSD is a sporadic illness; usually only one family member is affected, even though many siblings play with the same kitten. However, clusters do occur, with family cases within weeks of one another. Anecdotal reports have implicated other sources, such as dog scratches, wood splinters, fishhooks, cactus spines, and porcupine quills. PATHOGENESIS The pathologic findings in the primary inoculation papule |
7,365 | and affected lymph nodes are similar. Both show a central avascular, necrotic area with surrounding lymphocytes, giant cells, and histiocytes. Three stages of involvement occur in affected nodes, sometimes simultaneously in the same node. The first stage consists of generalized enlargement with thickening of the cortex and hypertrophy of the germinal center and with a predominance of lymphocytes. Epithelioid granulomas with Langerhans giant cells are scattered throughout the node. The second stage is characterized by granulomas that increase in density, fuse, and become infiltrated with polymorphonuclear leukocytes, with beginning central necrosis. In the third stage, necrosis progresses with formation of large, pus filled sinuses. This purulent material may rupture into sur rounding tissue. Similar granulomas have been found in the liver, spleen, and osteolytic lesions of bone when those organs are involved. Chapter 255 Bartonella Rachel C. Orscheln Table 255.1 Bartonella Species Causing the Majority of Human Disease DISEASE ORGANISM VECTOR PRIMARY RISK FACTOR Bartonellosis (Carrin disease) B. bacilliformis Sandfly (Lutzomyia verrucarum) Living in endemic areas (Andes Mountains) Cat scratch disease B. henselae B. clarridgeiae Cat Cat scratch or bite Trench fever B. quintana Human body louse Body louse infestation during outbreak Bacteremia, endocarditis B. henselae B. elizabethae B. vinsonii B. quintana Cat for B. henselae Rat for B. elizabethae Vole for B. vinsonii Human body louse for B. quintana Severe immunosuppression Bacillary angiomatosis B. henselae B. quintana Cat for B. henselae Human body louse for B. quintana Severe immunosuppression Peliosis hepatis B. henselae B. quintana Cat for B. henselae Human body louse for B. quintana Severe immunosuppression 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 255 u Bartonella 1813 CLINICAL MANIFESTATIONS After an incubation period of 7 12 days (range: 3 30 days), one or more 3 to 5 mm red papules develop at the site of cutaneous inoculation, often reflecting a linear cat scratch. These lesions are often overlooked because of their small size but are found in at least 65 of patients when careful examination is performed (Fig. 255.1). Lymphade nopathy is generally evident within 1 4 weeks (Fig. 255.2). Chronic regional lymphadenitis is the hallmark, affecting the first or second set of nodes draining the entry site. Affected lymph nodes in order of frequency include the axillary, cervical, submandibular, preauricular, epitrochlear, femoral, and inguinal nodes. Involvement of one or more groups of nodes occurs in 1020 of patients, although at a given site, half the cases involve several nodes. Nodes involved are usually tender and have overlying erythema but without cellulitis. They usually range between 1 and 5 cm in size, although they can become much larger. From 10 to 40 eventually suppurate. The duration of enlargement is usually 1 2 months, with persistence up to 1 year in rare cases. Fever occurs in approximately 30 of patients, usually 3839C (100.4102.2F). Other nonspecific symptoms, including malaise, anorexia, fatigue, and |
7,366 | headache, affect less than one third of patients. Transient rashes, which may occur in approximately 5 of patients, are mainly truncal maculopapu lar rashes. Erythema nodosum, erythema multiforme, and erythema annulare have also been reported. CSD is usually a self limited infection that spontaneously resolves within a few weeks to months. The most common ocular presentation of CSD is Parinaud oculoglandular syndrome, which is unilateral conjunctivitis followed by preauricular lymphadenopathy and occurs in 5 of patients with CSD (Fig. 255.3). Direct eye inoculation as a result of rubbing with the hands after cat contact is the presumed mode of spread. A conjunctival granuloma may be found at the inoculation site. The involved eye is usually not painful and has little or no dis charge but may be quite red and swollen. Submandibular or cervical lymphadenopathy may also occur. More severe, disseminated illness occurs up to 14 of patients and is characterized by presentation with high fever, often persisting for several weeks. Other prominent symptoms include significant abdomi nal pain and weight loss. Hepatosplenomegaly may occur, although hepatic dysfunction is rare (Fig. 255.4). Granulomatous changes may be seen in the liver and spleen. Another common site of dissemination is bone, with the development of multifocal granulomatous osteo lytic lesions associated with localized pain but without erythema, Fig. 255.1 A child with typical cat scratch disease demonstrating the original scratch injuries and the primary papule that soon thereafter de veloped proximal to the middle finger. (Courtesy Dr. V.H. San Joaquin, University of Oklahoma Health Sciences Center, Oklahoma City.) Fig. 255.2 Right axillary lymphadenopathy followed the scratches and development of a primary papule in this child with typical cat scratch disease. (From Mandell GL, Bennett JE, Dolin R, eds. Princi ples and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2006:2737.) Fig. 255.3 The granulomatous conjunctivitis of Parinaud oculoglan dular syndrome is associated with ipsilateral local lymphadenopathy, usually preauricular and, less often, submandibular. (From Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2006:2739.) Fig. 255.4 In this CT scan of a patient with hepatic involvement of cat scratch disease, the absence of enhancement of the multiple lesions after contrast infusion is consistent with the granulomatous inflamma tion of this entity. Treated empirically with various antibiotics without improvement before establishment of this diagnosis, the patient subse quently recovered fully with no further antimicrobial therapy. (Courtesy Dr. V.H. San Joaquin, University of Oklahoma Health Sciences Center, Oklahoma City.) 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. 1814 Part XV u Infectious Diseases tenderness, or swelling. Other uncommon manifestations are neuro retinitis with papilledema and stellate macular exudates, encephalitis, endocarditis, and atypical pneumonia. DIAGNOSIS In most cases the diagnosis can be strongly suspected on clinical grounds in a patient with history of exposure to a cat. Serologic testing can be used |
7,367 | to confirm the diagnosis. Most patients have elevated IgG antibody titers at presentation. However, the IgM response to B. hense lae has frequently resolved by the time testing is considered. There is cross reactivity among Bartonella spp., particularly B. henselae and B. quintana. If tissue specimens are obtained, bacilli may be visualized with Warthin Starry and Brown Hopps tissue stains. Bartonella DNA can be identified through PCR analysis of tissue specimens. Culturing of the organism is not generally practical for clinical diagnosis. Next generation sequencing and 16S rRNA sequencing have been used to identify Bartonella species on tissue that is fresh or formalinfixed, as well as on body fluids other than blood. Differential Diagnosis The differential diagnosis of CSD includes virtually all causes of lymphadenopathy (see Chapter 539). The more common enti ties include pyogenic (suppurative) lymphadenitis, primarily from staphylococcal or streptococcal infections, atypical mycobacterial infections, and malignancy. Less common entities are tularemia, brucellosis, and sporotrichosis. Epstein Barr virus, cytomegalovirus, and Toxoplasma gondii infections usually cause more generalized lymphadenopathy. LABORATORY FINDINGS Routine laboratory tests are not helpful. The erythrocyte sedimenta tion rate is often elevated. The white blood cell count may be normal or mildly elevated. Hepatic transaminases are often normal but may be elevated in systemic disease. Ultrasonography or CT may reveal many granulomatous nodules in the liver and spleen; the nodules appear as hypodense, round, irregular lesions and are usually mul tiple. However, CSD presenting as a solitary splenic lesion has been reported. TREATMENT Antibiotic treatment of CSD is not always needed and is not clearly beneficial. For most patients, treatment consists of conservative symp tomatic care and observation. Studies show a significant discordance between in vitro activity of antibiotics and clinical effectiveness. For many patients, diagnosis is considered in the context of failure to respond to lactam antibiotic treatment of presumed staphylococcal lymphadenitis. A small prospective study of oral azithromycin (500 mg on day 1, then 250 mg on days 2 5; for smaller children, 10 mgkg24 hr on day 1 and 5 mgkg24 hr on days 2 5) showed a decrease in initial lymph node volume in 50 of patients during the first 30 days, but after 30 days there was no difference in lymph node volume. No other clinical benefit was found. For the majority of patients, CSD is self limited, and resolution occurs over weeks to months without antibiotic treatment. Azithromycin, clarithro mycin, trimethoprim sulfamethoxazole (TMP SMX), rifampin, ciprofloxacin, and gentamicin appear to be the best agents if treat ment is considered. Suppurative lymph nodes that become tense and extremely pain ful may require surgical drainage for both therapeutic and diagnostic purposes. Children with hepatosplenic CSD appear to respond well to treat ment with azithromycin with or without the addition of rifampin. COMPLICATIONS Encephalopathy can occur in as many as 5 of patients with CSD and typically manifests 1 3 week after the onset of lymphadenitis as the sudden onset of neurologic symptoms, which often include sei zures, combative or bizarre behavior, and altered |
7,368 | level of conscious ness. Imaging studies are generally normal. The cerebrospinal fluid is normal or shows minimal pleocytosis and protein elevation. Recovery occurs without sequelae in almost all patients but may take place slowly over many months. Other neurologic manifestations include peripheral facial nerve paralysis, myelitis, radiculitis, compression neuropathy, and cerebel lar ataxia. One patient has been reported to have encephalopathy with persistent cognitive impairment and memory loss. Stellate macular retinopathy is associated with several infec tions, including CSD. Children and young adults present with uni lateral or, rarely, bilateral loss of vision with central scotoma, optic disc swelling, and macular star formation from exudates radiat ing out from the macula. The findings usually resolve completely, with recovery of vision, generally within 2 3 months. The optimal treatment for the neuroretinitis is unknown, although treatment of adults with doxycycline and rifampin for 4 6 weeks has had good results. Hematologic manifestations include hemolytic anemia, thrombo cytopenic purpura, nonthrombocytopenic purpura, and eosinophilia. Leukocytoclastic vasculitis, similar to Henoch Schnlein purpura, has been reported in association with CSD in one child. A systemic presentation of CSD with pleurisy, arthralgia or arthritis, mediastinal masses, enlarged nodes at the head of the pancreas, and atypical pneu monia also has been reported. PROGNOSIS The prognosis for CSD in a normal host is generally excellent, with resolution of clinical findings over weeks to months. Recovery is occa sionally slower and may take as long as 1 year. PREVENTION Person to person spread of Bartonella infections is not known. Isolation of the affected patient is not necessary. Prevention would require elimination of cats from households, which is not practi cal or necessarily desirable. Awareness of the risk of cat (and par ticularly kitten) scratches should be emphasized to parents. Cat scratches or bites should be washed immediately. Cat flea control is helpful. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 255.2 Bartonellosis (Bartonella bacilliformis) Rachel C. Orscheln The first human Bartonella infection described was bartonellosis, a geographically distinct disease caused by B. bacilliformis. There are two predominant forms of illness caused by B. bacilliformis: Oroya fever, a severe, febrile hemolytic anemia, and verruca peruana (verruga peruana), an eruption of hemangioma like lesions. B. bacilliformis also causes asymptomatic infection. Bartonellosis is also called Carrin disease. ETIOLOGY B. bacilliformis is a small, motile, gram negative organism with a brush of 10 unipolar flagella, which appear to be important com ponents for invasiveness. An obligate aerobe, it grows best at 28C (82.4F) in semisolid nutrient agar containing rabbit serum and hemoglobin. EPIDEMIOLOGY Bartonellosis is a zoonosis found only in mountain valleys of the Andes Mountains in Peru, Ecuador, Colombia, Chile, and Bolivia at altitudes and environmental conditions favorable for the vector, which is the sandfly, Lutzomyia verrucarum. 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 255 u Bartonella 1815 PATHOGENESIS After the sandfly bite, Bartonella |
