ACP medicine, 3rd Edition

Infectious Disease

Enteric Infections Due to Campylobacter, Salmonella, Shigella, Yersinia, Vibrio, and Helicobacter

Marcia B. Goldberg MD1

Director of Research in the Division of Infectious Diseases

1Massachusetts General Hospital; Associate Professor, Harvard Medical School

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

August 2006

In the United States, diarrhea is the third most common medical complaint, with an annual incidence of 1.5 to 5.0 illnesses per person. Rates of occurrence are highest in children, followed by the elderly. Worldwide, diarrhea is the second most common cause of death for all age groups and the leading cause of death in children.

The most common bacterial causes of diarrhea in the United States are gram-negative bacteria. Of these, Salmonella and Campylobacterspecies are the most common reported infectious organisms (41% and 36%, respectively), followed by Shigella (14%), Escherichia coli O157 (3%), Yersinia (1%), and Vibrio (0.8%).1 Each of these gram-negative bacteria is a more common cause of diarrhea than either Listeria, the most frequent gram-positive bacterial cause of diarrhea, or Cryptosporidium, the most frequent parasitic cause of diarrhea.2

Campylobacter Infections

Epidemiology

Campylobacter organisms are the most common cause of bacterial gastroenteritis in the United States, with 2.1 to 2.4 million cases estimated to occur each year and approximately 13 cases per 100,000 population reported each year.1,3 This disease is most common in children. The incidence of Campylobacter enteritis is higher in HIV-infected persons than in the general population; however, the frequency and severity of infection in HIV-positive persons has decreased significantly since the introduction of highly active antiretroviral therapy (HAART).4

In 80% of cases, Campylobacter infection is acquired by ingestion of contaminated foodstuffs. Improper handling of uncooked chicken and consumption of undercooked chicken are the most common food-related causes. Exposure to infected dogs, unpasteurized milk, contaminated unchlorinated water, and infected persons has also been reported to spread the organism. Neonates born to infected mothers are at extremely high risk for infection, which can be life threatening. The infectious inoculum is only approximately 800 organisms5; therefore, secondary infection occurs in as many as two thirds of household contacts.

The Campylobacter species that most often causes enteritis is C. jejuni. In HIV-positive persons, other species of Campylobacter, particularly C. coli and C. upsaliensis (for which dogs are the normal host), are also common causes of enteritis. Systemic Campylobacterinfection is most commonly caused by C. fetus. Two thirds of patients with systemic Campylobacter infection are males. Many of these are men in their middle 50s; more than 25% are farm workers, butchers, or abattoir workers; and most have a chronic underlying illness, such as alcoholism, cirrhosis, diabetes, lymphoproliferative disorder, or valvular or atherosclerotic heart disease. Therefore, C. fetus infection in a patient without known predisposing factors should trigger a search for underlying disease.

Pathogenesis

Signs and symptoms of Campylobacter enteritis result from bacterial invasion of the intestinal epithelium, the elaboration of a cytotoxin (CDT) by the bacterium, and bacterial induction of inflammatory cytokines.6 Intestinal lesions are similar to those of granulomatous or idiopathic ulcerative colitis. Guillain-Barré syndrome, the most important complication of Campylobacter infection, occurs in 0.3% of cases of Campylobacter diarrhea.7 It develops when antibodies raised against certain Campylobacter surface polysaccharides cross-react with host ganglioside molecules.8 Postinfectious arthritis occurs in 1% of cases of Campylobacter diarrhea and is also believed to be an autoimmune process. Molecular biologic techniques that permit the analysis of Campylobacter gene function are now available, and genome analysis of aCampylobacter strain has been completed; these developments will allow rapid progress on the molecular characterization of the pathogenesis of Campylobacter infection in the future.

Diagnosis

Clinical Manifestations

The incubation period for Campylobacter enteritis is usually 2 to 5 days. Illness typically begins with crampy periumbilical pain and fever, which is followed by diarrhea with profuse, watery, foul-smelling stools. Abdominal pain can range from mild to severe, mimicking acute appendicitis, bowel perforation, or intussusception. Stool is grossly bloody or melanotic in 30% of patients and guaiac positive in 60%.9

Campylobacter bacteremia occurs in less than 1% of patients, usually in the setting of underlying immunocompromise or chronic disease. Patients with bacteremia present with symptoms common to many bacteremias: fever, malaise, headache, chills, night sweats, anorexia, and abdominal pain. Lethargy and confusion may occur without focal neurologic findings. A nonproductive cough may be present in the absence of focal pulmonary findings. Endocarditis may occur in 10% of patients. Meningitis is uncommon, although neonates are at extremely high risk.

Physical Examination

Physical findings in both Campylobacter enteritis and systemic Campylobacter infection are nonspecific.

Laboratory Tests

In Campylobacter enteritis, stool examination may reveal the diagnosis in as many as two thirds of cases. In fresh stool, Campylobacterorganisms are small, motile, comma- or corkscrew-shaped; in Gram stains, they appear as gull-winged, curved, gram-negative organisms. Leukocytes are present in the stool in about 75% of cases.

Campylobacter organisms do not grow on standard media used in the detection of enteric pathogens but, rather, require specific media and specific environmental conditions.10 If a stool sample cannot be delivered to a laboratory quickly, storage of the sample in an airtight container at 4° C or inoculation of transport medium (e.g., Cary-Blair) can improve the recovery of organisms.

Diagnosis of systemic Campylobacter infection is based on the isolation of the organism in blood cultures. Campylobacter organisms may grow slowly, so cultures should be incubated for 2 weeks or longer. In both systemic and intestinal infection, leukocytosis is common.

Differential Diagnosis

In patients with acute onset of watery diarrhea, fever, and abdominal pain, Campylobacter infection should be considered. The differential diagnosis of diarrheal disease with polymorphonuclear leukocytes in the stool is enteritis caused by Campylobacter, Salmonella, Shigella, Yersinia enterocolitica, or invasive E. coli infection or by inflammatory bowel disease. Salmonella and Yersinia infections are less likely when there is grossly visible blood in the stool. Systemic Campylobacter infection cannot be easily distinguished from other bacteremias.

Treatment

Campylobacter enteritis is usually self-limited, making specific therapy unnecessary. However, it may be prudent to administer antibiotics to patients with moderately severe disease (i.e., those with high fever, bloody diarrhea, or bacteremia or those who pass more than eight stools a day); patients with AIDS or those who are immunosuppressed from other causes; pregnant women; or patients with symptoms that worsen or persist more than 7 days after diagnosis. Administration of antibiotics before laboratory confirmation of infection has been shown to reduce the median duration of symptoms from 10 days to 5 days.11 However, empirical institution of antibiotics for diarrheal syndromes suggestive of enterohemorrhagic E. coli may increase the risk of hemolytic-uremic syndrome.12

Erythromycin is the treatment of choice for Campylobacter enteritis [see Table 1]. The newer extended-spectrum macrolide azithromycin is also effective [see Table 1]. Fluoroquinolones are commonly used for the treatment of diarrhea, including that caused by Campylobacter. However, resistance of Campylobacter to fluoroquinolones is increasing rapidly worldwide; in the United States, such resistance increased from less than 1% of isolates in 1989–1990 to 18% of isolates in 2001.13 Because of concern that fluoroquinolone use in poultry was leading to increased resistance of clinical isolates of Campylobacter, in 2005, the Food and Drug Administration suspended use of the fluoroquinolone enrofloxacin for treatment of infections in poultry.

