Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

57. Vibrio & Campylobacter

Gary W. Procop MD

Frank R. Cockerill III MD

VIBRIO INFECTIONS

VIBRIO CHOLERAE INFECTIONS

Essentials of Diagnosis

  • History of exposure, particularly travel to endemic or epidemic locales.
  • Acute onset of voluminous, watery diarrhea, with low-grade fever and mild abdominal pain, which are disproportionate to the amount of diarrhea.
  • During outbreaks, the presence of straight-to-curved gram-negative bacilli, with a single polar flagellum, in the stool of infected patients.
  • In wet preparations, these organisms demonstrate a characteristic darting or “shooting star” motility. The identification may be confirmed by motility inhibition with specific antisera.
  • Cultures of V choleraefrom stool with differential media, such as thiosulfate-citrate-bile salts-sucrose (TCBS) medium.
  • Bacterial growth in nutrient broth, without 1% NaCl supplementation. This characteristic is useful for separating V choleraefrom most other Vibrio species.
  • Detection of V choleraetoxin by latex agglutination or enzyme-linked immunosorbent assay (ELISA) or the detection of V cholerae-specific nucleic acid sequences by polymerase chain reaction (PCR)-based methods.

General Considerations

  1. Epidemiology.Cholera is a disease of antiquity and probably represents some of the diarrheal illnesses described by Hippocrates and other early physicians. Robert Koch discovered V choleraein 1884. Since the 17th century, at least eight epidemics of cholera have swept the globe. At least seven of the eight pandemics originated from the Ganges River delta, where cholera is endemic. V cholerae is transmitted by the fecal-oral route, often by way of contaminated water supplies.

The areas where cholera remains endemic lack adequate sewage disposal systems and water treatment facilities. Cholera epidemics often occur during war, when basic human needs are not met. Throughout the past 30 years, cholera epidemics have repeatedly occurred in overcrowded refugee camps. In the 1994 Rwandan refugee camps, a significant proportion of the deaths were caused by cholera. During this time, 600,000 people are believed to have been infected with V cholerae 01, which resulted in ~ 45,000 deaths.

  1. Microbiology.The Vibrionaceaeshare many characteristics with the Pseudomonadaceae and the Enterobacteriaceae. Genera in this family that cause human disease include Vibrio, Aeromonas, and Plesiomonas. The genus Vibrio consists of gram-negative bacilli that are straight or curved and are motile usually by means of a single polar flagellum. Most species are oxidase producers, have the ability to ferment glucose, and can grow in the presence or absence of oxygen.

During cholera outbreaks, the clinical diagnosis may be supported by examination of the stool. In cholera, a preponderance of straight-to-curved gram-negative bacilli with a single polar flagellum may be seen. In wet preparations, these exhibit a characteristic darting or “shooting star” motility. Motility inhibition, after exposure to type-specific antiserum, confirms the identity of these organisms.

The culturing of V cholerae from stool is most effectively achieved with TCBS agar. The colonies of V cholerae are able to ferment the sucrose in TCBS and appear yellow. Suspicious colonies should be subcultured to a nonselective agar, such as blood or chocolate agar, and after sufficient growth is present, oxidase testing and agglutination testing with polyvalent V cholerae antiserum can be performed.

V cholerae and a closely related species, V mimicus, unlike other Vibrio species, are able to grow in nutrient broth without 1% NaCl supplementation. Additional biochemical features, such as the ability to decarboxylate lysine and ornithine and the inability to hydrolyze arginine, are characteristics that may help to separate V cholerae and V mimicus from other vibrios. V cholerae and V mimicus may be easily separated, since V cholerae ferments sucrose, while V mimicus does not.

 

CLINICAL SYNDROMES

Cholera is a fulminant diarrheal disease caused by V cholerae (Box 57-1). Patients with cholera develop frequent, watery stools, which may reach volumes ≤1 L/h. If these patients are untreated, they will develop rapid dehydration and electrolyte abnormalities, which may result in death within hours from the onset of disease. Therefore cholera is a medical emergency.

V cholerae is noninvasive and produces diarrhea by the elaboration of a potent enterotoxin. This enterotoxin consists of two subunits that have been well characterized. The circular, pentameric B-subunit binds monosialosyl ganglioside residues on the surface of the intestinal epithelial cell and introduces the enzymatic A-subunit into the cytoplasm. The A-subunit functions as an adenosine diphosphate (ADP) ribosylase and transfers an ADP-ribose moiety from cytoplasmic nicotinamide adenine dinucleotide (NAD) to the cell-membrane–associated adenylate cyclase. ADP-ribosylation renders adenylate cyclase unresponsive to feedback inhibition. The result is dramatically increased intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cytoplasmic cAMP levels cause massive fluid and electrolyte transit into the bowel lumen, resulting in the characteristic “rice water” stool of cholera.