7,369 | organisms enter the endothelial cells of blood vessels, where they proliferate. Found throughout the reticuloendothelial system, they then reenter the bloodstream and parasitize erythrocytes. They bind on the cells, deform the mem branes, and then enter intracellular vacuoles. The resultant hemo lytic anemia may involve as many as 90 of circulating erythrocytes. Patients who survive this acute phase may or may not experience the cutaneous manifestations, which are nodular hemangiomatous lesions or verrucae ranging in size from a few millimeters to several centimeters. CLINICAL MANIFESTATIONS The incubation period is 2 14 weeks. Patients may be totally asymp tomatic or may have nonspecific symptoms such as headache and mal aise without anemia. Oroya fever is characterized by fever with rapid development of anemia. Clouding of the sensorium and delirium are common symptoms and may progress to overt psychosis. Physical exami nation demonstrates signs of severe hemolytic anemia, includ ing icterus and pallor, sometimes in association with generalized lymphadenopathy. In the preeruptive stage of verruca peruana (Fig. 255.5), patients may complain of arthralgias, myalgias, and paresthesias. Inflamma tory reactions such as phlebitis, pleuritis, erythema nodosum, and encephalitis may develop. The appearance of verrucae is pathog nomonic of the eruptive phase. Lesions vary greatly in size and number. DIAGNOSIS The diagnosis of bartonellosis is established on clinical grounds in conjunction with a blood smear demonstrating organisms or with blood culture. The anemia is macrocytic and hypochromic, with reticulocyte counts as high as 50. B. bacilliformis may be seen on Giemsa stain preparation as red violet rods in the erythrocytes. In the recovery phase, organisms change to a more coccoid form and disappear from the blood. In the absence of anemia, the diagnosis depends on blood cultures. In the eruptive phase, the typical verruca confirms the diagnosis. Antibody testing has been used to document infection. TREATMENT B. bacilliformis is sensitive to many antibiotics, including rifampin, tet racycline, and chloramphenicol. Treatment is highly effective in rap idly diminishing fever and eradicating the organism from the blood. Chloramphenicol (50 75 mgkgday) is considered the drug of choice because it is also useful in the treatment of concomitant infections such as Salmonella. Fluoroquinolones are used successfully as well. Blood transfusions and supportive care are critical in patients with severe anemia. Antimicrobial treatment for verruca peruana is considered when there are 10 cutaneous lesions, if the lesions are erythematous or violaceous, or if the onset of the lesions was 1 month before pre sentation. Oral rifampin is effective in the healing of lesions. Surgical excision may be needed for lesions that are large and disfiguring or that interfere with function. PREVENTION Prevention depends on avoidance of the vector, particularly at night, by the use of protective clothing and insect repellents (see Chapter 218). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 255.3 Trench Fever (Bartonella quintana) Rachel C. Orscheln ETIOLOGY The causative agent of trench fever was first designated Rickettsia quin tana, was then assigned to the genus Rochalimaea, and now has been reassigned as Bartonella quintana. EPIDEMIOLOGY Trench |
7,370 | fever was first recognized as a distinct clinical entity during World War I, when more than a million troops in the trenches were infected. Infection with B. quintana is currently rare in the United States and primarily occurs in the setting of conditions favorable to body lice infestations, such as homelessness, crowding, and poor sani tation. When pooled samples of head and body lice have been collected from homeless populations, up to 33 of individuals have lice pools that test positive for B. quintana. Humans are the only known reservoir. No other animal is naturally infected, and usual laboratory animals are not susceptible. The human body louse, Pediculus humanus var. corporis, is the vector and is capa ble of transmission to a new host 5 6 days after feeding on an infected person. Lice excrete the organism for life; transovarian passage does not occur. Humans may have prolonged asymptomatic bacteremia for years. CLINICAL MANIFESTATIONS The incubation period for trench fever averages about 22 days (range: 4 35 days). The clinical presentation is highly variable. Symptoms can be very mild and brief. About half of infected persons have a single febrile illness with abrupt onset lasting 3 6 days. In other patients, prolonged, sustained fever may occur. More commonly, patients have periodic febrile illness with three to eight episodes lasting 4 5 days each, sometimes occurring over 1 year or more. This form is remi niscent of malaria or relapsing fever (Borrelia recurrentis). Afebrile bacteremia can occur. Clinical findings usually consist of fever (typically with a tempera ture of 38.540C 101.3104F), malaise, chills, sweats, anorexia, and severe headache. Common findings include marked conjunctival injection, tachycardia, myalgias, arthralgias, and severe pain in the neck, back, and legs. Crops of erythematous macules or papules may occur on the trunk on as many as 80 of patients. Splenomegaly and mild liver enlargement may be noted. Fig. 255.5 A single large lesion of verruca peruana on the leg of an inhabitant of the Peruvian Andes. Such lesions are prone to superficial ulceration, and their vascular nature may lead to copious bleeding. Ec chymosis of the skin surrounding the lesion is also evident. (Courtesy Dr. J.M. Crutcher, Oklahoma State Department of Health, Oklahoma City.) 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. 1816 Part XV u Infectious Diseases DIAGNOSIS In nonepidemic situations, it is impossible to establish a diagnosis of trench fever on clinical grounds because the findings are not distinc tive. A history of body louse infection or having been in an area of epi demic disease should heighten suspicions. B. quintana can be cultured from the blood with modification to include culture on epithelial cells. Serologic tests for B. quintana are available, but there is cross reaction with B. henselae. TREATMENT There are no controlled trials of treatment, but bacteremia with Bar tonella treated with a combination of |
7,371 | gentamicin and doxycycline increases the rate of cure compared with other regimens, such as doxy cycline or lactam antibiotics alone. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 255.4 Bacillary Angiomatosis and Bacillary Peliosis Hepatis (Bartonella henselae and Bartonella quintana) Rachel C. Orscheln Both B.henselae and B.quintana cause vascular proliferative disease in severely immunocompromised persons, primarily adult patients with acquired immune deficiency syndrome (AIDS), persons receiving cancer chemotherapy, and organ transplant recipients. The subcutaneous and lytic bone lesions of bacillary angiomatosis can be caused by infection with either B. henselae or B. quintana. The lesions of peliosis hepatis are almost exclusively associated with B. henselae. BACILLARY ANGIOMATOSIS Lesions of cutaneous bacillary angiomatosis, also known as epitheli oid angiomatosis, are the most easily identified and recognized form of Bartonella infection in immunocompromised hosts. They are found primarily in patients with AIDS who have very low CD4 counts. The clinical appearance can be quite diverse. The vasoproliferative lesions of bacillary angiomatosis may be cutaneous or subcutaneous and may resemble the vascular lesions (verruca peruana) of B. bacilliformis in immunocompetent persons, characterized by erythematous papules on an erythematous base with a collarette of scale. They may enlarge to form large, pedunculated lesions and may ulcerate. Trauma may result in profuse bleeding. Bacillary angiomatosis may be clinically indistinguishable from Kaposi sarcoma. Other considerations in the differential diagnosis are pyogenic granuloma and verruca peruana (B. bacilliformis). Deep soft tissue masses caused by bacillary angiomatosis may mimic a malignancy. Osseous bacillary angiomatosis lesions typically involve the long bones. These lytic lesions are very painful and highly vascular and are occasionally associated with an overlying erythematous plaque. The high degree of vascularity produces a positive result on a technetium 99m methylene diphosphonate bone scan, resembling that of a malig nant lesion. Lesions can be found in virtually any organ, producing similar vascular proliferative lesions. They may appear raised, nodular, or ulcerative when seen on endoscopy or bronchoscopy. They may be associated with enlarged lymph nodes with or without an obvi ous local cutaneous lesion. Brain parenchymal lesions have been described. BACILLARY PELIOSIS Bacillary peliosis affects the reticuloendothelial system, primarily the liver (peliosis hepatis) and, less frequently, the spleen and lymph nodes. It is a vasoproliferative disorder characterized by random pro liferation of venous lakes surrounded by fibromyxoid stroma harbor ing numerous bacillary organisms. Clinical findings include fever and abdominal pain in association with abnormal liver function test results, particularly a greatly increased alkaline phosphatase level. Cutaneous bacillary angiomatosis with splenomegaly may be associated with thrombocytopenia or pancytopenia. The vascular proliferative lesions in the liver and spleen appear on CT scan as hypodense lesions scat tered throughout the parenchyma. The differential diagnosis includes hepatic Kaposi sarcoma, lymphoma, and disseminated infection with Pneumocystis jirovecii or Mycobacterium avium complex. BACTEREMIA AND ENDOCARDITIS B. henselae, B. quintana, B. vinsonii, and B. elizabethae all are reported to cause bacteremia or endocarditis. They are associated with symp toms such as prolonged fevers, night sweats, and profound weight loss. A cluster of cases in Seattle |
7,372 | in 1993 occurred in a homeless population with chronic alcoholism. These patients with high fever or hypothermia were thought to represent urban trench fever, but no body louse infestation was associated. Some cases of culture negative endocarditis may represent Bartonella endocarditis. One report described central nervous system involvement with B. quintana infection in two children. DIAGNOSIS The diagnosis of bacillary angiomatosis is made initially by biopsy. The characteristic small vessel proliferation with mixed inflamma tory response and the staining of bacilli by Warthin Starry silver dis tinguish bacillary angiomatosis from pyogenic granuloma or Kaposi sarcoma (see Chapter 304). Travel history can usually preclude ver ruca peruana. Culture is impractical for CSD but is the diagnostic procedure for suspected bacteremia or endocarditis. Lysis centrifugation technique or fresh chocolate or heart infusion agar with 5 rabbit blood and pro longed incubation may increase the yield of culture. PCR on tissue can also be a useful tool, and positive serologic testing can provide support for the diagnosis. TREATMENT Bartonella infections in immunocompromised hosts caused by both B. henselae and B. quintana have been treated successfully with antimicrobial agents. Bacillary angiomatosis responds rapidly to erythromycin, azithromycin, and clarithromycin, which are the drugs of choice. Alternative choices are doxycycline or tetracycline. Severely ill patients with peliosis hepatis or patients with osteomyelitis may be treated initially with a macrolide or doxycycline and the addition of rifampin or gentamicin. The use of doxycycline for 6 weeks with the addition of an aminoglycoside for a minimum of 2 weeks is associ ated with improved prognosis in endocarditis. A Jarisch Herxheimer reaction may occur. Relapses may follow, and prolonged treatment for several months may be necessary. PREVENTION Immunocompromised persons should consider the potential risks of cat ownership because of the risks for Bartonella infections as well as toxoplasmosis and enteric infections. Those who elect to obtain a cat should adopt or purchase a cat 1 year old and in good health. Prompt washing of any wounds from cat bites or scratches is essential. 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 256 u Botulism (Clostridium botulinum) 1817 There are three naturally occurring forms of human botulism, charac terized by mode of acquisition: infant botulism (intestinal toxemia), food borne botulism, and wound botulism. Infant botulism is the most common form in the United States. Under rare circumstances of altered intestinal anatomy, physiology, and microflora, older children and adults may contract infant type botulism (adult intestinal tox emia). Two other forms, both human made, also occur: inhalational botulism, from inhaling accidently aerosolized toxin, and iatrogenic botulism, from overdosage of botulinum toxin used for therapeutic or cosmetic purposes. ETIOLOGY Botulism is the acute, flaccid paralysis caused by the neurotoxin pro duced by Clostridium botulinum or, infrequently, an equivalent neu rotoxin produced by the related species Clostridium butyricum and |
7,373 | Clostridium baratii. C. botulinum is a gram positive, spore forming, obligate anaerobe whose natural habitat worldwide is soil, dust, and marine sediments. The organism is found in a wide variety of fresh and cooked agricultural products. Remarkably, the spores of some C. botulinum strains endure boiling for several hours, enabling the organ ism to survive efforts at food preservation. In contrast, botulinum toxin is heat labile and easily destroyed by heating at 85C (185F) for 5 minutes. Neurotoxigenic C. butyricum has been isolated from soils near Lake Weishan in China, the site of food borne botulism outbreaks associated with this organism, and from vegetables, soured milk, and cheeses. Although first recognized in China, cases of infant botulism caused by C. butyricum have now been identified in Japan, Europe, and the United States. Little is known about the ecology of neurotoxigenic C. baratii. Botulinum toxin is synthesized as a 150 kDa precursor protein that enters the circulation and is transported to the neuromuscular junction. The toxin is only released by actively replicating (vegetative) bacteria and not the spore form. At the neuromuscular junction, toxin binds to the neuronal membrane on the presynaptic side of the neural synapse. It undergoes proteolysis to a 100 kDa heavy chain and a 50 kDa light chain. These chains are joined via disulfide bond formation. The heavy chain contains the neuronal attachment sites that mediate binding to presynaptic nerve terminals. It also mediates translocation of the light chain into the cell cytoplasm after binding. The light chain, a key com ponent of the toxin, is a member of the zinc metalloprotease family and mediates cleavage of the fusogenic SNARE (Soluble NSF Attachment REceptor) protein family member, SNAP 25. Cleavage of this protein precludes release of acetylcholine from axons at the presynaptic ter minal, abrogating nerve signaling and producing paralysis. Botulinum toxin is among the most potent poisons known to humankind; indeed, the parenteral human lethal dose is estimated to be on the order of 106 mgkg. The toxin blocks neuromuscular transmission and causes death through airway and respiratory muscle paralysis. At least nine anti genic toxin types, designated by letters A H and X, are distinguished serologically by demonstration of the inability of neutralizing antibody against one toxin type to protect against a different type. Toxin types are further differentiated into subtypes by differences in the nucleotide sequences of their toxin genes. The gene for botulinum toxin for some toxin types and subtypes resides on a plasmid. Some toxins are fully activated by the bacteria that produce them (proteolytic strains of types A, B, and F), and some require exogenous proteolytic activation (types E and nonproteolytic types B and F). The toxin types serve as convenient clinical and epidemiologic mark ers. Toxin types A, B, E, and F are well established causes of human botulism, whereas types C and D cause illness in other animals. Toxin types A and B cause the majority of cases of infant botulism in the United States. Neurotoxigenic C. butyricum strains |