Table 1 Selected Therapies for Enteric Pathogens

Pathogen

Drug (Trade Name)

Dose

Relative Efficacy

Cost ($)

Comment

Campylobacter

Erythromycin

Adults: 250 mg p.o., q.i.d., for 5–7 days

Drug of choice

0.72–1.24/day

Campylobacterenteritis strains resistant to erythromycin and related drugs have been isolated but are infrequent

Children: 30–50 mg/kg/day in divided doses for 5–7 days

Azithromycin (Zithromax)

500 mg p.o., q.d., for 3 days

Has been used successfully

15.70/day

Campylobacterenteritis strains resistant to azithromycin and related drugs have been isolated but are infrequent

Ciprofloxacin (Cipro)

500 mg p.o., b.i.d., for 3 days

Has been used successfully

11.60/day

Ciprofloxacin resistance may occur in as many as 18% ofCampylobacterisolates

Salmonellaenteritis

Ciprofloxacin (Cipro)

500 mg p.o. twice a day for 2–3 days or until afebrile

Drug of choice

11.60/day

Antibiotic therapy for individuals at risk for extraintestinal spread of infection

Trimethoprim-sulfamethoxazole (Bactrim)

1 double-strength tablet p.o., b.i.d., for 2–3 days or until afebrile

For susceptible isolates only

0.30–4.00/day

Antibiotic therapy for individuals at risk for extraintestinal spread of infection

Amoxicillin

1 g p.o. three times a day for 2–3 days or until afebrile

For susceptible isolates only

3.30–3.48/day

Antibiotic therapy for individuals at risk for extraintestinal spread of infection

Ceftriaxone (Rocephin)

2 g I.V. daily for 2–3 days or until afebrile

Drug of choice for isolates resistant to ampicillin and trimethoprim-sulfamethoxazole

112.32/day

Antibiotic therapy for individuals at risk for extraintestinal spread of infection

Salmonella carrier state

Amoxicillin

1 g p.o., t.i.d., for 3 mo

For susceptible isolates only

3.30–3.48/day

Eliminates carrier state in 80% of patients with susceptible isolate

Ciprofloxacin (Cipro)

750 mg p.o., b.i.d., for 4 wk

For susceptible isolates only

17.40/day

Trimethoprim-sulfamethoxazole (Bactrim)

1 double-strength tablet p.o., b.i.d., for 3 mo

For susceptible isolates only

0.30–4.00/day

Salmonellaenteric fever

Ciprofloxacin (Cipro)

500 mg p.o., b.i.d., for 5–7 days (uncomplicated disease) or 10–14 days (severe disease); 10 mg/kg b.i.d. for 10–14 days for quinolone-resistant isolates

Drug of choice

11.60/day

Antimicrobial therapy for uncomplicatedSalmonella enteric fever; must confirm organism susceptibility to nalidixic acid and ciprofloxacin; if nalidixic-acid resistant, use higher doses of ciprofloxacin (10 mg/kg b.i.d.)

Amoxicillin

1–1.5 g p.o., q. 6 hr, for 14 days

For susceptible isolates only

3.30–3.48/day

 

Trimethoprim-sulfamethoxazole (Bactrim)

1 double-strength tablet p.o., b.i.d., for 14 days

For susceptible isolates only

0.30–4.00/day

 

Azithromycin (Zithromax)

500 mg p.o., q.d., for 7 days

For susceptible isolates only

15.70/day

 

Ceftriaxone (Rocephin)

20 mg/kg I.V. daily for 10–14 days for uncomplicated disease; 30 mg/kg I.V. b.i.d. for severe disease

Drug of choice for severe disease in which the isolate is resistant to quinolones

112.32/day

 

Dexamethasone

3 mg/kg I.V. once, then 1 mg/kg I.V. q. 6 hr for 48 hr

Adjunct to antimicrobial therapy when disease is accompanied by shock, coma, stupor, obtundation, or delirium

80.00–89.99/day

Glucocorticosteroid therapy forSalmonella enteric fever; continuation beyond 48 hr may increase the risk of relapse

Shigella

Ciprofloxacin (Cipro)

500 mg p.o., b.i.d., for 3 days

Treatment of choice

11.60/day

Antibiotic therapy for Shigellaenteritis acquired in the United States or anywhere worldwide; fluoroquinolone resistance occurs occasionally in the Asian subcontinent and Southeast Asia

Levofloxacin (Levaquin)

500 mg p.o., q.d., for 3 days

Treatment of choice

13.33/day

Antibiotic therapy for Shigellaenteritis acquired in the United States or anywhere worldwide; fluoroquinolone resistance occurs occasionally in the Asian subcontinent and Southeast Asia

Azithromycin

500 mg p.o. once for 1 day, then 250 mg p.o., q.d., for 4 days

Alternative treatment

47.00/course of therapy

 

Trimethoprim-sulfamethoxarole (Bactrim)

1 double-strength tablet p.o., b.i.d., for 3–5 days

Alternative therapy for isolates known to be susceptible to trimethoprim-sulfamethoxazole

0.30–4.00/day

 

Yersinia

Gentamicin

5 mg/kg/day in divided doses

Suggested therapy

21.50/day

Antibiotic therapy for Y. enterocoliticasepticemia; may be used alone or in combination with other antibiotics listed as therapy for Y. enterocolitica in this table

Doxycycline

100 mg I.V. q. 12 hr

Suggested therapy

28.32/day

Antibiotic therapy for Y. enterocoliticasepticemia or Y. pseudotuberculosissepticemia

Trimethoprim-sulfamethoxazole

Trimethoprim, 8–10 mg/kg/day I.V. in divided doses, q. 6 hr

Suggested therapy

42.00/day

Antibiotic therapy for Y. enterocoliticasepticemia

Ciprofloxacin (Cipro)

200–400 mg I.V. q. 12 hr

Suggested therapy

30.00–60.00/day

Antibiotic therapy for Y. enterocoliticasepticemia

Ampicillin

100–200 mg/kg/day I.V. in divided doses

Suggested therapy

25.00/day

Antibiotic therapy for Y. pseudotuberculosissepticemia

Streptomycin

20–30 mg/kg/day I.M.

Suggested therapy

17.50/day

Antibiotic therapy for Y. pseudotuberculosissepticemia

Tetracycline

20–30 mg/kg/day p.o. or I.V. in divided doses

Suggested therapy

0.43/day for p.o. dosing

Antibiotic therapy for Y. pseudotuberculosissepticemia

Vibrio

Doxycycline

300 mg p.o. once

Treatment of choice for adults

4.60–15.78

Antibiotic therapy for V. cholerae; patients with mild diarrhea do not require antibiotic treatment

Ciprofloxacin (Cipro)

1 g p.o. once

Alternative therapy

11.60

Antibiotic therapy for V. cholerae; patients with mild diarrhea do not require antibiotic treatment

Trimethoprim-sulfamethoxazole (Bactrim)

1 double-strength tablet b.i.d. for 3 days

Treatment of choice for pregnant women

0.30–4.00/day

Antibiotic therapy for V. cholerae

Helicobacter

Trimethoprim-sulfamethoxazole (Bactrim)

Trimethoprim, 5 mg/kg, and sulfamethoxazole, 25 mg/kg, twice a day for 3 days

Treatment of choice for children

0.30–4.00/day

Antibiotic therapy for V. cholerae

Erythromycin

250 mg p.o., q.i.d., for 3 days

For tetracycline-resistant or trimethoprim-sulfamethoxazole-resistant strains

0.72–1.24/day

Antibiotic therapy for V. cholerae

Azithromycin (Zithromax)

20 mg/kg up to 1 g maximum dose p.o. once

Treatment for children with trimethoprim-sulfamethoxazole-resistant strains

Up to 31.40

Antibiotic therapy for V. cholerae

Proton-pump inhibitor:
  Omeprazole
  (Prilosec) or
  Lansoprazole
  (Prevacid) or
  Rabeprazole
(Aciphex)

Omeprazole, 20 mg, orlansoprazole, 30 mg, orrabeprazole, 20 mg p.o., b.i.d., for 7–14 days

Suggested therapy

48–308/mo
252–338/mo
330/mo

 

plus

 

 

 

Amoxicillin

1 g p.o., b.i.d., for 7–14 days

2.20–2.32/day

 

plus

 

 

Clarithromycin (Biaxin)

500 mg p.o., b.i.d., for 7–14 days

8.90–9.32/day

 

Proton-pump inhibitor:
  Omeprazole (Prilosec)
  or lansoprazole
  (Prevacid) or
  rabeprazole
  (Aciphex)

Omeprazole, 20 mg, orlansoprazole, 30 mg, orrabeprazole, 20 mg p.o., b.i.d., for 7–14 days

 

48–308/mo
252–338/mo
330/mo

 

plus

 

 

 

 

Bismuth subsalicylate (Pepto-Bismol)

525 mg p.o., q.i.d., for 7–14 days

Suggested therapy

0.50–0.74/day

Metronidazole may cause nausea, metallic taste, headaches, or disulfiram-like reaction (avoid alcohol)

plus

 

 

Tetracyline

500 mg p.o., q.i.d., for 7–14 days

0.48/day

plus

 

 

Metronidazole (Flagyl)

500 mg p.o., t.i.d., for 7–14 days

0.63–13.68 day

 

Symptomatic treatment of Campylobacter enteritis consists principally of fluid replacement as needed. On the basis of data for Shigella andSalmonella enteritis, antimotility agents (e.g., diphenoxylate hydrochloride with atropine sulfate [Lomotil]) should probably be avoided.

