Diagnosis and Management of Clostridium difficile Infection

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1216 –1223

PERSPECTIVES IN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Diagnosis and Management of Clostridium difficile Infection HERBERT L. DUPONT Center for Infectious Diseases, University of Texas School of Public Health; Department of Medicine, Baylor College of Medicine; and Internal Medicine Service, St. Luke’s Episcopal Hospital, Houston, Texas

This article has an accompanying continuing medical education activity on page e73. Learning Objectives—At the end of this activity, the successful learner will be able to appraise the various fecal diagnostic tests in Clostridium difficile-associated diarrhea (CDAD) and give the pros and cons of each; distinguish between the various CDAD drugs and treatments and have an approach to management of mild vs severe diseases; and discuss the options and advantages of potential treatments for the patient with multiple recurrences of CDAD.

Clostridium difficile infection (CDI) is increasing in frequency and severity in and out of the hospital, with a high probability of recurrence after treatment. The recent literature on CDI was reviewed using PubMed to include recent publications dealing with diagnosis and therapy. Real-time polymerase chain reaction is a sensitive and useful diagnostic test for CDI but there are growing concerns of falsepositive test results if the rate of CDI is low in the patient population providing samples and/or if the population being studied commonly includes people with C difficile colonization. Recommended therapy of CDI includes oral metronidazole for milder cases of CDI and oral vancomycin or fidaxomicin for more severe cases, each given for 10 days. Colectomy is being performed more frequently in patients with fulminant CDI. For treatment of first recurrences the drug used in the first bout can be used again and for second recurrences longer courses of vancomycin often are given in a tapered dose or intermittently to allow gut flora reconstitution, or other treatments including fidaxomicin may be used. Bacteriotherapy with fecal transplantation is playing an increasing role in therapy of recurrent cases. Metagenomic studies of patients with CDI during successful therapy are needed to determine how best to protect the flora from assaults from antibacterial drugs and to develop optimal therapeutic approaches. Immunotherapy and immunoprophylaxis offer opportunities to prevent CDI, to speed up recovery from CDI, and to eliminate recurrent infection. Humanized monoclonal antitoxin antibodies and active immunization with vaccines against C difficile or its toxins are both in development and appear to be of potential value. Keywords: Clostridium difficile Infection; Antibiotic-associated Diarrhea; Fidaxomicin; Oral Vancomycin; Metronidazole; Microbiome.

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efore the 1970s, antibiotic-associated diarrhea and colitis were believed to be caused by Staphylococcus aureus treated with oral vancomycin, now standard therapy for Clostridium difficile infection (CDI).1 In 1974, pseudomembranous colitis was identified in patients who had received clindamycin,2 and 4 years later Bartlett et al3 identified toxigenic C difficile as a cause of the disease. We are now seeing an emerging crisis in hospitals in the United States with a tripling of the CDI rate and the infection increasingly is occurring in the community.4 CDI is occurring with increased rates in patients with inflammatory bowel disease,5 where the diagnosis may be difficult to establish.6 In this review we discuss the diagnosis of CDI and consider the pathogenesis of the disease in developing principles of disease management.

Diagnosis of Clostridium difficile Infection Short-term asymptomatic excretion of C difficile occurs commonly in hospital populations7 as a result of the close proximity of patients receiving antibiotics and free movement of fecal organisms between patients on contaminated hands, fomites, and the environment. The rate of C difficile colonization increases during hospitalization, increasing with length of time in the hospital.8 This explains why only unformed stools should be tested for C difficile unless the patient has active ileus on examination,9 to reduce false-positive test results. In Table 1, the available tests and procedures used to make the diagnosis of CDI are outlined.

Fecal Diagnostic Tests Anaerobic toxigenic culture of C difficile and the cell culture cytotoxicity assay, with neutralization with clostridial Abbreviations used in this paper: CDI, Clostridium difficile infection; GDH, glutamate dehydrogenase; NAP1, North American pulse-field type 1; PPV, positive predictive value; RT-PCR, real-time polymerase chain reaction. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.03.016

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Table 1. Tests to Establish a Diagnosis of CDI Test or procedure Fecal enzyme immunoassay test for toxin A or toxin B or both Cell culture cytotoxicity assay

Result suggesting CDI

Comments

Positive test

Glucose dehydrogenase

Positive test with neutralization using antiClostridium toxin antibodies Positive with confirmation that the strain has genes for toxin(s) Negative test effectively rules out CDI