7,374 | produce a type E toxin, whereas neurotoxigenic C. baratii strains produce a type F toxin. Type G toxin has not been established as a cause of either human or animal disease. Some strains produce two toxins such as B and A or B and F; rare strains may produce three toxins. Dual (bivalent) toxin mediated disease tends to be more severe than single toxin production. EPIDEMIOLOGY Infant botulism has been reported from all inhabited continents except Africa. Notably, in a typical case the infant is the only family member who is ill. The most striking epidemiologic feature of infant botulism is its age distribution: approximately 90 of cases involving infants 3 weeks to 6 months of age, with a broad peak spanning 2 4 months of age. Cases have been recognized in infants as young as 1.5 days or as old as 382 days at onset. Identified risk factors for the illness include breastfeeding, the ingestion of honey, a slow intestinal transit time (1 stoolday), and ingestion of untreated well water (Fig. 256.1). Although breastfeeding appears to provide protection against fulminant sudden death from infant botulism, cases can occur in breastfed infants at the time of introduction of nonhuman milk for feeding. Although infant botulism is an uncommon and often unrecog nized illness, it is the most common form of human botulism in the United States, with approximately 80 140 hospitalized cases diagnosed annually. The Council of State and Territorial Epidemiologists (CSTE) maintains a National Botulism Surveillance System for intensive sur veillance for cases of botulism in the United States (https:www.cdc.go vbotulismsurveillance.html). In 2017, 182 laboratory confirmed bot ulism cases were reported to Centers for Disease Control and Preven tion (CDC). Botulism was predominately observed in infants, with 141 such cases reported. A total of 19 (10) foodborne cases and 19 (10) wound cases were reported. Infant botulism cases were reported from 26 states and the District of Columbia, with California reporting the Environmental events Host susceptibility factors Gut permissivenessSpores Noninhibitory gut flora High soil concentration of spores Soil disruption Consumption of honey Very young infant Perturbation at weaning Antibiotic disruption Decreased gut motility Colonization Outgrowth Toxin elaboration Toxin absorption Fig. 256.1 Environmental, host, and pathophysiologic events in infant botulism. (From Arnon SS, Long SS. Clostridium botulinum Botulism. In Long SS, Prober CG, Fischer M, Kimberlin DW, eds. Principles and Practice of Pediatric Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2023: Fig. 189.3, p. 1019.) Chapter 256 Botulism (Clostridium botulinum) Mark R. Schleiss Section 6 Anaerobic Bacterial Infections 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. 1818 Part XV u Infectious Diseases most (n 48, 34). Toxin type B (n 88) predominated. The median age of infants was 4 months (range: 0 12 months), and no deaths were reported. Food borne botulism results from the ingestion of a food in which C. botulinum has multiplied |
7,375 | and produced toxin. Although the tra ditional view of food borne botulism has been thought of as result ing chiefly from ingestion of home canned foods, in fact, outbreaks in North America have been more often associated with restaurant prepared foods, including nacho cheese in convenience stores, sauted onions, chopped garlic, and seal blubber (in Alaska). Other outbreaks in the United States have occurred from commercial foods sealed in plastic pouches that relied solely on refrigeration to prevent outgrowth of C. botulinum spores. Uncanned foods responsible for food borne botulism cases include peyote tea, hazelnut flavoring added to yogurt, sweet cream cheese, sauted onions in patty melt sandwiches, potato salad, and fresh and dried fish, including botulism type E that has been acquired by eating an Egyptian salt cured fish dish called fesikh. For foodborne botulism cases reported to the 2017 National Botulism Sur veillance System, the median age of patients was 42 years (range: 14 85 years), and three deaths were reported. Most of the continental U.S. outbreaks resulted from proteolytic type A or type B strains, whereas in Alaska and Canada, most food borne outbreaks have resulted from nonproteolytic type E strains. A further hazard of type E strains is their ability to grow at the temperatures maintained by household refrigera tors (5C 41F). Wound botulism is an exceptionally rare disease, with 400 cases reported worldwide, but it is important to pediatrics because ado lescents and children may be affected. Although many cases have occurred in young, physically active males who are at the greatest risk for traumatic injury, wound botulism also occurs with crush injuries in which no break in the skin is evident. In recent years, wound botu lism from injection has become increasingly common in adult heroin abusers in the western United States and in Europe, not always with concomitant evidence of abscess formation or cellulitis. A single outbreak of inhalational botulism was reported in 1962 in which three laboratory workers in Germany were exposed uninten tionally to aerosolized botulinum toxin. Some patients in the United States have been hospitalized by accidental overdose of therapeutic or cosmetic botulinum toxin. PATHOGENESIS All forms of botulism produce disease through a final common path way. Botulinum toxin is carried by the bloodstream to peripheral cho linergic synapses, where it binds irreversibly, blocking acetylcholine release and causing impaired neuromuscular and autonomic trans mission. Infant botulism results from ingesting the spores of botu linum toxinproducing strains, with subsequent spore germination, multiplication, and production of botulinum toxin in the large intes tine. This sequence is distinct from food borne botulism, which is an intoxication that results when preformed botulinum toxin contained in an improperly preserved or inadequately cooked food is swallowed. Wound botulism results from spore germination and colonization of traumatized tissue by C. botulinum; the pathogenesis of this form of botulism is similar in this respect to that of tetanus. Inhalational botu lism occurs when aerosolized botulinum toxin is inhaled and could conceivably be a route of exposure generated by |
7,376 | a bioterrorist attack. Because botulinum toxin is not a cytotoxin, it does not cause overt macroscopic or microscopic pathology. Pathologic changes (pneumo nia, petechiae on intrathoracic organs) may be found at autopsy, but these are secondary changes and not primarily attributable to botuli num toxin. No diagnostic technique is available to identify botulinum toxin binding at the neuromuscular junction. Nerve conduction veloc ity studies are typically normal. Electromyography (EMG) findings are often nonspecific and nondiagnostic (see later). The healing process in botulism consists of sprouting new terminal unmyelinated motor neurons. Movement resumes when these new nerve terminals locate noncontracting muscle fibers and reinnervate them by inducing for mation of a new motor end plate. In experimental animals, this process takes about 4 weeks. CLINICAL MANIFESTATIONS The full clinical spectrum of infant botulism ranges from mild to ful minant sudden death. Botulinum toxin is distributed hematogenously. Because relative blood flow and density of innervation are greatest in the bulbar musculature, all forms of botulism manifest neurologically as a symmetric, descending, flaccid paralysis beginning with the cranial nerve musculature and progressing over hours to days. Bulbar palsies may manifest with such symptoms as poor feeding, weak suck, feeble cry, drooling, and even obstructive apnea. These clinical clues unfortu nately may not be recognized as bulbar in origin (Fig. 256.2). Patients with evolving illness may already have generalized weakness and hypo tonia in addition to bulbar palsies when first examined. The brain itself is spared in infant botulism, because botulinum toxin does not cross the blood brain barrier. In contrast to botulism caused by C. botulinum, a majority of the rare cases caused by intestinal colonization with C. butyricum are associ ated with a Meckel diverticulum accompanying abdominal distention, often leading to misdiagnosis as an acute abdomen. The also rare C. baratii type F infant botulism cases have been characterized by very young age at onset, rapidity of onset, and greater severity but shorter duration of paralysis. In older children with food borne or wound botulism, the onset of neurologic symptoms follows a characteristic pattern of diplopia, pto sis, dry mouth, dysphagia, dysphonia, and dysarthria, with decreased gag and corneal reflexes. Importantly, because the toxin acts only on motor nerves, paresthesias are not seen in botulism, except when a patient hyperventilates from anxiety. The sensorium remains clear, but this fact may be difficult to ascertain because of the slurred speech. Food borne botulism begins with gastrointestinal (GI) symptoms of nausea, vomiting, or diarrhea in approximately 30 of cases. These symptoms are thought to result from metabolic by products of growth of C. botulinum or from the presence of other toxic contaminants in the food, because GI distress is rarely observed in wound botulism. Constipation may occur in food borne botulism once flaccid paralysis becomes evident. Illness usually begins 12 36 hours after ingestion of Fig. 256.2 A 3 mo old infant with botulism just before intubation. Note bilateral ptosis and facial palsy and the absence of tears. (From Arnon SS, Long SS. Clostridium |
7,377 | botulinum Botulism. In: Long SS, Prober CG, Fischer M, Kimberlin DW, eds. Principles and Practice of Pediatric Infectious Diseases, 6th ed. Philadelphia: Elsevier; 2023: Fig. 189.4, p. 1020.) 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 256 u Botulism (Clostridium botulinum) 1819 the contaminated food but can range from as short as 2 hours to as long as 8 days. The incubation period in wound botulism is 4 14 days. Fever may be present in wound botulism but is absent in food borne botulism unless a secondary infection (often pneumonia) is present. All forms of botulism display a wide spectrum of clinical severity, from the very mild, with minimal ptosis, flattened facial expression, minor dysphagia, and dysphonia, to the fulminant, with rapid onset of exten sive paralysis, frank apnea, and fixed, dilated pupils. Fatigability with repetitive muscle activity is the clinical hallmark of botulism. Infant botulism differs in apparent initial symptoms of illness only because the infant cannot verbalize them. Clinical progression can be more rapid and more severe in very young infants. The incuba tion period in infant botulism is estimated to be 3 30 days. Usually, the first indication of illness is a decreased frequency or even absence of defecation, and indeed, constipation may be the chief complaint (although this sign is also frequently overlooked). Parents typically notice inability to feed, lethargy, weak cry, and diminished spontane ous movement. Dysphagia may be evident, and an increase in secre tions drooling from the mouth may be noted. Gag, suck, and corneal reflexes all diminish as the paralysis advances. Oculomotor palsies may be evident. Paradoxically, the pupillary light reflex may be unaf fected until the child is severely paralyzed, or it may be initially slug gish. Loss of head control is typically a prominent sign. Opisthotonos may be observed. Respiratory arrest may occur suddenly from airway occlusion by unswallowed secretions or from obstructive flaccid pha ryngeal musculature. Death from botulism results either from airway obstruction or paralysis of the respiratory muscles. Occasionally, the diagnosis of infant botulism is suggested by a respiratory arrest that occurs after the infant is curled into position for lumbar puncture or after the administration of an aminoglycoside antibiotic administered for suspected sepsis (see later). In mild cases or in the early stages of illness, the physical signs of infant botulism may be subtle and easily missed. Eliciting cranial nerve palsies and fatigability of muscular function requires careful examina tion. Ptosis may not be seen unless the head of the child is kept erect. DIAGNOSIS Definitive diagnosis of botulism is made by specialized laboratory test ing that requires hours to days to complete. Therefore clinical diagnosis is the foundation for early recognition of and response to all forms of botulism. Routine laboratory studies, including those of the cerebro spinal fluid (CSF), are normal in botulism unless dehydration, under nourishment |