For systemic Campylobacter infection, imipenem or gentamicin, or a combination of the two, is the treatment of choice. Chloramphenicol, other aminoglycosides, and tetracyclines are also effective. Most isolates are resistant to penicillin, cephalosporins, vancomycin, and rifampin.

Complications

Postinfectious arthritis occurs in approximately 1% of patients, Guillain-Barré syndrome (or its variant, Miller Fisher syndrome) occurs in approximately 0.3%,7 and hemolytic-uremic syndrome occurs rarely. Postinfectious arthritis presents as a sterile monoarticular or migratory polyarticular arthritis that begins 7 to 10 days after the onset of diarrhea and may persist for months or become chronic. The most commonly involved joint is the knee. Sixty percent of patients carry the HLA-B27 haplotype, which is associated with an increased prevalence of ankylosing spondylitis and related spondyloarthropathies. Evidence of recent Campylobacter infection can be found in up to 40% of all patients with Guillain-Barré syndrome.14 Of patients with Campylobacter-associated Guillain-Barré syndrome, 20% are left with some long-term disability and 5% die of the syndrome or its complications.

Prognosis

Recurrence or relapse of Campylobacter infection may occur. Severe, persistent, or bacteremia-associated enteritis may occur in HIV-positive patients who are severely immunocompromised.

Salmonella Infections

Epidemiology

Disease caused by Salmonella organisms can be divided into two categories: typhoidal and nontyphoidal. Typhoidal disease can be caused byS. typhi or S. paratyphi. Nontyphoidal disease can be caused by any other serovar that infects humans, with S. typhimurium and S. enteriditis being the most common. In the United States, nontyphoidal Salmonella (which is responsible for approximately 1.4 million cases annually) and Campylobacter are the most frequently isolated causes of bacterial diarrhea.1,15

More than 95% of nontyphoidal Salmonella infections are food-borne; the remainder are nosocomial infections or are acquired from pets (reptiles and birds), from infected persons, or from contaminated water, drugs, or solutions. Outbreaks have been linked to eggs, cheese, fresh fruits and vegetables, juice, dry cereal, and ice cream premix.16 Salmonella organisms can be passed transovarially from chicken to egg, and most S. enteriditis cases are traced to undercooked eggs.16 Salmonella organisms are commonly carried by farm animals, and antibiotic resistance—particularly of S. typhimurium—has been linked to the use of antibiotics in animal feed.17

In the United States, S. typhi and S. paratyphi cause fewer than 1,000 infections annually, more than 70% of which are acquired abroad.15Humans are the only host for these pathogens, and spread is person-to-person or via contaminated foodstuffs or water.

The inoculum for Salmonella infection is approximately 105 to 109 organisms but is lower in infants, in persons with pernicious anemia, and in persons taking antacids or H2 receptor blockers. Additional risk factors are old age, alteration of the endogenous bowel flora (e.g., by recent antimicrobial therapy), HIV infection, therapeutic immunosuppression, alteration of the reticuloendothelial system (e.g., by malaria or Bartonella infection), sickle-cell disease, splenectomy, diabetes, malignancy, and rheumatologic disorders, including lupus. HIV-infected persons have a 20- to 100-fold increased risk of Salmonella infection and a significantly increased risk of severe invasive disease. Clinical analyses of whether proton pump inhibitors alter host resistance to Salmonella infection are scarce.

Classification of Salmonella organisms is confusing because disease may be caused by more than 2,500 serovars, all of which belong to a single species, designated S. enterica or S. choleraesuis. However, in clinical settings, serovars are commonly referred to as species (e.g.,S. enterica serovar enteriditis is called S. enteriditis), as will be done herein.

Pathogenesis

Typhoidal Salmonella infection likely involves internalization of organisms by intestinal M cells, which are specialized epithelial cells that overlie Peyer patches and are abundant in the ileum. Organisms are transported to the lymphoid tissue of the Peyer patches and may enter the systemic circulation. Salmonella organisms have specialized mechanisms for entry into cells and for survival inside of macrophages. Recruitment of inflammatory cells, including macrophages, into the Peyer patches may lead to their enlargement and necrosis after several weeks of infection. During nontyphoidal Salmonella enteritis, organisms likely internalize into enterocytes more diffusely and induce inflammatory responses in the lamina propria.

Salmonella serovars vary in their pathogenesis. S. anatum, S. derby, and S. newport are usually limited to the intestine. S. choleraesuisrapidly enters the bloodstream and causes little damage in the intestine. S. typhi bacteremia often leads to seeding of the liver and biliary tree.

Gastroenteritis

Diagnosis

Clinical manifestations

The incubation period for gastroenteritis caused by Salmonella organisms typically ranges from 6 to 72 hours. Symptoms of the disorder include nausea, vomiting, fever, diarrhea, and abdominal cramps. Stools are typically loose, of moderate volume, and do not contain blood. In rare cases, the presentation may mimic appendicitis or inflammatory bowel disease. Diarrhea is generally self-limited, lasting 3 to 7 days.

Physical examination

Physical findings are nonspecific. Fever with temperatures to 39° C (102° F) for 1 to 2 days, mild abdominal tenderness, and hyperactive bowel sounds may be present. A more prolonged or more hectic fever pattern suggests bacteremia, metastatic foci, or both.

Laboratory tests

Microscopic examination of stool reveals leukocytes and, rarely, red blood cells. Salmonella organisms are readily cultured from stool on selective media used routinely in clinical microbiology laboratories. Isolation of Salmonella organisms from otherwise sterile body fluids is also accomplished using routine media. The mean duration of fecal carriage after resolution of diarrhea for nontyphoidal Salmonellaorganisms is 1 month in adults and 7 weeks in young children.18

Differential Diagnosis

The presentation of Salmonella gastroenteritis is similar to that of other febrile diarrheal syndromes, including infection caused byCampylobacter, Shigella, or Y. enterocolitica, and inflammatory bowel disease. Frankly bloody diarrhea is more suggestive of Shigella or enterohemorrhagic E. coli infection than of Salmonella infection.

Treatment

Antibiotics are not recommended for patients with uncomplicated gastroenteritis, because the illness is generally self-limited, and antibiotic therapy may prolong intestinal carriage.19

Antibiotics should be administered to patients who are severely ill or at risk for extraintestinal spread of infection; these patients include infants, persons older than 50 years, patients with cardiac valvular or mural abnormalities, patients with prosthetic vascular grafts, and patients who are receiving immunosuppressive therapy. Effective therapeutic agents include fluoroquinolones, trimethoprim-sulfamethoxazole, amoxicillin or ampicillin, and third-generation cephalosporins [see Table 1]. Because resistance to ampicillin, trimethoprim-sulfamethoxazole, or sulfamethoxazole is common [see Table 2], treatment with a fluoroquinolone or a third-generation cephalosporin is appropriate when susceptibilities of the isolate are not known. Duration of therapy should be only 48 to 72 hours or until the patient becomes afebrile; longer therapy may increase the likelihood of long-term carriage.