Clinical Findings

  1. Signs and Symptoms.Patients with cholera initially develop increased peristalsis, a feeling of fullness, and occasionally vomiting. Diarrhea develops rapidly and soon becomes watery. Abdominal pain and high fever are usually minimal or absent and distinctly disproportionate to the amount of diarrhea. Fever, when present, is usually caused by dehydration. Electrolyte abnormalities, from voluminous diarrhea, may manifest as muscle weakness, intestinal ileus, or even cardiac dysrhythmia. The clinical manifestations of infection and the possibility of severe complications correlate with the patient's hydration and electrolyte abnormalities. Mental status changes secondary to hypoglycemia may also occur. Without urgent fluid and electrolyte replacement therapy, hypovolemic shock and death may occur rapidly.
  2. Laboratory Findings.The stool from patients with cholera tends to lose its fecal odor as the disease progresses and may develop a sweet odor. Also, as the disease progresses and normal fecal material is passed, the stool becomes watery, turbid, and gray. Small flecks of mucus in this gray water give these stools their “rice water” appearance. Blood and neutrophils are generally not present in choleric stools. In the appropriate clinical and epidemiological context (eg, during outbreaks of cholera), a direct examination of stool can be useful for the presumptive identification of V cholerae.A microscopic examination of stool that discloses straight or curved bacilli with rapid, darting, or “shooting star” motility is suggestive of V cholerae. Inhibition of the motility of the organism by V cholerae O1 antiserum further supports the diagnosis of cholera.

Stool from patients with diarrheal disease suspected to be caused by V cholerae should be cultured on a selective and differential media, such as TCBS. Latex agglutination and ELISA-based methods to detect the presence of cholera toxin have been developed. These methods are rapid and may be useful in rapidly detecting patients with cholera in the early phases of disease. Polymerase chain reaction based methods of organism detection have been used successfully to detect V cholerae nucleic acids from choleric stools.

  1. Imaging.Rarely, patients with cholera may develop an ileus as an early manifestation of disease. Abdominal imaging techniques are especially important in such patients since excessive fluid accumulation and visceral rupture may occur.
  2. Differential Diagnosis.Salmonellaspecies, Shigella species, Yersinia enterocolitica, Campylobacter species, and the enteric pathogenic E coli; viruses such as rotavirus and Norwalk agent; and parasites, such as Giardia lamblia and species of Cyclospora and Cryptosporidium are common pathogens that should be considered in the differential diagnosis of diarrheal disease. The diagnosis of these pathogens is achieved by a careful history combined with laboratory testing.
  3. Complications.Profound dehydration and hypoglycemia may result in altered mental status, unconsciousness, seizures, and renal failure. Electrolyte abnormalities may manifest as muscle weakness, intestinal ileus, or sudden death caused by cardiac arrhythmia. Vomiting exacerbates the dehydration, makes oral rehydration difficult, and may lead to aspiration pneumonia. During pregnancy the fluid and electrolyte imbalances may result in fetal death.

 

Rarely, patients with cholera may develop an intestinal ileus. These patients may accumulate large amounts of fluid in the lumen of the intestine. When this occurs at the onset of disease, the patient may be suspected to have an acute abdomen and cholera may not be suspected. If an ileus develops later in the course of disease and stool volume is used as a basis of fluid replacement, these patients may be inadequately rehydrated and viscus rupture could occur.

BOX 57-1 Clinical Syndromes of Cholera

More Common

· Exposure to unsafe drinking water, particularly in areas where cholera is endemic or epidemic

· Acute onset of watery diarrhea

· Low-grade fever and minimal abdominal pain distinctly out of proportion to the degree of diarrhea

Less Common

· Ileus

Treatment

  1. Primary Therapy.Primary therapy of cholera consists of fluid and electrolyte replacement. Published guidelines for fluid and electrolyte replacement in cholera are available. Either a citrate (10 mmol/L)- or bicarbonate (30 mmol/L)-based solution may be used for oral rehydration. These should contain sodium (90 mmol/L), potassium (20 mmol/L), chloride (80 mmol/L), and glucose (111 mmol/L). The glucose is actively transported into enterocytes. This osmotically drives water from the lumen and into the body. In developing countries, the water residua from boiled rice may be used for rehydration. This is an inexpensive and excellent source of oligosaccharides, which like glucose, aid in the osmotic shifting of water from the lumen to the body.

Intravenous fluid replacement therapy is necessary for patients with severe dehydration (≥10% of their body weight) and acidosis (pH <7.2). These patients should be rehydrated with 50% normal saline with 44 mmol/L of bicarbonate. Potassium replacement may be given as needed.

If vomiting is not prominent, oral replacement is usually adequate. If mental status changes are present, hypoglycemia should be treated with intravenous glucose infusion (bolus 3–4 mL/kg of a 25% glucose solution, followed by continuous infusion of 10 mg/kg/h).

  1. Antimicrobial Therapy.Treatment with tetracycline will shorten the duration of cholera (Box 57-2). Pregnant women and children who develop cholera should be treated with ampicillin. If allergies to penicillin exist, trimethoprim-sulfamethoxazole and furazolidone are also effective.

Prognosis

The prognosis for patients infected during cholera epidemics is often poor. This directly parallels the lack of basic medical care, such as fluid and electrolyte replacement, which exists in the situations that foster epidemic cholera. If patients with cholera are given appropriate fluid, electrolyte, and glucose replacements, the prognosis is good. In many instances, the fluid replacement is roughly based on the volume lost. Patients who are not recognized to have an intestinal ileus may fare poorly. These patients may initially be misdiagnosed or if recognized to have cholera may not receive adequate fluid and electrolyte replacement.