7,378 | (metabolic acidosis and ketosis), or secondary infection is present. The classic triad of botulism is the acute onset of a symmetric, flac cid descending paralysis with clear sensorium, no fever, and no par esthesias. Suspected botulism represents a medical and public health emergency that is immediately reportable by telephone in most U.S. health jurisdictions. State health departments (first call) and the CDC (770 488 7100 at any time) can arrange for diagnostic testing, epide miologic investigation, and provision of equine antitoxin. The diagnosis of botulism is unequivocally established by demon stration of the presence of botulinum toxin in serum or of C. botuli num toxin or organisms in wound material, enema fluid, or feces. C. botulinum is not part of the normal resident intestinal flora of humans, and its presence in the setting of acute flaccid paralysis is diagnostic. An epidemiologic diagnosis of food borne botulism can be established when C. botulinum organisms and toxin are found in food eaten by patients. Electromyography can sometimes distinguish between causes of acute flaccid paralysis, although results may be variable, including nor mal, in patients with botulism. The distinctive EMG finding in botu lism is facilitation (potentiation) of the evoked muscle action potential at high frequency (50 Hz) stimulation. In infant botulism, a character istic pattern known as BSAP (Brief, Small, Abundant motor unit action Potentials) is present only in clinically weak muscles. Nerve conduc tion velocity and sensory nerve function are normal in botulism. Infant botulism requires a high index of suspicion for early diagnosis (Table 256.1). Rule out sepsis remains the most common admission diagnosis. If a previously healthy infant (usually 2 4 months of age) demonstrates weakness with difficulty in sucking, swallowing, crying, or breathing, infant botulism should be considered a likely diagnosis. A careful cranial nerve examination is then quite helpful. Rare instances of co infection with Clostridioides difficile, respiratory syncytial virus, or influenza virus have occurred. Differential Diagnosis Botulism is frequently misdiagnosed, most often as a polyradiculo neuropathy (Guillain Barr or Miller Fisher syndrome), myasthenia gravis, or a central nervous system (CNS) disease (Table 256.2). In the United States, botulism is more likely than Guillain Barr syndrome, intoxication, or poliomyelitis to cause a cluster of cases of acute flac cid paralysis. Botulism differs from other flaccid paralyses in its initial and prominent cranial nerve palsies that are disproportionate to milder weakness and hypotonia below the neck, in its symmetry, and in its absence of sensory nerve damage. Spinal muscular atrophy may closely mimic infant botulism at presentation. Additional diagnostic procedures may be useful in rapidly excluding botulism as the cause of paralysis. The CSF is unchanged in botulism but is abnormal in many CNS diseases. Although the CSF protein con centration is eventually elevated in Guillain Barr syndrome, it may be normal early in the illness. Imaging of the brain, spine, and chest may reveal hemorrhage, inflammation, or neoplasm. A test dose of edrophonium chloride briefly reverses paralytic symptoms in many patients with myasthenia gravis and, reportedly, in |
7,379 | some with botu lism, although this is rarely performed in infants. A close inspection of the skin, especially the scalp, may reveal an attached tick that is caus ing paralysis. Possible organophosphate intoxication should be pur sued aggressively, because specific antidotes (oximes) are available and because the patient may be part of a commonly exposed group, some of whom have yet to demonstrate illness. Other tests that require days for results include stool culture for Campylobacter jejuni as a precipitant of Guillain Barr syndrome, spinal muscular atrophy and other genetic (including mitochondrial) disorders, and assays for the autoantibodies that cause myasthenia gravis, Lambert Eaton syndrome, and Guillain Barr syndrome. Table 256.1 Mimics of Initial Diagnosis of Infant Botulism NEUROMUSCULAR Spinal muscular atrophy (type 1) Congenital myasthenia gravis GuillainBarr syndrome and its variants Poliomyelitis Acute flaccid paralysis Transverse myelitis ADEM Congenital myopathy Encephalitis (viral, autoimmune) Global developmental delay Leukodystrophy METABOLIC Medium chain acetyl coenzyme A deficiency Carnitine deficiency Congenital disorders of glycosylation Urea cycle defects Mitochondrial disorders Glutaric aciduria type 1 Maple syrup urine disease INFECTIOUS Enteroviral and parechovirus encephalitis Sepsis OTHERS Hypothyroidism Drug ingestion Organophosphate poisoning Heavy metal poisoning (lead, arsenic) 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. 1820 Part XV u Infectious Diseases TREATMENT Human botulism immune globulin, given intravenously (BIG IV, also referred to as BabyBIG), is licensed for the treatment of infant botulism caused by type A or B botulinum toxin. The purified immunoglobu lin is derived from pooled adult plasma from individuals immunized with pentavalent botulinum toxoid who were selected for their high titers of neutralizing antibody against botulinum neurotoxins type A and B. Treatment with BIG IV consists of a single intravenous infu sion of 50 mgkg (see package insert) that should be given as soon as possible after infant botulism is suspected so as to immediately end the toxemia that is the cause of the illness and arrest progression of paralysis. When the diagnosis of infant botulism is suspected, treatment should not be delayed for laboratory confirmation. In the United States, for clinical consultation for a patient with suspected infant botulism, the patients physician should contact the Infant Botulism Treatment and Prevention Program (IBTPP) on call physician at (510) 231 7600 (247365). To obtain BabyBIG for a patient with suspect infant botu lism, the physician must contact the IBTPP on call physicians (https :www.infantbotulism.orgphysicianobtain.php). The use of BIG IV shortens mean hospital stay from approximately 6 weeks to 2 weeks. Most of the decrease in hospital stay results from shorter duration of mechanical ventilation and reduced days in intensive care. Older patients with suspected food, wound, or inhalational botu lism may be treated with one vial of licensed equine heptavalent (A G) botulinum antitoxin (HBAT). (https:www.cdc.govmmwrpreview mmwrhtmlmm5910a4.htm), which is available in the United States through the CDC by way of state and local health departments. Antibiotic therapy |
7,380 | is not part of the treatment of uncomplicated infant or food borne botulism, because the toxin is primarily an intracellular molecule that is released into the intestinal lumen with vegetative bac terial cell death and lysis. Indeed, there is a theoretical concern that antibiotics with clostridiocidal activity may increase the amount of free toxin in the large bowel and actually worsen an infants clinical sta tus. Antibiotic use in infant botulism patients is indicated only for the treatment of secondary infections. In these patients, aminoglycosides in particular should be avoided, because this class of antibiotics can potentiate the action of botulinum toxin at the neuromuscular junc tion. Wound botulism requires aggressive treatment with antibiotics and antitoxin in a manner analogous to that for tetanus (see Chapter 257) and may require wound debridement to remove the source of the toxin. SUPPORTIVE CARE Management of botulism rests on the following three principles: (1) fatigability with repetitive muscle activity is the clinical hallmark of the disease, (2) complications are best avoided by anticipating them, and (3) meticulous supportive care is a necessity. The first principle applies mainly to feeding and breathing. Correct positioning is imperative to protect the airway and improve respiratory mechanics. The patient should be positioned face up on a rigid bottomed crib (or bed), the head of which is tilted at 30 degrees. A small cloth roll is placed under the cervical vertebrae to tilt the head back so that secretions drain to the posterior pharynx and away from the airway. In this tilted posi tion, the abdominal viscera pull the diaphragm down, thereby improv ing respiratory mechanics. The patients head and torso should not be elevated by bending the middle of the bed; in such a position, the hypo tonic thorax would slump into the abdomen, and breathing would be compromised. About half of patients with infant botulism require endotracheal intubation, which is best done prophylactically. The indications include diminished gag and cough reflexes and progressive airway obstruction by secretions. Enteral nutrition should be undertaken using a naso gastric or nasojejunal tube until sufficient oropharyngeal strength and coordination enable oral feeding by breast or bottle. Expressed breast milk is the most desirable food for infants, in part because of its immu nologic components (e.g., secretory IgA, lactoferrin, leukocytes). Tube feeding also assists in the restoration of peristalsis, a nonspecific but probably essential part of eliminating C. botulinum from the intestinal flora. Intravenous feeding (hyperalimentation) is discouraged because of the potential for infection and the advantages of tube feeding. Because sensation and cognitive function remain fully intact, provid ing auditory, tactile, and visual stimuli is beneficial. Maintaining strong central respiratory drive is essential, so sedatives and CNS depressants should be avoided. Full hydration and stool softeners such as lactulose may mitigate the protracted constipation. Cathartics are not recom mended. Patients with food borne and infant botulism excrete C. botu linum toxin and organisms in their feces, often for many weeks, and care should be taken in handling their excreta, with |
7,381 | full engagement of hospital infection control staff. When bladder palsy occurs in severe cases, gentle suprapubic pressure with the patient in the sitting posi tion with the head supported may help attain complete voiding and reduce the risk for urinary tract infection (UTI). Families of affected patients may require emotional and financial support, especially when the paralysis of botulism is prolonged. COMPLICATIONS Almost all the complications of botulism are nosocomial, and a few are iatrogenic (Table 256.3). Some critically ill, toxin paralyzed patients who must spend weeks or months on ventilators in intensive care units inevitably experience some of these complications. Suspected relapses of infant botulism usually reflect premature hospital dis charge or an inapparent underlying complication such as pneumonia, UTI, or otitis media. PROGNOSIS When the regenerating nerve endings have induced formation of a new motor end plate, neuromuscular transmission is restored. In the absence of complications, particularly those related to hypoxia, the prognosis in infant botulism is for full and complete recovery. Hos pital stay in untreated infant botulism averages 5.7 weeks but differs significantly by toxin type, with patients with untreated type B disease being hospitalized a mean of 4.2 weeks and those with untreated type A disease being hospitalized a mean of 6.7 weeks. In the United States, the case fatality ratio for hospitalized cases of infant botulism is 1. After recovery, patients with untreated infant botulism appear to have an increased incidence of strabismus that requires timely screening and treatment. The case fatality ratio in food borne and wound botulism varies by age, with younger patients having the best prognosis. Some adults with botulism have reported chronic weakness and fatigue for 1 year as sequelae of the illness. Table 256.2 Conditions Considered in the Differential Diagnosis of Food Borne Botulism and Wound Botulism Acute gastroenteritis Myasthenia gravis Guillain Barr syndrome Organophosphate poisoning Meningitis Encephalitis Transverse myelitis Psychiatric illness Cerebrovascular accident Poliomyelitis Hypothyroidism Genetic disorder Aminoglycoside associated paralysis Tick paralysis Hypocalcemia Hypermagnesemia Carbon monoxide poisoning Hyperemesis gravidarum Laryngeal trauma Diabetic complications Inflammatory myopathy Overexertion 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 257 u Tetanus (Clostridium tetani) 1821 PREVENTION Food borne botulism is best prevented by adherence to safe methods of home canning (pressure cooker and acidification), by avoiding sus picious foods, and by heating all home canned foods to 85C (185F) for 5 minutes. Wound botulism is best prevented by not using illicit drugs and by treating contaminated wounds with thorough cleansing, surgical debridement, and provision of appropriate antibiotics. Many patients with infant botulism are presumed to have inhaled and then swallowed airborne clostridial spores; these cases cannot be prevented. However, a clearly identified and avoidable source of botu linum spores for infants is honey. Honey is an unsafe food for any child 1 year old. Corn syrups were once thought to be a possible source of botulinum |
7,382 | spores, but evidence indicates otherwise. Breastfeeding appears to slow the onset of infant botulism and to diminish the risk for sudden death in infants in whom the disease develops. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 256.3 Complications of Infant Botulism Acute respiratory distress syndrome Aspiration Clostridioides difficile enterocolitis Hypotension Inappropriate antidiuretic hormone secretion Long bone fractures Misplaced or plugged endotracheal tube Nosocomial anemia Otitis media Pneumonia Pneumothorax Recurrent atelectasis Seizures secondary to hyponatremia Sepsis Subglottic stenosis Tracheal granuloma Tracheitis Transfusion reaction Urinary tract infection ETIOLOGY The clinical syndrome of tetanus involves an acute, spastic paralytic illness caused by a neurotoxin produced by Clostridium tetani. Thus tetanus can be considered a toxin mediated process more than an acute infectious process per se, because there are few, if any, symptoms elic ited either by the presence of replicating microorganisms or through elicitation of the host inflammatory response. Unlike other pathogenic clostridia species, C. tetani is not a tissue invasive organism. Instead, it causes illness through the toxin, tetanospasmin, more commonly referred to as tetanus toxin. Tetanospasmin is the second most poison ous substance known, surpassed in potency only by botulinum toxin. The human lethal dose of tetanus toxin is estimated to be 105 mgkg. C. tetani is a motile, gram positive, spore forming obligate anaerobe. The organisms natural habitat worldwide is soil, dust, and the alimen tary tracts of various animals. Chapter 257 Tetanus (Clostridium tetani) Mark R. Schleiss C. tetani forms spores terminally, with a classic morphologic appear ance resembling a drumstick or tennis racket when viewed micro scopically. The formation of spores is a critical aspect of the organisms persistence in the environment. Spores can survive boiling but not autoclaving, whereas the vegetative cells are killed by antibiotics, heat, and standard disinfectants. EPIDEMIOLOGY Tetanus occurs worldwide and is endemic in many developing coun tries, although its incidence varies considerably. Public health efforts in recent years have had an impressive impact on tetanus associated mortality, but many challenges remain. In 1990, 314,000 people died because of tetanus, whereas in 2017 there were just slightly over 38,000 deaths. Over half of these deaths (approximately 18,000) were in chil dren under 5 years of age (Fig. 257.1A). Individuals age 15 49 years represent the second most common group to suffer tetanus related mortality. Global mortality in adults is largely driven by maternal tetanus, which results from postpartum, postabortal, or postsurgical wound infection with C. tetani. Most mortality related to neonatal tet anus (also referred to as umbilical tetanus) occurs in South Asia and sub Saharan Africa. The mortality of neonatal tetanus has been sub stantially reduced globally, driven by increased rates of maternal teta nus vaccination, although the disease remains endemic in a number of countries (see Fig. 257.1B). Reported tetanus cases in the United States have declined more than 95 since 1947, and deaths caused by tetanus have declined by more than 99 in that same period. From 2009 to 2017, a total of 264 cases and 19 deaths from |