Table 2 Percentage of Salmonella and Shigella Isolates Resistant to Selected Antibiotics64

Antibiotic

Nontyphoidal Salmonella

Typhoidal Salmonella

Shigella

Amikacin

0

0

0

Amoxicillin-clavulanate

5

0

3

Ampicillin

13

6

77

Cefoxitin

4

0

< 1

Ceftriaxone

< 1

0

0

Cephalothin

5

1

7

Chloramphenicol

9

6

8

Ciprofloxacin

< 1

0

0

Gentamicin

1

0

< 1

Kanamycin

4

0

1

Nalidixic acid

2

24

2

Streptomycin

13

7

54

Sulfamethoxazole

13

6

32

Tetracycline

15

7

31

Trimethoprim-sulfamethoxazole

1

7

37

Complications

Infants are at high risk for central nervous system infection. In some patients, Salmonella organisms invade the intestinal epithelium and enter the bloodstream, causing septicemia. Septicemia may in turn cause metastatic infection of other organs, including endovascular sites, the hepatobiliary tract, the spleen, bone, and, less commonly, the brain.

Carrier State

The carrier state, defined as carriage of Salmonella organisms in the stool for more than 1 year after initial infection, occurs in 0.2% to 0.6% of persons infected with nontyphoidal Salmonella and 3% of persons infected with S. typhi.20 The site of chronic infection is the biliary tree. The presence of biliary stones or scarring makes eradication more difficult. Long-term carriage may occur more rarely in the urinary tract, particularly in the setting of obstructive uropathy, tuberculosis, or schistosomiasis.

Diagnosis

Clinical manifestations

The carrier state is generally asymptomatic. If the carrier state is accompanied by obstructive uropathy or gallstones, symptoms associated with that condition may be present.

Physical examination

The physical examination of a patient in the carrier state is unremarkable.

Laboratory tests

The carrier state is documented by culture of Salmonella organisms utilizing routine techniques.

Treatment

A long course of ampicillin, amoxicillin, ciprofloxacin, or trimethoprim-sulfamethoxazole [see Table 1] will eradicate the Salmonellaorganisms in 80% of persons with the carrier state. Alternatively, long-term gallbladder carriage can be effectively eliminated by cholecystectomy accompanied by 10 to 14 days of any of the regimens recommended for treatment of bacteremia; however, this approach should be reserved for patients in whom long-term antibiotic therapy fails and in whom eradication is required for public health reasons (e.g., food handlers and health care workers).

Bacteremia and Vascular Infection

Nontyphoidal Salmonella organisms have a propensity to colonize sites of vascular abnormality, such as prosthetic vascular grafts, atherosclerotic plaques, and aneurysms.21

Diagnosis

Clinical manifestations

Patients with endovascular infection typically have high fevers that persist even after several days of therapy.

Physical examination

The physical examination may reveal tenderness at the site of the infection, but it may also yield normal results.

Laboratory tests

High-grade bacteremia (i.e., bacterial growth in more than 50% of three or more blood cultures) suggests endovascular infection. Echocardiography and other imaging studies should be conducted to search for endovascular lesions.

Treatment

Life-threatening bacteremia, endovascular infection, or focal metastatic infection should be empirically treated with both a fluoroquinolone and a third-generation cephalosporin until antibiotic susceptibilities are known. For documented or suspected endovascular infection, 6 weeks of intravenous therapy with a β-lactam antibiotic, such as ampicillin or a third-generation cephalosporin, should be administered. For low-grade bacteremia, 7 to 14 days of I.V. therapy is adequate. Endovascular infection may require surgical intervention. However, in cases in which surgical resection of infected grafts is not feasible, lifelong oral suppressive therapy has been successful.22

In patients with AIDS, a first episode of Salmonella bacteremia should be treated with 7 to 14 days of I.V. antibiotics, followed by 4 weeks of an oral fluoroquinolone. Since the introduction of HAART, relapse after a 6-week course of antibiotics appears to have become infrequent.23 AIDS patients who experience relapses of Salmonella bacteremia should be treated and then receive long-term suppression with an oral fluoroquinolone or trimethoprim-sulfamethoxazole.

Enteric Fever

Diagnosis

Clinical manifestations

After ingesting typhoidal Salmonella organisms, persons generally remain asymptomatic for 7 to 14 days and then develop fever and flulike symptoms, including headache, malaise, anorexia, nausea, abdominal pain, myalgias, arthralgia, cough, and sore throat.24 Diarrhea may occur, particularly in children and HIV-infected persons; in otherwise healthy adults, constipation or normal bowel patterns are more common. During the first week, the fever is typically low, but during the second week, it may rise to 39° to 40° C (102.2° to 104° F) and be sustained. Intermittent confusion, apathetic affect, and, in children, seizures may also occur.24 Symptoms resolve spontaneously after 2 to 4 weeks, but 5% to 10% of patients experience relapse 2 to 3 weeks later.

Physical examination

Findings on physical examination vary depending on the phase of the illness. About half of patients have splenomegaly and hepatomegaly. In 30% of patients, rose spots (2 to 4 mm, slightly raised, discrete, irregular, blanching pink macules) appear on the anterior chest in crops of five to 15. The spots last 3 to 4 days and fade without a scar. During the toxemic phase of the illness, the patient's condition is acute.

Laboratory tests

Leukopenia, anemia, moderately elevated liver function test results, and moderately elevated muscle enzyme levels are common. Leukocytosis, transient thrombocytopenia, and clotting abnormalities are less common. The probability of culturing the organism from various sites varies during the course of illness [see Table 3].25 Cultures of bone marrow and punch biopsies of rose spots may be positive when other cultures are negative, particularly during or after antibiotic therapy.

Table 3 Probability of Positive Cultures from Various Sites during Enteric Fever25

Phase of Illness (Time since Initial Exposure)

Disease Manifestations

Cultures

Blood

Stool

Urine

Bone Marrow

Rose Spots

Incubation period (0–1 wk)

Diarrhea in 10%–20%; constipation in some

Negative

Transiently positive

Negative

Negative

Negative

Active invasion (1–2 wk)

Fever, headache, malaise, anorexia, myalgia, arthralgia, cough, and sore throat

80%–90% positive

Negative

Negative

Negative

Negative

Established disease (2–4 wk)

Systemic toxemia, neuropsychiatric manifestations (psychosis and confusion), coryza, cough, sore throat, chest pain, nausea, vomiting, and abdominal pain

80%–90% positive

80% positive

25% positive

90% positive

60% positive

Convalescent period (4–5 wk)

Negative, except with ongoing disease or relapse

50% positive

10% positive

Decreasingly positive

Decreasingly positive

Late focal complications (> 5 wk)

Cholecystitis, osteomyelitis, soft tissue abscess

Negative, except with ongoing disease or relapse

Decreasingly positive

Decreasingly positive

Differential Diagnosis

Enteric fever may be confused with other systemic febrile illnesses.

Treatment

Fluoroquinolones, such as ciprofloxacin, are the drugs of choice for the treatment of enteric fever [see Table 1].24 For uncomplicated cases, treatment should be for 5 to 7 days; for severe disease, treatment should be for 10 to 14 days. Alternative agents include amoxicillin, chloramphenicol, trimethoprim-sulfamethoxazole, azithromycin, and third-generation cephalosphorins [see Table 1]. Full resistance of S. typhi to fluoroquinolones is currently rare in the United States [see Table 2]. However, given the prevalence of organisms resistant to ampicillin and third-generation cephalosporins among isolates from the Indian subcontinent, Southeast Asia, and Africa,26 therapy should consist of a fluoroquinolone or trimethoprim-sulfamethoxazole until antibiotic susceptibilities are known. If the isolate is resistant to fluoroquinolones and the disease is uncomplicated, azithromycin, a third-generation cephalosphorin, or high doses of a fluoroquinolone will be effective [see Table 1].24 If the isolate is resistant to fluoroquinolones and the disease is severe, third-generation cephalosporins are the drugs of choice [see Table 1].24 Patients with delirium, obtundation, stupor, coma, or shock should receive prompt treatment with dexamethasone [see Table 1]; administration of dexamethasone for 48 hours has been associated with a decrease in mortality from 50% to 10%, although continuation of steroids beyond 48 hours may increase the rate of relapse.24,27

Several enteric fever vaccines are available [see Table 4]. Vaccination is recommended for persons traveling to developing countries who will have prolonged exposure to contaminated food and drink; for household contacts of carriers of S. typhi; and for certain laboratory workers. For travelers, vaccination is an adjunct to, not a replacement for, careful eating and drinking.

