Definition

The first report of antibiotic-associated diarrhea (AAD) was found in the Bulletin of the Johns Hopkins Hospital of 1893, where John Finney and Sir William Osler described the case of a young woman who died of a severe case of “diphtheric colitis” shortly after gastric surgery. ¹ It was not until the mid-1900s, with the use of preoperative antibiotics, that AAD became a common medical problem.

For years, the cause of the pseudomembranous colitis remained elusive; indeed, the term staphylococcal enterocolitis was used, reflecting the belief that the disease was commonly caused by staphylococci. In the 1970s, important clinical observations of clindamycin-associated pseudomembranous colitis and the demonstration of the potent cytopathic effects of Clostridium difficile–derived toxin in animal models established the cause and pathogenesis of this condition. ²

Today, the term antibiotic-associated diarrhea refers to a benign, self-limited diarrhea following the use of antimicrobials. Typically, no pathogens are identified and the diarrhea is caused by changes in the composition and function of the intestinal flora. Most patients respond to supportive measures and discontinuation of antibiotics. On the other hand, C. difficile diarrhea refers to a wide spectrum of diarrheal illnesses caused by the potent toxins produced by this organism, including cases of severe colitis with or without the presence of pseudomembranes.

Back to Top

Prevalence

The occurrence of AAD varies greatly and is influenced by a number of factors, including nosocomial outbreaks, patterns of antimicrobial use, and individual susceptibility. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics will develop AAD. Most important, twice as many will become asymptomatic carriers. Risk factors include compromised immune status, advanced age, abdominal surgery, comorbidity, types and prolonged use of antibiotics, and the length of hospitalization. For example, infection rates for C. difficile are reported to be around 10% after 2 weeks of hospitalization but may reach 50% after 4 or more weeks. ²

All groups of antibiotics may cause AAD, but those with broad-spectrum coverage—in particular cephalosporins, extended-coverage penicillins, and clindamycin—are the most common culprits. ³ C. difficile diarrhea is largely a nosocomial disease and is the most frequent cause of diarrhea in hospitalized patients. Its occurrence in the outpatient setting other than in patients confined to nursing homes is much less common. ²

Epidemiologic studies have shown that C. difficile is often isolated in hospital wards, including the floors, door handles, and furniture, even weeks after patients with AAD have been removed from the area. Less frequently, similar observations have been made among asymptomatic medical personnel and in hospital wards occupied by unaffected patients. Patients re-admitted after recent hospitalizations are found to have a high prevalence of C. difficile colonization, representing an important source of infection. Because of the sporulating properties of this organism, all these observations have suggested an important role for cross-contamination between patients, contact with environmental surfaces, and transmission via hands of medical personnel. ⁴ During the past few years, there has been renewed interest in C. difficile diarrhea reflecting a form of disease that is more frequent, more severe, and more refractory to standard treatment. These observations are explained by the presence of a new strain of C. difficile, designated NAP-1, that produces more toxins A and B in vitro, produces binary toxin that is of uncertain significance, and is resistant to fluoroquinolones. ¹⁶

Back to Top

Pathogenesis

The prolonged use of multiple antibiotics, especially broad-spectrum agents with poor intestinal absorption or high biliary excretion, induces a change in the composition and function of the intestinal flora and therefore results in a higher incidence of AAD. ^2,5 The degree of alteration will be influenced by the ability of the normal flora to resist colonization and the type of antibiotic used. A decrease in the colonic anaerobic flora interferes with carbohydrate and bile acid metabolism. Osmotic or secretory diarrhea may occur. Overgrowth of opportunistic pathogens takes place as a result of microbiologic and metabolic alterations.

C. difficile, an anaerobic gram-positive rod, accounts for 15% to 20% of all AAD cases. In particular, this organism can be isolated in a great number of AAD cases with evidence of colitis and in all those with pseudomembranes. It is widely present in the environment, may survive for a considerable time, and is transmitted by the fecal-oral route to susceptible individuals. It is considered part of the normal flora of infants and can be isolated in about 5% of healthy adults and in up to one third of asymptomatic or colonized hospitalized patients.

