Clostridium difficile is a spore-forming organism responsible for an infectious colitis that affects 1 of every 200 patients who are admitted to the hospital. Increasingly implicated as a significant cause of morbidity and mortality among hospitalized patients, C difficile colitis should also be recognized among outpatient populations. Prior antibiotic exposure remains the most significant risk factor for development of disease.
Several synonymous terms are used to refer to the spectrum of disease attributable to C difficile infections (CDI); these terms include C difficile –associated diarrhea (CDAD), antibiotic-associated colitis, C difficile colitis, and pseudomembranous colitis (PMC). C difficile is the primary pathogen of antibiotic-associated colitis and accounts for up to 25% of nosocomial antibiotic associated diarrhea.[1] Pseudomembranous colitis specifically describes the formation of a membranous exudate in the colon, which occurs in approximately 50% of cases of CDI. However, because endoscopy is now used less frequently in the evaluation of antibiotic-associated diarrhea, many articles reference this entity under the umbrella term of CDI. CDI, CDAD, PMC, and C difficile colitis essentially represent the same disease process; severity of the patient presentation dictates treatment.
An image depicting pseudomembranous colitis can be seen below.
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Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.
In 1893, Finney first reported pseudomembranous colitis in a patient who died after developing severe diarrhea after gastric surgery. Later, in the 1950s, both Staphylococcus aureus and Candida albicans were considered etiologic sources after isolation from the stools of affected patients. In 1977, C difficile and its toxins were established as the cause of antibiotic-associated colitis.
In the last decade, an increasing number of C difficile infections have been reported, and the proportion of cases complicated by severe outcomes has increased. This may be partially due to the spread of virulent clonal strains. In 2003, an outbreak in Quebec and 8 U.S. states received significant media attention. More than 80% of the isolates tested were of the same strain (designated PFGE NAP1, or PCR-ribotype 027), which was notable for the production of binary toxin and a deletion in the regulatory gene tcdC.[2, 3, 4] Multiple other outbreaks have been reported with other strains. The molecular epidemiology of C difficile in health care facilities is dynamic and incompletely understood.[5, 6]
Any antibiotic can increase the risk of C difficile disease, including metronidazole and vancomycin, which are used in the treatment of CDI. Disease has been reported following as little as one dose of antibiotic. Although the attributable risk has varied among studies, fluoroquinolones, macrolides, clindamycin, beta-lactam/beta-lactamase inhibitors, and all 3 generations of cephalosporins have consistently been shown to pose a significant risk for the development of CDI. Antineoplastic agents and proton pump inhibitors have also been associated with CDI.
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) updated clinical practice guidelines regarding the diagnosis and management of Clostridium difficile infection in 2010.[7]
C difficile is an anaerobic, toxigenic, spore-forming, gram-positive rod. The spores can survive for months on hospital environmental surfaces, and patients can remain asymptomatic carriers. The risk of colonization increases with length of hospital stay; nearly 20% of hospitalized patients have asymptomatic fecal colonization,[8] as opposed to the 1-3% rate in healthy community residents. Children under the age of 1 year have the highest rate of asymptomatic carriage, up to 60%.[9]
The use of antibiotics alters the normal bowel flora, predisposing to the overgrowth of C difficile and the production of its toxins. CDI results from the inflammatory reaction of the bowel wall to luminal toxins produced by C difficile. Continuation of inflammatory process can lead to formation of pseudomembranes, a mixture of inflammatory cells, fibrin, and bacterial and cellular components, which exudes from the bowel mucosa. Not all strains of C difficile are toxigenic. See the image below.
View Image
Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.
Toxigenic C difficile produces 2 similar large molecular weight toxins that disrupt the barrier function of the colonic mucosa.
Toxin A is an enterotoxin that binds to receptors in the bowel wall, leading to activation of the inflammatory cascade and disruption of the intercellular tight junctions, causing fluid secretion, mucosal injury, edema, and inflammation.
Toxin B is the primary cytotoxin responsible for C difficile infection. It appears to act as a cytoskeletal disruptor, leading to mucosal injury and further activation of the inflammatory cascade.
