InternalMed_Harrison

InternalMed_Harrison. After crossing the epithelial layer of the small intestine, S. typhi and S. paratyphi, which cause enteric (typhoid) fever, are phagocytosed by macrophages. These salmonellae survive the antimicrobial environment of the macrophage by sensing environmental signals that trigger alterations in regulatory systems of the phagocytosed bacteria. For example, PhoP/PhoQ (the best-characterized regulatory system) triggers the expression of outer-membrane proteins and mediates modifications in lipopolysaccharide so that the altered bacterial surface can resist microbicidal activities and potentially alter host cell signaling. In addition, salmonellae encode a second type III secretion system that directly delivers bacterial proteins across the phagosome membrane into the macrophage cytoplasm. This secretion system functions to remodel the Salmonella-containing vacuole, promoting bacterial survival and replication.


InternalMed_Harrison

InternalMed_Harrison. Once phagocytosed, typhoidal salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow). Patients have relatively few or no signs and symptoms during this initial incubation stage. Signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages and epithelial cells in response to bacterial products that are recognized by innate immune receptors when a critical number of organisms have replicated. Over time, the development of hepatosplenomegaly is likely to be related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. typhi colonization. The recruitment of additional mononuclear cells and lymphocytes to Peyer’s patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis 1050 of the Peyer’s patches, which may


InternalMed_Harrison

InternalMed_Harrison. mononuclear cells and lymphocytes to Peyer’s patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis 1050 of the Peyer’s patches, which may be mediated by bacterial products that promote cell death as well as the inflammatory response. In contrast to enteric fever, which is characterized by an infiltration of mononuclear cells into the small-bowel mucosa, NTS gastroenteritis is characterized by massive polymorphonuclear leukocyte infiltration into both the largeand small-bowel mucosa. This response appears to depend on the induction of interleukin 8, a strong neutrophil chemotactic factor, which is secreted by intestinal cells as a result of Salmonella colonization and translocation of bacterial proteins into host cell cytoplasm. The degranulation and release of toxic substances by neutrophils may result in damage to the intestinal mucosa, causing the inflammatory diarrhea observed with nontyphoidal gastroenteritis. An


InternalMed_Harrison

InternalMed_Harrison. The degranulation and release of toxic substances by neutrophils may result in damage to the intestinal mucosa, causing the inflammatory diarrhea observed with nontyphoidal gastroenteritis. An additional important factor in the persistence of nontyphoidal salmonellae in the intestinal tract and the organisms’ capacity to compete with endogenous flora is the ability to utilize the sulfur-containing compound tetrathionate for metabolism in a microaerophilic environment. In the presence of intestinal inflammation, tetrathionate is generated from thiosulfate produced by epithelial cells through inflammatory cell production of reactive oxygen species.


InternalMed_Harrison

InternalMed_Harrison. Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi. The disease was initially called typhoid fever because of its clinical similarity to typhus. In the early 1800s, typhoid fever was clearly defined pathologically as a unique illness on the basis of its association with enlarged Peyer’s patches and mesenteric lymph nodes. In 1869, given the anatomic site of infection, the term enteric fever was proposed as an alternative designation to distinguish typhoid fever from typhus. However, to this day, the two designations are used interchangeably.


InternalMed_Harrison

InternalMed_Harrison. In contrast to other Salmonella serotypes, the etiologic agents of enteric fever—S. typhi and S. paratyphi serotypes A, B, and C—have no known hosts other than humans. Most commonly, food-borne or waterborne transmission results from fecal contamination by ill or asymptomatic chronic carriers. Sexual transmission between male partners has been described. Health care workers occasionally acquire enteric fever after exposure to infected patients or during processing of clinical specimens and cultures.


InternalMed_Harrison

InternalMed_Harrison. With improvements in food handling and water/sewage treatment, enteric fever has become rare in developed nations. Worldwide, however, there are an estimated 27 million cases of enteric fever, with 200,000–600,000 deaths annually. The annual incidence is highest (>100 cases/100,000 population) in south-central and Southeast Asia; medium (10–100 cases/100,000) in the rest of Asia, Africa, Latin America, and Oceania (excluding Australia and New Zealand); and low in other parts of the world (Fig. 190-1). A high incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water. In endemic regions, enteric fever is more common in urban than rural areas and among young children and adolescents than among other age groups. Risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access,


InternalMed_Harrison

InternalMed_Harrison. or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, and evidence of prior Helicobacter pylori infection (an association probably related to chronically reduced gastric acidity). It is estimated that there is one case of paratyphoid fever for every four cases of typhoid fever, but the incidence of infection associated with S. paratyphi A appears to be increasing, especially in India; this increase may be a result of vaccination for S. typhi.


InternalMed_Harrison

InternalMed_Harrison. Multidrug-resistant (MDR) strains of S. typhi emerged in the 1980s in China and Southeast Asia and have since disseminated widely. These strains contain plasmids encoding resistance to chloramphenicol, ampicillin, and trimethoprim—antibiotics long used to treat enteric fever. With the increased use of fluoroquinolones to treat MDR enteric fever in the 1990s, strains of S. typhi and S. paratyphi with decreased ciprofloxacin susceptibility (DCS; minimal inhibitory concentration [MIC], 0.125–0.5 μg/mL) or ciprofloxacin resistance (MIC, ≥1 μg/mL) have emerged on the Indian subcontinent, in southern Asia, and (most recently) in sub-Saharan Africa and have been associated with clinical treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic acid detects many but not all strains with reduced susceptibility to ciprofloxacin and is no longer recommended. Strains of S. typhi and S. paratyphi producing extended-spectrum β-lactamases have emerged


InternalMed_Harrison

InternalMed_Harrison. detects many but not all strains with reduced susceptibility to ciprofloxacin and is no longer recommended. Strains of S. typhi and S. paratyphi producing extended-spectrum β-lactamases have emerged recently, primarily in India and Nepal.


InternalMed_Harrison

InternalMed_Harrison. Approximately 300 cases of typhoid and 150 cases of paratyphoid fever are reported annually in the United States. Of 1902 cases of S. typhi–associated enteric fever reported to the Centers for Disease Control and Prevention in 1999–2006, 79% were associated with recent international travel, most commonly to India (47%), Pakistan (10%), Bangladesh (10%), Mexico (7%), and the Philippines (4%). Only 5% of travelers diagnosed with enteric fever had received S. typhi vaccine. Overall, 13% of S. typhi isolates in the United States were resistant to ampicillin, chloramphenicol, and trimethoprimsulfamethoxazole (TMP-SMX), and the proportion of DCS isolates increased from 19% in 1999 to 58% in 2006. Infection with DCS


InternalMed_Harrison

InternalMed_Harrison. S. typhi was associated with travel to the Indian subcontinent. Of the 25–30% of reported cases of enteric fever in the United States that are domestically acquired, the majority are sporadic, but outbreaks linked to contaminated food products and previously unrecognized chronic carriers continue to occur. Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal pain—are variable. While fever is documented at presentation in >75% of cases, abdominal pain is reported in only 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a person presents with fever and a history of recent travel to a developing country.


InternalMed_Harrison

InternalMed_Harrison. The incubation period for S. typhi averages 10–14 days but ranges from 5 to 21 days, depending on the inoculum size and the host’s health and immune status. The most prominent symptom is prolonged fever (38.8°–40.5°C; 101.8°–104.9°F), which can continue for up to 4 weeks if untreated. S. paratyphi A is thought to cause milder disease than S. typhi, with predominantly gastrointestinal symptoms. However, a prospective study of 669 consecutive cases of enteric fever in Kathmandu, Nepal, found that the infections caused by these organisms were clinically indistinguishable. In this series, symptoms reported on initial medical evaluation included headache (80%), chills (35–45%), cough (30%), sweating (20–25%), myalgias (20%), malaise (10%), and arthralgia (2–4%). Gastrointestinal manifestations included anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%) more commonly than constipation (13–16%). Physical findings included coated tongue (51–56%),


InternalMed_Harrison

InternalMed_Harrison. included anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%) more commonly than constipation (13–16%). Physical findings included coated tongue (51–56%), splenomegaly (5–6%), and abdominal tenderness (4–5%).


InternalMed_Harrison

InternalMed_Harrison. High (>100/100,000/year) Medium (10–100/100,000/year) Low (<10/100,000/year) FIGuRE 190-1 Annual incidence of typhoid fever per 100,000 population. (Adapted from JA Crump et al: The global burden of typhoid fever. Bull World Health Organ 82:346, 2004.) FIGuRE 190-2 “Rose spots,” the rash of enteric fever due to Salmonella typhi or Salmonella paratyphi. Early physical findings of enteric fever include rash (“rose spots”; 30%), hepatosplenomegaly (3–6%), epistaxis, and relative bradycardia at the peak of high fever (<50%). Rose spots (Fig. 190-2; see also Fig. 25e-9) make up a faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash is evident in ~30% of patients at the end of the first week and resolves without a trace after 2–5 days. Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.


InternalMed_Harrison

InternalMed_Harrison. The development of severe disease (which occurs in ~10–15% of patients) depends on host factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (10–20%) and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration (Fig. 190-3). Both complications are life-threatening and require immediate fluid resuscitation and surgical intervention, with broadened antibiotic coverage for polymicrobial peritonitis (Chap.


InternalMed_Harrison

InternalMed_Harrison. 159) and treatment of gastrointestinal hemorrhages, including bowel resection. Neurologic manifestations occur in 2–40% of patients and include meningitis, Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as “muttering delirium” or “coma vigil”), with picking at bedclothes or imaginary objects. Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis, glomerulonephritis, pyelonephritis and hemolytic-uremic syndrome, severe pneumonia, arthritis, osteomyelitis, endophthalmitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2–3 weeks of fever resolution and in association with the same strain type and susceptibility profile. Up to 10% of untreated patients with typhoid fever excrete


InternalMed_Harrison

InternalMed_Harrison. Up to 10% of untreated patients with typhoid fever excrete S. typhi in the feces for up to 3 months, and 1–4% develop chronic FIGuRE 190-3 Typical ileal perforation associated with Salmonella typhi infection. (From JM Saxe, R Cropsey: Is operative management effective in treatment of perforated typhoid? Am J Surg 189:342, 2005.) asymptomatic carriage, shedding S. typhi in either urine or stool for >1 year. Chronic carriage is more common among women, infants, and persons who have biliary abnormalities or concurrent bladder infection with Schistosoma haematobium. The anatomic abnormalities associated with the latter conditions presumably allow prolonged colonization.


