Ann IM 2006;145:758; Nejm 2002;346:334; Am J Gastro 1997;92:739

Cause: Clostridium difficile (C. diff), an anaerobic, spore-forming bacillus.

Epidem: The reported disease incidence has been rising steadily, probably as a result of better detection, physician awareness, and the emergence of virulent strains. The illness is more common in the elderly, in pts who have been hospitalized, in renal pts, in surgical pts, in IBD pts (Gut 1983;24:713), in pts taking PPIs (CMAJ 2004;171:33) and in those with malignancy. Carriage rates in Europe and the U.S. are 0-3% in healthy adult subjects and 35-65% in healthy neonates. The organism is frequently acquired in the hospital through the ingestion of spores. The spores resist digestion and become vegetative when they reach the colon. Infected pts are a disease reservoir. The organism can be recovered from many surfaces in pt care areas. It is transmitted via healthcare workers’ hands or stethoscopes (J Antimicrob Chemother 1998;41[suppl C]:59).

Pathophys: Antibiotic-associated diarrhea is a mild, self-limited illness of unknown mechanism that is associated with many antibiotics, clears with cessation of antibiotics, and causes no structural damage to the colon. C. diff causes a spectrum of illness, from diarrhea without obvious macroscopic colitis to more severe forms associated with inflammatory changes in the colonic mucosa. Before the discovery of C. diff, this illness was called pseudomembranous colitis because of the endoscopic and histologic findings, and it was thought to be due to Staphylococcus aureus. The discovery that 10% of pts given clindamycin developed pseudomembranous colitis led to the discovery that toxins produced by C. diff are the cause of the illness (BMJ 1995;310:1375). The use of broad-spectrum antibiotics is the initiating event in the vast majority of cases of C. diff colitis. Changes in the normal intestinal flora seem permissive for the proliferation of the organism. The organism is most often acquired
nosocomially from the environment. When the colonized pt is exposed to broad-spectrum antibiotics, there is rapid overgrowth of the organism. Almost all antibiotics have been implicated in C. diff colitis, including clindamycin, penicillins, cephalosporins, quinolones, erythromycin, tetracyclines, and sulfonamides. Disease is more likely to follow high-dose, prolonged courses of rx, especially if multiple agents are used.

C. diff causes colitis by the elaboration of toxins A and B in the colon lumen. Toxin A causes an inflammatory reaction and fluid secretion. Toxin B is a powerful cytotoxin in tissue culture but notenterotoxigenic in animals (Nejm 1994;330:257). A variety of other virulence factors may be important in promoting colonization and tissue destruction (J Antimicrob Chemother 1998;41[suppl C]:13). From 5% to 25% of strains do notproduce either toxin and do notcause diarrhea. The disease has increased in incidence and virulence in recent years with the emergence of an epidemic strain of C. diff designated B1/NAP1. This strain is characterized by high production of toxins A and B and other virulence factors (Ann IM 2006;145:758).

Sx: Pts with mild disease usually present with the sudden onset of watery diarrhea during or shortly after a course of antibiotics. However, there may be a delay of many weeks between antibiotic use and illness. Those with more severe illness may have severe diarrhea, substantial abdominal pain, and fever.

Si: In mild disease, there may be mild abdominal tenderness or FOBT-positive stool. In more severe disease, fever, ileus, signs of volume depletion, delirium, and abdominal distension may be seen. Localized peritoneal signs are common in severe illness and usually improve with appropriate rx. A small subgroup will present with fulminant colitis with toxic dilatation, diffuse peritonitis, or signs of perforation.

Crs: Relapse is frequent, occurring in 15-35% of pts (mean about 20%). Most treated ambulatory pts improve over 2-3 days with appropriate rx, and 95% are fully resolved after a 10-day course (Nejm 1994;330:257). However, the disease has become more virulent in the last decade with a dramatic rise in mortality and complications in hospitalized pts (Cmaj 2004;171:468).

Cmplc: Fulminant colitis with peritonitis, gram-negative sepsis, and perforation.

Diff Dx: C. diff disease needs to be distinguished from simple antibiotic-related diarrhea. In pts with mild sx, this means stopping the antibiotic and waiting. In pts with moderate illness, stool studies are done for C. diff. If these are negative and suspicion is high, endoscopic studies may be indicated. In pts who acquire diarrhea in the hospital, the likely causes are C. diff, drugs, or enteral feeding. The yield for other pathogens in hospital-acquired diarrhea is pathetically low, and routine stool cultures are usually wasteful.