Binary toxin is a third toxin produced by a small percentage (about 5%) of C difficile isolates. It is similar in structure to the iota toxin of Clostridium perfringens. Binary toxin may be associated with increased disease severity, as well as with community-acquired disease.
Hospital admissions complicated by C difficile –associated disease almost doubled between 2000 and 2003, increasing from 0.27% to 0.51% of all hospital admissions in the United States. In elderly patients (age >65), the increased incidence was even more pronounced.[10] The reported incidence rate of C difficile infection in 2005 (84 per 100,000 patient-days) was two and a half times the 1996 rate (31 per 100,000).
In a recent study of community hospitals in the Duke Infection Control Outreach Network, C difficile infection surpassed MRSA as the leading cause of nosocomial infections (0.28 cases per 1000 patient days vs 0.23 cases per 1000 patient days).[11]
International
Canada and Europe have historically reported similar rates of CDI as those noted in the United States. A 2004 report from a large university center in Canada noted an increase in incidence from 35.6 cases per 100,000 patient-days in 1991 to 156.3 per 100,000 in 2003; among patients aged 65 years or older, the rate increased from 102 to 866.5 per 100,000. A follow-up study by the same group reported an overall incidence of 65 cases per 100,000 patient-days in 2005.[12]
Mortality/Morbidity
CDI causes a significant burden on the health care system. The costs associated with each hospitalized case of CDI were $3,699 in excess health care costs and 3.6 extra days of hospitalization, according to a report of short-stay hospitals in 2002.
Infection with toxigenic C difficile is a potentially life-threatening disease process. Historically, the attributable mortality of CDI has been less than 2% of cases.[13, 14] However, the more severe NAP1/BI/027 strain noted in outbreaks in Canada was associated with a 6.9% directly attributable 30-day mortality.
Significant morbidity can result from recurrent disease. Up to 25% of patients will experience at least one additional episode of disease
Age
Persons over the age of 65 are at higher risk for developing CDI and recurrent disease than younger persons. Increasing age is highly predictive of severe outcome or mortality.[15] Infants and children have high rates of asymptomatic carriage, but clinical disease is uncommon (4.0 cases per 1000 admissions).[16]
The clinical course prior to development of C difficile infection (CDI) typically contains a history of antibiotic exposure, risk factors for colonization, and alterations in host physiology.
History of antibiotic exposure
Fluoroquinolones, macrolides, clindamycin, beta-lactam/beta-lactamase inhibitors, and all generations of cephalosporins have been most commonly associated with CDI.
All antibiotics, including those used to treat C difficile infection, can be associated with development of disease.
CDI symptoms typically develop 5-10 days after initiation of antibiotic therapy. However, they can develop after a single day of antibiotic use or can occur as late as 10 weeks after antibiotic cessation.
Both increased length of antimicrobial use and use of multiple antimicrobials increase the risk of CDI.
Some patients may develop CDI without a clearly identified antibiotic exposure.
Importantly, not all diarrhea cases following antibiotic use are due to C difficile. In fact, 70-80% of diarrhea following antibiotic use is due to changes in the osmotic pressure in the lumen after alteration of the bowel flora decreases the use and absorption of carbohydrates.
Colonization with C difficile
Generally, colonization occurs following ingestion of acid-resistant spores.
In the hospital environment, the spores are common contaminants from patients who harbor C difficile. The organism can be transmitted via fomites or the hands of health care providers.
Hospitalized patients and residents of long-term care facilities are at higher risk of colonization with C difficile.
Although less common, colonization can occur in the outpatient setting. Exposure to spores in soil, carriage by pets or other animals, and contaminated food or household contacts have all been implicated.[17]
Host factors that increase susceptibility to C difficile –associated diarrhea
Age greater than 65 years
Chronic debilitation or critical illness
Alteration in gut motility
Agents that affect the bowel, including enemas, stool softeners, and opioids, are identified as risk factors for disease development.
Patients who have undergone abdominal surgery with subsequent ileus are also at increased risk.