InternalMed_Harrison

InternalMed_Harrison. Because the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be considered in any febrile traveler returning from a developing region, especially the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 149). Other than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among children, during the first 10 days of illness, and in cases complicated by intestinal perforation or secondary infection. Other nonspecific laboratory findings include moderately elevated values in liver function tests and muscle enzyme levels. The definitive diagnosis of enteric fever requires the isolation of


InternalMed_Harrison

InternalMed_Harrison. The definitive diagnosis of enteric fever requires the isolation of S. typhi or S. paratyphi from blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The sensitivity of blood culture is only 40–80%, probably because of high rates of antibiotic use in endemic areas and the small number of S. typhi organisms (i.e., <15/mL) typically present in the blood. Because almost all S. typhi organisms in blood are associated with the mononuclear cell/platelet fraction, centrifugation of blood and culture of the buffy coat can substantially reduce the time to isolation of the organism but do not increase sensitivity.


InternalMed_Harrison

InternalMed_Harrison. Bone marrow culture is 55–90% sensitive, and, unlike that of blood culture, its yield is not reduced by up to 5 days of prior antibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive duodenal string test) can be positive despite a negative bone marrow culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield is >90%. Stool cultures, although negative in 60–70% of cases during the first week, can become positive during the third week of infection in untreated patients.


InternalMed_Harrison

InternalMed_Harrison. Serologic tests, including the classic Widal test for “febrile agglutinins,” and rapid tests to detect antibodies to outer- membrane proteins or O:9 antigen are available for detection of S. typhi in developing countries but have lower positive predictive values than blood culture. More sensitive antigen and nucleic acid amplification tests have been developed to detect S. typhi and 1052 S. paratyphi in blood but are not yet commercially available and remain impractical in many areas where enteric fever is endemic.


InternalMed_Harrison

InternalMed_Harrison. Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and results in a case-fatality rate of <1%. The initial choice of antibiotics depends on the susceptibility of the S. typhi and S. paratyphi strains in the area of residence or travel (Table 190-1). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effective class of agents, with cure rates of ~98% and relapse and fecal carriage rates of <2%. Experience is most extensive with ciprofloxacin. Short-course ofloxacin therapy is similarly successful against infection caused by quinolone-susceptible strains. However, the increased incidence of DCS S. typhi in Asia, which is probably related to the widespread availability of fluoroquinolones over the counter, is now limiting the use of this drug class for empirical therapy. Patients infected with DCS S. typhi strains should be treated with ceftriaxone, azithromycin, or high-dose ciprofloxacin. A 7-day course of


InternalMed_Harrison

InternalMed_Harrison. limiting the use of this drug class for empirical therapy. Patients infected with DCS S. typhi strains should be treated with ceftriaxone, azithromycin, or high-dose ciprofloxacin. A 7-day course of high-dose fluoroquinolone therapy for DCS enteric fever has been associated with delayed resolution of fever and high rates of fecal carriage during convalescence. Thus, for DCS strains, a 10to 14-day course of high-dose ciprofloxacin is preferred.


InternalMed_Harrison

InternalMed_Harrison. Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever, including that caused by DCS and fluoroquinolone-resistant strains. These agents clear fever in ~1 week, with failure rates of ~5–10%, fecal carriage rates of <3%, and relapse rates of 3–6%. Oral azithromycin results in defervescence in 4–6 days, with rates of relapse and convalescent stool carriage of <3%. Against DCS strains, azithromycin is associated with lower rates of treatment failure and shorter durations of hospitalization than are fluoroquinolones. Despite efficient in vitro killing of Salmonella, first-and second-generation cephalosporins as well as aminoglycosides are ineffective in the treatment of clinical infections. aOr another third-generation cephalosporin (e.g., cefotaxime, 2 g q8h IV; or cefixime, 400 mg bid PO). bOr 1 g on day 1 followed by 500 mg/d PO for 6 days. cOr ofloxacin, 400 mg bid PO for 2–5 days.


InternalMed_Harrison

InternalMed_Harrison. aOr another third-generation cephalosporin (e.g., cefotaxime, 2 g q8h IV; or cefixime, 400 mg bid PO). bOr 1 g on day 1 followed by 500 mg/d PO for 6 days. cOr ofloxacin, 400 mg bid PO for 2–5 days. Most patients with uncomplicated enteric fever can be managed at home with oral antibiotics and antipyretics. Patients with persistent vomiting, diarrhea, and/or abdominal distension should be hospitalized and given supportive therapy as well as a parenteral third-generation cephalosporin or fluoroquinolone, depending on the susceptibility profile. Therapy should be administered for at least 10 days or for 5 days after fever resolution.


InternalMed_Harrison

InternalMed_Harrison. In a randomized, prospective, double-blind study of criti cally ill patients with enteric fever (i.e., those with shock and obtundation) in Indonesia in the early 1980s, the administration of dexamethasone (an initial dose of 3 mg/kg followed by eight doses of 1 mg/kg every 6 h) with chloramphenicol was associated with a substantially lower mortality rate than was treatment with chloramphenicol alone (10% vs 55%). Although this study has not been repeated in the “post-chloramphenicol era,” severe enteric fever remains one of the few indications for glucocorticoid treatment of an acute bacterial infection.


InternalMed_Harrison

InternalMed_Harrison. The 1–5% of patients who develop chronic carriage of Salmonella can be treated for 4–6 weeks with an appropriate oral antibiotic. Treatment with oral amoxicillin, TMP-SMX, ciprofloxacin, or norfloxacin is ~80% effective in eradicating chronic carriage of susceptible organisms. However, in cases of anatomic abnormality (e.g., biliary or kidney stones), eradication often requires both antibiotic therapy and surgical correction. Theoretically, it is possible to eliminate the salmonellae that cause enteric fever because they survive only in human hosts and are spread by contaminated food and water. However, given the high prevalence of the disease in developing countries that lack adequate sewage disposal and water treatment, this goal is currently unrealistic. Thus, travelers to developing countries should be advised to monitor their food and water intake carefully and to strongly consider immunization against S. typhi.


InternalMed_Harrison

InternalMed_Harrison. Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S. typhi vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in a single dose, with a booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A and B vaccine is no longer licensed, largely because of significant side effects, especially fever. An acetone-killed whole-cell vaccine is available only for use by the U.S. military. The minimal age for vaccination is 6 years for Ty21a and 2 years for Vi CPS. In a recent meta-analysis of vaccines for preventing typhoid fever in populations in endemic areas, the cumulative efficacy was 48% for Ty21a at 2.5–3.5 years and 55% for Vi CPS at 3 years. Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy rates may be substantially lower than those for local populations in


InternalMed_Harrison

InternalMed_Harrison. and 55% for Vi CPS at 3 years. Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy rates may be substantially lower than those for local populations in endemic areas. Currently, there is no licensed vaccine for paratyphoid fever.


InternalMed_Harrison

InternalMed_Harrison. Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell–independent properties. In the more recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2to 4-year-olds, two injections of Vi-rEPA induced higher T cell responses and higher levels of serum IgG antibody to Vi than did Vi CPS in 5to 14-year-olds. In a two-dose trial in 2to 5-year-old children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 89% efficacy at 46 months and was very well tolerated. This vaccine is not yet commercially available in the United States. Efforts to improve the immunogenicity and reduce the number of doses of live attenuated oral vaccines are ongoing.


InternalMed_Harrison

InternalMed_Harrison. Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk of exposure to S. typhi, especially those who are traveling to southern Asia and other developing regions of Asia, Africa, the Caribbean, and Central and South America and who will be exposed to potentially contaminated food and drink. Typhoid vaccine should be considered even for persons planning <2 weeks of travel to high-risk areas. In addition, laboratory workers who deal with S. typhi and household contacts of known S. typhi carriers should be vaccinated. Because the protective efficacy of vaccine can be overcome by the high inocula that are commonly encountered in food-borne exposures, immunization is an adjunct and not a substitute for the avoidance of high-risk foods and beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or for the management of persons who may have been exposed in a common-source


InternalMed_Harrison

InternalMed_Harrison. avoidance of high-risk foods and beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or for the management of persons who may have been exposed in a common-source outbreak.


InternalMed_Harrison

InternalMed_Harrison. Enteric fever is a notifiable disease in the United States. Individual health departments have their own guidelines for allowing ill or colonized food handlers or health care workers to return to their jobs. The reporting system enables public health departments to identify potential source patients and to treat chronic carriers in order to prevent further outbreaks. In addition, because 1–4% of patients with S. typhi infection become chronic carriers, it is important to monitor patients (especially child-care providers and food handlers) for chronic carriage and to treat this condition if indicated.


InternalMed_Harrison

InternalMed_Harrison. In the United States, NTS causes ~12 million illnesses annually, and the incidence has remained relatively unchanged during the past two decades. In 2011, the incidence of NTS infection in this country was 16.5/100,000 persons—the highest rate among the 10 food-borne enteric pathogens under active surveillance. Five serotypes accounted for more than half of U.S. infections during the period 1996–2006: typhimurium (23%), enteritidis (16%), newport (10%), heidelberg (6%), and javiana (5%).


InternalMed_Harrison

InternalMed_Harrison. The incidence of nontyphoidal salmonellosis is highest during the rainy season in tropical climates and during the warmer months in temperate climates—a pattern coinciding with the peak in food-borne outbreaks. Rates of morbidity and mortality associated with NTS are highest among the elderly, infants, and immunocompromised individuals, including those with hemoglobinopathies, HIV infection, or infections that cause blockade of the reticuloendothelial system (e.g., bartonellosis, malaria, schistosomiasis, histoplasmosis). Unlike S. typhi and S. paratyphi, whose only reservoir is humans, NTS can be acquired from multiple animal reservoirs. Transmission is most commonly associated with food products of animal origin (especially eggs, poultry, undercooked ground meat, and dairy products), fresh produce contaminated with animal waste, and contact with animals or their environments.