Lab: Stool immunoassays for toxin A and B are the most widely used tests in the U.S. They are 90% sensitive and vary by brand of test. They are highly specific. A negative test in an affected pt is, therefore, notrare in clinical practice. Ordering a second test on a different day will increase the yield (Ann IM 1995;123:835). Variant strains of toxin can be missed by commercial assays (Ann IM 2001;135:434), and 1-2% of cases involve strains that produce only toxin B (Nejm 2002;346:334). Tissue culture is the most sensitive and specific test and is usually reserved for investigating outbreaks when identification of the strain may be important. Tissue culture for toxin B is cumbersome and only 90% sensitive. PCR of stool for toxin B may have the best combination of sensitivity, specificity, and cost but is notwidely available (Clin Gastroenterol Hepatol 2004;2:669). Latex agglutination detects a C. diff metabolic enzyme, notthe toxin (J Clin Microbiol 1991;29:2639). It detects
nonpathogenic strains and has other cross reactivities, making its specificity inadequate. Leukocytosis is common.

X-ray: KUB is usually normal in mild disease, but as disease progresses, there may be radiographic signs of colitis such as thumbprinting (irregularity in the mucosal outline of the colon about the size of a thumbprint) or toxic dilatation. CT scan, often done in severely ill pts before the dx is appreciated, may show thickening of the colonic wall due to colitis.

Endoscopy: In mild disease there is minimal or no gross colitis. When the disease progresses, there is a pathognomonic finding of pseudomembranes at colonoscopy. They are raised, yellowish plaques with a stuck-on appearance, varying from a few mm to more than a cm in diameter. In severe disease they may coalesce into large segments. They are easily stripped off by the endoscope (the origin of the term pseudomembrane) (Am J Gastro 1997;92:739). The intervening mucosa may be nearly normal or edematous, friable, and erythematous, depending on disease severity. In perhaps 10% of pts, the pseudomembranes are confined to the proximal colon and may be missed at sigmoidoscopy (GE 1982;83:1259). These pts may be difficult to dx because they may have less diarrhea given the relatively spared left colon. Neutropenic pts will nothave pseudomembranes, because they do nothave enough white cells to make them (BMJ 1995;310:1375).

Rx: Whenever possible, antibiotics should be stopped. Some experts suggest that since many cases will resolve spontaneously, antibiotic rx should notbe routinely given (Am J Gastro 1997;92:739). However, most clinicians only order a diagnostic test in pts who are significantly affected and rx all positives. Fluid and electrolyte replacement may be needed. Antimotility agents should be avoided since this prolongs the contact of the mucosa with toxin and may worsen the illness.

In pts with mild to moderate disease, oral metronidazole 250-500 mg po tid for 7-10 d is the drug of choice based on cost. Some strains are metronidazole-resistant, but this is uncommon. In mild disease metronidazole and oral vancomycin are equally effective, but in severe disease vancomycin is superior (Clin Infect Dis 2007;45:302). In pts with severe disease, who often cannot take oral rx, metronidazole is given as 500-750 mg iv q 6-8 d depending on body weight and severity of illness. Oral vancomycin is wildly expensive and should be used when pts do notrespond to metronidazole, cannot tolerate metronidazole, have more severe illness, or have a contraindication to metronidazole use (eg, pregnancy). The usual dosage for vancomycin is 125 mg po qid for 7-10 d, but doses up to 500 mg po qid are used in pts with severe illness. The drug can be given by NGT where needed. Oral vancomycin should probably be used concomitantly with iv metronidazole in pts who are critically ill.

Vancomycin given by iv does notwork because there is inadequate excretion into the colon, where the organism lies. Vancomycin enemas can be given as adjunctive rx in severely ill pts (Clin Infect Dis 2002;35:690), and iv immunoglobulin can be considered in these pts based on anecdotal evidence (Ann IM 2006;145:758).

Cholestyramine or colestipol bind the toxin (and vancomycin!) but are marginal therapies compared to antibiotics. Bacitracin is less effective than vancomycin (GE 1985;89:1038), and a variety of other agents have been used (Aliment Pharmacol Ther 1997;11:1003).