Receipt of enteral tube feeds
Use of proton-pump inhibitors (These may increase the rate of successful colonization after ingestion.)
Cancer chemotherapeutic agents are associated with an increased risk of C difficile disease. This may be due to the antimicrobial activity of some of these agents or due to impaired immunity with neutropenia.
Impaired humoral immunity (especially of the IgG subclasses) may increase the susceptibility to relapsing disease.
HIV infection: C difficile infection has become one of the most common causes of infectious diarrhea in persons with HIV.[18]
Infections are being increasingly recognized in patients previously considered low risk, such as women in the peripartum state.
The clinical presentation of C difficile –associated disease can range from mild self-limited diarrhea to severe colitis with pseudomembrane formation complicated by development of toxic megacolon or colonic perforation. The classic presentation is cramping abdominal pain with profuse, mucoid, greenish, malodorous watery stools.
Clinical signs
Diarrhea is usually fairly mild, with 3-6 stools per day. However, severe cases may have more than 20 stools per day.
Leukocytosis is found in 50-60% of patients. A patient who presents with a WBC count of 12,000-20,000 103/μL associated with minimal diarrhea and a lack of other presenting signs is common. However, 30% of patients have a WBC count of more than 30,000 103/μL.
Fever affects 30-50% of patients.
Abdominal pain or cramping affects 20-33% of patients and may have various presentations. Sometimes generalized, diffuse, or cramping, it can also manifest as focal pain that mimics acute abdomen. Evidence of peritoneal signs should immediately raise suspicion for fulminant colitis and toxic megacolon.
Other common findings include nausea, malaise, and anorexia.
Severe disease may lead to electrolyte disturbances, dehydration, hypotension, renal failure, sepsis, and death.
Constipation with or without dyspepsia is an atypical presentation, occurring in less than 1% of cases.[19]
Colitis can be present without accompanying diarrhea, particularly in patients with right-sided colonic involvement.
Toxic megacolon can complicate severe infection and can lead to bowel perforation.
Extraintestinal manifestations are rare and include the following:
The diagnosis of CDI relies primarily on an appropriate suggestive history. Physical examination findings may include fever, abdominal tenderness, and diarrhea. In cases of severe diarrhea, physical signs suggestive of dehydration (eg, dry mucous membranes, decreased skin turgor, orthostasis) may also be present.
C difficile –associated disease results from the action of toxins formed by the organism. Rarely, pseudomembranous colitis can be caused by other etiologies, such as Staphylococcus species or enterotoxigenic C perfringens,Campylobacter species, Listeria species, and Salmonella species.
Evaluation of C difficile infection primarily focuses on the detection of C difficile or its toxins in stool.[20, 7] The available testing modalities and their sensitivity/specificity may vary widely between laboratories.
In general, testing for C difficile should only be performed on unformed stools.
Testing of asymptomatic patients is not recommended (including as a test of cure)[7]
In the setting of an ileus, when stool is not obtainable, testing can be performed using a rectal swab.
Direct culture of C difficile from the stool provides the most sensitive diagnostic measure. This study is not commonly used clinically because of cost and turnaround time. However, with additional identification of toxigenic isolates, it has become the criterion standard against which other testing modalities are compared.
Cytotoxic assays are recommended over EIA for the diagnosis of C difficile.[7] Stool filtrate is mixed with mammalian tissue-culture cell lines and observed for cytopathic effect; turnaround time is roughly 48 hours. Cytotoxic assays are still only moderately sensitive in the detection of C difficile. For a single test, sensitivity ranges from 67-100% and specificity ranges from 85-100%.
Enzyme-linked immunosorbent assay (ELISA) techniques are used to detect the presence of toxin A and/or toxin B. A wide variety of these tests are commercially available. Reported sensitivities range from 63-99%, with specificities of 75-100%. Compared with cytotoxic assays, these tests are less expensive and yield quicker results but are less sensitive for the detection of C difficile.
Assays that detect both toxin A and B (rather than toxin A alone) are preferred, as an increasing number of circulating strains express only toxin B.