Table 4 Vaccination for Enteric Fever

Vaccine

Dose

Relative Efficacy

Cost ($)

Comment

Ty21a (Vivotif Berna)

One enteric-coated capsule 1 hr before a meal every day for 4 days

43%–96%; not effective if administered with concomitant antimicrobial or antimalarial therapy

19

Live-attenuated vaccine; not recommended for immunosuppressed or children younger than 6 yr; boost every 5 yr; few side effects

Vi capsular polysaccharide [ViCPS] (Typhim Vi)

25 µg in 0.5 ml I.M. once

55% in one study65

30

Side effects: fever (1%), headache (1.5%–3%), local erythema or induration (7%); not recommended for children younger than 2 yr; boost every 2 yr

Vi capsular polysaccharide conjugated toPseudomonas aeruginosaexotoxin A [Vi-rEPA]

22.5 µg Vi and 22 µg Vi-rEPA in 0.5 ml I.M. twice, 6 wk apart

92% in one study65

30

Side effects: fever (1%–2%), local erythema or induration (< 1%); potentially immunogenic for children younger than 2 yr

Heat-killed whole organismSalmonella typhi

0.5 ml I.M. for 2 doses administered more than 4 wk apart

51%–77%

9

Side effects: fever (17%–29%), severe headache (10%), pain at injection site (35%–60%), rare severe reactions; boost (0.1 ml) every 3 yr; dose for children 6 mo to 10 yr of age is 0.25 ml

Complications

Nonmetastatic complications of Salmonella infection, which include pneumonia (5% of cases), intestinal hemorrhage (3% to 20% of cases), intestinal perforation (2% to 3% of cases), acute cholecystitis (2% of cases), and myocarditis (1% to 2% of cases), often occur 2 to 4 weeks after the initial onset of symptoms. Less commonly, endocarditis, pericarditis, orchitis, and splenic or liver abscesses may occur. In the setting of intestinal perforation, repeat blood cultures should be drawn, and antibiotic therapy should be broadened to cover anaerobic and aerobic bowel flora. Relapse occurs in 5% to 10% of infected patients; treatment of a relapse is the same as for the initial infection.

Shigella Infections

Epidemiology

Shigella organisms are estimated to cause 450,000 cases of diarrhea annually in the United States,15 with approximately five cases per 100,000 population reported each year,1 and they are an important cause of diarrhea and death worldwide.28 Shigella includes four species:S. dysenteriae, S. sonnei, S. boydii, and S. flexneri. In industrialized countries, S. sonnei is currently most common, and S. flexneriaccounts for essentially all other cases. In developing countries, S. dysenteriae is also common. Humans are the only natural host ofShigella organisms, which are spread by fecal-oral contact or, in 20% of cases, through contaminated food or water.

The infectious inoculum is as few as 10 to 100 organisms.29 Consequently, outbreaks spread readily and recurrences are common in day care centers, mental institutions, and other crowded settings. Disease is most common in young children, and secondary infection rates in families are as high as 20%.

Pathogenesis

Initially, Shigella organisms colonize the proximal small bowel, where secretion of an enterotoxin probably causes the initial symptoms. The organisms then pass into the colon, where they invade and spread through the epithelial layer. Shigella organisms induce the release of inflammatory cytokines. Bacterial spread, in conjunction with the intense acute inflammatory response, leads to the formation of ulcerations and microabscesses in the colonic epithelium. Shigella organisms rarely gain access to the bloodstream or infect deeper tissues. AmongShigella species, the toxin Stx (formerly called Shiga toxin) is produced only by S. dysenteriae; it contributes to the more severe diarrhea that can accompany S. dysenteriae infection and is the cause of the hemolytic-uremic syndrome, a rare complication of S. dysenteriaeinfection. Other enterotoxins are produced by members of each Shigella species.

Diagnosis

Clinical Manifestations

The incubation period for Shigella organisms is typically 3 days, with a range of 1 to 7 days. Initial symptoms usually include fever, abdominal cramps, and watery diarrhea, which are followed by abdominal cramps, tenesmus, rectal urgency, and small-volume diarrhea. Diarrhea during this later stage is frequent (eight to 10 episodes a day), and stools may contain blood and mucus. If left untreated, disease is generally self-limited, lasting 7 days or less.

Physical Examination

Physical findings are nonspecific. Patients may appear toxic and have a high temperature (up to 41° C [106° F]). Abdominal tenderness, particularly in the left lower quadrant, and hyperactive bowel sounds are common.

Laboratory Tests

Stool cultures are usually positive during the acute illness. Later, Shigella organisms may be isolated by direct culture of material from rectal ulcerations. Direct microscopic examination of stool stained with methylene blue (or another stain) can be helpful, albeit nonspecific, because the presence of abundant leukocytes in the proper clinical setting strongly suggests infection with Shigella, Salmonella, Campylobacter, Y. enterocolitica, or invasive E. coli, as well as inflammatory bowel disease. The white blood cell count may be elevated, with an increase in the percentage of immature forms, and metabolic abnormalities may be present.

Differential Diagnosis

In the setting of high fever, tenesmus, rectal urgency, and diarrhea with blood- and mucus-containing stools, Shigella infection should be suspected. However, Shigella infection can resemble any febrile diarrheal syndrome, including those caused by Campylobacter, Y. enterocolitica, and Salmonella organisms or by inflammatory bowel disease.

Treatment

Patients with significant dehydration, particularly young children and the elderly, should receive rehydration. In severe cases, fluid may need to be given intravenously. Although many patients recover without antibiotics, administration of an antibiotic to which the organism is susceptible has been shown to shorten the course of clinical illness and the period of fecal excretion.30,31 Given the ease of person-to-person Shigella transmission and the increased mortality associated with bacteremic infection, treatment is indicated for food handlers, health care workers, children in day care, the elderly, HIV-positive patients, malnourished patients, and patients who appear toxic or are bacteremic. Moreover, since humans are the only natural reservoir of Shigella, most experts recommend that, for public health reasons, any patient with a stool culture that is positive for Shigella should be treated.

Given the increasing resistance to both ampicillin and trimethoprim-sulfamethoxazole worldwide, including in the United States [see Table 2], the treatment of choice for Shigella infection with an unknown antibiotic susceptibility pattern is a fluoroquinolone [see Table 1]. The alternative therapy for such infections is azithromycin [see Table 1]. Trimethoprim-sulfamethoxazole is an appropriate choice if the isolate is known to be susceptible to this agent. Cephalosporins have limited efficacy.

Complications

Complications are generally rare but include bacteremia (4% of cases), intestinal obstruction in the setting of severe colonic disease (2.5% of cases), colonic perforation (1.7% of fatal cases), toxic megacolon (3% of S. dysenteriae infections), proctitis, and, in children, rectal prolapse. Metabolic disturbances are relatively common, although severe dehydration is uncommon because stool volume is generally low. Seizures occur in approximately 5% of infected children, generally in the setting of high fever and metabolic abnormalities.32

Reactive arthritis may occur 1 to 2 weeks after diarrhea, either alone or accompanied by conjunctivitis and urethritis (Reiter syndrome); 70% of these patients have the HLA-B27 haplotype. Although most commonly caused by enterohemorrhagic E. coli infection, hemolytic-uremic syndrome may occur after infection with S. dysenteriae. Hemolytic-uremic syndrome is thought to be mediated by Stx.

Prognosis

Prognosis is generally excellent. Settings that predispose to recurrence of disease are those with suboptimal hygiene, such as day care centers or crowded living conditions.