Prevention & Control

A clean water supply and effective sanitation are essential for preventing epidemic cholera. The economic means for effective waste disposal and preventive healthcare are not available to the impoverished; therefore cholera persists. In sporadic cases, patient isolation with appropriate waste disposal and hand washing are important means of preventing the spread of disease.

Two vaccines are currently being studied for high-risk individuals to use. These are a B-subunit, killed whole-cell vaccine (BC-WC) and a live, recombinant attenuated, orally administered vaccine (CVD 103-HgR). These vaccines may offer some protection, but they are not an alternative for clean water. In refugee-type settings, in conjunction with preventive measures, these vaccines may help to diminish the spread and mortality of cholera.

OTHER VIBRIO INFECTIONS

Essentials of Diagnosis

  • History of ingestion of raw or possibly undercooked shellfish and/or exposure to seawater.
  • Enteritis: acute onset of predominantly watery diarrhea, which may contain blood and/or neutrophils.
  • Extraintestinal: cellulitis, wound infections, or septicemia, which may be associated with multiple bullous to ulcerative skin lesions, especially in patients with liver cirrhosis.
  • Culture of etiologic agent, with enhanced growth of most species after NaCl supplementation.

General Considerations

  1. Epidemiology.In the United States and other developed countries, Vibrio-associated disease is caused almost exclusively by species other than V cholerae.These vibrios are normal inhabitants of marine environments and are transmitted to humans through the ingestion of raw or undercooked shellfish, through the contamination of foods by seawater, or through exposure to seawater. These organisms may cause gastroenteritis, soft tissue infections, or both. Diseases caused by these organisms usually occur during summer or early fall. The warmer summer waters may enhance the growth of vibrios and water-associated recreational activities increase the risk of exposure.
  2. Microbiology.As may be expected, the vast majority of these marine vibrios require NaCl for optimal growth. In many instances, these organisms may grow suboptimally on general agar media, unless they are supplemented with NaCl. They grow better on media that contain salt, such as MacConkey and TCBS agar. On MacConkey agar, most of these organisms do not ferment lactose and would be considered possible enteric pathogens. Notable exceptions are Vibrio mimicus and Vibrio vulnificus, which are lactose positive and may be overlooked as normal enteric flora. V mimicus has many biochemical characteristics similar to V cholerae and also grows readily without additional NaCl. V mimicus is readily differentiated from V cholerae on TCBS agar, by its inability to ferment sucrose. The most common vibrio enteric pathogen in the United States, V parahaemolyticus, also is sucrose negative.

If a vibrio infection is suspected, TCBS agar should be used for the detection of possible pathogens. This selective and differential medium inhibits growth of many commensal organisms by the presence of bile (oxygall), sodium cholate, and sodium citrate, while the presence of sucrose and the indicator bromthymol blue allow for the differentiation of sucrose fermenters and nonfermenters. V cholerae, V alginolyticus, and a few other less commonly encountered vibrios are sucrose positive, whereas V parahaemolyticus, V vulnificus, and most of the remaining clinically significant isolates are sucrose negative.

Vibrios are facultative anaerobic gram-negative bacilli, which may appear pleomorphic in Gram stains. The clinically relevant Vibrio species may be subcategorized into six groups based on their growth requirements and ability to perform certain biochemical tests. The key biochemical reactions necessary to separate the vibrios into these six groups include the following: (1) the requirement of NaCl for growth in nutrient broth; (2) oxidase production; (3) nitrate reductive capacity; (4) myo-inositol fermentation; and (5) the presence or absence of arginine dehydrolase, lysine decarboxylase, and ornithine decarboxylase. Additional biochemical reactions may be used for complete speciation.

These tests are used in the microbiology laboratory to exclude certain diagnostic possibilities. Most vibrios are oxidase positive, with the exception of V metschnikovii. With the exception of V cholerae and V mimicus, isolates require 1% NaCl supplementation to adequately perform biochemical tests. The six groups are as follows:

  • Group 1 consists of V choleraeand V mimicus. These are readily distinguished from the other vibrios by their ability to grow in nutrient broth, without NaCl supplementation.
  • Group 2 consists of V metschnikovii, which is differentiated from other vibrios by its inability to produce oxidase and reduce nitrate to nitrite.
  • Group 3 consists of V cincinnatiensis, which is differentiated from other vibrios by its ability to ferment myo-inositol.
  • Group 4 consists of V hollisae, which is differentiated from other vibrios by its inability to hydrolyze arginine and to decarboxylate lysine and ornithine.
  • Group 5 consists of V damsela, V fluvialis, and V furnissii.Unlike some of the other vibrios, this group produces arginine dihydrolase.
  • Group 6 consists of V alginolyticus, V parahaemolyticus,


V vulnificus
, and V carchariae. These organisms are differentiated from other vibrios by a combination of their ability to produce lysine decarboxylase and their inability to hydrolyze arginine.