Both C. difficile toxins A and B exhibit potent enterotoxic and cytotoxic effects that are responsible for the clinical manifestations. The mechanism of action is by toxin binding on intestinal receptors, leading to disruption of the cellular skeleton and intracellular junctions. Protein synthesis and cell division are inhibited. Important inflammatory mediators will attract neutrophils and monocytes, increasing capillary permeability, tissue necrosis, hemorrhage, and edema.

Serum and fecal antibodies to C. difficile infection are detected in many infected patients. The host's immune response appears to be critical in the clinical outcome. Elevated levels of serum immunoglobulin G and A (IgG and IgA) and fecal IgA against toxin A have been demonstrated in asymptomatic patients and in those with mild forms of C. difficile colitis, in contrast to those with severe illness, showing that antibodies provide a protective function. ⁶

Histologically, three different stages in C. difficile colitis can be identified. Initially, focal epithelial necrosis, along with fibrin-rich exudates and neutrophils, is present. In the second phase, a marked exudate protruding through an area of mucosal ulceration represents the classic volcano lesion (Fig. 1). The third stage is characterized by diffuse and more severe mucosal ulceration and necrosis, often associated with a pseudomembrane composed of fibrin, leukocytes, and cellular debris.⁷

Back to Top

Signs and symptoms

The clinical manifestations of AAD may vary from mild diarrhea to fulminant colitis. ⁸ The severity of C. difficile colitis appears to be influenced by a myriad of factors, including age, comorbidity, host's immune response, and the use of antiperistaltic agents. Interestingly, bacterial genotype and toxin production appear to play minimal roles. ⁹ The cardinal symptom of the disease is diarrhea, which commonly develops during treatment but may appear as late as 8 weeks after discontinuation of antibiotics. In most cases of AAD, patients present with loose stools, minimal signs of colitis, and no constitutional symptoms. The diarrhea promptly responds to supportive measures and withdrawal of the antimicrobial agent. ⁸

In contrast, typical cases of C. difficile infection manifest with a profuse, mucous, foul-smelling diarrhea associated with cramps and tenesmus. Frank bleeding is rare, although fecal occult blood and leukocytes are frequently detected. The abdomen is generally soft, with increased bowel sounds and mild tenderness over the left lower quadrant. Constitutional symptoms are common, and include nausea, vomiting, dehydration, and low-grade fever. Mild leukocytosis is frequently present and may occur even in the absence of diarrhea. An occasional leukemoid reaction has been reported. For colitis limited to the right colon, prominent findings of localized abdominal pain, leukocytosis, and fever can be found in the presence of minimal diarrhea.

In severe cases, toxic megacolon may occur along with the deceiving findings of “improved diarrhea.” A dramatic clinical picture of marked colonic distention, peritoneal irritation, fever, and elevated white blood count is commonly found. Hypoalbuminemia, hypovolemia, and ascites are common. A plain abdominal x-ray may show marked colonic distention or thumbprinting, with or without pneumatosis intestinalis. Computed tomography often reveals colonic wall thickening, lumen obliteration, pericolonic fat stranding, and ascites. Surgical intervention is often required, and carries significant morbidity and mortality. ¹⁰

The diagnosis of AAD should be considered in any patient recently treated with antibiotics and presenting with new-onset diarrhea. Exposure up to 8 weeks before onset to any antimicrobial, includ-ing antifungal agents, should be considered. Clinical presentation, laboratory data, imaging studies, and endoscopic examinations are all useful. Atypical subtle presentations, especially in ambulatory patients with a remote and brief antibiotic exposure, require high suspicion. Leukocytosis, fecal leukocytes, and fecal occult blood are supportive of the diagnosis but not always present. Imaging studies, including plain radiographic films and computed tomography, are of marginal benefit as diagnostic tools but become helpful in severe cases to identify complications.