Yersinia Infections

Epidemiology

Each of the three Yersinia species—Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis—is pathogenic for humans. Y. enterocolitica and Y. pseudotuberculosis are widely distributed in nature and cause a variety of zoonoses. In the United States, Y. enterocolitica is estimated to cause approximately 100,000 cases of diarrhea (or 4 cases per million population) annually,1,15 predominantly in children. Y. pseudotuberculosis is a sporadic cause of purulent mesenteric adenitis. Y. pestis, which, in humans, causes bubonic plague and less commonly pneumonic plague, has become the focus of increased attention because of its potential as an agent of bioterrorism [see 8:V Bioterrorism]; it does not cause intestinal disease and will therefore not be discussed further in this chapter.

Transmission of Y. enterocolitica is usually by ingestion of contaminated foodstuffs, including meat, milk and other dairy products, mussels, tofu, oysters, and iceberg lettuce. Person-to-person transmission has also been reported, with a significant rate of secondary cases within families.33 Transfusion of Y. enterocolitica-contaminated red blood cells has been a cause of severe transfusion reactions with high mortality.34 Among the approximately 60 serogroups of Y. enterocolitica, three (O:3, O:8, and O:9) cause most human disease. Persons with underlying cirrhosis or hemochromatosis, particularly if they are being treated with desferrioxamine, are at increased risk for bacteremia and metastatic disease.

Pathogenesis

  1. enterocoliticaand Y. pseudotuberculosistransit the stomach, invade the mucosa of the terminal ileum at Peyer patches, and colonize mesenteric lymph nodes. Yersinia organisms modulate innate and adaptive immune defenses in a manner that enables the organisms to both replicate intracellularly and bind to macrophages without being phagocytosed.35 The inflammatory response that ensues in the terminal ileum may be clinically mistaken for appendicitis or Crohn ileitis. In addition, there are several case reports in the literature of Yersiniainfection mimicking intestinal tumors.36,37

Diagnosis

Clinical Manifestations

In older children and adults, Y. enterocolitica causes a febrile diarrheal syndrome in which the prominent symptom is colicky abdominal pain, predominantly localized to the right lower quadrant. In younger children, the illness may include vomiting and bloody diarrhea. Exudative pharyngitis has also been reported.38 Septicemia, which occurs in persons with iron overload or other chronic diseases, is often complicated by metastatic abscess formation. Y. pseudotuberculosis causes mesenteric adenitis, which mimics acute appendicitis, with fever and right lower quadrant pain.

Physical Examination

On physical examination, patients with Yersinia infection are typically found to have fever and right lower quadrant tenderness.

Laboratory Tests

Leukocytosis is common. Microscopic examination of the stool will reveal fecal leukocytes. Whereas isolation of Yersinia organisms from normally sterile body fluids is straightforward, isolation from stool is difficult because the organisms appear similar to and grow more slowly than other Enterobacteriacae organisms; selective media for Yersinia organisms have not been developed. Yersinia serology turns positive 1 to 2 weeks after infection. Although the diarrhea will have resolved by this time, positive identification of the causative agent may be useful, particularly if the patient develops one of the autoimmune syndromes that may complicate infection. Y. enterocolitica is carried in the stool for an average of 1 month after the resolution of symptoms. For patients who appear toxic or are febrile, blood cultures should be obtained.

Differential Diagnosis

The differential diagnosis of diarrheal disease with polymorphonuclear leukocytes in the stool is enteritis caused by infection withCampylobacter, Salmonella, Shigella, Y. enterocolitica, or invasive E. coli, or caused by inflammatory bowel disease. Mesenteric adenitis caused by Yersinia infection may mimic appendicitis.

Treatment

Enteritis and mesenteric adenitis caused by Y. enterocolitica or Y. pseudotuberculosis are generally self-limited, and no clear role for antibiotic therapy has been established. Although direct proof is lacking, in principle, antiperistaltic agents should be avoided.

Septicemia caused by either Y. enterocolitica or Y. pseudotuberculosis should be aggressively treated with antibiotics because mortality is high. The suggested agents for treatment of Y. enterocolitica septicemia are gentamicin, doxycycline, trimethoprim-sulfamethoxazole, or a fluoro-quinolone, alone or in combination [see Table 1]. Y. enterocolitica organisms produce a β-lactamase and are therefore resistant to penicillins and cephalosporins. The suggested agents for treatment of Y. pseudotuberculosis septicemia are ampicillin, streptomycin or another aminoglycoside antibiotic, and tetracycline [see Table 1]. Patients with suspected septicemia should be started on antibiotics pending culture results. Enteric precautions should be adopted for patients with Y. enterocolitica or Y. pseudotuberculosis infection.

Complications

Either reactive polyarthritis or erythema nodosum complicates 1% to 5% of Y. enterocolitica infections in adults in the United States and 10% to 30% of such infections in Scandinavia. On occasion, reactive polyarthritis or erythema nodosum complicates Y. pseudotuberculosisinfections in adults. Because these disorders may be the presenting complaint, Yersinia infection should be considered and serology and cultures should be performed in such patients. These complications of Yersinia infections rarely occur in young children.

Reactive polyarthritis develops 2 days to 1 month after the onset of gastrointestinal symptoms. It persists for more than a month in two thirds of patients and for more than 4 months in one third of patients. Knees, ankles, toes, fingers, and wrists may be involved. Synovial fluid usually contains fewer than 25,000 white blood cells/ml, with a preponderance of polymorphonuclear leukocytes, and cultures are usually negative. The disorder may be more common and may be particularly severe in persons with the HLA-B27 haplotype, presenting as full-blown ankylosing spondylitis or as Reiter syndrome.

Erythema nodosum develops 2 to 20 days after the onset of gastrointestinal symptoms. It typically resolves spontaneously within a month and is twice as common in women as in men. Skin lesions are usually on the legs and trunk.

Prognosis

The prognosis for Y. enterocolitica enteritis is excellent. In contrast, Y. enterocolitica septicemia is fatal in 50% of cases and Y. pseudotuberculosis septicemia is fatal in 75% of cases, despite appropriate antimicrobial therapy.

Vibrio Infections

Cholera

Epidemiology

The natural reservoir of V. cholerae is aquatic invertebrates in brackish or marine environments. Certain strains have become pathogenic for humans and have caused seven pandemics throughout history, the most recent of which began in Asia in 1961. There are 139 serotypes ofV. cholerae, defined by the O surface antigen. Initially, the seventh pandemic was caused by an O1 strain of biotype El Tor, but in 1992, a new strain emerged from the pandemic strain that carried a new O antigen, which was designated O139. The emergence of the new strain was concurrent with rapid spread of cholera through Latin America and Africa. Currently, the continuing pandemic is caused by two strains, O139 and an O1 strain that differs from the initial O1 strain and likely emerged from the O139 strain.39

Spread of cholera is primarily through ingestion of fecally contaminated water and food—especially, but not exclusively, seafood. Only about 50 cases of cholera are estimated to occur in the United States annually,15 predominantly in persons who acquire it while traveling in endemic areas. Two cases were reported in the fall of 2005, during the aftermath of hurricanes Katrina and Rita.40 The rate of secondary infection in households is very high, suggesting that person-to-person transmission is occurring. Because V. cholerae is sensitive to gastric acid, the infectious inoculum in normal hosts is 1010 organisms, but in persons who are taking antacids or who have achlorhydria, the inoculum may be 106 organisms or fewer.

Organisms excreted from an infected person are more infectious than those in the environment,41 which likely contributes to the high secondary infection rate in households. Natural immunity to cholera is long lasting, with specificity to the O1 antigen. Thus, in endemic areas, disease is most common in children, but nonimmune adults traveling in the region are susceptible. Furthermore, alteration of the O antigen, as seen with the shift from O1 to O139 in 1992, leads to widespread susceptibility in adults.