InternalMed_Harrison

InternalMed_Harrison. S. enteritidis infection associated with chicken eggs emerged as a major cause of food-borne disease during the 1980s and 1990s. S. enteritidis infection of the ovaries and upper oviduct tissue of hens results in contamination of egg contents before shell deposition. Infection is spread to egg-laying hens from breeding flocks and through contact with rodents and manure. The percentage of Salmonella outbreaks attributed to eggs has declined significantly in the United States, from 33% during 1998–1999 to 15% during 2006–2008. This decrease probably reflects the impact of the coordinated public health response to


InternalMed_Harrison

InternalMed_Harrison. S. enteritidis infection attributed to eggs, including improved on-farm control measures, refrigeration, and education of consumers and food-service workers. Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products. Despite these control efforts, outbreaks of S. enteritidis infection associated with shell eggs continue to occur. In 2010, a national outbreak of S. enteritidis infection resulted in more than 1900 reported illnesses and the recall of 500 million eggs.


InternalMed_Harrison

InternalMed_Harrison. Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries. Manufactured foods to which recent Salmonella outbreaks have been traced include peanut butter; milk products, including infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods. Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, cantaloupe, mangoes, papayas, and tomatoes; these items become contaminated by manure or water at a single site and then are widely 1053 distributed.


InternalMed_Harrison

InternalMed_Harrison. An estimated 6% of sporadic Salmonella infections in the United States are attributed to contact with reptiles or amphibians, especially iguanas, snakes, turtles, and lizards. Reptile-associated Salmonella infection more commonly leads to hospitalization and more frequently involves children, including infants, than do other Salmonella infections. Other pets, including African hedgehogs, birds, rodents, baby chicks, ducklings, dogs, and cats, are also potential sources of NTS.


InternalMed_Harrison

InternalMed_Harrison. Increasing antibiotic resistance in NTS species is a global prob lem and has been linked to the widespread use of antimicrobial agents in food animals and especially in animal feed. In the early 1990s, S. typhimurium definitive phage type 104 (DT104), characterized by resistance to at least five antibiotics (ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracyclines; R-type ACSSuT), emerged worldwide. In 2010, resistance to at least ACSSuT was reported in 4.3% of NTS isolates, including 18.6% of S. typhimurium isolates. Acquisition is associated with exposure to ill farm animals and to various meat products, including uncooked or undercooked ground beef. Although probably no more virulent than susceptible S. typhimurium strains, DT104 strains are associated with an increased risk of bloodstream infection and hospitalization. DCS and trimethoprim-resistant DT104 strains are emerging, especially in the United Kingdom.


InternalMed_Harrison

InternalMed_Harrison. Because of increased resistance to conventional antibiotics such as ampicillin and TMP-SMX, extended-spectrum cephalosporins and fluoroquinolones have emerged as the agents of choice for the treatment of MDR NTS infections. In 2010, 2.8% of all NTS strains were resistant to ceftriaxone. Most ceftriaxone-resistant isolates were from children <18 years of age, in whom ceftriaxone is the antibiotic of choice for treatment of invasive NTS infection. These strains contained plasmid-encoded AmpC β-lactamases that were probably acquired by horizontal genetic transfer from Escherichia coli strains in food-producing animals—an event linked to the widespread use of the veterinary cephalosporin ceftiofur.


InternalMed_Harrison

InternalMed_Harrison. Over the last decade, strains of DCS NTS (MIC, 0.125–1 μg/mL) have emerged and have been associated with delayed response and treatment failure. In 2009, 2.4% of NTS isolates in the United States were DCS or resistant to ciprofloxacin. These strains have diverse resistance mechanisms, including single and multiple mutations in the DNA gyrase genes gyrA and gyrB and plasmid-encoded quinolone resistance determinants that may not be reliably detected by nalidixic acid susceptibility testing. In 2012, the U.S. Clinical Laboratory Standards Institute proposed a lower ciprofloxacin susceptibility breakpoint (≥0.06 μg/mL) for all Salmonella species to address this issue. Currently, because commercial test systems do not contain ciprofloxacin concentrations low enough to allow use of these breakpoints, laboratories need to determine the ciprofloxacin MIC by Etest or another alternative method.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL MANIFESTATIONS Gastroenteritis Infection with NTS most often results in gastroenteritis indistinguishable from that caused by other enteric pathogens. Nausea, vomiting, and diarrhea occur 6–48 h after the ingestion of contaminated food or water. Patients often experience abdominal cramping and fever (38–39°C; 100.5–102.2°F). Diarrheal stools are usually loose, nonbloody, and of moderate volume. However, large-volume watery stools, bloody stools, or symptoms of dysentery may occur. Rarely, NTS causes pseudoappendicitis or an illness that mimics inflammatory bowel disease.


InternalMed_Harrison

InternalMed_Harrison. Gastroenteritis caused by NTS is usually self-limited. Diarrhea resolves within 3–7 days and fever within 72 h. Stool cultures remain positive for 4–5 weeks after infection and—in rare cases of chronic carriage (<1%)—for >1 year. Antibiotic treatment usually is not recommended and may prolong fecal carriage. Neonates, the elderly, and immunosuppressed patients (e.g., transplant recipients, HIV-infected persons) with NTS gastroenteritis are especially susceptible to dehydration and dissemination and may require hospitalization and antibiotic therapy. Acute NTS gastroenteritis was associated with a threefold increased risk of dyspepsia and irritable bowel syndrome at 1 year in a study from Spain.


InternalMed_Harrison

InternalMed_Harrison. 1054 Bacteremia and Endovascular Infections Up to 8% of patients with NTS gastroenteritis develop bacteremia; of these, 5–10% develop localized infections. Bacteremia and metastatic infection are most common with Salmonella choleraesuis and Salmonella dublin and among infants, the elderly, and immunocompromised patients, especially those with HIV infection. NTS endovascular infection should be suspected in high-grade or persistent bacteremia, especially with preexisting valvular heart disease, atherosclerotic vascular disease, prosthetic vascular graft, or aortic aneurysm. Arteritis should be suspected in elderly patients with prolonged fever and back, chest, or abdominal pain developing after an episode of gastroenteritis. Endocarditis and arteritis are rare (<1% of cases) but are associated with potentially fatal complications, including valve perforation, endomyocardial abscess, infected mural thrombus, pericarditis, mycotic aneurysms, aneurysm rupture, aortoenteric fistula, and


InternalMed_Harrison

InternalMed_Harrison. with potentially fatal complications, including valve perforation, endomyocardial abscess, infected mural thrombus, pericarditis, mycotic aneurysms, aneurysm rupture, aortoenteric fistula, and vertebral osteomyelitis. In some areas of sub-Saharan Africa, NTS may be among the most common causes—or even the most common cause—of bacteremia in children. NTS bacteremia among these children is not associated with diarrhea and has been associated with nutritional status and HIV infection.


InternalMed_Harrison

InternalMed_Harrison. Localized Infections • intraabdominal infections Intraabdominal infections due to NTS are rare and usually manifest as hepatic or splenic abscesses or as cholecystitis. Risk factors include hepatobiliary anatomic abnormalities (e.g., gallstones), abdominal malignancy, and sickle cell disease (especially with splenic abscesses). Eradication of the infection often requires surgical correction of abnormalities and percutaneous drainage of abscesses. central nervoUs system infections NTS meningitis most commonly develops in infants 1–4 months of age. It often results in severe sequelae (including seizures, hydrocephalus, brain infarction, and mental retardation), with death in up to 60% of cases. Other rare central nervous system infections include ventriculitis, subdural empyema, and brain abscesses.


InternalMed_Harrison

InternalMed_Harrison. pUlmonary infections NTS pulmonary infections usually present as lobar pneumonia, and complications include lung abscess, empyema, and bronchopleural fistula formation. The majority of cases occur in patients with lung cancer, structural lung disease, sickle cell disease, or glucocorticoid use. Urinary and genital tract infections Urinary tract infections caused by NTS present as either cystitis or pyelonephritis. Risk factors include malignancy, urolithiasis, structural abnormalities, HIV infection, and renal transplantation. NTS genital infections are rare and include ovarian and testicular abscesses, prostatitis, and epididymitis. Like other focal infections, both genital and urinary tract infections can be complicated by abscess formation.


InternalMed_Harrison

InternalMed_Harrison. bone, joint, and soft tissUe infections Salmonella osteomyelitis most commonly affects the femur, tibia, humerus, or lumbar vertebrae and is most often seen in association with sickle cell disease, hemoglobinopathies, or preexisting bone disease (e.g., fractures). Prolonged antibiotic treatment is recommended to decrease the risk of relapse and chronic osteomyelitis. Septic arthritis occurs in the same patient population as osteomyelitis and usually involves the knee, hip, or shoulder joints. Reactive arthritis can follow NTS gastroenteritis and is seen most frequently in persons with the HLA-B27 histocompatibility antigen. NTS rarely can cause soft tissue infections, usually at sites of local trauma in immunosuppressed patients.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of NTS infection is based on isolation of the organism from freshly passed stool or from blood or another ordinarily sterile body fluid. All salmonellae isolated in clinical laboratories should be sent to local public health departments for serotyping. Blood cultures should be done whenever a patient has prolonged or recurrent fever. Endovascular infection should be suspected if there is high-grade bacteremia (>50% of three or more positive blood cultures). Echocardiography, computed tomography (CT), and indium-labeled white cell scanning are used to identify localized infection. When another localized infection is suspected, joint fluid, abscess drainage, or cerebrospinal fluid should be cultured, as clinically indicated.


InternalMed_Harrison

InternalMed_Harrison. Antibiotics should not be used routinely to treat uncomplicated NTS gastroenteritis. The symptoms are usually self-limited, and the duration of fever and diarrhea is not significantly decreased by antibiotic therapy. In addition, antibiotic treatment has been associated with increased rates of relapse, prolonged gastrointestinal carriage, and adverse drug reactions. Dehydration secondary to diarrhea should be treated with fluid and electrolyte replacement.


InternalMed_Harrison

InternalMed_Harrison. Preemptive antibiotic treatment (Table 190-2) should be considered for patients at increased risk for invasive NTS infection, including neonates (probably up to 3 months of age); persons >50 years of age with suspected atherosclerosis; and patients with immunosuppression, cardiac valvular or endovascular abnormalities, or significant joint disease. Treatment should consist of an oral or IV antibiotic administered for 48–72 h or until the patient becomes afebrile. Immunocompromised persons may require up to 7–14 days of therapy. The <1% of persons who develop chronic carriage of NTS should receive a prolonged antibiotic course, as described above for chronic carriage of S. typhi.