Pts with a substantial symptomatic relapse should simply receive a second course of rx with metronidazole, since the cause of relapse is rarely drug resistance. Alternatively, they can be treated with vancomycin. Relapse occurs by germination of spores in the colon, by reinfection in the hospital setting, or due to another course of antibiotics. There is no well-defined approach to pts with multiple relapses. Some experts use a prolonged course of
oral vancomycin; others use intermittent vancomycin (125 mg po q 2-7 d for 1 or 2 months, tapered with a nonscientific flourish). The hope is to kill vegetative forms newly developed from the spores that escape the antibiotic. Other forms of rx include lactobacillus preparations (ineffective by RCT [Mayo Clin Proc 2001;76:883]), oral Saccharomyces boulardii (Aliment Pharmacol Ther 1998;12:807; GE 1989;96:981), fecal enemas, donor feces by NGT (Clin Infect Dis 2003;36:580), and iv gamma globulin (Gut 2002;51:456).

Pts with severe disease may require surgery for perforation or fulminant colitis with a mortality of 25-67%. Retrospective reviews suggest that pts are more likely to survive if they have subtotal colectomy rather than simple diversion or lesser degrees of colectomy (Am J Gastro 2008;103:3195). Pts with diarrhea should be isolated to prevent spread of disease. Hand washing with soap and water is more effective than using alcohol-based hand cleaners, which do notkill spores effectively. The load of spores and vegetative forms is reduced by thorough disinfection of equipment and by cleaning the environment with 10% bleach. Rx of asymptomatic carriers with metronidazole or vancomycin is ineffective (Ann IM 1992;117:297).

Gastroenterol Clin North Am 2001;30:709; Clin Lab Med 1999;19:489

Cause: Most human Campylobacter infections are caused by Campylobacter jejunii, but other species, including C. coli and any of 12 other subspecies, may cause human disease. The organisms are gram-negative, and are curved or spiral-shaped rods.

Epidem: Campylobacter is the most common of the bacterial causes of diarrhea after C. diff. There is a bimodal peak of incidence (infants and young adults), but it affects all ages. Sporadic cases are usually associated with undercooked or mishandled poultry and less often with other meats, untreated water, or raw milk. Epidemics are associated with raw milk or contaminated water.

Pathophys: The ingestion of as few as 500 organisms can result in infection. The bug colonizes the distal ileum and colon, where invasion occurs and intestinal absorption is inhibited, resulting in diarrhea.

Sx: The incubation period is 1-5 d. Pts typically present with crampy pain, watery diarrhea (often mixed with blood and mucus), and fever. Headache may be especially prominent and a clue to the etiology.

Crs: The typical course is a 4- to 5-d illness with 1-2 wk for complete resolution. Of those seeking medical attention, 20% have sx for longer than a wk (Am J Gastro 1993;88:1667). The relapse rate is 10-20%.

Cmplc: There is firm serologic and culture-based evidence that Campylobacter infection can result in Guillain-Barré syndrome (Clin Microbiol Rev 1998;11:555; Infect Dis Clin North Am 1998;12:173). A syndrome of reactive arthritis in HLA-B27-positive pts may occur (within 1-3 wk) and resolve within 6 months (Arch IM 1983;143:215). Pancreatitis has been reported in 6% of pts sick enough to be hospitalized (Arch IM 1983;143:215).

Lab: Stool culture is the test of choice. Since the organism is fastidious, a single culture may notbe adequate (Am J Gastro 1993;88:1667). An experienced observer may be able to pick out the
organism on a Gram stain using carbol fuchsin as a counterstain because it is a curved rod, giving a gull wing appearance. There are no other rapid methods of adequate sensitivity and specificity for commercial use.

Endoscopy: Usually endoscopy is notindicated, but if done, it shows features of a nonspecific colitis with erythema, edema, and loss of the vascular pattern in involved segments.

Rx: Antibiotic treatment shortens the course of illness by about a day and is more effective if given early in the course (Clin Infect Dis 2007;44:696). However, the illness is usually self-limited, and antibiotic resistance is growing. Pts who are slow to recover, who have continued sx of dysentery, or who are immunocompromised should be treated with erythromycin 250 mg po qid for 5 d. In a subgroup of ill pts, rx with a quinolone (eg, ciprofloxacin 500 mg po bid × 5 d) given on presentation before the culture results are available may further shorten the illness (p 16). However, increasing quinolone resistance limits the value of this approach. In Europe and Asia, quinolone resistance ranges from 41-88% and in North America the rate has climbed to over 10% (GE 2000;118:S48). Azithromycin 500 mg daily is an alternative to erythromycin.