Stool samples should be refrigerated or frozen (depending on laboratory requirements) after collection if a delay in further processing is expected. The toxin may degrade to undetectable levels within 4 hours after collection if stored at room temperature
Newer EIA assays for glutamate dehydrogenase (GDH, C difficile common antigen) have been developed. Detection of GDH has fairly poor specificity for the toxin producing strains of C difficile that cause disease, but when used in conjunction with a toxin assay, it may greatly improve the negative predictive value of testing.
PCR technology can be used to detect the presence of toxins A or B; these tests are both sensitive and specific. PCR may eventually replace cytotoxic assays as the test of choice; however, it is not yet widely standardized. Several commercial PCR tests have received FDA approval.
Despite a relatively lack of sensitivity, repeated testing (ie, 3 samples) is no longer recommended. Studies have shown repeat samples add minimal utility and are not cost effective.[21, 22]
Other items to consider in the laboratory analysis include fecal leukocytes and fecal lactoferrin assays. These test lack specificity and have limited roles.
Imaging studies do not aid in confirming the diagnosis of early or mild colitis.
In patients with severe disease, radiographic studies can aid in detecting complications (eg, toxic dilation, perforation). These studies may also be indicated to investigate other possible diagnoses.
CT scanning of the abdomen can be helpful by revealing the presence of bowel wall edema (>4 mm) and inflammation, particularly in cases involving the right colon; however, these findings are generally nonspecific. One retrospective study of CT scan findings showed an association between complicated CDI and both pleural effusion and colonic wall thickness of greater than 15 mm.[23]
Barium enema has no role in the diagnosis of early colitis and can be catastrophic in the setting of dilatation due to toxic megacolon or perforation.
Toxic megacolon is characterized radiographically by dilation of the transverse colon to greater than 6 cm and loss of colonic haustrations (possible “thumbprinting”).
Pseudomembranes can be visualized in up to 50% of patients with CDI via endoscopic examination. Flexible sigmoidoscopy is sufficient in 90% of cases; few may require full colonoscopy.
In mild cases, pseudomembranes may not be grossly present, and diagnosis must be confirmed with biopsy.
The classic appearance of 2-mm to 10-mm raised yellow nodules is pathognomonic. These lesions are usually discrete but may become confluent plaques in more advanced cases. The pseudomembranes can be easily removed during endoscopy, revealing an erythematous inflamed mucosa.
Sigmoidoscopy is not routinely used in the diagnosis of CDI because of its invasiveness.
Macroscopically, pseudomembranes are appreciated as patchy flecks of tan-to-black nodules, loosely adherent to the erythematous bowel wall with superficial erosions, punctate in mild forms, and more confluent in advanced disease.
Microscopically, the earliest sign is focal necrosis of surface epithelial cells in the glandular crypts, with neutrophilic infiltration and fibrin plugging of capillaries in the lamina propria and mucus hypersecretion in adjacent crypts. This leads to the formation of crypt abscesses. As the disease progresses, necrosis and denudation of the mucosa occurs with thrombosis of submucosal venules. The bowel wall inflammation tends to remain superficial; however, exposure of unprotected submucosa to the fecal stream can lead to global dysfunction of the colonic musculature and subsequent dilatation.
Prospectively validated severity scores for patients with C difficile infection are lacking. The following criteria were used in the 2010 SHEA/ISDA clinical guidelines:
Mild-to-moderate disease
WBC count less than 15,000 cells/mL
Serum creatinine less than 1.5 times baseline
Severe disease
WBC greater than 15,000 cells/mL
Serum creatinine greater than 1.5 times baseline
Severe, complicated disease
Hypotension or shock
Ileus
Toxic megacolon
The clinical trail that demonstrated superiority of vancomycin for severe disease used 6 variables to characterize severe disease: age older than 60 years, temp higher than 38.3° C, albumin level below 2.5mg/dL, WBC greater than 15,000 cells/mL, evidence of pseudomembranous colitis, and ICU admission.[24]
Stop the offending agent if possible. In about 20% of patients, CDI resolves within 2-3 days of antibiotic discontinuation, without further therapy.