InternalMed_Harrison

InternalMed_Harrison. Because of the increasing prevalence of antibiotic resistance, empirical therapy for life-threatening NTS bacteremia or focal NTS infection should include a third-generation cephalosporin or a fluoroquinolone (Table 190-2). If the bacteremia is low-grade (<50% of positive blood cultures), the patient should be treated for 7–14 days. Patients with HIV/AIDS and NTS bacteremia should receive 1–2 weeks of IV antibiotic therapy followed by 4 weeks of oral therapy with a aConsider for neonates; persons >50 years of age with possible atherosclerotic vascular disease; and patients with immunosuppression, endovascular graft, or joint prosthesis. bOr ofloxacin, 400 mg bid (PO). cConsider on an individualized basis for patients with severe diarrhea and high fever who require hospitalization. dOr cefotaxime, 2 g q8h (IV).


InternalMed_Harrison

InternalMed_Harrison. fluoroquinolone. Patients whose infections relapse after this regimen should receive long-term suppressive therapy with a fluoroquinolone or TMP-SMX, as indicated by bacterial sensitivities.


InternalMed_Harrison

InternalMed_Harrison. If the patient has endocarditis or arteritis, treatment for 6 weeks with an IV β-lactam antibiotic (such as ceftriaxone or ampicillin) is indicated. IV ciprofloxacin followed by prolonged oral therapy is an option, but published experience is limited. Early surgical resection of infected aneurysms or other infected endovascular sites is recommended. Patients with infected prosthetic vascular grafts that cannot be resected have been maintained successfully on chronic suppressive oral therapy. For extraintestinal nonvascular infections, a 2to 4-week course of antibiotic therapy (depending on the infection site) is usually recommended. In chronic osteomyelitis, abscess, or urinary or hepatobiliary infection associated with anatomic abnormalities, surgical resection or drainage may be required in addition to prolonged antibiotic therapy for eradication of infection.


InternalMed_Harrison

InternalMed_Harrison. Despite widespread efforts to prevent or reduce bacterial contamination of animal-derived food products and to improve food-safety education and training, recent declines in the incidence of NTS in the United States have been modest compared with those of other food-borne pathogens. This observation probably reflects the complex epidemiology of NTS. Identifying effective risk-reduction strategies requires monitoring of every step of food production, from handling of raw animal or plant products to preparation of finished foods. Contaminated food can be made safe for consumption by pasteurization, irradiation, or proper cooking. All cases of NTS infection should be reported to local public health departments because tracking and monitoring of these cases can identify the source(s) of infection and help authorities anticipate large outbreaks. Lastly, the prudent use of antimicrobial agents in both humans and animals is needed to limit the emergence of MDR Salmonella.


InternalMed_Harrison

InternalMed_Harrison. shigellosis Philippe J. Sansonetti, Jean Bergounioux The discovery of Shigella as the etiologic agent of dysentery—a clinical syndrome of fever, intestinal cramps, and frequent passage of small, bloody, mucopurulent stools—is attributed to the Japanese microbi-ologist Kiyoshi Shiga, who isolated the Shiga bacillus (now known as 191 Shigella dysenteriae type 1) from patients’ stools in 1897 during a large and devastating dysentery epidemic. Shigella cannot be distinguished from Escherichia coli by DNA hybridization and remains a separate species only on historical and clinical grounds. Shigella is a non-spore-forming, gram-negative bacterium that, unlike


InternalMed_Harrison

InternalMed_Harrison. E. coli, is nonmotile and does not produce gas from sugars, decarboxylate lysine, or hydrolyze arginine. Some serovars produce indole, and occasional strains utilize sodium acetate. Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei (serogroups A, B, C, and D, respectively) can be differentiated on the basis of biochemical and serologic characteristics. Genome sequencing of E. coli K12, S. flexneri 2a, S. sonnei, S. dysenteriae type 1, and S. boydii has revealed that these species have ~93% of genes in common. The three major genomic “signatures” of Shigella are (1) a 215-kb virulence plasmid that carries most of the genes required for pathogenicity (particularly invasive capacity); (2) the lack or alteration of genetic sequences encoding products (e.g., lysine decarboxylase) that, if expressed, would attenuate pathogenicity; and (3) in S. dysenteriae type 1, the presence of genes 1055 encoding Shiga toxin, a potent cytotoxin.


InternalMed_Harrison

InternalMed_Harrison. The human intestinal tract represents the major reservoir of Shigella, which is also found (albeit rarely) in the higher pri mates. Because excretion of shigellae is greatest in the acute phase of disease, the bacteria are transmitted most efficiently by the fecal-oral route via hand carriage; however, some outbreaks reflect foodborne or waterborne transmission. In impoverished areas, Shigella can be transmitted by flies. The high-level infectivity of Shigella is reflected by the very small inoculum required for experimental infection of volunteers (100 colony-forming units [CFU]), by the very high attack rates during outbreaks in day-care centers (33–73%), and by the high rates of secondary cases among family members of sick children (26–33%). Shigellosis can also be transmitted sexually.


InternalMed_Harrison

InternalMed_Harrison. Throughout history, Shigella epidemics have often occurred in settings of human crowding under conditions of poor hygiene—e.g., among soldiers in campaigning armies, inhabitants of besieged cities, groups on pilgrimages, and refugees in camps. Epidemics follow a cyclical pattern in areas such as the Indian subcontinent and sub-Saharan Africa. These devastating epidemics, which are most often caused by S. dysenteriae type 1, are characterized by high attack and mortality rates. In Bangladesh, for instance, an epidemic caused by S. dysenteriae type 1 was associated with a 42% increase in mortality rate among children 1–4 years of age. Apart from these epidemics, shigellosis is mostly an endemic disease, with 99% of cases occurring in the developing world and the highest prevalences in the most impoverished areas, where personal and general hygiene is below standard. S. flexneri isolates predominate in the least developed areas, whereas


InternalMed_Harrison

InternalMed_Harrison. S. flexneri isolates predominate in the least developed areas, whereas S. sonnei is more prevalent in economically emerging countries and in the industrialized world.


InternalMed_Harrison

InternalMed_Harrison. Prevalence in the Developing World In a review published under the auspices of the World Health Organization (WHO), the total annual number of cases in 1966–1997 was estimated at 165 million, and 69% of these cases occurred in children <5 years of age. In this review, the annual number of deaths was calculated to range between 500,000 and 1.1 million. More recent data (2000–2004) from six Asian countries indicate that, even though the incidence of shigellosis remains stable, mortality rates associated with this disease may have decreased significantly, possibly as a result of improved nutritional status. However, extensive and essentially uncontrolled use of antibiotics, which may also account for declining mortality rates, has increased the rate of emergence of multidrug-resistant Shigella strains. A 2013 prospective matched case-control study of children <5 years of age emphasizes the importance of Shigella in the burden and etiology of diarrheal diseases in developing countries.


InternalMed_Harrison

InternalMed_Harrison. strains. A 2013 prospective matched case-control study of children <5 years of age emphasizes the importance of Shigella in the burden and etiology of diarrheal diseases in developing countries. Shigella is one of the top four pathogens associated with moderate to severe diarrhea and is now ranked first among children 12–59 months of age. These moderate to severe cases account for an 8.5-fold increase in mortality incidence over the average diarrheal disease–related mortality. The study’s authors conclude that Shigella remains a major pathogen to be targeted by health care programs.


InternalMed_Harrison

InternalMed_Harrison. An often-overlooked complication of shigellosis is the shortand long-term impairment of the nutritional status of infected children in endemic areas. Combined with anorexia, the exudative enteropathy resulting from mucosal abrasions contributes to rapid deterioration of the patient’s nutritional status. Shigellosis is thus a major contributor to stunted growth among children in developing countries. Peaking in incidence in the pediatric population, endemic shigellosis is rare among young and middle-aged adults, probably because of naturally acquired immunity. Incidence then increases again in the elderly population.


InternalMed_Harrison

InternalMed_Harrison. Prevalence in the Industrialized World In pediatric populations, local outbreaks occur when proper and adapted hygiene policies are not implemented in group facilities like day-care centers and institutions for the mentally retarded. In adults, as in children, sporadic cases occur among travelers returning from endemic areas, and rare outbreaks of varying size can follow waterborne or food-borne infections.


InternalMed_Harrison

InternalMed_Harrison. 1056 PATHOGENESIS AND PATHOLOGY 28S ribosomal RNA. This process leads to inhibition of binding of the Shigella infection occurs essentially through oral contamination via amino-acyl-tRNA to the 60S ribosomal subunit and thus to a general direct fecal-oral transmission, the organism being poorly adapted to shutoff of cell protein biosynthesis. Shiga toxins are translocated from survive in the environment. Resistance to low-pH conditions allows the bowel into the circulation. After binding of the toxins to target cells shigellae to survive passage through the gastric barrier, an ability that in the kidney, pathophysiologic alterations may result in hemolytic-may explain in part why a small inoculum (as few as 100 CFU) is suf-uremic syndrome (HUS; see below). ficient to cause infection. The watery diarrhea that usually precedes the dysenteric syndrome CLINICAL MANIFESTATIONS is attributable to active secretion and abnormal water reabsorption—a The presentation and severity of shigellosis


InternalMed_Harrison

InternalMed_Harrison. diarrhea that usually precedes the dysenteric syndrome CLINICAL MANIFESTATIONS is attributable to active secretion and abnormal water reabsorption—a The presentation and severity of shigellosis depend to some extent secretory effect at the jejunal level described in experimentally infected on the infecting serotype but even more on the age and the immuno rhesus monkeys. This initial purge is probably due to the combined logic and nutritional status of the host. Poverty and poor standards of action of an enterotoxin (ShET-1) and mucosal inflammation. The hygiene are strongly related to the number and severity of diarrheal dysenteric syndrome, manifested by bloody and mucopurulent stools, episodes, especially in children <5 years old who have been weaned. reflects invasion of the mucosa. Shigellosis typically evolves through four phases: incubation, watery


