Published: June 2014
The term antibiotic-associated diarrhea (AAD) 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, Clostridium difficile diarrhea refers to a wide spectrum of diarrheal illnesses caused by the toxins produced by this organism, including cases of severe colitis with or without the presence of pseudomembranes.
The occurrence of AAD varies greatly and is influenced by a number of factors, including nosocomial outbreaks, patterns of antimicrobial prescription, 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, reduced gastric acid, 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.1
All groups of antibiotics may cause AAD, but those with broad-spectrum coverage -- in particular cephalosporins, fluoroquinolones, extended-coverage penicillins, and clindamycin -- are the most common culprits.2 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.1 Although a few earlier studies have not shown an association between gastric acid suppression and C. difficile infection (CDI), recent meta-analysis suggests a significant association.3
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 have suggested an important role for cross-contamination between patients, contact with environmental surfaces, and transmission via hands of medical personnel.4 The overall incidence and severity of CDI has been increasing since the last decade. 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.
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.1,5 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. The spores are widely present in the environment, may survive for a considerable time, and are 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 attract neutrophils and monocytes, increasing capillary permeability, tissue necrosis, hemorrhage, and edema.
Serum and fecal antibodies to CDI 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
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, a host’s immune response, and the use of antiperistaltic agents. Bacterial genotype and toxin production may also play a role.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 CDI 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, and lactic acidosis 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, including 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.
Until a few years ago the diagnostic method of choice for C. difficile colitis was the enzyme-linked immunosorbent assay (ELISA), based on toxin detection in the stool. While ELISA is fast, relatively inexpensive, and has excellent specificity; its sensitivity, however, is variable and ranges between 75% and 85%. The other ELISA test is based on the detection of the enzyme glutamate dehydrogenase (GDH). However, the test is non-specific as nontoxigenic strains of C. difficile, may also produce this enzyme. GDH can be used as a screening test but must be followed by another confirmatory test. The newest and current preferred methods of diagnosis are the nucleic acid amplification (LAMP) tests. These may include the real-time polymerase chain reaction (PCR) and the loop-mediated isothermal amplification tests. Both the tests detect the toxin A and B genes responsible for the production of toxins. They have a sensitivity of 90% to 100% and a specificity of 94% to 100%. Only loose stools from symptomatic patients suspected of CDI should be tested, as PCR can also detect asymptomatic carriers. There is no benefit to testing multiple stool specimens or repeat testing following a positive test (test of cure).
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.
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).11 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 In patients with suspected or confirmed CDI, the use of antiperistalitic agents to control diarrhea should be limited or avoided as they may obscure symptoms.
|Box 1 Guidelines for the Treatment of Clostridium Difficile Colitis|
|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 clinicians and current guidelines.11 Multiple studies have reported initial response rates greater than 90% and comparable failure rates of 15% to 20%.12 Current ACG guidelines for management of CDI are based on classification of disease severity as mild, moderate and severe.11 Mild disease is defined as CDI with diarrhea as the only symptom; moderate disease is defined as CDI with diarrhea but without additional symptoms/signs meeting the definition of severe or complicated CDI; severe disease is CDI with hypoalbuminemia (serum albumin < 3g/dl) and either of the following: white blood cell count >15,000 cells/mm3 or abdominal tenderness. Complicated CDI presents with or develops at least one of the following: admission to intensive care unit, hypotension with or without required use of vasopressors, fever ≥ 38.5°C, ileus, or significant abdominal distention, mental status changes, white blood cell count ≥ 35,000 cells/mm3 or <2,000 cells/mm3, serum lactate levels >2.2 mmol/L, or any evidence of end organ failure.11 For mild-to-moderate CDI, metronidazole at a dosage of 500 mg orally three times daily for 10 days 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. Fidaxomicin is a macrocyclic antibiotic and has recently been approved by the U.S. Food and Drug Administration for the treatment of C. difficile colitis. For mild-to-moderate CDI the dosage is 200 mg orally two times per day for 10 days. It has been shown to be associated with a decrease risk of recurrent disease for patients infected with non-NAP-1 strains of the organism.13
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. Patients with severe CDI should be treated with vancomycin at a dosage of 125 mg orally four times daily for 10 days. It 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.