The cornerstone of the diagnosis of C. difficile colitis is identification of C. difficile toxins in the stool. Culture assays are considered to be the gold standard, based on the demonstration of toxin B cytopathic effects on cell culture monolayers. This test carries great specificity and sensitivity, detecting minimal toxin concentrations. Unfortunately, cell culture tests are expensive, time-consuming, and rarely used in clinical practice.

The most preferred diagnostic method in C. difficile colitis is the enzyme-linked immunosorbent assay (ELISA), based on toxin detection in the stool. Today, most commercially available methods detect both A and B toxins, obviating the problems of missing certain C. difficile strains that produce only toxin B. ELISA is fast, relatively inexpensive, and has excellent specificity; its sensitivity, however, is 75% to 85%. Serial stool determinations on different days are suggested for suspected cases with initial negative results.

The latex agglutination test is based on the detection of the enzyme glutamate dehydrogenase rather than on C. difficile toxin. Nontoxigenic strains of C. difficile, as well as other colonic organisms, may produce this enzyme. Latex agglutination tests are rarely used today because of their lack of specificity.

Endoscopy is a rapid but invasive and expensive diagnostic test for C. difficile colitis. Often, nonspecific findings of colitis such as edema, erythema, and loss of vascular pattern are the only findings. In cases of pseudomembranous colitis, endoscopy is diagnostic, because it may reveal typical raised, yellow nodules over areas of normal mucosa or minimal erythema. In more severe cases, coalescent nodules forming extensive areas of pseudomembranes over a background of inflammation and ulcerations are found (Fig. 2). In most cases, pseudomembranes are distributed throughout the colon and are readily identified within the reach of the sigmoidoscope. In a few cases, the pseudomembranes are confined to the right colon. Endoscopy should be used with caution and reserved for patients with severe colitis of unclear cause in whom a prompt diagnosis is needed.

Back to Top

Treatment

The current guidelines from the American College of Gastroenterology (ACG) for the initial management of C. difficile colitis are clear and widely accepted (Box 1). ⁵ In the vast majority of patients AAD is a mild and self-limited illness that responds to the discontinuation of antibiotics, supportive care, and fluid and electrolyte replacement. On the other hand, in cases in which signs and symptoms of colitis develop, the use of effective oral antimicrobial agents against C. difficile is often necessary. Although the diagnosis of C. difficile colitis should always be established before antimicrobial therapy is implemented, we strongly agree with the current ACG guidelines in that empirical therapy should be initiated in highly suggestive cases of severely ill patients. ¹¹

Pharmacologic Agents

Many antimicrobials have been used to treat C. difficile colitis. Oral vancomycin and metronidazole used for 7 to 10 days are considered the first line of therapy by most clinicians and current guidelines. ¹¹ Multiple studies have reported initial response rates greater than 90% and comparable failure rates of 15% to 20%. ¹² Metronidazole at a dosage of 250 mg four times daily is recommended by most clinicians and ACG guidelines as the drug of choice for the initial treatment of C. difficile colitis. These recommendations are largely based on efficacy, lower costs, and concerns about the development of vancomycin-resistant strains. Major disadvantages of metronidazole include a less desirable drug profile and contraindications for children and pregnant women.

An albumin level of 2.5 g/L and intensive care unit stay were predictors of failure of metronidazole therapy for C. difficile–associated diarrhea. These patients may benefit from oral vancomycin at the outset. Vancomycin at a dosage of 125 mg four times daily, is safe, well tolerated, and achieves stool levels 20 times the required minimal inhibitory concentration required for the treatment of C. difficile. Higher doses of the drug have failed to show significant benefits. ¹² Main disadvantages with this agent are cost and the potential development of vancomycin-resistant strains. We concur with the current ACG guideline in considering vancomycin the drug of choice for severely ill patients and for those in whom the use of metronidazole is precluded.