Pathogenesis

  1. choleraecolonize the proximal small intestine and secrete one major and at least two minor enterotoxins. The major toxin, cholera toxin (CTX), binds the ganglioside GM1 on the intestinal epithelium and activates adenylate cyclase, which in turn leads to the accumulation of cyclic adenosine monophosphate (cAMP). Increased levels of cAMP cause chloride secretion and inhibit sodium absorption, resulting in the characteristic profuse isotonic watery diarrhea.
  2. choleraeis minimally invasive of intestinal tissue, and there is no tissue inflammatory response. Absorptive processes unaffected by cAMP, including glucose-facilitated salt and water absorption, are unaltered, allowing oral rehydration with glucose-electrolyte solutions.

Diagnosis

Clinical manifestations

The hallmark of cholera is massive watery diarrhea consisting of thin, gray-brown, mucus-containing fluid (so-called rice-water stools). The diarrhea begins a few days after initial exposure to V. cholerae and is soon followed by copious vomiting without retching. Notably absent are fever (which occurs in only 5% of cases), abdominal pain, and tenesmus. Muscle cramps may occur as a result of electrolyte shifts. Dehydration ranges from mild to severe. A rare variant in the presentation is so-called cholera sicca, in which abdominal ileus and distention occur, and diarrhea is absent. If left untreated, symptoms of cholera resolve in 1 to 7 days.

Physical examination

Patients appear anxious and restless, with sunken eyes, dry mucous membranes, poor skin turgor, hyperactive bowel sounds, hypotension, and tachycardia. Obtundation may occur with severe dehydration. As much as 1 L/hr of fluid may be excreted in stools.

Laboratory tests

Microscopic examination of Gram stains of stool reveals the small (1 to 3 µm long), comma-shaped, gram-negative organisms. V. choleraegrow well on a variety of selective media; TCBS (thiosulfate-citrate-bile salt-sucrose) agar is commonly used.

In patients with moderate to severe dehydration, blood studies show elevations of packed cell volume, serum specific gravity, and total protein levels. Severe disease is characterized by prerenal azotemia, metabolic acidosis with an elevated anion gap, normal to low serum potassium levels, normal to slightly low serum sodium and chloride levels, and leukocytosis.

Differential Diagnosis

In patients with severe dehydration, cholera resembles little else. In patients with mild to moderate dehydration, the presentation is similar to that of enterotoxigenic E. coli (ETEC) or rotavirus infection.

Treatment

The cornerstone of management is prompt replacement of lost fluid and electrolytes. Replacement fluid and electrolytes should be administered intravenously for patients with severe dehydration, patients with moderate dehydration who do not tolerate oral intake, and patients who are purging large amounts of fluid (10 to 20 ml/kg/hr). Initially, replacement fluid should consist of lactated Ringer solution or a solution containing 5 g NaCl, 4 g NaHCO3, and 1 g KCl for each liter of sterile distilled water. The goal is to return the patient to normal hydration status within 4 hours, which, in severely dehydrated persons, may require administration of fluids at 50 to 100 ml/kg/hr. Once rehydration has been accomplished, as determined by hemodynamic status and urine production, normal hydration status should be maintained by replacement of continuing losses of fluid. For those patients with mild disease, rehydration can be accomplished by oral administration of a glucose-electrolyte solution that consists of 20 g glucose, 3.5 g NaCl, 2.5 g NaHCO3, and 1.5 g KCl for each liter of water.

Antibiotics are an adjunct to rehydration therapy and are recommended for patients with disease that is severe enough to lead to dehydration; they can reduce the duration of symptoms and infection, as well as the overall fluid requirements. Doxycycline is the drug of choice for adults [see Table 1]; ciprofloxacin is an alternative, and trimethoprim-sulfamethoxazole is recommended for children or pregnant women. Tetracycline-resistant isolates have been identified in Latin America, Bangladesh, Tanzania, and Laos; trimethoprim-sulfamethoxazole-resistant isolates have been identified in Bangladesh, India, Mozambique, and Laos; appropriate therapy for these isolates is ciprofloxacin, erythromycin, or azithromycin. Currently, no cholera vaccine is available in the United States; the killed parenteral vaccine that was available previously has been discontinued.

Complications and Prognosis

Acute renal failure is a complication of cholera that can occur in patients with severe dehydration who do not receive proper rehydration. In patients with severe dehydration who receive no treatment, mortality is about 50%.

Other Infections Caused by Vibrio Species

In the United States, other Vibrio species are estimated to cause approximately 8,000 cases of disease annually.15 These species include V. parahaemolyticus, V. vulnificus, and nontoxigenic strains of V. cholerae.

  1. parahaemolyticus
  2. parahaemolyticusis a common cause of diarrhea in the Chesapeake Bay area, the Gulf Coast region, and the Pacific Northwest; three cases were reported during the fall of 2005 in persons who had lived in states struck by Hurricane Katrina.42The organism is ubiquitous in coastal waters and is typically acquired by ingestion of raw or undercooked shellfish. Clinical illness most commonly consists of explosive watery diarrhea, crampy abdominal pain, and low-grade fever. Wound infections and septicemia also occur. The organism can be cultured from stool on selective media such as TCBS and from sterile body fluids in routine blood culture media or on blood agar plates. The illness is self-limited, lasting fewer than 7 days. Antibiotic treatment has not been shown to shorten the course of the illness, although if administered, tetracycline or ciprofloxacin is probably the best choice because of its documented efficacy against V. cholerae.

Occasionally, V. parahemolyticus causes severe infections in wounds that have come into contact with seawater; it can also cause septicemia, most commonly in persons with underlying liver disease or diabetes. For these infections, mortality is high43; treatment is as forV. vulnificus infection (see below).

  1. vulnificus
  2. vulnificus, an important cause of serious disease, can be isolated from waters of the eastern and western coasts of the United States, as far north as Cape Cod and the northern Pacific coast,44particularly during the summer months. Several cases were reported during the fall of 2005, in the aftermath of Hurricane Katrina.42In immunocompromised persons, particularly those with chronic liver disease or iron-overload states but also other immunosuppressed persons, V. vulnificus can cause an overwhelming sepsis, accompanied by metastatic cutaneous lesions in the form of hemorrhagic bullae or vesicles that evolve into necrotic ulcers. This syndrome with bacteremia is fatal in over 50% of cases. More than 90% of patients have consumed raw oysters within a week before the onset of illness. Therapy consists of rapid adequate debridement and parenteral antibiotics; the case-fatality rate increases significantly when the initiation of therapy is delayed.45 A combination of antibiotics that includes tetracycline, such as tetracycline plus cefotaxime, is recommended45,46; ciprofloxacin is an alternative.

In both immunocompromised and healthy hosts, V. vulnificus can cause a second syndrome: a rapidly progressive cellulitis, fasciitis, or myositis that follows infection of a superficial wound, typically after cleaning shellfish. In addition to antimicrobial treatment, patients often require incision and drainage with debridement.

Non-O1 V. cholerae

Strains of V. cholerae (non-O1 V. cholerae) that do not produce cholera toxin can cause an acute febrile gastroenteritis. Non-O1 V. choleraeare distributed worldwide in saltwater and freshwater. Exposure is generally by ingestion of raw shellfish, particularly oysters. Diarrhea can range from mild to severe. Usually, no treatment is necessary, but in severe disease, rehydration and doxycycline or ciprofloxacin are recommended.

Helicobacter Infections

Epidemiology

Helicobacter pylori is directly linked to the development of duodenal ulcer, gastric ulcer disease, and gastritis and to the long-term complications of gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The organism is believed to be the cause of peptic ulcer disease in 90% of persons with duodenal ulcers and in 70% to 90% of persons with gastric ulcers. Whether H. pylori also plays a role in peptic ulcer disease in the setting of nonsteroidal anti-inflammatory drug usage is less clear. Most infected persons are asymptomatic. H. pylori infection is epidemiologically associated with a degree of protection from diarrheal diseases47 and, possibly, esophageal adenocarcinomas.48 Whether the observed association with decreased diarrheal disease is a result of a protective effect of H. pylori infection or a result of associated confounding variables is not yet clear. Nevertheless, these observations raise questions about the appropriateness of treating asymptomatic infected patients [see Treatment, below].