7,383 | tetanus were reported in the United States. Sixty (23) cases were in persons 65 years of age or older, 168 (64) were in persons 20 through 64 years of age, and 36 (13) were in persons younger than 20 years, including 3 cases of neo natal tetanus. The majority of childhood cases of tetanus in the United States have occurred in unimmunized children whose parents objected to vaccination. Most non neonatal cases of tetanus are associated with a traumatic injury, often a penetrating wound inflicted by a dirty object such as a nail, splinter, fragment of glass, or unsterile injection. Tetanus may also occur in the setting of illicit drug injection. The disease has been associated with the use of contaminated suture material and after intramuscular injection of medicines, most notably quinine for chloroquine resistant falciparum malaria. The disease may also occur in association with animal bites, abscesses (including dental abscesses), ear and other body piercing, chronic skin ulceration, burns, compound fractures, frostbite, gangrene, intestinal surgery, ritual scarification, infected insect bites, and female circumcision. Rarely, cases may pres ent to clinical attention without an antecedent history of trauma. Teta nus is not transmitted person to person. PATHOGENESIS Tetanus typically occurs after spores (introduced by traumatic injury) germinate, multiply, and produce tetanus toxin. A plasmid carries the toxin gene. Toxin is produced only by the vegetative cell, not the spore. It is released after the vegetative phase of replication, with replication occurring under anaerobic conditions. The low oxidation reduction potential of an infected injury site therefore provides an ideal environ ment for transition from the spore to the vegetative stage of growth. After bacterial cell death and lysis, tetanospasmin is produced. The toxin has no known function for clostridia in the soil environment where they normally reside. Tetanus toxin is a 150 kDa simple pro tein consisting of a heavy chain (100 kDa) and a light (50 kDa) chain joined by a single disulfide bond. Tetanus toxin binds at the neuro muscular junction and enters the motor nerve by endocytosis, after which it undergoes retrograde axonal transport, facilitated by dyneins, to the cytoplasm of the motoneuron. In the sciatic nerve, the trans port rate was found to be 3.4 mmhr. The toxin exits the motoneuron in the spinal cord and next enters adjacent spinal inhibitory interneu rons, where it prevents release of the neurotransmitters glycine and aminobutyric acid (GABA). Tetanus toxin thus blocks the normal inhibition of antagonistic muscles on which voluntary coordinated movement depends; as a consequence, affected muscles sustain maxi mal contraction and cannot relax. This aspect of pathogenesis lead to Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1822 Part XV u Infectious Diseases 1990 20171995 2000 2005 2010 0A B 50,000 100,000 150,000 200,000 250,000 300,000 Under 5 70 years 5069 years 1549 years 514 years No data no cases 0 |
7,384 | 10 20 30 40 50 Fig. 257.1 Evolving epidemiology of tetanus. A, Deaths from tetanus, by age, globally from 1990 to 2017. Most cases of tetanus occur in chil dren under the age of 5, and this group accounts for 50 of the global mortality attributable to this infection. (Source: Institute for Health Metrics and Evaluation, Global Burden of Disease). B, Global distribution of neonatal tetanus. Number of new cases of neonatal tetanus per million, 2016. Sources: World Health Organization and UN Population Prospects, 2017. (From Behrens H, Ochmann S, Dadonaite B, Roser M. Tetanus. Published online at OurWorldInData.org, 2019. Retrieved from https:ourworldindata.orgtetanus.) the term lockjaw, classically applied to the clinical manifestations of tet anus in the affected individual. Neurotransmission at neuromuscular junctions in the autonomic nervous system are also rendered unstable in tetanus, producing autonomic storm (described later). The phenomenal potency of tetanus toxin is enzymatic. The 50 kDa light chain (A chain) of tetanus toxin is a zinc containing endoprotease whose substrate is synaptobrevin, a constituent protein of the docking complex that enables the synaptic vesicle to fuse with the terminal neu ronal cell membrane. The cleavage of synaptobrevin is the final target of tetanus toxin, and even in low doses the neurotoxin will inhibit neu rotransmitter exocytosis in the inhibitory interneurons. The blockage of GABA and glycine causes the physiologic effects of tetanus toxin. The 100 kDa heavy chain (B chain) of the toxin contains its binding and internalization domains. It binds to disialogangliosides (GD2 and GD1b) on the neuronal membrane. The translocation domain aids the movement of the protein across that membrane and into the neuron. Because C. tetani is not an invasive organism, its toxin producing vegetative cells remain where introduced into the wound, which may display local inflammatory changes and a mixed bacterial flora. CLINICAL MANIFESTATIONS Tetanus is most often generalized but may also be localized. The incu bation period typically is 2 14 days but may be as long as months after the injury. In generalized tetanus, the presenting symptom in about half of cases is trismus (masseter muscle spasm, or lockjaw). Head ache, restlessness, and irritability are early symptoms, often followed by stiffness, difficulty chewing, dysphagia, and neck muscle spasm. The so called sardonic smile of tetanus (risus sardonicus) results from intractable spasms of facial and buccal muscles. When the paralysis extends to abdominal, lumbar, hip, and thigh muscles, the patient may assume an arched posture of extreme hyperextension of the body, or opisthotonos, with the head and the heels bent backward and the body bowed forward. In severe cases, only the back of the head and the heels of the patient are noted to be touching the supporting surface. Opisthotonos is an equilibrium position that results from unrelenting total contraction of opposing muscles, all of which display the typical boardlike rigidity of tetanus. Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxiation. Because tetanus toxin does not affect sensory nerves or cortical function, the patient unfortu nately remains |
7,385 | conscious, in extreme pain, and in fearful anticipation of the next tetanic seizure. The seizures are characterized by sudden, severe tonic contractions of the muscles, with fist clenching, flexion, and adduction of the arms and hyperextension of the legs. Without treatment, the duration of these seizures may range from a few sec onds to a few minutes in length with intervening respite periods. As the illness progresses, the spasms become sustained and exhausting. The smallest disturbance by sight, sound, or touch may trigger a tetanic spasm. Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur. Fever, occasionally as high as 40C (104F), is common and is caused by the substantial metabolic energy consumed by spastic muscles. Notable autonomic effects include tachy cardia, dysrhythmias, labile hypertension, diaphoresis, and cutaneous vasoconstriction. The tetanic paralysis usually becomes more severe in the first week after onset, stabilizes in the second week, and ameliorates gradually over the ensuing 1 4 weeks. Neonatal tetanus, the infantile form of generalized tetanus, typically manifests within 3 12 days of birth. It presents as progressive difficulty in feeding (sucking and swallowing), associated hunger, and crying. Paralysis or diminished movement, stiffness and rigidity to the touch, and spasms, with or without opisthotonos, are characteristic. The umbilical stump, which is typically the portal of entry for the microor ganism, may retain remnants of dirt, dung, clotted blood, or serum, or it may appear relatively benign. Localized tetanus results in painful spasms of the muscles adjacent to the wound site and may precede generalized tetanus. Cephalic teta nus is a rare form of localized tetanus involving the bulbar muscula ture and cranial nerves (particularly cranial nerve VII) that occurs with wounds or foreign bodies in the head, nostrils, or face. It also occurs in association with chronic otitis media. Cephalic tetanus is characterized by retracted eyelids, deviated gaze, trismus, risus sardonicus, and spas tic paralysis of the tongue and pharyngeal musculature and may mimic a cerebrovascular accident. DIAGNOSIS The picture of tetanus is one of the most dramatic in medicine, and the diagnosis may be established clinically. The typical setting is an unim munized patient (andor mother) who was injured or born within the preceding 2 weeks, who presents with trismus, dysphagia, generalized muscle rigidity and spasm, and a clear sensorium. Results of routine laboratory studies are usually normal. A periph eral leukocytosis may result from a secondary bacterial infection of the wound or may be stress induced from the sustained tetanic spasms. The cerebrospinal fluid analysis is normal, although the intense muscle contractions may raise intracranial pressure. Serum muscle enzymes (creatine kinase, aldolase) may be elevated. Neither the electroencephalogram nor the electromyogram (EMG) shows a characteristic pattern, although EMG may show a continuous dis charge of motor subunits and shortening or absence of the silent interval normally observed after an action potential. An assay for antitoxin levels is not readily available, although a serum antitoxin level of 0.01 IUmL or higher is generally considered protective and makes |
7,386 | the diagnosis of tetanus less likely. C. tetani is not always visible on Gram stain of wound material and is isolated by culture in only approximately 30 of cases. The spatula test is a simple diagnostic 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 257 u Tetanus (Clostridium tetani) 1823 bedside test that involves touching the oropharynx with a spatula or tongue blade. Normally this maneuver will elicit a gag reflex, as the patient tries to expel the spatula (negative test). If tetanus is present, patients develop a reflex spasm of the masseters and bite the spatula (positive test). This bedside diagnostic maneuver is said to have a high sensitivity and specificity. Differential Diagnosis Florid and generalized tetanus is typically not mistaken for any other disease. However, trismus may result from parapharyngeal, retropha ryngeal, or dental abscesses or, rarely, from acute encephalitis involving the brainstem. Either rabies or tetanus may follow an animal bite, and rabies may manifest as trismus with seizures. Rabies may be distin guished from tetanus by hydrophobia, marked dysphagia, predomi nantly clonic seizures, and pleocytosis (see Chapter 320). Although strychnine poisoning may result in tonic muscle spasms and general ized seizure activity, it seldom produces trismus, and unlike in teta nus, general relaxation usually occurs between spasms. Hypocalcemia may produce tetany that is characterized by laryngeal and carpopedal spasms, but trismus is absent. Occasionally, epileptic seizures, narcotic withdrawal, or other drug reactions may suggest tetanus. TREATMENT Management of tetanus requires eradication of C. tetani, correction of wound environment conditions conducive to its anaerobic replication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation, provision of meticulous supportive care, and, finally, prevention of recurrences. Surgical wound excision and debridement are often needed to remove the foreign body or devitalized tissue that created the anaerobic growth conditions necessary for vegetative replication. Surgery should be performed promptly after administration of human tetanus immu noglobulin (TIG) and antibiotics. Excision of the umbilical stump in the neonate with tetanus is no longer recommended. Tetanus toxin cannot be neutralized by TIG after it has begun its axo nal ascent to the spinal cord. However, TIG should be given as soon as possible, with the goal of neutralizing toxin that diffuses from the wound into the circulation before the toxin can bind at distant muscle groups. The optimal dose of TIG has not been determined. Most experts recom mend that a single intramuscular (IM) injection of 500 units of TIG is sufficient to neutralize systemic tetanus toxin; although doses as high as 3,0006,000 have been recommended by some experts, they do not seem to confer better outcomes. Infiltration of part of the dose of TIG into the wound is no longer recommended by the Red Book Commit tee of the American Academy of Pediatrics, and the entire dose can be administered IM. If |