The treatment of patients with severe ileus is challenging and not clearly addressed by the ACG practice guidelines. Most reports have suggested the use of parenteral metronidazole in these patients. In animal studies, intravenous metronidazole has been shown to achieve reasonable concentrations in the intestinal lumen. Unfortunately, most studies are based on small clinical trials with contradictory results. ¹³ Few anecdotal reports of vancomycin enemas can be found in the literature, but good scientific data are lacking to recommend its use in these patients.

Because of their potential role in binding C. difficile toxin, anion exchange resins such as cholestyramine and colestipol were introduced in the management of AAD in an attempt to decrease relapses. These agents, in particular colestipol, have been shown to reduce titers, concentration, and time exposure of the C. difficile toxin in the colons of infected patients. ¹⁴ Although subsequent binding of vancomycin occurs with cholestyramine, the minimal inhibitory concentration for C. difficile is maintained. Other antimicrobial agents, in particular bacitracin and teicoplanin, were used with some success in the past. Today, however, their use is limited to special situations in which metronidazole or vancomycin cannot be used or has failed. ¹⁵

The NAP-1 strain has forced a closer look at the current therapeutic options; therefore, newer drugs have been proposed for treatment. Nitazonide, a nitrothiazolide, has been found to have high in vitro activity against C. difficile and achieves high colonic levels after oral administration. This drug can be used for patients who fail to respond to metronidazole therapy or those who cannot take metronidazole. Another drug used for treatment and under consideration is tolevamer, a nonantibiotic anionic polymer that binds C. difficile toxins A and B to neutralize biologic activity. ¹⁶

Probiotics, a group of agents designed to resist colonization and restore normal flora have been tried in AAD. The most promising probiotic agent is Saccharomyces boulardii, a live nonpathogenic yeast shown to have some benefit in the treatment of AAD by binding to the glycoprotein receptor site for toxin A at the intestinal brush border. When given prophylactically to patients receiving antibiotics in a prospective, double-blind, controlled study, ¹⁷ S. boulardii was shown to be safe and beneficial in reducing the incidence of C. difficile colitis in comparison with placebo (22% versus 9.5%). Unfortunately, S. boulardii is not commercially available in the United States. ¹⁷ Lactobacillus GG, another popular probiotic, has been shown to improve intestinal immunity by increasing IgG and IgA levels at the intestinal mucosal level. Clinical studies have been tried but with limited success. ¹⁸

Surgical Treatment

Surgical treatment of C. difficile colitis is rarely needed. It is reserved for patients with toxic megacolon who do not respond to medical therapy and carries a mortality rate close to 40%. Comorbidity and late intervention are largely responsible for the poor outcomes of these patients. Segmental resections are commonly ineffective. Early intervention with total colectomy and diversion is the recommended approach. ¹⁰

Relapses

The most difficult problem in the management of C. difficile–associated colitis is relapse, reported to occur in 15% to 20% of cases, regardless of the initial treatment used. Relapse appears to be facilitated by the sporulating properties of C. difficile. Some conditions identified as potential markers for relapse include previous relapses, chronic renal failure, marked leukocytes, and continued antibiotic use. ¹⁹

For a first relapse, the current guidelines of the ACG recommend treating patients with a second course of metronidazole or vancomycin for a total of 7 to 10 days. ¹¹ Nevertheless, most studies have advocate for a longer course of treatment, a total of 2 weeks.