BOX 57-2 Treatment of Cholera

Principal Consideration

Fluid and Electrolyte Replacement, Acid-Base, and Glucose Management

 

Children1

Adults

First Choice

· Ampicillin, 250 mg orallyor IV every 6 h for 5 d

· Tetracycline, 250 mg orally or IV every 6 h for 5 d

· During pregnancy, ampicillin is the drug of choice (dosage as below)

Second Choice

· TMP/SMX2 orally or IV (>2 months old); TMP, 3–6 mg, + SMX, 15–30 mg/kg every 12 h for 5 d

· Ampicillin, 250 mg orally or IV every 6 h for 5 d

Penicillin Allergic

· TMP/SMX2 (dosage as above)
OR
Furazolidone (liquid = 3.33 mg/ml): >5 years old, 7.5–15 ml; 1–4 years old, 5.0–7.5 ml; 1 month–1 year old, 2.5–5.0 ml orally every 6 h for 5 d

· Tetracycline (dosage as above)

OR

· TMP/SMX2 orally or IV: TMP, 160 mg, + SMX, 800 mg orallyor IV every 12 h for 5 d
OR

· Furazolidone, 100 mg orally every 6 h for 5 d

1Tetracycline and the quinolones are generally not given to children because of potential toxicity; however, in cases in which strains of V cholerae are resistant to other drugs and severe disease is present, tetracycline or quinolones may be considered.
2TMP/SMX, Trimethoprim sulfamethoxazole; treatment may be changed based on susceptibility studies.

CLINICAL SYNDROMES

Noncholera vibrios cause both enteritis and extraintestinal disease (Box 57-3). In the United States, Vibrio species other than V cholerae are far more common causes of Vibrio-associated gastroenteritis. These agents include V parahaemolyticus, V mimicus, V hollisae, and others. The enteritis caused by these organisms is characterized by fever, mild-to-moderate abdominal pain and cramping, and diarrhea, which may be either watery or bloody. Many of the pathogenic, noncholera vibrios are also halophilic (NaCl enhances growth) and have been associated with the consumption of raw or undercooked shellfish. V parahaemolyticus is the most common cause of shellfish-associated gastroenteritis in the United States. In most instances, the enteritis is self-limited, but complications may occur. Septicemia with severe morbidity and death has occurred following noncholera Vibrio gastroenteritis.

BOX 57-3 Clinical Syndromes of Other Vibrio Species

Enteric Disease

· Recent ingestion of raw or undercooked shellfish

· Acute onset of diarrhea, which is usually watery, but may be bloody and dysenteric

· Low-grade fever, chills, and mild-to-moderate abdominal cramping

Extraintestinal Disease

· Exposure of a wound to seawater or recent ingestion of raw or undercooked shellfish

· Poor wound healing with suppuration, cellulitis, and possibly subcutaneous abscess formation

· A sepsislike syndrome associated with hemorrhagic vesicular or bullous skin lesions, especially in individuals with liver cirrhosis or another immunocompromising condition

Extraintestinal disease may be caused by V vulnificus or V alginolyticus. These organisms are also halophilic and are associated with shellfish ingestion and saltwater exposure. Manifestations of extraintestinal disease may include wound infections, cellulitis, bullous skin lesions, or septicemia. Patients with cellulitis and wound infections caused by these organisms often report exposure to saltwater. In immunocompromised patients, such as those with cirrhosis or diabetes mellitus, fatal septicemia may occur. If these organisms are suspected clinically, the clinician should notify the laboratory, since NaCl supplementation is required for optimal growth.

NONCHOLERA GASTROENTERITIS

Clinical Findings

  1. Signs and Symptoms.Noncholera gastroenteritis is often associated with recent ingestion of raw or undercooked shellfish and often occurs in the summer or early fall in the United States. A typical presentation includes explosive diarrhea, low-grade fever and chills, and mild-to-moderate abdominal pain with cramping. The diarrhea is usually watery but may contain blood and neutrophils.

Dehydration is not as severe as that seen with Vibrio cholerae infections, but deaths may occur in children and the elderly. The incubation period is ~1 day but ranges from 5 h to 4 days. The diarrhea produced is probably secondary to a combination of exotoxin production and superficial invasion. The patients in which exotoxin production predominates may demonstrate a more watery stool. When mucosal invasion occurs, a dysenteric stool similar to that present in shigellosis may be seen. Secondary spread of these organisms is rare.

  1. Laboratory Findings.Dehydration and electrolyte abnormalities are usually less severe than those present in cholera but may become profound in children and the elderly. Culture and biochemical identification of the isolate is the standard method of establishing the etiologic agent of disease. The key biochemical reactions for rapidly subcategorizing Vibriospecies are listed in the Microbiology section. Many of the group characteristics are based on an organism's ability to perform particular biochemical tests. Therefore it is important to remember that 1% NaCl supplementation is required for some organisms to adequately perform biochemical reactions. NaCl enrichment broths or tellurite-taurocholate-peptone broth may be used for enhanced recovery of these organisms.
  2. Differential Diagnosis.See differential diagnosis for V choleraeinfection.