7,387 | TIG is unavailable, use of human intravenous immu noglobulin (at a dose of 200 400 mgkg) can be considered. Intravenous immunoglobulin contains 4 90 unitsmL of TIG; the optimal dosage of intravenous immunoglobulin for treating tetanus is not known, and its use is not approved for this indication. In parts of the world where it is available, another alternative may be equine derived tetanus antitoxin (TAT). This product is no longer available in the United States. A dose of 1,500 3,000 U is recommended and should be administered after appropriate testing for sensitivity and desensitization, because up to 15 of patients given the usual dose of TAT will experience serum sickness. The human derived immunoglobulins are much preferred because of their longer half lives (30 days) and the virtual absence of allergic and serum sickness adverse effects. Results of studies examining the poten tial benefit of intrathecal administration of TIG are conflicting. The TIG preparation available for use in the United States is neither licensed nor formulated for intrathecal or intravenous use. Oral (or intravenous) metronidazole (30 mgkg per day, given at 6 hour intervals; maximum dose, 4 gday) decreases the number of vegetative forms of C. tetani and is currently considered the antibiotic of choice. Parenteral penicillin G (100,000 Ukg per day, administered at 4 to 6 hour intervals, with a daily maximum of 12 million U) is an alternative treatment. Antimicrobial therapy for a total duration of 7 10 days is recommended (https:publications.aap.orgredbook book347chapterabstract5757094TetanusLockjaw). Supportive care and pharmacologic interventions targeted at control of tetanic spasms are of critical importance in the management of tetanus. In light of this goal, all patients with generalized tetanus should receive muscle relaxants. Diazepam provides both relaxation and seizure control. For neonatal tetanus, an initial dose of 0.1 0.2 mgkg every 3 6 hours given intravenously is subsequently titrated to control the tetanic spasms (con tinuous IV infusion doses of 1540 mgkgday have been recommended, titrated to control the spasm). After 57 days, the dosage can be decreased by 510 mgday, with the drug given orally or by the nasogastric route, after which the effective dose is sustained for 2 6 weeks before a tapered withdrawal. Magnesium sulfate may be useful in controlling autonomic dysfunction: a loading dose of 40 mgkg IV over 30 minutes has been rec ommended in a study in tetanus patients 15 years of age, in which the loading dose was followed by 2 ghr continuously for patients weighing 45 kg, or 1.5 ghr continuously for patients weighing 45 kg. For neonatal tetanus, a loading dose of 50 mgkg of magnesium sulfate, followed by a maintenance infusion of 3050 mgkghr (titrated against clinical effect) has been recommended. Monitoring of serum magnesium levels at least every 6 hours is recommended. In addition to diazepam, other benzodiaz epines (midazolam), chlorpromazine, dantrolene, and baclofen are also used. Intrathecal baclofen produces such complete muscle relaxation that apnea often ensues; like most other agents listed, baclofen should be used only in an intensive care |
7,388 | unit setting. Favorable survival rates in general ized tetanus have been described with the use of neuromuscular blocking agents such as vecuronium and pancuronium, which produce a general flaccid paralysis that is then managed by mechanical ventilation. Auto nomic instability is regulated with standard or (or both) blocking agents; morphine has also proved useful. SUPPORTIVE CARE Meticulous supportive care in a quiet, dark, secluded setting is most desirable. Because tetanic spasms may be triggered by minor stimuli, the patient should be sedated and protected from all unnecessary sounds, sights, and touch, and all therapeutic and other manipulations must be carefully scheduled and coordinated. Endotracheal intubation may not be required, but it should be done to prevent aspiration of secretions before laryngospasm develops. A tracheostomy kit should be immediately at hand for unintubated patients. Endotracheal intuba tion and suctioning easily provoke reflex tetanic seizures and spasms, so early tracheostomy should be considered in severe cases not man aged by pharmacologically induced flaccid paralysis. Therapeutic botu linum toxin has been used for this purpose (i.e., to overcome trismus). Cardiorespiratory monitoring, frequent suctioning, and maintenance of the patients substantial fluid, electrolyte, and caloric needs are fun damental. Careful nursing attention to mouth, skin, bladder, and bowel function is needed to avoid ulceration, infection, and obstipation. Pro phylactic subcutaneous heparin has been suggested to be of value, but it must be balanced with the risk for hemorrhage. Enoxaparin would be an alternative for the patient for whom deep venous thrombosis (DVT) prophylaxis is warranted. COMPLICATIONS The seizures and the severe, sustained rigid paralysis of tetanus pre dispose the patient to many complications. Aspiration of secretions with attendant pneumonia is an important complication to consider and may be present at the time of the initial diagnosis. Maintaining airway patency often mandates endotracheal intubation and mechani cal ventilation with their attendant hazards, including pneumothorax and mediastinal emphysema. The seizures may result in lacerations of the mouth or tongue, in intramuscular hematomas or rhabdomyolysis with myoglobinuria and renal failure, or in long bone or spinal frac tures. Venous thrombosis, pulmonary embolism, gastric ulceration with or without hemorrhage, paralytic ileus, and decubitus ulcer ation are described as complications. Excessive use of muscle relax ants, which are an integral part of care, may produce iatrogenic apnea. Cardiac arrhythmias, including asystole, unstable blood pressure, and labile temperature regulation, reflect disordered autonomic nervous system control that may be aggravated by inattention to maintenance of intravascular volume needs. 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. 1824 Part XV u Infectious Diseases PROGNOSIS Recovery in tetanus occurs through regeneration of synapses within the spinal cord that results in restoration of muscle relaxation. Interest ingly, an episode of tetanus does not result in the production of toxin neutralizing antibodies, presumably because the infinitesimally small amounts of toxin required to cause disease are not sufficient to elicit an |
7,389 | immune response. Therefore active immunization with tetanus toxoid during convalescence andor at discharge, with provision for comple tion of the primary vaccine series, is mandatory. The most important factor that influences outcome is the quality of supportive care. Mortality is highest in the very young and the very old. A favorable prognosis is associated with a long incubation period, absence of fever, and localized disease. An unfavorable prognosis is associated with onset of trismus 7 days after injury and with onset of generalized tetanic spasms 3 days after onset of trismus. Sequelae of hypoxic brain injury, especially in infants, include cerebral palsy, diminished mental abilities, and behavioral difficulties. Most fatalities occur within the first week of illness. Reported case fatality rates for generalized tetanus are 535, and for neonatal tetanus they extend from 10 with intensive care treatment to 75 without it. Cephalic tetanus has an especially poor prognosis because of breathing and feed ing difficulties. PREVENTION Tetanus is an entirely and easily preventable disease. A serum antibody titer of 0.01 unitsmL is considered protective. Active immunization should begin in early infancy with combined diphtheria toxoidtetanus toxoidacellular pertussis (DTaP) vaccine at 2, 4, 6, and 15 18 months of age, with boosters at 4 6 years (DTaP) and 11 12 years (Tdap) of age, and at 10 year intervals thereafter throughout adult life with tetanus and reduced diphtheria toxoid (Td). Recovery from tetanus does not confer permanent protective immunity, so immunization is recom mended in those who have survived documented infection. Immuni zation of women with tetanus toxoid prevents neonatal tetanus, and pregnant women should receive one dose of reduced diphtheria and pertussis toxoids (Tdap) during each pregnancy, preferably at 27 36 weeks of gestation. Recommended immunization schedules are regu larly updated; the most current versions may be found at http:www. cdc.govvaccinesschedules. Arthus reactions (type III hypersensitivity reactions), a localized vasculitis associated with deposition of immune complexes and activa tion of complement, are reported rarely after tetanus vaccination. Mass immunization campaigns in developing countries have occasionally provoked a widespread hysterical reaction. Wound Management Tetanus prevention measures after trauma consist of inducing active immunity to tetanus toxin and of passively providing antitoxic anti body (Table 257.1). Tetanus prophylaxis is an essential part of all wound management, but specific measures depend on the nature of the injury and the immunization status of the patient. Prevention of tetanus must be included in planning for the consequences of bomb ings, natural disasters, and other possible civilian mass casualty events. Tetanus toxoid should always be given after a dog or other animal bite, even though C. tetani is infrequently found in canine mouth flora. Nonminor wounds require human TIG except those in a fully immu nized patient (i.e., 3 doses of adsorbed tetanus toxoid). In any other circumstance (e.g., patients with an unknown or incomplete immuni zation history; crush, puncture, or projectile wounds; wounds contam inated with saliva, soil, or feces; avulsion injuries; compound fractures; or frostbite), TIG 250 units should be administered intramuscularly, regardless |
7,390 | of the patients age or weight. If TIG is unavailable, use of human intravenous immunoglobulin may be considered. If neither of these products is available, then 3,000 5,000 units of equine derived TAT (in regions of the world where it is available) may be given intra muscularly after testing for hypersensitivity. Serum sickness may occur with this agent. Human monoclonal antibodies against the tetanus neurotoxin have recently been generated and characterized, but these are not yet available for clinical use. The wound should undergo immediate, thorough surgical cleans ing and debridement to remove foreign bodies and any necrotic tissue in which anaerobic conditions might develop. Tetanus toxoid should be given to stimulate active immunity and may be administered con currently with TIG (or TAT); if a tetanus toxoidcontaining vaccine and TIG are administered at the same time, then separate syringes and sites should be used. A tetanus toxoid booster (preferably Tdap) is administered to all persons with any wound if the tetanus immuni zation status is unknown or incomplete. A booster is administered to injured persons who have completed the primary immunization series if (1) the wound is clean and minor, but 10 or more years have passed since the last booster, or (2) the wound is more serious, and 5 or more years have passed since the last booster (see Table 257.1). Persons who experienced an Arthus reaction after a dose of tetanus toxoidcontain ing vaccine should not receive Td more frequently than every 10 years, even for tetanus prophylaxis as part of wound management. In a situ ation of delayed wound care, active immunization should be started at once. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 257.1 Tetanus Vaccination and Immune Globulin Use in Wound Management HISTORY OF ABSORBED TETANUS TOXOID CLEAN, MINOR WOUNDS ALL OTHER WOUNDS DTaP, Tdap, OR Td TIG DTaP, Tdap, Or TD TIG Uncertain or 3 doses Yes No Yes Yes 3 or more doses No, if 10 yr since last dose of tetanus containing vaccine No No, if 5 yr since last tetanus containing vaccine No Yes, if 10 yr since last dose of tetanus containing vaccine No Yes, if 5 yr since last tetanus containing vaccine dose No Including but not limited to wounds contaminated with dirt, feces, and saliva; puncture wounds; avulsions; wounds resulting from missiles, crushing, burns, and frostbite. DTaP is used for children younger than 7 yr. Tdap is preferred over Td for underimmunized children 7 yr and older who have not received Tdap previously. Intravenous immune globulin should be used when TIG is unavailable. More frequent boosters are not needed and can accentuate adverse events. DT, Diphtheria and tetanus toxoid vaccine; DTaP, combined diphtheria toxoidtetanus toxoidacellular pertussis vaccine; Td, tetanus toxoid and reduced diphtheria toxoid vaccine; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; TIG, tetanus immune globulin. Data from American Academy of Pediatrics. Tetanus (lockjaw). In Kiberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious |
7,391 | Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics, 2021;750755. 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 258 u Clostridioides difficile Infection 1825 Clostridioides difficile (formerly Clostridium difficile) infection (CDI), also known as pseudomembranous colitis or C. difficileassociated diarrhea, refers to gastrointestinal (GI) colonization with C. difficile resulting in a diarrheal illness. It is a common cause of antibiotic associated diarrhea and the most common cause of healthcare associated infections in the United States, accounting for 12 of these infections. An increase in inpatient and outpatient (community) acqui sition of CDI has been observed, and additional risk factors have been identified. ETIOLOGY C. difficile is a gram positive, spore forming, anaerobic bacillus that is resistant to killing by alcohol. It is acquired from the environment or by the fecal oral route. Organisms causing symptomatic intestinal disease produce toxin A andor toxin B. These toxins affect intracel lular signaling pathways, resulting in inflammation and cell death. The cytotoxic binary toxin, which belongs to the AB toxin family, is not present in the majority of strains but has been detected in epi demic strains. EPIDEMIOLOGY The incidence of CDI is increasing in pediatric patients, and the set ting of acquisition is changing. There is both high incidence in hos pitalized children and an emergence of community onset infection. National data from the Centers for Disease Control and Prevention (CDC) estimate three cases of community acquired CDI in children for every healthcare acquired case. In addition to an overall increase in all strains, a hypervirulent strain, denoted NAP1BI027 (also called BI), has emerged and is estimated to cause 1020 of pediatric infec tions. This strain produces binary toxin and exhibits 16 and 23 fold increases in the production of toxins A and B, respectively. Asymptomatic carriage occurs with potentially pathogenic strains and is common in neonates and infants 1 year old. A carrier fre quency rate of 50 may occur in children 1 year old. Colonization rates decrease to less than 5 in healthy children 5 years old. Asymp tomatic colonization with C. difficile is common in recently hospital ized patients, with rates of 20. Carriers can infect other susceptible individuals. Risk factors for CDI include the use of broad spectrum antibiotics, hospitalization, exposure to a household member with diarrhea or an asymptomatic carrier, GI surgery, inflammatory bowel disease (IBD), Hirschsprung disease, chemotherapy, enteral tube feeding, proton pump inhibitor (PPI) or H2 receptor antagonist use, malnutrition, and chronic illness. PATHOGENESIS Disease is caused by GI infection with a toxin producing strain. Any process that disrupts normal flora, impairs the acid barrier defense, alters the normal GI immune response (e.g., IBD), or inhibits intestinal motility may lead to infection. Normal bowel flora appears to be pro tective, conferring colonization resistance. By affecting intracellular signaling pathways and cytoskeletal orga nization, toxins induce an inflammatory response and cell |