InternalMed_Harrison

InternalMed_Harrison. The pathogenesis of Shigella is essentially determined by a large diarrhea, dysentery, and the postinfectious phase. The incubation virulence plasmid of 214 kb comprising ~100 genes, of which 25 period usually lasts 1–4 days but may be as long as 8 days. Typical iniencode a type III secretion system that inserts into the mem-tial manifestations are transient fever, limited watery diarrhea, malaise, brane of the host cell to allow effectors to transit from the bacterial and anorexia. Signs and symptoms may range from mild abdominal cytoplasm to the host cell cytoplasm (Fig. 191-1). Bacteria are thereby discomfort to severe cramps, diarrhea, fever, vomiting, and tenesmus. able to invade intestinal epithelial cells by inducing their own uptake The manifestations are usually exacerbated in children, with tempera-after the initial crossing of the epithelial barrier through M cells (the tures up to 40°–41°C (104.0°–105.8°F) and more severe anorexia and specialized translocating epithelial


InternalMed_Harrison

InternalMed_Harrison. with tempera-after the initial crossing of the epithelial barrier through M cells (the tures up to 40°–41°C (104.0°–105.8°F) and more severe anorexia and specialized translocating epithelial cells in the follicle-associated epi-watery diarrhea. This initial phase may represent the only clinical manithelium that covers mucosal lymphoid nodules). The organisms festation of shigellosis, especially in developed countries. Otherwise, induce apoptosis of subepithelial resident macrophages. Once inside dysentery follows within hours or days and is characterized by uninthe cytoplasm of intestinal epithelial cells, Shigella effectors trigger the terrupted excretion of small volumes of bloody mucopurulent stools cytoskeletal rearrangements necessary to direct uptake of the organism with increased tenesmus and abdominal cramps. At this stage, Shigella into the epithelial cell. The Shigella-containing vacuole is then quickly produces acute colitis involving mainly the distal colon and the rectum.


InternalMed_Harrison

InternalMed_Harrison. and abdominal cramps. At this stage, Shigella into the epithelial cell. The Shigella-containing vacuole is then quickly produces acute colitis involving mainly the distal colon and the rectum. lysed, releasing bacteria into the cytosol. Unlike most diarrheal syndromes, dysenteric syndromes rarely present Intracellular shigellae next use cytoskeletal components to propel with dehydration as a major feature. Endoscopy shows an edematous themselves inside the infected cell; when the moving organism and the and hemorrhagic mucosa, with ulcerations and possibly overlying host cell membrane come into contact, cellular protrusions form and exudates resembling pseudomembranes. The extent of the lesions corare engulfed by neighboring cells. This series of events permits bacte-relates with the number and frequency of stools and with the degree of rial cell-to-cell spread. protein loss by exudative mechanisms. Most episodes are self-limited Cytokines released by a growing number of infected


InternalMed_Harrison

InternalMed_Harrison. number and frequency of stools and with the degree of rial cell-to-cell spread. protein loss by exudative mechanisms. Most episodes are self-limited Cytokines released by a growing number of infected intestinal epi-and resolve without treatment in 1 week. With appropriate treatment, thelial cells attract increased numbers of immune cells (particularly recovery takes place within a few days to a week, with no sequelae. polymorphonuclear leukocytes [PMNs]) to the infected site, thus Acute life-threatening complications are seen most often in chilfurther destabilizing the epithelial barrier, exacerbating inflammation, dren <5 years of age (particularly those who are malnourished) and leading to the acute colitis that characterizes shigellosis. Evidence and in elderly patients. Risk factors for death in a clinically severe indicates that some type III secretion system–injected effectors can case include nonbloody diarrhea, moderate to severe dehydration, control the extent of


InternalMed_Harrison

InternalMed_Harrison. factors for death in a clinically severe indicates that some type III secretion system–injected effectors can case include nonbloody diarrhea, moderate to severe dehydration, control the extent of inflammation, thus facilitating bacterial survival. bacteremia, absence of fever, abdominal tenderness, and rectal pro-Shiga toxin produced by S. dysenteriae type 1 increases disease lapse. Major complications are predominantly intestinal (e.g., toxic severity. This toxin belongs to a group of A1-B5 protein toxins whose megacolon, intestinal perforations, rectal prolapse) or metabolic B subunit binds to the receptor globotriaosylceramide on the target (e.g., hypoglycemia, hyponatremia, dehydration). Bacteremia is rare cell surface and whose catalytic A subunit is internalized by receptor-and is reported most frequently in severely malnourished and HIV-mediated endocytosis and interacts with the subcellular machinery to infected patients. Alterations of consciousness, including seizures,


InternalMed_Harrison

InternalMed_Harrison. is reported most frequently in severely malnourished and HIV-mediated endocytosis and interacts with the subcellular machinery to infected patients. Alterations of consciousness, including seizures, inhibit protein synthesis by expressing RNA N-glycosidase activity on delirium, and coma, may occur, especially in children <5 years old, and are associated with a poor prognosis; fever and severe metabolic alterations are more often the major causes of altered consciousness than is meningitis or the Ekiri syndrome (toxic encepha- lopathy associated with bizarre posturing, cerebral edema, and fatty degeneration of viscera), which Activation of has been reported mostly in Japanese children.NF-°B caused by IcsA Pneumonia, vaginitis, and keratoconjunctivitis due to Shigella are rarely reported. In the absence of serious malnutrition, severe and very unusual clinical manifestations, such as meningitis, may be IpaB type III linked to genetic defects in innate immune func secretion tions (i.e.,


InternalMed_Harrison

InternalMed_Harrison. the absence of serious malnutrition, severe and very unusual clinical manifestations, such as meningitis, may be IpaB type III linked to genetic defects in innate immune func secretion tions (i.e., deficiency in interleukin 1 receptor–IL-1˜ IpaA associated kinase 4 [IRAK-4]) and may require


InternalMed_Harrison

InternalMed_Harrison. Disruption of epithelial genetic investigation. permeability barrier by PMNs Macrophage apoptosis Two complications of particular importance are toxic megacolon and HUS. Toxic megacolon Massive invasion of Bacterial survival is a consequence of severe inflammation extending epithelium


InternalMed_Harrison

InternalMed_Harrison. Initiation of inflammation to the colonic smooth-muscle layer and causing paralysis and dilation. The patient presents with abdominal distention and tenderness, with or FIGuRE 191-1 Invasive strategy of Shigella flexneri. IL, interleukin; NF-κB, nuclear factor without signs of localized or generalized peritoniκB; NLR, NOD-like receptor; PMN, polymorphonuclear leukocyte. tis. The abdominal x-ray characteristically shows marked dilation of the transverse colon (with the greatest distention in the ascending and descending segments); thumbprinting caused by mucosal inflammatory edema; and loss of the normal haustral pattern associated with pseudopolyps, often extending into the lumen. Pneumatosis coli is an occasional finding. If perforation occurs, radiographic signs of pneumoperitoneum may be apparent. Predisposing factors (e.g., hypokalemia and use of opioids, anticholinergics, loper-amide, psyllium seeds, and antidepressants) should be investigated.


InternalMed_Harrison

InternalMed_Harrison. Shiga toxin produced by S. dysenteriae type 1 has been linked countries, where enterohemorrhagic E. coli (EHEC) predominates as the etiologic agent of this syndrome. HUS is an early complication that most often develops after several days of diarrhea. Clinical examination shows pallor, asthenia, and irritability and, in some cases, bleeding of the nose and gums, oliguria, and increasing edema. HUS is a nonimmune (Coombs test–negative) hemolytic anemia defined by a diagnostic triad: microangiopathic hemolytic anemia (hemoglobin level typically <80 g/L [<8 g/dL]), thrombocytopenia (mild to moderate in severity; typically <60,000 platelets/μL), and acute renal failure due to thrombosis of the glomerular capillaries (with markedly elevated creatinine levels). Anemia is severe, with fragmented red blood cells (schizocytes) in the peripheral smear, high serum concentrations of lactate dehydrogenase and free circulating hemoglobin, and elevated reticulocyte counts. Acute renal failure occurs


InternalMed_Harrison

InternalMed_Harrison. red blood cells (schizocytes) in the peripheral smear, high serum concentrations of lactate dehydrogenase and free circulating hemoglobin, and elevated reticulocyte counts. Acute renal failure occurs in 55–70% of cases; however, renal function recovers in most of these cases (up to 70% in various series). Leukemoid reactions, with leukocyte counts of 50,000/ μL, are sometimes noted in association with HUS.


InternalMed_Harrison

InternalMed_Harrison. The postinfectious immunologic complication known as reactive arthritis can develop weeks or months after shigellosis, especially in patients expressing the histocompatibility antigen HLA-B27. About 3% of patients infected with S. flexneri later develop this syndrome, with arthritis, ocular inflammation, and urethritis—a condition that can last for months or years and can progress to difficult-to-treat chronic arthritis. Postinfectious arthropathy occurs only after infection with S. flexneri and not after infection with the other Shigella serotypes.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis in patients with a dysenteric syn drome depends on the clinical and environmental context. In developing areas, infectious diarrhea caused by other invasive pathogenic bacteria (Salmonella, Campylobacter jejuni, Clostridium difficile, Yersinia enterocolitica) or parasites (Entamoeba histolytica) should be considered. Only bacteriologic and parasitologic examinations of stool can truly differentiate among these pathogens. A first flare of inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis (Chap. 351), should be considered in patients in industrialized countries. Despite the similarity in symptoms, anamnesis discriminates between shigellosis, which usually follows recent travel in an endemic zone, and these other conditions.


InternalMed_Harrison

InternalMed_Harrison. Microscopic examination of stool smears shows erythrophagocytic trophozoites with very few PMNs in E. histolytica infection, whereas bacterial enteroinvasive infections (particularly shigellosis) are characterized by high PMN counts in each microscopic field. However, because shigellosis often manifests only as watery diarrhea, systematic attempts to isolate Shigella are necessary.


InternalMed_Harrison

InternalMed_Harrison. The “gold standard” for the diagnosis of Shigella infection remains the isolation and identification of the pathogen from fecal material. One major difficulty, particularly in endemic areas where laboratory facilities are not immediately available, is the fragility of Shigella and its common disappearance during transport, especially with rapid changes in temperature and pH. In the absence of a reliable enrichment medium, buffered glycerol saline or Cary-Blair medium can be used as a holding medium, but prompt inoculation onto isolation medium is essential. The probability of isolation is higher if the portion of stools that contains bloody and/or mucopurulent material is directly sampled. Rectal swabs can be used, as they offer the highest rate of successful isolation during the acute phase of disease. Blood cultures are positive in fewer than 5% of cases but should be done when a patient presents with a clinical picture of severe sepsis.