 

EXTRAINTESTINAL DISEASE

Clinical Findings

  1. Signs and Symptoms.Patients with septicemia, wound infections, or ear infections caused by a Vibriospecies frequently have a history of shellfish ingestion or saltwater exposure. Clinical manifestations vary depending on the site of infection. Healing wounds, in appropriately exposed individuals, may become secondarily infected by marine vibrios. Suppuration may occur, and subcutaneous abscesses may form. A spreading, violaceous appearance around the wound, which is warm to the touch is indicative of cellulitis. The clinical findings of V alginolyticus-associated otitis media are nonspecific. Findings in V alginolyticus-associated otitis externa include a reddened, often painful external auditory canal.

In immunocompromised and debilitated patients, especially those with liver cirrhosis, a septicemia syndrome, with multiple bullous skin lesions may occur. This is usually caused by V vulnificus and is often fatal. V vulnificus, which may be introduced by the ingestion of raw or undercooked shellfish, may transmigrate the intestinal mucosa and invade the bloodstream with little or no gastrointestinal symptomatology. Infected patients often develop signs and symptoms of septic shock, such as fever, chills, and hypotension. Shortly thereafter, erythematous skin lesions occur, which develop into hemorrhagic vesicles-bullae and finally ulcerate. Although this syndrome is rare, it is important to recognize it, since its mortality rate is ~50%.

  1. Laboratory Findings.Hematopoietic findings are variable and may demonstrate either leukocytosis or leukopenia with left-shifted hematopoiesis. The isolation of vibrios from patients with extraintestinal disease is usually not difficult. The selective and differential agars are not required since the sites of culture are normally sterile. Vibrios causing extraintestinal disease are usually isolated on routine 5% sheep's blood agar. If an extraintestinal Vibrioinfection is suspected, the microbiology laboratory should be notified. The supplementation of media with 1% NaCl may aid in the more rapid identification of the Vibriospecies.
  2. Imaging.Ultrasound or computerized tomography guidance may be useful for identifying and assisting in drainage of deep abscesses.
  3. Differential Diagnosis.Improperly cared for wounds may be colonized and infected by a variety of bacteria. When these wounds have been exposed to salt water or the patient has recently eaten raw or undercooked shellfish, a vibrio infection should be considered.

Although immunocompromised patients may be infected by a variety of microbes, an extraintestinal vibrio infection should be considered when skin lesions and a sepsislike syndrome are present in association with the recent ingestion of raw or undercooked shellfish.

  1. Complications.The diarrhea that results from noncholera vibrio infections rarely results in significant dehydration, except in children and the elderly. The hydration status of pregnant women should be carefully monitored to prevent severe dehydration and possible fetal loss.

Extraintestinal vibrio infections may result from septicemia following ingestion of raw shellfish or from direct inoculation of marine vibrios. If septicemia occurs, metastatic foci of infection may be present in virtually any organ. The consequences of extraintestinal vibrio infections during pregnancy are unclear because of the paucity of cases.

Treatment

  1. Primary Therapy.Enteritis caused by V parahaemolyticusis usually self-limited and requires no therapy. In severe cases of noncholera Vibrio gastroenteritis, the principles of cholera therapy should be followed. Patients with extraintestinal disease due to V vulnificus, and V alginolyticus should undergo appropriate wound débridement and abscess drainage as indicated and should be treated with antimicrobial agents (Box 57-4). Patients with systemic symptomatology may also require extensive supportive measures for survival.
  2. Antimicrobial Therapy.Antimicrobial therapy does not shorten the duration of noncholera enteritis and is not recommended in uncomplicated cases. If enteritis is complicated by septicemia, specific antimicrobial therapy should be determined based on the antimicrobial susceptibility profile.

Extraintestinal vibrio infections may be treated with tetracycline, cefotaxime, or possibly ciprofloxacin until the antimicrobial susceptibility profile becomes available.

Prognosis

The prognosis for noncholera gastroenteritis is usually excellent. The prognosis may become guarded in children, the elderly, and pregnant women with severe dehydration.

If appropriate surgical and medical therapy is given, the prognosis for extraintestinal Vibrio infections is usually good in the immunocompetent host. In immunocompromised patients, especially those with cirrhosis or diabetes mellitus, the prognosis is guarded to poor.

Prevention & Control

Noncholera vibrio enteritis and many cases of extraintestinal vibrio infections may easily be avoided by abstinence from raw shellfish (Box 57-5). The thorough cooking of shellfish renders it safe for consumption. Regardless of the hazards, raw oysters and clams remain popular in many parts of the world. Warnings concerning the possible health hazards should be posted in plain view in restaurants that serve these dishes, and additional caution should be directed specifically to individuals with liver disease or other immunocompromising conditions. Individuals with healing wounds should avoid exposing the wounds to seawater.