7,392 | death, lead ing to diarrhea and pseudomembrane formation. Antibodies against toxin A have been shown to confer protection against symptomatic disease, and failure of antibody production occurs in patients with recurrent disease. CLINICAL MANIFESTATIONS Infection with toxin producing strains of C. difficile leads to a spec trum of disease ranging from mild, self limited diarrhea, to explosive, watery diarrhea with occult blood or mucus, to pseudomembranous colitis, and even death. Pseudomembranous colitis is characterized by bloody diarrhea with accompanying fever, abdominal paincramps, nausea, and vomiting. Rarely, small gut involvement, toxic megaco lon, bacteremia, abscess formation, intestinal perforation, and death can occur. Symptoms of CDI generally begin less than a week after colonization and may develop during or weeks after antibiotic exposure. Symptoms are generally more severe in certain populations, including patients receiving chemotherapy, patients with chronic GI disease (e.g., IBD), and some patients with cystic fibrosis (CF). CDI associated reactive arthritis is an occasional complication, occurring in approximately 1.4 of children with CDI. Reactive arthritis begins a median of 10 days after initial GI symptoms, often accompanied by fever or rash. Joint involvement may be migratory or polyarticular and may resemble septic arthritis. DIAGNOSIS Evaluation for CDI should be reserved for children with diarrhea, defined as the passage of at least three loose stools within a 24 hour period or bloody diarrhea (Fig. 258.1 and Table 258.1). CDI is diag nosed by the detection of a C. difficile toxin in the stool of a symptom atic patient. Most patients present with a history of recent antibiotic Chapter 258 Clostridioides difficile Infection David P. Galloway and Mitchell B. Cohen Patient with suspected CDI Start with a highly sensitive test: GDH or NAAT Negative Not CDI Positive CDI Positive Proceed to more specific test: Toxin EIA 1. Not CDIcolonized OR 2. False negative Toxin EIA OR 3. Toxin levels below the threshold of detection Negative Consider other possible causes of symptoms Consider NAAT in GDHnegative patients with high clinical suspicion Empiric treatment if high clinical suspicion Fig. 258.1 Proposed algorithm for testing of Clostridioides difficile in fection (CDI). EIA, Enzyme immunoassay; GDH, glutamate dehydroge nase; NAAT, nucleic acid amplification testing. (From Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile in infections. Am J Gastroen terol. 2021;116:11241147, Fig. 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. 1826 Part XV u Infectious Diseases use, but the absence of antibiotic exposure should not dissuade the clinician from considering this diagnosis and ordering the appropri ate test. Conversely, high carriage rates without illness among infants should prompt careful consideration when testing and treating chil dren 3 years old. The standard test for toxin is the enzyme immunoassay (EIA), a same day test for toxin A andor toxin B with sufficient specificity (94 100) but less than ideal sensitivity (8893). |
7,393 | Many laboratories use nucleic acid amplification tests (NAATs) to supplement or supplant EIA with the goal of improving sensitivity. The sensitivities of the real time polymerase chain reaction (PCR) assay for toxin AB are superior compared with EIA for toxin AB (95 vs 35, respectively), and the specificity is equal (100). However, some have questioned the clinical significance of low copy numberpositive tests. For example, positive C. difficile PCR results occur with similar frequency in patients with IBD with and without an IBD exacerbation. A positive result in a highly sensitive PCR assay that detects low copy numbers of a toxin gene in C. difficile may reflect colonization in a subset of patients (e.g., with IBD), confounding clinical decision making in managing disease exac erbations. To address this, NAAT positive tests may be confirmed by toxin assays. In addition, eliminating certain high carrier populations from testing (e.g., children under 1 year of age) will increase the posi tive predictive value of laboratory testing. Because sensitivity is so high with molecular tests, if the first test is negative, repeat testing during the same episode of diarrhea is discouraged, as repeat testing in this setting is more likely to result in another negative or a false positive test than a true positive test. Because shedding of C. difficile in stool can persist for several months after symptom resolution, tests of cure are impractical and are not performed. Culture for organism isolation is a sensitive test but is labor intensive, taking several days. Culture alone is not specific because it does not dif ferentiate between toxin producing and nontoxin producing strains. Pseudomembranous nodules and characteristic plaques may be seen in colonoscopy or sigmoidoscopy, but endoscopy is usually not per formed to make the diagnosis. TREATMENT Initial treatment of CDI involves discontinuation of any nonvital anti biotic therapy and administration of fluid and electrolyte replacement. For mild cases, this treatment may be curative. Drugs that decrease intestinal motility should be avoided. Asymptomatic patients should not be treated. Persistent symptoms or moderate to severe disease war rant antimicrobial therapy directed against C. difficile. Oral metronidazole or vancomycin is the first line therapy for mild to moderate CDI in children (Table 258.2). In adults, vancomycin or fidaxomicin are the preferred first line therapies. For more severe infection, oral vancomycin is approved by the U.S. Food and Drug Administration (FDA) for CDI. Vancomycin exhibits ideal pharmaco logic properties for treatment of this enteric pathogen because it is not absorbed in the gut. Vancomycin is suggested as a first line agent for severe disease, as manifested by hypotension, peripheral leukocytosis, or severe pseudomembranous colitis. Fidaxomicin is approved for use in children at least 6 months of age and is a narrow spectrum mac rolide antibiotic with noninferior efficacy to vancomycin but superior recurrence prevention. Because treatment of CDI continues to evolve, adult based protocols (Table 258.3) may be relevant to older children and adolescents. PROGNOSIS AND RECURRENCE The response rate to initial treatment of CDI can reach 95. |
7,394 | Studies have demonstrated a variation in response rates based on the severity of CDI and the treatment agent. Treatment failure and recurrence have been increasing; the risk of subsequent reappearance increases with each recurrence. Recurrences occur in 520 of patients, are diagnosed clinically, and generally occur within 4 weeks of treatment. Some recurrences result from incomplete eradication of the original strain, and others are caused by reinfection with a different strain. Treatment for the initial recurrence involves retreatment with the original antibiotic course. Table 258.1 Diagnosis of C. difficile Disease Clostridium difficile (renamed Clostridioides difficile) infection is diagnosed by a combination of clinical and laboratory findings. Diagnosis requires a positive test for the presence of C. difficile toxins. Glutamate dehydrogenase (GDH), produced by C. difficile, can be detected in stool. However, it is not specific and can be produced by nontoxigenic C. difficile. Enzyme immunoassay testing for toxin A andor B has a variable sensitivity and specificity, a turnaround time of about 24 hours and correlates well with disease activity. Polymerase chain reaction testing has a high sensitivity and specificity, a turnaround time of less than 4 hours, and correlates less with disease activity, thus identifying patients with colonization and active infection. Increasingly, combination testing is being employed to improve diagnostic accuracy. Laboratory testing for C. difficile toxins should only be performed on patients with at least three unformed stools per 24 hours, who are not on laxatives, and is not useful as a test of cure. Pathologic findings can help to confirm the diagnosis. From Semel JD. Clostridioides difficile colitis. In: Kellerman RD, Rakel DP, Heidelbaugh JJ, Lee EM, eds. Conns Current Therapy 2023. Philadelphia: Elsevier; 2023:561. Table 258.2 Treatment Recommendations for Clostridioides difficile Infection in Children CDI CLASSIFICATION ANTIBIOTIC REGIMEN First episode or first recurrence, nonsevere Metronidazole 7.5 mgkgdose (max 500 mgdose) PO tid 10 days; OR Vancomycin 10 mgkgdose (max 125 mgdose) PO qid 10 days Second or subsequent recurrence, nonsevere Vancomycin in a tapered and pulsed regimen; OR Vancomycin (dosing and duration as above) followed by rifaximin 10 mgkgdose (max 400 mgdose) PO tid 20 days; OR Fidaxomicin 16 mgkgdose (max 200 mgdose) PO bid 10 days; OR Fecal microbiota transplantation Severefulminant (first or recurrent episode) Vancomycin 10 mgkgdose (max 500 mgdose) PO qid 10 days If critically ill, consider adding metronidazole 7.5 mgkgdose (max 500 mgdose) IV tid 10 days For first recurrence, consider vancomycin if metronidazole was used to treat initial episode. Recommend tapered and pulsed regimen if vancomycin was used for the initial infection. Tapered and pulsed regimen: vancomycin 10 mgkgdose (max 125 mgdose) qid 10 14 days, then 10 mgkgdose (max 125 mgdose) bid 1 wk, then 10 mgkgdose (max 125 mgdose) qd 1 wk, and then 10 mgkgdose (max 125 mgdose) every 2 3 days for 2 8 wk. Pediatric rifaximin dosing is not available and not FDA approved for children younger than 12 yr. Definitions for severe and fulminant CDI are based on expert consensus for adult patients and have |
7,395 | not been validated. Severe: leukocytosis with a white blood cell count of 15,000 cellsL or a serum creatinine level 1.5 mgdL. Fulminant: hypotension or shock, ileus, megacolon. If treating a recurrent episode that is severefulminant, consider extending vancomycin in a pulsed, tapering fashion as indicated above or fecal microbiota transplantation when clinically improved. Data from McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66(7):e1e48. 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 258 u Clostridioides difficile Infection 1827 Table 258.3 Recommendations for the Treatment of C. difficile Infection in Adults CLINICAL DEFINITION SUPPORTIVE CLINICAL DATA RECOMMENDED TREATMENT STRENGTH OF RECOMMENDATIONQUALITY OF EVIDENCE Initial infection Leukocytosis with white blood cell count of 15,000 cellsmL and serum creatinine level 1.5 mgdL Fidaxomicin 200 mg bid 10 days Stronghigh Vancomycin 125 mg qid 10 days Stronghigh Alternate if previous agents are unavailable: metronidazole 500 mg tid PO 10 14 days Weakhigh Fulminant Hypotension or shock, ileus, megacolon Vancomycin 500 mg qid PO or by nasogastric tube Strongmoderate (oral vancomycin), weaklow (rectal vancomycin), strongmoderate (intravenous metronidazole)If ileus, consider adding rectal instillation of vancomycin; intravenous metronidazole (500 mg every 8 hr) should be administered with oral or rectal vancomycin, particularly if ileus is present Recurrence First recurrence, nonsevere Fidaxomicin 200 mg bid 10 days, or bid 5 days, then qod for 20 days or Weaklow Use prolonged tapered and pulsed vancomycin regimen (if standard regimen was used for initial episode) 125 mg qid for 10 14 days, bid for 1 wk, qd for 1 wk, and then every 2 or 3 days for 2 8 wk, or Weaklow Vancomycin 125 mg qid 10 days (if metronidazole was used for the initial episode) Weakmoderate Second or subsequent recurrence Fidaxomicin 200 mg bid 10 days, or bid 5 days, then qod for 20 days Weaklow Vancomycin in a tapered or pulsed regimen or Weaklow Vancomycin 125 mg qid 10 days, followed by rifaximin 400 mg tid 20 days, or Weaklow Fecal microbiota transplantation Strongmoderate All randomized trials have compared 10 day treatment courses, but some patients (particularly those treated with metronidazole) may have delayed response to treatment, and clinicians should consider extending treatment duration to 14 days in those circumstances. The opinion of the panel is that appropriate antibiotic treatments for at least two recurrences (i.e., three CDI episodes) should be tried before offering fecal microbiota transplantation. For adult patients with a recurrent CDI episode within the last 6 months, current guidelines suggest using bezlotoxumab in addition to appropriate antibiotics as the first approach. PO, Orally (by mouth); qd, once daily; bid, twice daily; tid, 3 times daily; qid, 4 times daily; qod, every other day. Adapted |
7,396 | from McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1e48, Table 1; and Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029e1044, Table 1. Recurrences of CDI may be caused by a suboptimal immune response, failure to kill organisms that have sporulated, or failure of delivery of antibiotic to the site of infection in the case of ileus or toxic megacolon. Subsequent treatment with pulsed or tapered vancomycin decreases recurrence rates. In addition to this approach, other antibiot ics (rifaximin or nitazoxanide), toxin binding polymers (Tolevamer), and probiotics (Saccharomyces boulardii or Lactobacillus GG) have been used as adjunctive therapy. For adult patients with a recurrent CDI episode within the last 6 months, guidelines suggest using bezlo toxumab, a humanized monoclonal antibody against C. difficile toxin B, as a co intervention. Because treatment of CDI continues to evolve, adult based protocols (see Table 258.3) may be applicable for treatment of older children and adolescents. Because failure to manifest an adequate antitoxin immune response is associated with a higher frequency of recurrent CDI, intravenous immune globulin has been used to treat recurrent dis ease. In the case of ileus or toxic megacolon, an enema of vancomy cin may be used to place the antibiotic directly at the site of infection, although most often intravenous therapy is first attempted in this circumstance. 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. 1828 Part XV u Infectious Diseases Fecal microbiota transplantation (FMT) has been used to address the disruption in normal gut flora thought to allow colonization with C. difficile (see Table 258.3). FMT involves the instillation of fecal mate rial from a healthy donor into the patients GI tract by nasoenteric tube, enema, capsules, or colonoscopy. Published FMT results in children with recurrent CDI are limited to case reports and small case series. There are few data to guide clinicians on the indications, route, efficacy, and safety of FMT in children. Initial reports indicate an overall suc cess rate of approximately 90 in patients with recurrent CDI. Current approaches to FMT are not specific and involve complete reconstitu tion of the gut microbiome. The gut microbiota has been shown to influence susceptibility to genetic and environmentally acquired con ditions. Transplantation of healthy donor fecal material to patients with CDI may reestablish the normal composition of the gut micro biota but has the theoretical concern of adding new, microbiome based susceptibilities derived from the donor microbiome. The FDA has approved an orally administered |