Given the potential morbidity of C difficile infection, treatment should be initiated immediately rather than waiting for potential resolution of symptoms. In mild cases that are brought to clinical attention and are diagnosed after the resolution of symptoms, withholding antibiotics may be reasonable.
Provide supportive care for the diarrhea, including repletion of fluid and electrolyte losses.
Antiperistaltic agents and opiates should be avoided, as slowing of fecal transit time is thought to result in extended toxin-associated damage.
Test confirmation of C difficile involvement is indicated prior to treatment, provided the patient is not critically ill. Empiric treatment prior to confirmation of diagnosis is recommended in critically ill patients, but stool samples for analysis should be obtained within 48 hours of therapy initiation.
Implement contact isolation precautions (gowns and gloves) to reduce the spread of C difficile to other hospitalized patients.
Patients generally respond to 10-14 days of metronidazole or vancomycin therapy (see Medication); however, patients with severe colitis or underlying GI conditions (eg, irritable bowel syndrome, lactose intolerance) may require prolonged courses of therapy.
Treatment of completely asymptomatic carriers (including health care workers) remains controversial, although a significant reduction in carriage rate has been successfully reported with oral vancomycin
Surgical intervention is usually indicated for patients whose conditions are complicated by toxic megacolon with subsequent risk for perforation or existing perforation. The frequency of surgical intervention is low, reported at 0.39-3.6% of cases of C difficile –associated colitis. The overall mortality rate for patients requiring colectomy for severe, complicated CDAD is reportedly as high as 75%, reflecting its use as a therapy of last resort. Several studies have emphasized the importance of early surgical intervention if indicated (eg, prior to end organ failure or lactate >5).[25] Less invasive approaches including laparoscopic creation of a diverting ostomy have been described[26] ; these may improve mortality by facilitating earlier intervention.
Recommendations should be based on the severity of the symptoms. For moderate-to-severe cases, a clear liquid diet is recommended until the patient’s diarrhea resolves.
Oral metronidazole and oral vancomycin have similar efficacy in the treatment of mild-to-moderate C difficile -associated diarrhea. However, metronidazole is the empiric treatment of choice because of cost and the risk of selection for vancomycin-resistant enterococci in the stool with oral vancomycin.
In adults, oral metronidazole is dosed at 500 mg TID for 10-14 days.
For severe CDI, oral vancomycin is the drug of choice. It has been shown to have improved efficacy in this subset of patients.
Oral vancomycin is dosed at 125 mg qid for 10-14 days. (Dosing at 250 mg may also be used but has not been shown superior to the lower dose.)
Other situations in which vancomycin may be the drug of choice are as follows:
When metronidazole fails to elicit a response after 5-7 days of treatment
When organisms resistant to metronidazole are present (Metronidazole resistance remains uncommon in the United States. The NAP1 strain responsible for multiple outbreaks in the United States and Canada has been uniformly susceptible to metronidazole. However, surveillance reports from China, France, and Spain have noted resistance rates as high as 14%.[27] )
Patients who are pregnant or younger than 10 years
For severe, complicated C difficile (ie, critically ill, ileus, toxic megacolon,) oral vancomycin can be dosed as high as 500 mg qid.
In the setting of ileus, vancomycin retention enema (500 mg in 100 cc normal saline QID) can be used.
Metronidazole 500 mg IV q8 can also be used as an adjunct.
Despite the lack of conclusive clinical trials, intravenous metronidazole, 500 mg q8h, is generally recognized as adequate therapy for mild to moderate C difficile in patients who cannot tolerate oral therapy,[28] although failures have been documented. Intravenous vancomycin therapy is not adequate because no significant delivery of vancomycin to the bowel lumen occurs.
In 2005, a Cochrane review of antibiotic treatment for CDI determined that metronidazole, vancomycin, bacitracin, teicoplanin, fusidic acid, and rifaximin were equally effective for the initial treatment of C difficile infection.[29] Several other second-line treatments exist as follows:[30, 31]
Anion-exchange resin agents (eg, cholestyramine): These provide a 63% clearance rate as a single therapy; however, they bind antibiotic agents, limiting their clinical usefulness in more severe disease.