BOX 57-4 Treatment of V vulnificus and V alginolyticus Infections

Principal Consideration

Surgical Débridement and Abscess Drainage Combined with Antimicrobial Therapy

 

Children1

Adults

First Choice

· Cefotaxime IV: newborn to 1 wk, 50 mg/kg/dose every 12 h; 1–4 wk, 50 mg/kg/dose every 8 h; 1 month–12 years & <50 kg, 50–180 mg/kg/d divided every 4–6 h; 1 month–12 years & >50 kg, adult dose until symptoms have subsided

· Tetracycline, 250 mg IV every 6 h until symptoms have subsided

· During pregnancy, cefotaxime is the drug of choice (dosage as below)

Second Choice

· Tetracycline IV: 25–50 mg/kg/d divided every 8–12 h

· Cefotaxime, 2 g IV every 4–8 h until symptoms have subsided
OR

· Ciprofloxacin, 400 mg IV every 12 h until symptoms have subsided

Penicillin Allergic

· Tetracycline (dosage as above)

· Tetracycline (dosage as above)

1Tetracycline may discolor the teeth of young patients. Treatment may be changed based on susceptibility studies.

Large-scale commercial oyster and clam farming is becoming more established. In the future, this may present additional hazards. The colonization of an entire mollusk bed by pathogenic vibrios could occur if abundant shellfish are present in close proximity. Additionally, the spread of pathogenic vibrios among mollusk beds could result if numerous beds are located in close proximity. This could result in large numbers of contaminated shellfish being present in the same harvest and could result in epidemics. Therefore, in the future, adequate monitoring systems may be needed more than ever before to prevent possible outbreak situations.

BOX 57-5 Control of Vibrio Infections

Prophylactic Measures

· Clean water and effective sanitation

· Avoidance of raw or undercooked shellfish

· Avoidance of seawater

Isolation Precautions

· Avoidance of stool from infected patients

CAMPYLOBACTER INFECTIONS

Essentials of Diagnosis

  • History of ingestion of appropriate foodstuffs.
  • Causes enteritis, characterized by rapid onset of watery to bloody diarrhea with low-grade to moderate fever and moderate-to-severe abdominal cramping.
  • Extraintestinal infections include sepsis, thrombophlebitis, endocarditis, and infection of aortic aneurysm.
  • Laboratory isolation of a gram-negative “seagull” shaped bacteria, which becomes coccoid as the culture ages.
  • These bacteria grow optimally in a microaerophilic, 5–10% oxygen environment; the growth of some species is enhanced by culture at 42°C.

 

General Considerations

  1. Epidemiology.Campylobacterspecies are intestinal commensals in many animals, including cattle, pigs, sheep, chickens, and turkeys. Contamination of foodstuffs during meat and dairy processing is thought to significantly contribute to the spread of disease. Unpasteurized dairy products, undercooked meats, and contaminated water serve as the vehicles for Campylobacter and other bacterial pathogens. Human-to-human transmission by way of a fecal-oral route or through contaminated blood is also possible.

In developing countries where overcrowding and poor sanitation conditions exist, the carriage rate of Campylobacter jejuni from healthy individuals is much higher and human-to-human transmission may be greater. Campylobacter is one of the etiologic agents of the infantile and childhood diarrhea diseases in developing countries. Although carrier rates are elevated in adults, symptomatic disease is less common; this is presumably because of enhanced immunity. In tropical climates, the incidence is higher during the rainy season and may be related to the corresponding overcrowding and contamination of local water supplies.

In developed countries, the carriage rate is very low (< 1%). This may result from more effective treatment of human waste, requisite pasteurization of dairy products, and educational efforts regarding the thorough cooking of meat products. In developed countries, campylobacteriosis tends to occur sporadically and year round, with peak incidence in months of the spring or fall. In many instances, infections can be linked to the ingestion of undercooked meats, contaminated milk, or contaminated water supplies.

  1. Microbiology.Campylobacterare weakly gram-negative, curved or “seagull” shaped bacteria, with single polar flagella (Figure 57-1). Although usually bacillary, many Campylobacter species become coccoid as the culture ages. Special culture conditions, including selective media, a microaerophilic environment (5–10% oxygen), and for some species, culture at 42°C (vs 35–37°C), are required for optimal recovery of Campylobacter species.
 

Figure 57-1. Curved, “seagull”-shaped, Campylobacter fetus in a blood culture. (Gram stain, 1000)

  1. Several Campylobacterspecies cause human disease (Box 57-6). C jejuniand C fetus are the prototypic etiologic agents for enteric and extraintestinal disease, respectively. Table 57-1 shows the principal biochemical reactions used to separate these and other Campylobacter species.
  2. Pathogenesis.Establishment of infection in the small bowel and colon requires that an adequate inoculum is ingested and sufficient organisms survive after passage through the stomach and that the organisms attach and possibly invade enterocytes. Studies with volunteers have shown that as few as 500–1000 organisms may cause disease. Approximately 9000 organisms reportedly provide the highest illness-to-infection ratio; however, strain variation occurs.

Like Salmonella, Campylobacter organisms are susceptible to hydrochloric acid. Entry with foods that buffer stomach acid is important for gastric passage of viable organisms. C jejuni thrives in the small intestine and colon and is able to replicate in human bile. Infection is initiated by adhesion and colonization. Bacterial proteins that are important for this phase of infection include the superficial bacterial antigen PEB1, and possibly the newly characterized periplasmic binding protein P29. Peritrichous, piluslike structures that are present only when the organism is grown in the presence of bile, may also aid in adhesion.