InternalMed_Harrison

InternalMed_Harrison. In addition to quick processing, the use of several media increases 1057 the likelihood of successful isolation: a nonselective medium such as bromocresol-purple agar lactose; a low-selectivity medium such as MacConkey or eosin-methylene blue; and a high-selectivity medium such as Hektoen, Salmonella-Shigella, or xylose-lysine-deoxycholate agar. After incubation on these media for 12–18 h at 37°C (98.6°F), shigellae appear as non-lactose-fermenting colonies that measure 0.5–1 mm in diameter and have a convex, translucent, smooth surface. Suspected colonies on nonselective or low-selectivity medium can be subcultured on a high-selectivity medium before being specifically identified or can be identified directly by standard commercial systems on the basis of four major characteristics: glucose positivity (usually without production of gas), lactose negativity, H2S negativity, and lack of motility. The four Shigella serogroups (A–D) can then be differentiated by additional


InternalMed_Harrison

InternalMed_Harrison. glucose positivity (usually without production of gas), lactose negativity, H2S negativity, and lack of motility. The four Shigella serogroups (A–D) can then be differentiated by additional characteristics. This approach adds time and difficulty to the identification process; however, after presumptive diagnosis, the use of serologic methods (e.g., slide agglutination, with group-and then type-specific antisera) should be considered. Group-specific antisera are widely available; in contrast, because of the large number of serotypes and subserotypes, type-specific antisera are rare and more expensive and thus are often restricted to reference laboratories.


InternalMed_Harrison

InternalMed_Harrison. As an enteroinvasive disease, shigellosis requires antibiotic treatment. Since the mid-1960s, however, increasing resis tance to multiple drugs has been a dominant factor in treatment decisions. Resistance rates are highly dependent on the geographic area. Clonal spread of particular strains and horizontal transfer of resistance determinants, particularly via plasmids and transposons, contribute to multidrug resistance. The current global status—i.e., high rates of resistance to classic first-line antibiotics such as amoxicillin—has led to a rapid switch to quinolones such as nalidixic acid. However, resistance to such early-generation quinolones has also emerged and spread quickly as a result of chromosomal mutations affecting DNA gyrase and topoisomerase IV; this resistance has necessitated the use of later-generation quinolones as first-line antibiotics in many areas. For instance, a review of the antibiotic resistance history of Shigella in India found that, after their


InternalMed_Harrison

InternalMed_Harrison. necessitated the use of later-generation quinolones as first-line antibiotics in many areas. For instance, a review of the antibiotic resistance history of Shigella in India found that, after their introduction in the late 1980s, the second-generation quinolones norfloxacin, ciprofloxacin, and ofloxacin were highly effective in the treatment of shigellosis, including cases caused by multidrug-resistant strains of S. dysenteriae type 1. However, investigations of subsequent outbreaks in India and Bangladesh detected resistance to norfloxacin, ciprofloxacin, and ofloxacin in 5% of isolates. The incidence of multidrug resistance parallels the widespread, uncontrolled use of antibiotics and calls for the rational use of effective drugs.


InternalMed_Harrison

InternalMed_Harrison. Because of the ready transmissibility of Shigella, current public health recommendations in the United States are that every case be treated with antibiotics. Ciprofloxacin is recommended as first-line treatment. A number of other drugs have been tested and shown to be effective, including ceftriaxone, azithromycin, pivmecillinam, and some fifth-generation quinolones. Whereas infections caused by non-dysenteriae Shigella in immunocompetent individuals are routinely treated with a 3-day course of antibiotics, it is recommended that S. dysenteriae type 1 infections be treated for 5 days and that Shigella infections in immunocompromised patients be treated for 7–10 days. Treatment for shigellosis must be adapted to the clinical context, with the recognition that the most fragile patients are children <5 years old, who represent two-thirds of all cases worldwide. There are few data on the use of quinolones in children, but Shigella-induced dysentery is a well-recognized indication


InternalMed_Harrison

InternalMed_Harrison. Azithromycin 6–20 mg/kg 1–1.5 g Cost Rapid emergence of resistance and spread to other bacteria Source: WHO Library Cataloguing-in-Publication Data: Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1 (www.who.int/cholera/ publications/shigellosis/en/). for their use. The half-life of ciprofloxacin is longer in infants than in older individuals. The ciprofloxacin dose generally recommended for children is 30 mg/kg per day in two divided doses. Adults living in areas with high standards of hygiene are likely to develop milder, shorter-duration disease, whereas infants in endemic areas can develop severe, sometimes fatal, dysentery. In the former setting, treatment will remain minimal and bacteriologic proof of infection will often come after symptoms have resolved; in the latter setting, antibiotic treatment and more aggressive measures, possibly including resuscitation, are often required.


InternalMed_Harrison

InternalMed_Harrison. Shigella infection rarely causes significant dehydration. industrialized countries) are uncommon. In developing countries, malnutrition remains the primary indicator for diarrhea-related death, highlighting the importance of nutrition in early management. Rehydration should be oral unless the patient is comatose or presents in shock. Because of the improved effectiveness of reduced-osmolarity oral rehydration solution (especially for children with acute noncholera diarrhea), the WHO and UNICEF now recommend a standard solution of 245 mOsm/L (sodium, 75 mmol/L; chloride, 65 mmol/L; glucose [anhydrous], 75 mmol/L; potassium, 20 mmol/L; citrate, 10 mmol/L). In shigellosis, the coupled transport of sodium to glucose may be variably affected, but oral rehydration therapy remains the easiest and most efficient form of rehydration, especially in severe cases.


InternalMed_Harrison

InternalMed_Harrison. Nutrition should be started as soon as possible after completion of initial rehydration. Early refeeding is safe, well tolerated, and clinically beneficial. Because breast-feeding reduces diarrheal losses and the need for oral rehydration in infants, it should be maintained in the absence of contraindications (e.g., maternal HIV infection). NONSPECIFIC, SYMPTOM-BASED THERAPY Antimotility agents have been implicated in prolonged fever in volunteers with shigellosis. These agents are suspected of increasing the risk of toxic megacolon and are thought to have been responsible for HUS in children infected by EHEC strains. For safety reasons, it is better to avoid antimotility agents in bloody diarrhea.


InternalMed_Harrison

InternalMed_Harrison. There is no consensus regarding the best treatment for toxic mega-colon. The patient should be assessed frequently by both medical and surgical teams. Anemia, dehydration, and electrolyte deficits (particularly hypokalemia) may aggravate colonic atony and should be actively treated. Nasogastric aspiration helps to deflate the colon. Parenteral nutrition has not been proven to be beneficial. Fever persisting beyond 48–72 h raises the possibility of local perforation or abscess. Most studies recommend colectomy if, after 48–72 h, colonic distention persists. However, some physicians recommend continuation of medical therapy for up to 7 days if the patient seems to be improving clinically despite persistent megacolon without free perforation. Intestinal perforation, either isolated or complicating toxic megacolon, requires surgical treatment and intensive medical support.


InternalMed_Harrison

InternalMed_Harrison. Rectal prolapse must be treated as soon as possible. With the health care provider using surgical gloves or a soft warm wet cloth and the patient in the knee-chest position, the prolapsed rectum is gently pushed back into place. If edema of the rectal mucosa is evident (rendering reintegration difficult), it can be osmotically reduced by the application of gauze impregnated with a warm solution of saturated magnesium sulfate. Rectal prolapse often relapses but usually resolves along with the resolution of dysentery. HUS must be treated by water restriction, including discontinuation of oral rehydration solution and potassium-rich alimentation. Hemofiltration is usually required.


InternalMed_Harrison

InternalMed_Harrison. HUS must be treated by water restriction, including discontinuation of oral rehydration solution and potassium-rich alimentation. Hemofiltration is usually required. Hand washing after defecation or handling of children’s feces and before handling of food is recommended. Stool decontamination (e.g., with sodium hypochlorite), together with a cleaning protocol for medical staff as well as for patients, has proven useful in limiting the spread of infection during Shigella outbreaks. Ideally, patients should have a negative stool culture before their infection is considered cured. Recurrences are rare if therapeutic and preventive measures are correctly implemented. Although several live attenuated oral and subunit parenteral vaccine candidates have been produced and are undergoing clinical trials, no vaccine against shigellosis is currently available. Especially given the rapid progression of antibiotic resistance in Shigella, a vaccine is urgently needed.


InternalMed_Harrison

InternalMed_Harrison. Infections due to Campylobacter 192 and Related Organisms Martin J. Blaser Bacteria of the genus Campylobacter and of the related genera Arcobacter and Helicobacter (Chap. 188) cause a variety of inflammatory conditions. Although acute diarrheal illnesses are most common, these organisms may cause infections in virtually all parts of the body, especially in compromised hosts, and these infections may have late nonsuppurative sequelae. The designation Campylobacter comes from the Greek for “curved rod” and refers to the organism’s vibrio-like morphology.


InternalMed_Harrison

InternalMed_Harrison. Campylobacters are motile, non-spore-forming, curved, gram-negative rods. Originally known as Vibrio fetus, these bacilli were reclassified as a new genus in 1973 after their dissimilarity to other vibrios was recognized. More than 15 species have since been identified. These species are currently divided into three genera: Campylobacter, Arcobacter, and Helicobacter. Not all of the species are pathogens of humans. The human pathogens fall into two major groups: those that primarily cause diarrheal disease and those that cause extraintestinal infection. The principal diarrheal pathogen is Campylobacter jejuni, which accounts for 80–90% of all cases of recognized illness due to campylobacters and related genera. Other organisms that cause diarrheal disease include Campylobacter coli, Campylobacter upsaliensis, Campylobacter lari, Campylobacter hyointestinalis, Campylobacter fetus, Arcobacter butzleri, Arcobacter cryaerophilus, Helicobacter cinaedi, and Helicobacter fennelliae. The two


InternalMed_Harrison

InternalMed_Harrison. upsaliensis, Campylobacter lari, Campylobacter hyointestinalis, Campylobacter fetus, Arcobacter butzleri, Arcobacter cryaerophilus, Helicobacter cinaedi, and Helicobacter fennelliae. The two Helicobacter species causing diarrheal disease, H. cinaedi and H. fennelliae, are intestinal rather than gastric organisms; in terms of the clinical features of the illnesses they cause, these species most closely resemble Campylobacter rather than Helicobacter pylori (Chap. 188) and thus are considered in this chapter. The pathogenic roles of Campylobacter concisus, Campylobacter ureolyticus, Campylobacter troglodytis, and Campylobacter pyloridis are uncertain. A new subspecies—C. fetus subspecies testudinum—has been described, chiefly in Asian patients; its close resemblance to strains isolated from reptiles suggests a food source.