Teicoplanin has an efficacy that is similar to that of vancomycin but is not available in the United States.[32]
Although effective, fusidic acid has poor tolerability due to gastrointestinal adverse effects when compared to vancomycin and is not available in the United States.[33]
Nitazoxanide is a nitrothiazolide with broad activity against intestinal parasites and enteric pathogens.[34] In a 2006 prospective, randomized, double-blind study, the efficacy of nitazoxanide was at least as effective as metronidazole in treating C difficile colitis.
Rifaximin is a poorly absorbed rifamycin that has been FDA approved for traveler's diarrhea. It was successfully used in conjunction with oral vancomycin in a case series of patients with multiple recurrences of CDI. The patients underwent a 2-week course of rifaximin after completing treatment with vancomycin.[35] A phase III trial is underway.
Other antibiotics, such as rifampin, linezolid, and fluoroquinolones, have some activity against C difficile and have been used as adjunctive therapy in refractory cases of CDI.
Several other potential therapies are still undergoing clinical trails (or results are not yet published).[17]
Ramoplanin - Poorly absorbed glycolipodepsipeptide with efficacy similar to that of vancomycin[36]
PAR 101 (OPT-80, tiacumicin B) - Novel nonabsorbed macrocycle with minimal activity against enteric organisms other than C difficile[37]
Tolevamer is a high molecular weight anionic polymer that covalently binds C difficile toxins A and B. A 2006 randomized controlled trial showed that tolevamer 6 g/d was not inferior to oral vancomycin.[38] However, subsequent studies have shown tolevamer to be inferior to both vancomycin and metronidazole for initial infection.
Oritavancin and rifalazil are other antibiotics still in preclinical testing.
Immunization with C difficile toxoid (toxins A and B)[39, 40]
Monoclonal antibodies[41] (A study of 200 patients showed a significant reduction in recurrence rate (7% vs 25%) after a single IV infusion of antibiodies against toxins A and B, used in conjunction with metronidazole for vancomycin therapy.[42] )
Tinidazole is a structural analog of metronidazole that was previously available only in Europe. In 2004, the FDA approved it for use in parasitic infections. It retains good in vitro activity against C difficile strains that are resistant to metronidazole but has not yet been evaluated in a clinical trial.[43]
Treatment of recurrent disease
Recurrent disease is an increasingly prevalent problem.[44, 45, 46] Estimates of reoccurrence (within 90 days) average around 25%.
Note that recurrence of disease is not commonly associated with resistance.
No randomized controlled trials are available to guide therapy of recurrent disease. A retrospective review showed that metronidazole and vancomycin had equivalent efficacy in the treatment of a first recurrence; furthermore, treatment of the first recurrence with the same or a different agent did not affect the outcome. The first recurrence should be treated with a repeat treatment course of oral vancomycin or metronidazole.
With further recurrences, use of tapered or pulsed vancomycin should be considered.[47]
A typical tapered regimen might be as follows: 125 mg 4 times per day for 14 days, then 2 times per day for 7 days; then 125 mg once daily for 7 days, and then 125 mg every 2 or 3 days for 2-8 weeks. The goal of such tapered dosing is to allow restoration of the bowel flora while inhibiting activation of the C difficile spore forms.
After the first reoccurrence, use of metronidazole is not recommended, due to the risk of neurotoxicity with prolonged use.
The use of nitazoxanide and vancomycin plus rifampin have been proposed for treatment of a third or subsequent recurrence.
Other nonantibiotic therapies that have been used successfully as adjuncts in severe relapsing disease include stool transplant,[48] IVIG,[49, 50] and probiotics. However, these remain poorly studied.
The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection.
Clinical Context:
First-line agent. Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. If unable to tolerate PO, may administer IV as second-line therapy.
Further inpatient care is required only if the patient continues to have significant diarrhea, related fluid losses, or other medical issues; otherwise, outpatient therapy may be appropriate
Proper stewardship of antibiotics may limit the risk of CDI.