Motility and the adhesion properties of the flagellar protein flagellin are additional virulence factors important for bacterial infection. The pathologic changes in the bowel wall and the occasional detection of C jejuni bacteremia are highly suggestive of bacterial invasion. Mild infections may show only an increased cellularity of the lamina propria due to neutrophils, lymphocytes, plasma cells, and histiocytes. Severe cases may disclose exudative enteritis with ulceration and crypt abscesses.

Extracellular toxins that cause cytopathic changes have been demonstrated. Additionally, a choleralike exotoxin has been suggested as a mechanism of diarrhea. The importance of these toxins remains to be elucidated, since non–toxin-producing strains have also been shown to cause disease.

C fetus is the Campylobacter species most frequently isolated from blood and is an important agent of extraintestinal disease. Enhanced invasion in a mouse model has been associated with the presence of a surface S protein. The S protein serves as a capsule and imparts an antiphagocytic property to the bacterium. This antiphagocytic property is due in part to the inhibition of the opsonizing complement component C3b. The S protein is antigenically variable as a result of rearrangements between highly homologous protein-encoding genes.

 

BOX 57-6 Clinical Syndromes of Campylobacteriosis

 

Intestinal (C jejuni)

Extraintestinal (C fetus)

More Common

· Acute onset of diarrhea, which may be watery or bloody

· Associated low-grade-to-moderate fever, nausea, vomiting, malaise, and moderate-to-severe abdominal pain

· Septicemia, fever, chills, and myalgias, without definitive localization

· Endocarditis

· Thrombophlebitis with vessel necrosis

· Fetal loss

Less Common

· Electrolyte abnormalities caused by volume depletion

· Guillain-Barré syndrome

· Pericarditis

· Cellulitis

· Salpingitis

· Reiter's syndrome

· Meningoencephalitis

· Septic arthritis

· Spontaneous bacterial peritonitis

· Guillain-Barré syndrome

· Osteomyelitis

· Empyema

CAMPYLOBACTER ENTERITIS

Clinical Findings

  1. Signs and Symptoms.The incubation period for Campylobacterenteritis is between 1 and 7 days. The rapidity of onset and the severity of disease appear to be related to the inoculating dose. Prodromal fever, headache, malaise, and myalgias are often present 1–2 days before the onset of diarrhea. Campylobacter-induced diarrhea is variable in consistency and ranges from watery to bloody. The diarrhea is often accompanied by a low-grade to moderate fever and moderate-to-severe abdominal cramping, which is relieved by defecation. The disease is usually self-limited over several days; however, relapses can occur in 5–10% of untreated patients.
  2. Laboratory Findings.Direct examination of stool specimens often demonstrate curved, vibriolike rods with a characteristic darting motility. Leukocytes are present in 75% of patients with Campylobacterenteritis. Culture on selective media with incubation at 42°C, in a microaerophilic environment, is used for the enhanced detection of most of the enteropathic Campylobacter species (Figure 57-2). The most common causes of Campylobacter enteritis, C jejuni and C coli, both grow well at 42°C in a microaerophilic environment and are resistant to cephalothin. Therefore a selective antibiotic media containing cephalothin is often used. Under these conditions, colonies appear gray and spreading and are oxidase positive. Gram stain reveals gram-negative, curved organisms. The differentiation of C jejuni from C coli depends principally on the ability of the isolate to hydrolyze hippurate (C jejuni subspecies jejuni hydrolyzes hippurate and C coli do not). These techniques, however, will not identify the far rarer cases of enteritis caused by C fetus and some other Campylobacter species, which do not grow well at 42°C and are inhibited by cephalothin.
 

Figure 57-2. Stool culture of patient with campylobacteriosis due to Campylobacter jejuni. The extensive watery diarrhea has flushed the bowel of normal enteric flora; note the absence of growth on both the MacConkey and the Hektoen-Enteric agar.

Table 57-1. Important reactions for Campylobacter species.

 

Species

Hippurate Hydrolysis

Growth at

Susceptibility to

25°C

42°C

Nalidixic Acid

Cephalothin

More 
Common

· C jejuni

· C coli

· C fetus

+
-
-

-
-
+

+
+
-

Variable
Susceptible
Variable

Resistant
Resistant
Susceptible

Less 
Common

· C upsaliensis

· C hyointestinalis

-
-

-
+

+
+

Susceptible
Resistant

Susceptible
Susceptible

 

EXTRAINTESTINAL CAMPYLOBACTERIOSIS

Clinical Findings

  1. Signs and Symptoms.Campylobacter fetus, a less frequent cause of enteritis, is the most common cause of extraintestinal disease; other Campylobacterspecies that may also cause extraintestinal disease include C jejuni, C coli, C laridis, C sputorum, and C hyointestinalis. C fetus infection may manifest as fever, chills, and myalgias, without definitive localization; additionally, this organism displays a propensity to infect vascular structures. Endocarditis, intravascular infection of abdominal aortic aneurysms, and septic thrombophlebitis with vessel necrosis have been reported. Fetal death, even with appropriate antibiotic therapy, may occur. Fetal complications most commonly occur during the second trimester of pregnancy. Additional manifestations may include pericarditis, meningoencepalitis, septic arthritis and osteomyelitis, spontaneous bacterial peritonitis, salpingitis, empyema, and cellulitis.
  2. Laboratory Findings.In cases of suspected extraintestinal campylobacteriosis, cultures should be plated on nonselective 5% sheep's blood agar and incubated at 37°C in a microaerophilic environment. Subcultures from blood culture broth systems should be handled in a similar fashion. Identification ofC fetusmay be accomplished by testing susceptibility to cephalothin (susceptible), growth inhibition at 42°C, positive catalase reaction, and characteristic Gram stain morphology.