In cases of more than one failure, when the relapse rate could be as high as 65%, a different approach is needed. Confirmation of the diagnosis and avoidance of unnecessary antibiotics is strongly advised. Different agents, regimens, doses, and even unusual forms of therapy, such as fecal enemas, have been tried, with varying success. Limitations in the actual management of repetitive relapses are acknowledged in the ACG practice guidelines. ¹¹ However, most of the recommended regimens available, although reported to be effective, are based on small uncontrolled studies ( Table 1 ). ^19,20

Based on stool clearance by culture, toxin detection, and some limited clinical data, vancomycin appears to be a superior agent for cases of multiple relapse. Probably the most popular approach today is the use of vancomycin in a tapered dose regimen over several weeks or in combination with other agents, including anion-binding resins and rifampin. ^20–23 The design of most of these regimens is based on the sporulating properties of C. difficile, and combine the antimicrobial action of different agents along with the constipating effects and potential for toxin-binding properties of anion resins. Probiotics such as S. boulardii in combination with vancomycin or metronidazole are frequently used in Europe for relapse prevention. When available, this agent may play a more important role in the future management of these patients in other parts of the world. Tolevamer can also be used to prevent relapses. ¹⁶ In case of multiple relapses or refractory disease, consider the use of probiotics, immunoglobulin, or steroids. However, in all cases, strict isolation of the patient is essential for controlling the spread of the disease to other patients.

Back to Top

Outcomes

Most AAD cases are mild and self limited. Most patients will recover completely with supportive measures and antibiotic withdrawal. Relapses are unlikely in this group of patients. In cases of well-established colitis that is probably associated with C. difficile infection, specific antimicrobial therapy is needed. Most patients will respond to treatment and recover without sequelae, but relapses are common. The rates of recurrence in this group of patients vary but can be as high as 65% after the first recurrence. Antibiotic use in the months to come should be avoided unless strictly necessary.

In general, medical therapy is effective and surgical intervention is rarely necessary. Medical failures, particularly in cases of fulminant colitis, require prompt surgical intervention. These patients tend to be older and suffering from other comorbid conditions. Total colectomy with ileostomy is the recommended approach. Mortality in these patients has been reported to be as high as 40%, in contrast with the minimal mortality in medically treated patients. Preventive strategies are based on the fact that AAD is usually a nosocomial disease. Preventive measures for colonization of hospitalized patients with C. difficile are widely recommended and supported, as stated in the ACG guidelines. ¹¹ Avoidance of unnecessary use of antibiotics is of paramount importance. Hospital antibiotic use should be limited and regulated. Medical personnel should be enforced to follow simple enteric precautions and educated about the disease and its epidemiology.

Summary

• Antibiotic-associated diarrhea is the most common cause of diarrhea in hospitalized patients, representing an important source of morbidity, mortality, and cost.
• Although no infectious agent is found in most cases of AAD, Clostridium difficile is frequently identified in patients with signs and symptoms of colitis.
• All types of antimicrobial agents have been implicated, leading to a wide range of clinical manifestations, from asymptomatic carrier state to severe pseudomembranous colitis.
• Most cases of AAD respond to supportive measures and withdrawal of antibiotics.
• In patients with severe and persistent symptoms, effective antibiotic therapy is available, but relapses are common.

Back to Top

Suggested Readings

• New drugs for Clostridium difficile infection. Clin Infect Dis. 43: 2006; 428-431.
• Clostridium difficile–associated diseases: Comparison of symptomatic infection versus carriage on the basis of risk factors, toxin production, and genotyping results. Clin Infect Dis. 25: 1997; 157-158.
• Epidemiology of antibiotic-associated colitis. Isolation of Clostridium difficile from the hospital enviroment. Am J Med. 70: 1981; 906-908.
• Guidelines for the diagnosis and management of Clostridium difficile–associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 92: 1997; 739-750.
• Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet.. 2: 1987; 1519.
• Clostridium difficile colitis in the critically ill. Dis Colon Rectum. 39: 1996; 619-623.
• Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 320: 1989; 204-210.
• Pseudomembranous colitis. J Clin Pathol. 30: 1977; 1-12.
• Treatment of recurrent antibiotic-associated pseudomembranous colitis. Am J Gastroenterol. 77: 1982; 220-221.