Antibiotic-Associated Diarrhea

Antibiotic Associated Diarrhea

Published February 10, 2003

Ronnie R.
Pimentel, MD

Cleveland Clinic
Florida

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Antibiotic-associated diarrhea (AAD) 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.

Definition

Prevalence

Pathogenesis

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

National Guidelines

Diagnosis and management of Clostridium difficile-associated diarrhea and colitis (ACG)

Related Material from The Cleveland Clinic Algorithms for the MICU
Diarrhea in the ICU

DEFINITION

The first report of AAD is found in the Bulletin of the John 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 "diphteric 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 C difficile-derived toxin in animal models established the etiology 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 due to 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 is used to describe 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.

PREVALENCE

The occurrence of AAD varies greatly and is influenced by multiple 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, type 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 it 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 readmitted 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 suggest an important role for cross-contamination between patients, contact with environmental surfaces, and transmission via hands of medical personnel.⁴

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 enterotoxin and cytotoxic effects that are responsible for the clinical manifestations. The mechanism of action is by toxin binding on intestinal receptors, leading to the disruption of the cellular skeleton and the 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 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

Typical Volcano Lesion

Figure 1

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 (Figure 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

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 that 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 present 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. 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 roentgenogram 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 (Figure 2). Surgical intervention is often required, and carries a significant morbidity and mortality.¹⁰

Thickened Cecun

Figure 2

DIAGNOSIS

The diagnosis of AAD should be considered in any patient recently treated with antibiotics and presenting with new onset of diarrhea. Exposure up to 8 weeks before onset to any antimicrobial, including antifungal agents, should be considered.

Clinical presentation, laboratory data, imaging, 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 quite 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, is relatively inexpensive, and has excellent specificity; its sensitivity, however, is 75% to 85%. Serial stool determinations on different days are suggested in 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 due to a lack of specificity.

Pseudomembranous Colitis

Figure 3

Endoscopy is a rapid but an invasive and expensive diagnostic test for C difficile colitis. Quite 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 as 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 (Figure 3). In most cases, pseudomembranes are distributed throughout the colon and are readily identified within the reach of the sigmoidoscope. In a very 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 etiology in whom a prompt diagnosis is needed.

THERAPY

The current guidelines from The American College of Gastroenterology (ACG) for the initial management of C. difficile colitis are quite clear and widely accepted (Table 1).¹² 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, I strongly agree with the current ACG guidelines in that empiric therapy should be initiated in highly suggestive cases of severely ill patients.¹²

Table 1:

Guidelines for the Treatment of
Clostridium Difficile Colitis

Discontinue antibiotics.Initiate supportive therapy. Prophylactic antibiotic therapy should not be given routinely.Once the diagnosis of C difficile diarrhea is confirmed and specific therapy is indicated, metronidazole given orally is preferred.If diagnosis is highly likely and the patient is seriously ill, metronidazole may be given empirically before the diagnosis is established.Vancomycin given orally is reserved for the following conditions:

The patient has failed therapy with metronidazole.
The patient's organism is resistant to metronidazole.
The patient is allergic, cannot tolerate metronidazole, or is being treated with ethanol-containing solutions.
The patient is either pregnant or a child under 10 years of age.
The patient is critically ill because of C difficile-associated diarrhea or colitis.
There is evidence suggesting the diarrhea is caused by Staphylococcus aureus.

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 authors and current guidelines.¹² Multiple studies have reported initial response rates greater than 90% and comparable failure rates of 15% to 20%.¹¹ Metronidazole at a dose of 250 mg four times a day is recommended by most authors 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 on concerns about the development of vancomycin-resistant strains. Major disadvantages of metronidazole include a less desirable drug profile and contraindications in children and pregnant women.

On the other hand, vancomycin at a dose of 125 mg four times a day, 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.¹¹ Main disadvantages with this agent are cost and the potential development of vancomycin-resistant strains. I concur with the current ACG guideline in considering vancomycin the drug of choice in severely ill patients and in cases in which the use of metronidazole is precluded.

The treatment of patients with severe ileus is quite challenging and not clearly addressed by the ACG practice guidelines. Most authors suggest 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 is lacking to recommended 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 colon of infected patients.¹⁴ Although subsequent binding of vancomycin occurs with cholestyramine, the minimal inhibitory concentration for C difficile is maintained.¹⁴ Other antimicrobial agents, in particular bacitracin and teicoplatin, have been used with some success in the past. Today, their use is limited to very special situations in which metronidazole or vancomycin cannot be used or has failed.¹⁵

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,¹⁶ 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.¹⁶ Lactobacillus GG, another popular probiotic has been shown to improve intestinal immunity by increasing IgG and IgA at the intestinal mucosal level. Clinical studies have been tried but with limited clinical success.¹⁷

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 close to 40%. Comorbidity and late intervention are largely responsible for the poor outcome 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.¹⁸

For a first relapse, the current guidelines of the American College of Gastroenterology (ACG) recommend treating patients with a second course of metronidazole or vancomycin for a total of 7-10 days.¹² Nevertheless most authors 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 variable success. Limitations in the actual management of repetitive relapses are acknowledged in The American College of Gastroenterology practice guidelines.¹² Indeed, most of the recommended regimens available, although reported to effective, are based on small, uncontrolled studies (Table 2).^18,19

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.^{19, 20, 21} 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.

OUTCOMES

The majority of AAD cases are mild and self-limited. Most patients will recover completely with simply supportive measures and antibiotic withdrawal. Relapses are quite unlikely in this group of patients. In cases of well established colitis and likely 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 rate 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 quite effective and surgical intervention is rarely necessary. Medical failures and in particular 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 as high as 40% in contrast with the minimal mortality in the medically treated patients.

Preventive strategies are based in the fact that AAD is largely a nosocomial disease. Preventive measures for colonization of hospitalized patients with C difficile are widely recommended and supported as stated in the ACG guidelines.¹² 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.

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Published February 10, 2003

Cleveland Clinic Florida

Cleveland Clinic
Florida