Differential Diagnosis

The differential diagnosis for Campylobacter enteritis includes all enteric bacterial, viral, and parasitic pathogens. This differential is usually resolved by clinical history, stool culture, ova and parasite examination, and, if necessary, viral testing (ELISA, culture, or electron microscopy).

The differential diagnosis for extraintestinal campylobacteriosis varies according to the site involved. Although C fetus may be identified by routine blood culture methods, the incubation conditions used are not optimal for isolation. A high index of suspicion must be maintained since special bacterial culturing techniques may be necessary for optimal recovery of the organism.

Complications

Like other bacterial enteritides, complications of Campylobacter enteritis include volume depletion and electrolyte imbalances. Patients with an HLA-B27 phenotype may develop postinfectious arthropathies (Reiter's syndrome) similar to that produced by other bacterial enteric pathogens. Guillain-Barré syndrome rarely occurs following Campylobacter enteritis. Guillain-Barré syndrome has been associated with autoantibodies directed to N-acetylgalactosaminyl GD1a, GD1b or similar epitopes. Similar epitopes have been shown to occur in the lipopolysaccharides of C jejuni and may represent the immunogenic stimulus.

Extraintestinal disease may occur as the result of septicemia and include septic thrombophlebitis, abscess formation, and endocarditis.

Treatment

Fluid and electrolyte replacement therapy is of principal importance (Box 57-7). The benefit of antibiotic therapy for enteric campylobacteriosis remains to be determined. Antibiotic treatment is indicated in patients with high fever, bloody stools, worsening clinical symptoms, or greater than eight stools per day. Erythromycin is the drug of choice for children. Ciprofloxacin is an alternative therapy for adults. Point mutations in the DNA gyrase gene, gyrA, have been shown to confer quinolone resistance. This may occur during therapy; therefore both antimicrobial susceptibility data and close clinical follow-up are required.

BOX 57-7 Treatment of Campylobacteriosis

 

Children

Adults

First Choice

· Erythromycin, 30–50 mg/kg/d in divided doses for 5–7 d

· Erythromycin, 250 mg orally every 6 h for 5–7 d

Second Choice

 

· Ciprofloxacin, 500 mg orally every 12 h for 5–7d

Parenteral antibiotics should be administered for extraintestinal disease based on the results of antimicrobial susceptibility testing. Endocarditis requires at least 4 weeks of therapy. Depending on susceptibility, central nervous system infections should be treated with ampicillin, a third-generation cephalosporin, or chloramphenicol.

Prognosis

Severe dehydration and electrolyte imbalances may cause death. This most frequently occurs in children, particularly in underdeveloped and impoverished areas that lack adequate healthcare. Long-term sequelae such as Reiter's syndrome or Guillain-Barré syndrome, although infrequent, may be disabling.

Extraintestinal disease caused by C fetus may contribute significantly to morbidity and mortality in immunocompromised patients. These patients may be at increased risk for bacterial enteric infections and associated extraintestinal disease. Infections may be persistent and more severe than in normal hosts. In these patients, the time to initiation of appropriate antibiotic therapy is an important prognostic indicator.

BOX 57-8 Control of Campylobacteriosis

Prophylactic Measures

· Avoidance of undercooked food

· Adequate handwashing

Prevention

Pasteurization, washing foods when feasible, thorough cooking, and hand washing are useful preventive measures (Box 57-8).

REFERENCES

Blaser MJ: Campylobacter and related species. In Mandell GL et al: Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995, pp. 1948.

Carpenter CCJ: Other pathogenic vibrios. In Mandell GL et al: Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.

Greenough WB III: Vibrio cholerae and cholera. In Mandell GL et al: Principles and Practice of Infectious Diseases, 4th ed. Churchill Livingstone, 1995.

Kaper JB et al: Cholera. Clin Microbiol Rev 1995;8:48.

Keusch GT: Cholera. In JD Wilson et al: Harrison's Principles of Internal Medicine, 12th ed. McGraw-Hill, 1991.

Kuzniec S et al: Abdominal aortic aneurysm infected with Campylobacter fetus spp. fetus. Report of a case and review of the literature. Rev Hosp Clin Fac Med Sao Paulo 1995;50:284.

McLaughlin JC: Vibrio. In Murray PR et al: Manual of Clinical Microbiology, 6th ed. American Society for Microbiology Press, 1995, 465.

Nachamkin I: Campylobacter and Arcobacter. In Murray PR et al: Manual of Clinical Microbiology, 6th ed. American Society for Microbiology Press, 1995.

Wallis MR: The pathogenesis of Campylobacter jejuni. Br J Biomed Sci 1994;51:57.