7,397 | commercially avail able fecal microbiotic product for patients 18 years old, following antibiotic therapy for recurrent CDI. The goal is to prevent recurrence of CDI. Fecalderived live bacteria from screened donors is adminis tered once daily for 3 days. It is important to recognize that postinfectious diarrhea may result from other causes, such as postinfectious irritable bowel syndrome, microscopic colitis, and IBD. PREVENTION The strategies for prevention of CDI include recognition of common sites of acquisition (hospitals, childcare settings, extended care facili ties); effective environmental cleaning (i.e., use of chlorinated cleaning solutions); appropriate antibiotic (antibiotic stewardship) and PPI pre scription practices; cohorting of infected patients; contact precautions; and proper handwashing with soap and water. Probiotics may possibly reduce the incidence of C. difficileassociated diarrhea. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Anaerobic bacteria are among the most numerous organisms col onizing humans and are also present widely in the soil. Obligate anaerobes are markedly or entirely intolerant of exposure to oxy gen. Facultative anaerobes can survive in the presence of envi ronmental oxygen but grow better in settings of reduced oxygen tension. This chapter concentrates on obligate anaerobes and asso ciated infections. Infections with endogenous anaerobes usually occur adjacent to mucosal surfaces, often as polymicrobial infections with aerobes. In many of these polymicrobial infections, it is unclear how direct a role anaerobes are playing in illness versus just being present by vir tue of breached mucosal barriers. Traumatized areas that have been devascularized with resultant low oxygen tension provide ideal sites for anaerobic infection. Abscess formation can evolve over days to weeks and generally involves both aerobes and anaerobes. An example of such an infection is ruptured appendicitis leading to secondary peritonitis and intrabdominal abscesses. Pure anaero bic infections from endogenous bacteria are much less common Chapter 259 Other Anaerobic Infections Michael E. Russo (although certain relevant clinical syndromes such as Lemierre syn drome are discussed later). The most common and clinically relevant anaerobic bacteria in pedi atrics are listed in Table 259.1 and discussed further later in the chapter. The taxonomy has undergone significant changes over the years, and many species that would not have been easily identifiable may now be identified in clinical specimens with the widespread use of matrix assisted laser desorptionionization time of flight mass spectrometry (MALDI TOF MS). Our understanding of anaerobic bacteria in infec tions is largely limited to easily culturable species. As many anaerobes of the human microbiota remain unculturable, our understanding of anaerobic infections will continue to evolve with culture independent methods such as metagenomic sequencing. Bacteroides fragilis and related species are the predominant anaer obes of the large intestine and thus are involved in complicated intraabdominal infections. Prevotella spp., Porphyromonas spp., and Fusobacterium spp. reside in the upper respiratory tract and intes tine and are most frequently involved in complications of pharyngitis and sinusitis or in aspiration pneumonia. The gram positive anaero bic cocci (GPAC) have undergone significant taxonomic changes in recent years, with most prior Peptostreptococcus spp. being reclassified into |
7,398 | the genera of Finegoldia, Parvimonas, Anaerococcus, and Pepto niphilus. It is not clear yet how clinically relevant this reclassification is Collectively, the GPAC are normal flora of the skin and upper respi ratory, intestinal, and genital mucosa. They may be involved in com plications of infections of any of these areas, but they are relatively less virulent than other anaerobic bacteria, and their recovery in culture may or may not be clinically relevant. The gram positive anaerobic bacilli can be divided into spore forming (Clostridium spp.) and non spore forming (Cutibacterium acnes formerly Propionibacterium acnes and Actinomyces spp.). C. acnes lives within hair follicles and sebaceous glands and is an important cause of prosthetic infections, particularly related to ventricular shunts. Some Actinomyces spp. are obligate or facultative anaerobes and are discussed in Chapter 235. Clostridium spp. cause disease by proliferation and often by produc tion of toxins. Of the 60 species that have been identified, only a few cause infections in humans. The most frequently implicated Clostridium spp. are C. difficile (see Chapter 258), C. perfringens (dis cussed further later), C. botulinum (see Chapter 256), and C. tetani (see Chapter 257). CLINICAL MANIFESTATIONS Anaerobic infections occur in a variety of sites throughout the body, with examples including complications of pharyngitis such as peri tonsillar abscess and Lemierre syndrome (see Chapter 432), den tal abscesses (see Chapter 358), complications of sinusitis such as orbital cellulitis (see Chapter 674) and brain abscess (see Chapter 644), aspiration pneumonia (see Chapter 447) and lung abscess (see Chapter 453), secondary peritonitis (see Chapter 419), appendici tis (see Chapter 391), necrotizing enterocolitis (see Chapter 136), and pelvic inflammatory disease and tubo ovarian abscesses (see Chapter 163). Table 259.1 Clinically Relevant Anaerobic Bacteria in Common Pediatric Infections Gram positive cocci Peptostreptococcus, Finegoldia, Parvimonas, Anaerococcus, and Peptoniphilus spp. Gram positive, spore forming rods Clostridium spp. Gram positive, nonspore forming rods Cutibacterium acnes Some Actinomyces spp. Gram negative bacilli Bacteroides fragilis Prevotella, Porphyromonas, and Fusobacterium spp. 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 259 u Other Anaerobic Infections 1829 Anaerobic Bacteremia Anaerobic bacteremia is relatively rare in children, and the yield of routine anaerobic blood cultures in various settings and patient populations continues to be debated. There is wide practice varia tion on the routine collection of anaerobic blood culture bottles, and multiple studies have failed to consistently identify predictive risk factors for anaerobic bacteremia in children. B. fragilis bacteremia has been seen most frequently (albeit uncommonly) in two settings: early onset sepsis in premature infants and sepsis in those with com promised lower gastrointestinal tract mucosa (perforation, surgery, or chemotherapy induced mucositis). Fusobacterium spp. bacte remia is typically seen in the setting of Lemierre syndrome: septic thrombophlebitis of the internal jugular vein as a complication of pharyngitis. Myonecrosis (Gas Gangrene) C. perfringens is the major etiologic cause of myonecrosis, a |
7,399 | rapidly progressive anaerobic soft tissue infection. Gas gangrene usually affects muscles compromised by surgical or trauma sites that become contam inated with C. perfringens spores from soil or other foreign material. Infection progresses rapidly (within 24 hours) with swelling, edema, crepitus, and myonecrosis. Severe shock and multiorgan dysfunction are common. A clue to the diagnosis of gas gangrene is pain out of pro portion to the clinical appearance of the wound. Exudate from surgical specimens reveals gram positive bacilli but few leukocytes. Early and complete debridement with excision of necrotic tissue is key to control ling the infection. Repeated, frequent assessment of tissue viability in the operating room is required; however, the prognosis is poor, and morbidity and mortality are high. The role of adjunctive hyperbaric oxygen therapy is uncertain. Food Poisoning C. perfringens can also produce an enterotoxin that causes food poi soning. This intoxication results in the acute onset of watery diarrhea and crampy abdominal pain. Therapy is mainly supportive and con sists of rehydration and electrolyte replacement if necessary. The ill ness resolves spontaneously within 24 hours of onset, and thus specific etiologic diagnosis is rarely made unless a large outbreak is investigated by public health authorities. Frequent sources of infection include meat and other animal products served in group settings during which food is allowed to sit for hours at temperatures warm enough to promote growth of C. perfringens. DIAGNOSIS The diagnosis of anaerobic infection requires a high index of sus picion and the collection of appropriate and adequate specimens for anaerobic culture (Table 259.2). Culture specimens should be obtained in a manner that protects them from contamination with mucosal bacteria. Aspirates of infected sites, abscess material, and biopsy specimens are appropriate for anaerobic culturing. Specimens should be protected from atmospheric oxygen and transported to the laboratory immediately. Anaerobic transport medium increases the likelihood of recovery of obligate anaerobes. Gram staining is use ful, because even if the organisms do not grow in culture, they can be seen on the smear. Once growth has occurred, many clinically relevant anaerobes may now be identified by MALDI TOF MS. 16S ribosomal RNA (rRNA) gene sequencing at a reference laboratory can identify less common bacteria. Antimicrobial resistance among anaerobes has increased over time, and the susceptibility of anaerobes to certain antibiotics has become less predictable. A rapid and simple screening test for lactamase production and presumptive penicillin resistance can be performed on some anaerobic gram negative bacilli. More detailed susceptibility testing is usually only available at reference laboratories and may be recommended for isolates recovered from sterile body sites that are deemed clinically important and are known to have variable or unique susceptibilities. Because anaerobic bacteria are less routinely submitted for susceptibility testing, local antibiogram data are frequently limited and extrapolated from larger national case series. TREATMENT Treatment of anaerobic infections usually requires adequate drainage and appropriate antimicrobial therapy. Anaerobes can be generally lumped into groups of predicted susceptibility, but because most anaer obic infections are polymicrobial, the choice |
7,400 | of agents is frequently driven by the aerobic bacteria suspected or proven to be involved. The specific dose, frequency, and duration vary widely by the specific clini cal syndrome. ANAEROBIC GRAM NEGATIVE BACILLI Most B. fragilis produces a lactamase that hydrolyzes penicillins but is inhibited by most lactamase inhibitors (clavulanate, sulbactam, and tazobactam but not avibactam). They also produce a cephalosporinase that hydrolyzes most cephalosporins but not cephamycins. Neither of the enzymes hydrolyzes carbapenems. Hence, most isolates are sus ceptible to ampicillin sulbactam, amoxicillin clavulanate, piperacillin tazobactam, cefoxitin, and carbapenems (imipenem, meropenem, doripenem, and ertapenem). Notably, ceftazidime avibactam is the exception to the reliability of lactamase inhibitors and does not have reliable B. fragilis activity. Prevotella, Porphyromonas, and Fusobac terium spp. are all generally less resistant than Bacteroides. They less frequently produce a lactamase, and many remain susceptible to penicillin. Fusobacterium spp. are usually susceptible to cephalospo rins such as ceftriaxone, but Prevotella and Porphyromonas have more variable susceptibility. Metronidazole is reliably active against nearly all anaerobic gram negative bacilli. Clindamycin resistance in B. fragilis has increased over the years, and thus clindamycin is no longer recommended for empiric treatment, leading to the admonition against using clindamy cin for infections below the diaphragm. The other anaerobic gram negative bacilli are usually still susceptible to clindamycin. Because of increasing resistance, moxifloxacin is no longer recommended as first line therapy for infections involving anaerobic gram negative bacilli. ANAEROBIC GRAM POSITIVE ORGANISMS Most nonsporeforming, positive bacilli and some GPAC are resistant to metronidazole. Most are highly susceptible to penicillin but variably susceptible to clindamycin. Treatment of clostridial infections varies widely by the specific clinical syndrome and may or may not involve antibiotics andor specific antitoxins. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 259.2 Clues to the Presumptive Diagnosis of Anaerobic Infections Infection contiguous to or near a mucosal surface colonized with anaerobic bacteria (oropharynx, intestinal genitourinary tract) Severe tissue necrosis, abscesses, gangrene, or fasciitis Gas formation in tissues (crepitus on exam or gas visible on imaging) Failure to culture organisms using conventional aerobic microbiologic methods, despite the presence of visible organisms on Gram stain Toxin mediated syndromes: botulism, tetanus, gas gangrene, food poisoning, pseudomembranous colitis Suspicion of anaerobic infection is critical before specimens are sampled for culture to ensure optimal microbiologic techniques. 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. 1830 Part XV u Infectious Diseases The treatment of mycobacterial infection and disease can be challeng ing. Patients require therapy with multiple agents, the offending patho gens commonly exhibit complex drug resistance patterns, and patients often have underlying conditions that affect drug choice and monitor ing. Several of the drugs have not been well studied in children, and cur rent recommendations are extrapolated from the experience in adults. Single drug therapy of Mycobacterium tuberculosis and nontubercu lous mycobacteria is not recommended because of the high likelihood |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.