Patients with complicated CDI should be treated with high dose oral vancomycin at a dosage of 500 mg, four times a day plus parenteral metronidazole, 500 mg three times a day. The treatment of patients with complicated CDI with severe ileus or toxic colitis is challenging. ACG practice guidelines suggest the use of oral vancomycin at the dosage of 500 mg four times daily and per rectum (vancomycin enema) at the dosage of 500 mg in 500 mL saline three times a day plus parenteral metronidazole at the dose of 500 mg three times a day.11
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 us to take a closer look at the current therapeutic options; therefore, newer drugs have been proposed for the treatment including Nitazoxanide and rifaximine both of which achieve high colonic levels and have been used for other indications and others including ramoplanin a new lipoglycodepsipeptide. Tolevamer, a nonantibiotic polymer that binds C. difficile toxins A and B to neutralize biologic activity had promising results in phase 2 clinical trials, but in phase 3 trials it was shown to be inferior to metronidazole and vancomycin for initial therapy; although relapse rates were significantly lower again suggesting the limitations of treating AAD with antibiotics.16
Probiotics, a group of agents designed to resist colonization and restore normal flora, have been tried in treating 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%). Lactobacillus GG, another popular probiotic, has been shown to improve intestinal immunity by increasing IgG and IgA levels at the intestinal mucosal level and may be effective against CDI. A recent meta-analysis on the efficacy of probiotics for the treatment and prevention of AAD suggests that probiotics are associated with a significant reduction in AAD.18
Surgical treatment of C. difficile colitis is reserved for patients with complicated CDI, toxic megacolon and those who do not respond to medical therapy. Surgical treatment is associated with significant morbidity and carries a mortality rate close to 40%. Comorbidity and late intervention are largely responsible for the poor outcomes of these patients. Early surgical consultation is therefore suggested for complicated CDI and has been shown to be associated with better outcomes. Segmental resections are commonly ineffective and associated with higher mortality than those treated with subtotal colectomy. Early intervention with subtotal colectomy with end-ileostomy is the recommended approach.10
The most difficult problem in the management of C. difficile-associated colitis is recurrence, reported to occur in 15% to 20% of cases within 30 days, regardless of the initial treatment used. Recurrence appears to be facilitated by the sporulating properties of C. difficile and is caused by the same strain or a different strain. The most important risk factor is antibiotic use initiated for another infection before completion of CDI treatment. Other conditions identified as potential markers for recurrence include previous recurrences, chronic renal failure, marked leukocytes, and continued antibiotic use.19
For a first recurrence, the current guidelines of the ACG recommends treating patients with the same regimen that was used for the initial episode.11 Patients with severe or complicated CDI should be treated with vancomycin (125 mg four times a day for 10 days).
After the first recurrence, rates of further recurrence are said to increase to 40% to 65%. Confirmation of the diagnosis and avoidance of unnecessary antibiotics is strongly advised. Patients with a second recurrence of CDI should be treated with a tapered or pulsed vancomycin regimen as continued use of metronidazole puts the patient at a cumulative risk of peripheral neuropathy. In patients with a third recurrence after a pulsed vancomycin therapy, fecal microbiota transplant (FMT) should be considered. FMT is a promising new modality of treatment for recurrent CDI and appears to be safe. In a randomized controlled trial of donor feces on patients with recurrent CDI, FMT was significantly more effective than the use of vancomycin.20 However, data from the long-term follow up of FMT is limited. Most of the recommended regimens, although reported to be effective, are based on small studies and should be interpreted with caution.
Currently, there is limited evidence for the use of adjunct probiotics to decrease recurrences in patients with recurrent CDI. However, in some smaller studies, probiotics such as S. boulardii in combination with vancomycin or metronidazole have been shown to have some benefit. Tolevamer can also be used to prevent recurrence.16 In cases of multiple recurrence or refractory disease, consider the use of probiotics, intravenous immunoglobulin, or steroids. However, in all cases, contact precautions and strict isolation of the patient is essential for controlling the spread of the disease to other patients.
Most AAD cases are mild and self-limited. Most patients 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 CDI, specific antimicrobial therapy is needed. Most patients respond to treatment and recover without sequelae, but recurrences 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.