Dis Mo 1999;45:268; Am J Gastro 1993;88:1667; South Med J 1978;71:1540

Cause: There are more than 2200 serotypes of Salmonella. The species most likely to cause gastroenteritis in the U.S. are S. typhimurium, S. enteritidis, S. heidelberg, and S. newport.

Epidem: About 40,000 cases are reported annually in the U.S., representing about 1-5% of the actual total. Transmission is by contaminated water or food, chiefly poultry, eggs, dairy products, and processed meats. Vertical transmission in hen eggs has created an enormous reservoir (Gut 1994;35:726). Fecal-oral spread is easily prevented by hand washing.

Pathophys: The bacteria invade intestinal and colonic epithelium, frequently resulting in bacteremia (5-10%). Pts with sickle cell disease, HIV, and immunosuppression are more prone to bacteremia. Infected pts most commonly develop gastroenteritis and less commonly extraintestinal infections (osteomyelitis, pneumonia, arteritis, and meningitis). Those infected with the typhoid-causing or paratyphoid-causing agents develop enteric fever (notfurther discussed here). Following acute infection, pts commonly excrete organisms for weeks to months. Pts are said to be chronic carriers if excretion lasts more than 1 yr. This occurs in 1% of pts infected with nontyphoidal Salmonella.

Sx: Pts most often present with a mild to moderate illness of crampy abdominal pain and diarrhea. A small subgroup will present with a more severe illness with high fever and bloody diarrhea. The pts with severe illness are more likely to be the very old, the very young, and the immunocompromised.

Si: Fever, abdominal tenderness (sometimes right sided if there is prominent ileal involvement), and blood in stool.

Crs: Usually self-limited illness of several d; prolonged stool excretion, with 1% of pts developing a carrier state (>1 yr of infection).

Cmplc: Extraintestinal infections from bacteremia as listed in Pathophys. Reactive arthritis may occur.

Lab: Stool C&S.

X-ray: KUB, if done, may show evidence of colitis with thick colonic folds and thumbprinting. CT may show evidence of colonic wall thickening.

Endoscopy: If done, shows nonspecific evidence of colitis. Bx shows acute colitis without the distortion of crypt architecture or loss of mucous glands seen in IBD (Gut 1994;35:726).

Rx: Antibiotic rx does not in general, shorten the course of the illness in otherwise healthy pts with mild to moderate illness. Rx with antibiotics should be reserved for pts with severe sx (such as high fever, bloody diarrhea, or the need to be hospitalized), pts at the extremes of age, or pts who are immunosuppressed. Choices include Tm/S 160/800 mg po bid, ciprofloxacin 500 mg po bid, or norfloxacin 400 mg po bid for 5-7 d depending on the speed of response (Am J Gastro 1997;92:1962). In the small number of pts who develop the chronic carrier state following enterocolitis, rx with a quinolone for 28 d could be considered, but this is by analogy to studies in typhoidal strains rather than by direct evidence (GE 2000;118:S48).

Gastroenterol Clin North Am 2001;30:709; Am J Gastro 1993;88:1667

Cause: There are 4 species of Shigella organisms—S. dysenteriae, S. flexneri, S. boydii, and S. sonnei.

Epidem: The only reservoirs for Shigella are humans and apes. In developed nations this is largely a pediatric disease because of person-to-person spread. In the West most infections are with S. sonnei, which is less virulent. In contrast, in developing nations, waterborne and foodborne spread is common, and disease is often with the more virulent S. flexneri or S. dysenteriae.

Pathophys: Small infectious doses are needed and usually resist stomach acid. Clinical illness usually begins within 12 hr as invasion of the small intestine begins. Over the next few d, the colon is invaded and the pt develops lower abdominal pain and in some cases bloody diarrhea.

Sx: The most common sx is large-volume diarrhea (bloody in about half of pts, the classic dysentery). Most pts develop abdominal pain that is crampy and may be severe. Fever and vomiting are common.

Si: Abdominal tenderness, fever, and blood in stool.

Crs: If untreated, the illness usually lasts 1 wk, with a range of 1-30 d. Chronic relapsing sx are rare.