Avoidance of unnecessary antibiotics, especially within the first few months after treatment for CDI, may limit the risk of recurrent disease.
Implementation of infection control procedures is imperative to control spread.
C difficile is shed in feces. Any surface or material that becomes contaminated with feces may serve as a reservoir for the C difficile spores.
Use contact isolation for infected patients, particularly those with bowel incontinence. Infected patients can be isolated in private rooms (preferred) or through cohorting of patients with C difficile infection.
In patients with severe diarrhea causing fecal incontinence and suspected C difficile, some advocate initiation of contact isolation while confirmatory testing is pending.
Contact isolation can be terminated when the diarrhea has resolved.
Discontinuation of contact precautions does not require negative C difficile testing.
Gloves and gowns should be used during all patient contact.
Dedicate equipment when possible.
Hands should be washed with soap and water. Alcohol-based hand solutions may not be as effective against spore-forming bacteria.
Hospital rooms must be appropriately cleaned to ensure sterilization of spores. Hypochlorite-based disinfectants (eg, chlorine bleach) have been used with some success.
Probiotics are not currently recommended for the primary prevention of C difficile infection. Probiotics have shown efficacy in reducing the incidence of simple antibiotic-associated diarrhea, but their efficacy in preventing C difficile infection is inconsistent. Studies to date on probiotics have generally been nonrandomized, small in size, and/or have used highly selected patient populations.
Saccharomyces boulardii yeast
S boulardii rapidly colonizes the bowel without significantly altering the remaining bowel flora, and it is cleared from the bowel after cessation of therapy.
Safety concerns exist regarding fungemia with use in immunocompromised patients.
It is available as the dietary supplement Florastor in the United States.
Lactobacillus
Lactobacillus is available as a "natural" product with limited quality control.
In 2004, a small randomized controlled trial showed a 50% reduction in the incidence of CDI when used as prophylaxis initiated at the time of antibiotic therapy.[51] Later studies have not shown a similar effect, potentially due to variations in the product used.
Bio-K+ CL1285
Bio-K+ is newer pharmaceutical grade product containing Lactobacillus acidophilus and Lactobacillus casei.
In a randomized, double-blind placebo trial of 255 hospitalized patients aged 50-70 receiving penicillin, cephalosporin, or clindamycin, use of this probiotic was associated with a reduction in the rates of CDI by over half.[52] This trial was one of the most stringent to date to evaluate use of a probiotic, but it targets a very narrow patient population.
Major complications of acute disease include development of toxic megacolon, transverse volvulus, or colon perforation. These complications can be avoided with early detection and treatment, avoidance of antimotility agents in patients with nosocomial diarrhea (until etiology is known), and early surgical consultation.
Recurrent colitis and diarrhea occur in approximately 25% of patients (depending on populations studied), typically 2 weeks to 2 months after successful therapy completion. Occasionally, numerous (>6) episodes may occur. The etiology is unclear; however, the persistence of spores is thought to be related. Recurrent colitis usually does not represent the development of resistant organisms.
Jennifer A Curry, MD, MPH, Attending Physician, Infectious Disease Clinic, Naval Medical Center Portsmouth; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences
Disclosure: Nothing to disclose.
Specialty Editors
Gary L Gorby, MD, Associate Professor, Departments of Internal Medicine and Medical Microbiology and Immunology, Division of Infectious Diseases, Creighton University School of Medicine; Associate Professor of Medicine, University of Nebraska Medical Center; Associate Chair, Omaha Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Disclosure: Nothing to disclose.
Additional Contributors
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government.
LCDR Jennifer Curry is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
Many thanks to Duane R Hospenthal, MD, PhD, Joseph Lee, MD, and Braden Hale, MD, MPH for their work on earlier versions of this topic.
Pullman J, Prieto J, Leach TS. Ramoplanin vs. Vancomycin in the treatment of Clostridium difficile diarrhea: A Phase 2 Study, poster presented at the 44th ICAAC, an annual meeting of the American Society for Microbiology, October 2004.
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