  1. pyloriinfection is the most common chronic bacterial infection worldwide, with the prevalence in many industrialized countries reaching 10% and in many developing countries, 80% to 90%. In the United States, the prevalence is twofold to threefold higher in African Americans and Hispanics than in non-Hispanic whites, which is at least partially a reflection of the impact of socioeconomic status and living conditions on transmission.49Among Hispanics, the prevalence has been shown to be highest in immigrants (31% infected), decreasing progressively among successive generations born in the United States.50

Evidence suggests that transmission occurs from person to person by the fecal-oral or oral-oral route, with mother-to-child being the most important route of transmission and many persons becoming infected by the age of 5.51,52 Humans appear to be the major reservoir, although the organism has also been isolated from other primates and domestic cats. H. pylori infection in children is associated with iron deficiency anemia,53,54 but whether this relationship is causal or a result of the link of each with low socioeconomic status has yet to be determined. A second Helicobacter species, H. heilmanii, has been observed in the stomachs of a small percentage of humans with dyspepsia,55 but whether it has a role in the pathogenesis of gastric disease is unknown.

Pathogenesis

  1. pyloriorganisms are strictly trophic for the gastric mucosa or sites of gastric metaplasia, where they colonize the gastric mucus and adhere to gastric epithelial cells; they do not adhere to intestinal epithelial cells. They colonize the stomach through interactions between bacterial adhesins and epithelial cell receptors. The organism is able to persist by avoiding host recognition, altering expression of certain host genes, and modulating the host T cell response.56H. pylori induces autocrine stimulation and inflammatory cytokine release, causing alterations in acid secretion and acute and chronic inflammation that, in turn, potentiate the disease process and contribute to the development of the malignant complications of infection.
  2. pyloridisplays remarkable genetic diversity,57which likely contributes to the ability of the organism to persist in the human stomach. Moreover, the genetic makeup of an isolate is a determinant in the risk that it will cause disease, with certain alleles in each of several genetic loci of the bacterium (cag, babA, vacA) being associated with more severe disease.58 A goal for the near future is to integrate the genetics of a particular isolate into decisions regarding treatment.

Diagnosis

Clinical Manifestations

Acute H. pylori infection produces symptoms of gastroenteritis in up to 60% of patients. Symptoms include nausea, vomiting, epigastric pain, and fever and last for 3 to 14 days. A few weeks after these symptoms resolve, a period of intense gastritis develops and leads to hypochlorhydria, which lasts 2 to 12 months. The symptoms of gastritis frequently bring patients to medical attention.

Physical Examination

During the acute gastroenteritis syndrome, physical findings are nonspecific. Epigastric tenderness and fever may be present. Long-term findings are those of gastritis or peptic ulcer disease.

Laboratory Tests

Diagnosis can be made on the basis of any of three noninvasive tests or by endoscopy with biopsy. When performed properly, each of these tests is diagnostically accurate to greater than 90% before treatment. The three noninvasive tests are (1) the carbon-13 (13C) urea breath test (UBT), (2) the stool antigen test (HpSA), and (3) the enzyme-linked immunosorbent assay (ELISA) serology test [see Table 5]. The UBT does not pose a significant radiation exposure risk and is therefore safe for pregnant women and children. Because proton pump inhibitors reduce the load of H. pylori, they should be stopped 2 weeks before either the UBT or the HpSA is performed.

Table 5 Sensitivity and Specificity of Tests for Helicobacter pylori Infection66,67,68,69

Test

Sensitivity (%)

Specificity (%)

Before Treatment

After Treatment

Before Treatment

After Treatment

UBT

95.3

88.5

97.7–100

99.4

HpSA

94.3

92.3

91.9

92

ELISA

> 90

Not useful

> 90

Not useful

ELISA—enzyme-linked immunosorbent assay   HpSA—H. pylori stool antigen   UBT—13C-urea breath test

Differential Diagnosis

The differential diagnosis of the acute gastroenteritis syndrome caused by H. pylori includes other causes of acute small intestinal infection, including toxin-induced gastroenteritis caused by Clostridium perfringens, Bacillus cereus, Staphylococcus aureus, or ETEC; giardiasis; and viral gastroenteritis.

Treatment

Although H. pylori infection is clearly a risk factor for the development of gastric cancer, and eradication of H. pylori is associated with regression of atrophic gastritis, there is at present little direct evidence that treatment of H. pylori prevents the development of cancer in persons with preexisting atrophy or intestinal metaplasia at the time of treatment.59 Prospective, randomized clinical trials designed to determine whether treatment prevents cancer in these individuals are in progress. Currently, because of the potential to prevent the development of cancer, there is general agreement that patients with symptomatic H. pylori infection should be treated and that first-degree relatives of gastric cancer patients should be screened; relatives who are found to be infected should also be treated.60 Many experts also recommend more general screening of populations in which the incidence of H. pylori-associated disease is high.60 Whether populations in which the incidence of H. pylori-associated disease is low should also be screened is controversial.

Recommended treatment regimens consist of combinations of antibiotics and antisecretory agents or a bismuth formulation [see Table 1]. Treatment with single agents leads to cure in only a minority of cases. The optimal regimen has not been determined, but commonly used regimens include a combination of a proton pump inhibitor, amoxicillin, and clarithromycin; or a combination of a proton pump inhibitor, bismuth subsalicylate, tetracycline, and metronidazole, each for 7 to 14 days [see Table 1]. Success rates range from 60% to 90% and have decreased in recent years, at least in part because of an increase in the prevalence of antibiotic resistance among isolates. Treatment with two agents rather than three or four, or lowering of the dose of metronidazole from 500 mg to 250 mg, is associated with lower success rates.

The clinician should determine whether treatment has eradicated the organism in all patients who have received treatment. Because serum antibody levels will remain elevated for at least 9 months, the optimal tests for confirmation are the UBT and the HpSA [see Table 5]. To ensure that any residual organisms have had the chance to multiply to detectable levels, UBT or HpSA should be delayed until at least 4 weeks after the course of therapy is completed, and proton pump inhibitors should be stopped 2 weeks before the test. H2 receptor antagonists can be continued until the day of testing because they have no effect on H. pylori.

As indicated above, resistance of isolates to components of the standard therapy regimens is increasing. Resistance to clarithromycin currently occurs in 13% of isolates in the United States, and resistance to metronidazole currently occurs in 25% of isolates.61 Two recent studies reported that sequential regimens (e.g., 5 days of amoxicillin and a proton pump inhibitor, followed by 5 days of clarithromycin, tinidazole—which is similar to metronidazole—and a proton pump inhibitor) have higher treatment success rates and can succeed despite resistance of the isolate.62,63 Future studies are needed to determine whether sequential therapy is reasonable after first-line therapy fails or whether it is warranted as first-line therapy.

Although information about the antibiotic susceptibility of the infecting strain is always useful, isolation of H. pylori requires invasive procedures (i.e., endoscopy and biopsy). Therefore, it is reasonable to treat suspected H. pylori infection empirically and to employ antibiotic susceptibility testing only if the initial therapy fails. In general, if a standard course of combination therapy fails, the possibility of resistance should be considered. Moreover, if the failed course of therapy included metronidazole or clarithromycin, antibiotic susceptibilities should be determined.

Complications

Epidemiologic evidence indicates that most MALT lymphomas and a large percentage of non-MALT gastric cancers are attributable to H. pylori infection.60 H. pylori gastritis can progress to chronic atrophic gastritis, which is thought to be a precursor for gastric adenocarcinoma. Therefore, treatment of H. pylori infection may reduce the risk of adenocarcinoma, as well as MALT lymphoma. However, gastric cancer will develop in only a minority of patients with H. pylori gastritis, and some gastric cancers occur in patients without evidence of prior H. pylori infection.

Prognosis

After completion of a course of combination therapy and after clinical demonstration of eradication, H. pylori infection is subsequently detected in a small but significant percentage of patients. The presence of H. pylori organisms usually represents recurrence rather than reinfection because, in such cases, most isolates are found to be identical to the original isolate. Such cases should be treated in the same way as cases for which primary therapy fails [see Table 1].

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Editors: Dale, David C.; Federman, Daniel D.