InternalMed_Harrison

InternalMed_Harrison. The major species causing extraintestinal illnesses is C. fetus. However, any of the diarrheal agents listed above may cause systemic or localized infection as well, especially in compromised hosts. Neither aerobes nor strict anaerobes, these microaerophilic organisms are adapted for survival in the gastrointestinal mucous layer. This chapter focuses on C. jejuni and C. fetus as the major pathogens in and prototypes for their groups. The key features of infection are listed by species (excluding C. jejuni, described in detail in the text below) in Table 192-1.


InternalMed_Harrison

InternalMed_Harrison. Campylobacters are found in the gastrointestinal tract of many animals used for food (including poultry, cattle, sheep, and swine) and many household pets (including birds, dogs, and cats). These microorganisms usually do not cause illness in their animal hosts. In most cases, campylobacters are transmitted to humans in raw or undercooked food products or through direct contact with infected animals. In the United States and other developed countries, ingestion of contaminated poultry that has not been suffi-1059 ciently cooked is the most common mode of acquisition (30–70% of cases). Other modes include ingestion of raw (unpasteurized) milk or untreated water, contact with infected household pets, travel to developing countries (campylobacters being among the leading causes of traveler’s diarrhea; Chaps. 149 and 160), oral-anal sexual contact, and (occasionally) contact with an index case who is incontinent of stool (e.g., a baby).


InternalMed_Harrison

InternalMed_Harrison. Campylobacter infections are common. Several studies indicate that, in the United States, diarrheal disease due to campylobacters is more common than that due to Salmonella and Shigella combined. Infections occur throughout the year, but their incidence peaks during summer and early autumn. Persons of all ages are affected; however, attack rates for C. jejuni are highest among young children and young adults, whereas those for C. fetus are highest at the extremes of age. Systemic infections due to C. fetus (and to other Campylobacter and related species) are most common among compromised hosts. Persons at increased risk include those with AIDS, hypogammaglobulinemia, neoplasia, liver disease, diabetes mellitus, and generalized atherosclerosis as well as neonates and pregnant women. However, apparently healthy nonpregnant persons occasionally develop transient Campylobacter bacteremia as part of a gastrointestinal illness.


InternalMed_Harrison

InternalMed_Harrison. In contrast, in many developing countries, C. jejuni infections are hyperendemic, with the highest rates among children <2 years old. Infection rates fall with age, as does the illness-to-infection ratio. These observations suggest that frequent exposure to C. jejuni leads to the acquisition of immunity. C. jejuni infections may be subclinical, especially in hosts in developing countries who have had multiple prior infections and thus are partially immune. Symptomatic infections mostly occur within 2–4 days (range, 1–7 days) of exposure to the organism in food or water. The sites of tissue injury include the jejunum, ileum, and colon. Biopsies show an acute nonspecific inflammatory reaction, with neutrophils, monocytes, and eosinophils in the lamina propria, as well as damage to the epithelium, including loss of mucus, glandular degeneration, and crypt abscesses. Biopsy findings may be consistent with Crohn’s disease or ulcerative colitis, but these “idiopathic”


InternalMed_Harrison

InternalMed_Harrison. Infections Due to Campylobacter and Related Organisms axillary abscesses; diarrhea aIn immunocompromised hosts, especially HIV-infected persons. bIn children. Source: Adapted from BM Allos, MJ Blaser: Clin Infect Dis 20:1092, 1995.


InternalMed_Harrison

InternalMed_Harrison. 1060 chronic inflammatory diseases should not be diagnosed unless infectious colitis, specifically including that due to infection with Campylobacter species and related organisms, has been ruled out. The high frequency of C. jejuni infections and their severity and recurrence among hypogammaglobulinemic patients suggest that antibodies are important in protective immunity. The pathogenesis of infection is uncertain. Both the motility of the strain and its capacity to adhere to host tissues appear to favor disease, but classic enterotoxins and cytotoxins (although they have been described and include cytolethal distending toxin, or CDT) appear not to play substantial roles in tissue injury or disease production. The organisms have been visualized within the epithelium, albeit in low numbers. The documentation of a significant tissue response and occasionally of C. jejuni bacteremia further suggests that tissue invasion is clinically significant, and in vitro studies are consistent


InternalMed_Harrison

InternalMed_Harrison. The documentation of a significant tissue response and occasionally of C. jejuni bacteremia further suggests that tissue invasion is clinically significant, and in vitro studies are consistent with this pathogenetic feature. The pathogenesis of C. fetus infections is better defined. Virtually all clinical isolates of C. fetus possess a proteinaceous capsule-like structure (an S-layer) that renders the organisms resistant to complement-mediated killing and opsonization. As a result, C. fetus can cause bacteremia and can seed sites beyond the intestinal tract. The ability of the organism to switch the S-layer proteins expressed—a phenomenon that results in antigenic variability—may contribute to the chronicity and high rate of recurrence of C. fetus infections in compromised hosts.


InternalMed_Harrison

InternalMed_Harrison. The clinical features of infections due to Campylobacter and the related Arcobacter and intestinal Helicobacter species causing enteric disease appear to be highly similar. C. jejuni can be considered the prototype, in part because it is by far the most common enteric pathogen in the group. A prodrome of fever, headache, myalgia, and/or malaise often occurs 12–48 h before the onset of diarrheal symptoms. The most common signs and symptoms of the intestinal phase are diarrhea, abdominal pain, and fever. The degree of diarrhea varies from several loose stools to grossly bloody stools; most patients presenting for medical attention have ≥10 bowel movements on the worst day of illness. Abdominal pain usually consists of cramping and may be the most prominent symptom. Pain is usually generalized but may become localized; C. jejuni infection may cause pseudoappendicitis. Fever may be the only initial manifestation of C. jejuni infection, a situation mimicking the early stages of typhoid


InternalMed_Harrison

InternalMed_Harrison. but may become localized; C. jejuni infection may cause pseudoappendicitis. Fever may be the only initial manifestation of C. jejuni infection, a situation mimicking the early stages of typhoid fever. Febrile young children may develop convulsions. Campylobacter enteritis is generally self-limited; however, symptoms persist for >1 week in 10–20% of patients seeking medical attention, and clinical relapses occur in 5–10% of such untreated patients. Studies of common-source epidemics indicate that milder illnesses or asymptomatic infections may commonly occur.


InternalMed_Harrison

InternalMed_Harrison. C. fetus may cause a diarrheal illness similar to that due to C. jejuni, especially in normal hosts. This organism also may cause either intermittent diarrhea or nonspecific abdominal pain without localizing signs. Sequelae are uncommon, and the outcome is benign. C. fetus may also cause a prolonged relapsing systemic illness (with fever, chills, and myalgias) that has no obvious primary source; this manifestation is especially common among compromised hosts. Secondary seeding of an organ (e.g., meninges, brain, bone, urinary tract, or soft tissue) complicates the course, which may be fulminant. C. fetus infections have a tropism for vascular sites: endocarditis, mycotic aneurysm, and septic thrombophlebitis may all occur. Infection during pregnancy often leads to fetal death. A variety of Campylobacter species and H. cinaedi can cause recurrent cellulitis with fever and bacteremia in immunocompromised hosts.


InternalMed_Harrison

InternalMed_Harrison. H. cinaedi can cause recurrent cellulitis with fever and bacteremia in immunocompromised hosts. Except in infection with C. fetus, bacteremia is uncommon, developing most often in immunocompromised hosts and at the extremes of age. Three patterns of extraintestinal infection have been noted: (1) transient bacteremia in a normal host with enteritis (benign course, no specific treatment needed); (2) sustained bacteremia or focal infection in a normal host (bacteremia originating from enteritis, with patients responding well to antimicrobial therapy); and (3) sustained bacteremia or focal infection in a compromised host. Enteritis may not be clinically apparent. Antimicrobial therapy, possibly prolonged, is necessary for suppression or cure of the infection.


InternalMed_Harrison

InternalMed_Harrison. Campylobacter, Arcobacter, and intestinal Helicobacter infections in patients with AIDS or hypogammaglobulinemia may be severe, persistent, and extraintestinal; relapse after cessation of therapy is common. Hypogammaglobulinemic patients also may develop osteomyelitis and an erysipelas-like rash or cellulitis.


InternalMed_Harrison

InternalMed_Harrison. Local suppurative complications of infection include cholecystitis, pancreatitis, and cystitis; distant complications include meningitis, endocarditis, arthritis, peritonitis, cellulitis, and septic abortion. All these complications are rare, except in immunocompromised hosts. Hepatitis, interstitial nephritis, and the hemolytic-uremic syndrome occasionally complicate acute infection. Reactive arthritis and other rheumatologic complaints may develop several weeks after infection, especially in persons with the HLA-B27 phenotype. Guillain-Barré syndrome or its Miller Fisher (cranial polyneuropathy) variant follows Campylobacter infections uncommonly—i.e., in 1 of every 1000–2000 cases or, for certain C. jejuni serotypes (such as O19), in 1 of every 100–200 cases. Despite the low frequency of this complication, it is now estimated that Campylobacter infections, because of their high incidence, may trigger 20–40% of all cases of Guillain-Barré syndrome. The presence of sialylated


InternalMed_Harrison

InternalMed_Harrison. of this complication, it is now estimated that Campylobacter infections, because of their high incidence, may trigger 20–40% of all cases of Guillain-Barré syndrome. The presence of sialylated lipopolysaccharides on C. jejuni strains is a form of molecular mimicry that promotes autoimmune recognition of sialylated cell surface molecules on axons. Asymptomatic Campylobacter infection also may trigger Guillain-Barré syndrome. Immunoproliferative small-intestinal disease (alpha chain disease), a form of lymphoma that originates in small-intestinal mucosa-associated lymphoid tissue, has been associated with C. jejuni; antimicrobial therapy has led to marked clinical improvement.


InternalMed_Harrison

InternalMed_Harrison. In patients with Campylobacter enteritis, peripheral leukocyte counts reflect the severity of the inflammatory process. However, stools from nearly all Campylobacter-infected patients presenting for medical attention in the United States contain leukocytes or erythrocytes. Gramor Wright-stained fecal smears should be examined in all suspected cases. When the diagnosis of Campylobacter enteritis is suspected on the basis of findings indicating inflammatory diarrhea (fever, fecal leukocytes), clinicians can ask the microbiology laboratory to attempt the visualization of organisms with characteristic vibrioid morphology by direct microscopic examination of stools with Gram’s staining or to use phase-contrast or dark-field microscopy to identify the organisms’ characteristic “darting” motility. Confirmation of the diagnosis of Campylobacter infection is based on identification of an isolate from cultures of stool, blood, or another site. Campylobacterspecific media should be used to


InternalMed_Harrison

InternalMed_Harrison. Confirmation of the diagnosis of Campylobacter infection is based on identification of an isolate from cultures of stool, blood, or another site. Campylobacterspecific media should be used to culture stools from all patients with inflammatory or bloody diarrhea. Because all Campylobacter species are fastidious, they will not be isolated unless selective media or other selective techniques are used. Not all media are equally useful for isolation of the broad array of campylobacters; therefore, failure to isolate campylobacters from stool does not entirely rule out their presence. Species-specific polymerase chain reaction techniques have been developed to facilitate exact diagnoses. The detection of the organisms in stool almost always implies infection; there is a brief period of post-convalescent fecal carriage and no obvious commensalism in humans. In contrast, Campylobacter sputorum and related organisms found in the oral cavity are commensals that only rarely have pathogenic


InternalMed_Harrison

InternalMed_Harrison. fecal carriage and no obvious commensalism in humans. In contrast, Campylobacter sputorum and related organisms found in the oral cavity are commensals that only rarely have pathogenic significance. Because of the low levels of metabolic activity of Campylobacter species in standard blood culture media, Campylobacter bacteremia may be difficult to detect unless laboratorians check for low-positive results in quantitative assays.


InternalMed_Harrison

InternalMed_Harrison. The symptoms of Campylobacter enteritis are not sufficiently unusual to distinguish this illness from that due to Salmonella, Shigella, Yersinia, and other pathogens. The combination of fever and fecal leukocytes or erythrocytes is indicative of inflammatory diarrhea, and definitive diagnosis is based on culture or demonstration of the characteristic organisms on stained fecal smears. Similarly, extraintestinal Campylobacter illness is diagnosed by culture. Infection due to Campylobacter should be suspected in the setting of septic abortion, and that due to C. fetus should be suspected specifically in the setting of septic thrombophlebitis. It is important to reiterate that (1) the presentation of Campylobacter enteritis may mimic that of ulcerative colitis or Crohn’s disease, (2) Campylobacter enteritis is much more common than either of the latter (especially among young adults), and (3) biopsy may not distinguish among these entities. Thus a diagnosis of inflammatory bowel disease


InternalMed_Harrison

InternalMed_Harrison. enteritis is much more common than either of the latter (especially among young adults), and (3) biopsy may not distinguish among these entities. Thus a diagnosis of inflammatory bowel disease should not be made until Campylobacter infection has been ruled out, especially in persons with a history of foreign travel, significant animal contact, immunodeficiency, or exposure incurring a high risk of transmission.


InternalMed_Harrison

InternalMed_Harrison. Fluid and electrolyte replacement is central to the treatment of diarrheal illnesses (Chap. 160). Even among patients presenting for medical attention with Campylobacter enteritis, not all clearly benefit from specific antimicrobial therapy. Indications for therapy include high fever, bloody diarrhea, severe diarrhea, persistence for >1 week, and worsening of symptoms. A 5to 7-day course of erythromycin (250 mg orally four times daily or—for children—30–50 mg/kg per day, in divided doses) is the regimen of choice. Both clinical trials and in vitro susceptibility testing indicate that other macrolides, including azithromycin (a 1or 3-day regimen), also are useful therapeutic agents. An alternative regimen for adults is ciprofloxacin (500 mg orally twice daily) or another fluoroquinolone for 5–7 days, but resistance to this class of agents as well as to tetracyclines is substantial; ~22% of U.S. isolates in 2010 were resistant to ciprofloxacin. Because macrolide resistance usually is


InternalMed_Harrison

InternalMed_Harrison. for 5–7 days, but resistance to this class of agents as well as to tetracyclines is substantial; ~22% of U.S. isolates in 2010 were resistant to ciprofloxacin. Because macrolide resistance usually is much less common (<10%), these drugs are the empirical agents of choice. Patients infected with antibiotic-resistant strains are at increased risk of adverse outcomes. Use of antimotility agents, which may prolong the duration of symptoms and have been associated with toxic megacolon and with death, is not recommended.


InternalMed_Harrison

InternalMed_Harrison. For systemic infections, treatment with gentamicin (1.7 mg/kg IV every 8 h after a loading dose of 2 mg/kg), imipenem (500 mg IV every 6 h), or chloramphenicol (50 mg/kg IV each day in three or four divided doses) should be started empirically, but susceptibility testing should then be performed. Ciprofloxacin and amoxicillin-clavulanate are alternative agents for susceptible strains. In the absence of immunocompromise or endovascular infections, therapy should be administered for 14 days. For immunocompromised patients with systemic infections due to C. fetus and for patients with endovascular infections, prolonged therapy (for up to 4 weeks) is usually necessary. For recurrent infections in immunocompromised hosts, lifelong therapy/prophylaxis is sometimes necessary.


InternalMed_Harrison

InternalMed_Harrison. Nearly all patients recover fully from Campylobacter enteritis, either spontaneously or after antimicrobial therapy. Volume depletion probably contributes to the few deaths that are reported. As stated above, occasional patients develop reactive arthritis or Guillain-Barré syndrome or its variants. Systemic infection with C. fetus is much more often fatal than that due to related species; this higher mortality rate reflects in part the population affected. Prognosis depends on the rapidity with which appropriate therapy is begun. Otherwise healthy hosts usually survive C. fetus infections without sequelae. Compromised hosts often have recurrent and/or life-threatening infections due to a variety of Campylobacter species. Matthew K. Waldor, Edward T. Ryan


InternalMed_Harrison

InternalMed_Harrison. Matthew K. Waldor, Edward T. Ryan Members of the genus Vibrio cause a number of important infectious syndromes. Classic among them is cholera, a devastating diarrheal disease caused by Vibrio cholerae that has been responsible for seven global pandemics and much suffering over the past two centuries. Epidemic cholera remains a significant public health concern in the developing world today. Other vibrioses caused by other Vibrio species include syndromes of diarrhea, soft tissue infection, or primary sepsis. All Vibrio species are highly motile, facultatively anaerobic, curved gram-negative rods with one or more flagella. In nature, vibrios most commonly reside in tidal rivers and bays under conditions of moderate salinity. They proliferate in the summer months when water temperatures exceed 20°C. As might be expected, the illnesses they cause also increase in frequency during the warm months.


InternalMed_Harrison

InternalMed_Harrison. Cholera is an acute diarrheal disease that can, in a matter of hours, result in profound, rapidly progressive dehydration and death. Accordingly, cholera gravis (the severe form) is a much-feared disease, particularly in its epidemic presentation. Fortunately, prompt aggressive fluid repletion and supportive care can obviate the high mortality that is historically associated with cholera. Although the term cholera has occasionally been applied to any severely dehydrating secretory diarrheal illness, whether infectious in etiology or not, it now refers to disease caused by V. cholerae serogroup O1 or O139—i.e., the serogroups with epidemic potential.


InternalMed_Harrison

InternalMed_Harrison. The species V. cholerae is classified into more than 200 serogroups based on the carbohydrate determinants of their lipopolysaccharide (LPS) O antigens. Although some non-O1 V. cholerae serogroups (strains that do not agglutinate in antisera to the O1 group antigen) have occasionally caused sporadic outbreaks of diarrhea, serogroup O1 was, until the emergence of serogroup O139 in 1992, the exclusive cause of epidemic cholera. Two biotypes of V. cholerae O1, classical and El Tor, are distinguished. Each biotype is further subdivided into two serotypes, termed Inaba and Ogawa. The natural habitat of V. cholerae is coastal salt water and brackish estuaries, where the organism lives in close relation to plankton. V. cholerae can also exist in freshwater in the presence of adequate nutrients and warmth. Humans become infected incidentally but, once infected, can act as vehicles for spread. Ingestion of water contaminated by human feces is the most common means of acquisition of


InternalMed_Harrison

InternalMed_Harrison. V. cholerae. Consumption of contaminated food also can contribute to spread. There is no known animal reservoir. Although the infectious dose is relatively high, it is markedly reduced in hypochlorhydric persons, in those using antacids, and when gastric acidity is buffered by a meal. Cholera is predominantly a pediatric disease in endemic areas, but it affects adults and children equally when newly introduced into a population. In endemic areas, the burden of disease is often greatest during “cholera seasons” associated with high temperatures, heavy rainfall, and flooding, but cholera can occur year-round. For unexplained reasons, susceptibility to cholera is significantly influenced by ABO blood group status; persons with type O blood are at greatest risk of severe disease if infected, whereas those with type AB are at least risk. Cholera is native to the Ganges delta in the Indian subcontinent. Since 1817, seven global pandemics have occurred. The current (seventh) pandemic—the


InternalMed_Harrison

InternalMed_Harrison. whereas those with type AB are at least risk. Cholera is native to the Ganges delta in the Indian subcontinent. Since 1817, seven global pandemics have occurred. The current (seventh) pandemic—the first due to the El Tor bio type—began in Indonesia in 1961 and spread in serial waves throughout Asia as V. cholerae El Tor displaced the endemic classical biotype, which is thought to have caused the previous six pandemics. In the early 1970s, El Tor cholera erupted in Africa, causing major epidemics