RT-PCR

Positive test

Fecal lactoferrin

Identifies mucosal inflammation and is not specific for CDI

Colon endoscopy (flexible sigmoidoscopy or colonoscopy) Abdominal CT scan

Required for confirmation of pseudomembranous colitis Patients with CDI often show colonic mucosal swelling

Fecal toxigenic culture for C difficile

The test lacks sensitivity but is rapid and available for all laboratories The test takes several days and is available only in research laboratories The test takes several days and is available only in research laboratories Positive samples should be confirmed using a second assay Test for toxin genes that is very sensitive; may not always differentiate between asymptomatic carriers and cases of CDI In a patient with positive fecal test for C difficile or its toxin(s), a positive lactoferrin strongly suggests CDI This is not normally needed in CDI cases Finding a positive CT scan shows moderate sensitivity and high specificity and has prognostic significance in a patient clinically suspected as having CDI

CT, computed tomography.

antitoxin, are the most sensitive for diagnosis of CDI but take multiple days to accomplish. The enzyme immunoassay became broadly used because of its rapidity in performance, however, the technique lacks sensitivity. A laboratory assay measuring the clostridial protein, glutamate dehydrogenase (GDH), represents a rapid and sensitive test for the bacterium but does not identify C difficile toxin(s). GDH can be used as a single test to identify CDI-negative cases with positive GDH stool samples confirmed as CDI through a secondary toxin test.10 In most laboratories, real-time polymerase chain reaction (RT-PCR) has become the preferred laboratory test for diagnosing CDI based on high test sensitivity.6 The test detects toxin genes and not active toxins and is not quantitative, making it of uncertain value in differentiating CDI from asymptomatic carriage of the organism. The overall accuracy for using RT-PCR for diagnosis depends on CDI prevalence and the rate of asymptomatic C difficile carriage in the population studied. In a meta-analysis of published studies it was estimated that if the actual rate of CDI was less than 10% of the samples submitted for testing, a positive RT-PCR test would have a positive predictive value (PPV) for CDI of 71% based on the greater proportion of stools identified from carriers identified as having CDI, and if the frequency of CDI was between 10% and 20% of samples submitted the PPV would increase to only 78%.11 In the same analysis, if true CDI rates were at a level of 20% of studied specimens, the PPV would improve to 93%, still with falsepositive results. In a separate study it was noted that in patients diagnosed with CDI by enzyme immunoassay or cell culture cytotoxicity assay the overall complication rate was more than 50% higher than that seen with RT-PCR, suggesting more frequent false-positive results with PCR.12 The movement to sole use of an RT-PCR in hospital laboratories is appropriate but the test should be fully validated. Two additions to PCR may optimize diagnoses of CDI. The first addition would be to develop a quantitative RT-PCR test. A second addition would be to use a standard RT-PCR accepting

all negative results followed by tests of the positive stool samples with a fecal marker of inflammation such as lactoferrin,13 or by using a secondary test for functional toxin(s). A repeat fecal test in a previously negative patient increases the diagnostic yield only minimally,14 although it may be needed in patients with inflammatory bowel disease with possible CDI.6 Molecular typing beyond PCR ribotyping may be required to distinguish the epidemic North American pulse-field type 1 (NAP) strain of C difficile and to look for strain clustering or outbreaks in the hospital.15

Endoscopy and Computed Tomography Scan of the Abdomen Sigmoidoscopy or colonoscopy is not usually part of the evaluation of CDI. Endoscopy is required to diagnose the presence of pseudomembranous colitis found in up to half of CDI patients.16 An abdominal computed tomography examination is useful in diagnosing CDI in a patient suspected with the disease in whom mucosal thickening of the colon is seen.17,18

Pathogenesis and Host Risk Factors as Related to Disease Management In Figure 1, the sequence of events in CDI development are outlined, identifying potential targets to which therapy can be directed. Patients who acquire CDI in the hospital are characteristically elderly with multiple medical comorbidities, factors that contribute to a more severe illness.19 The second step in CDI development is the reduction in intestinal colonization resistance by drugs that alter the microbiome, defined as totality of bacteria in the gut. Healthy gut microbiota influences epithelial cell proliferation and the gut immune system and can prevent colonization or infection by pathogens.20,21 Microbiota is altered by antibiotics that directly inhibit susceptible bacteria,22 or by

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Figure 1. Pathogenesis of CDI and potential therapeutic targets.

changes in the gut mucosa with altered epithelial function, regeneration, and permeability23,24 from intestinal inflammation caused by cancer chemotherapy, stem cell transplantation,25–29 or the presence of inflammatory bowel disease.30 CDI rates have increased in patients with inflammatory bowel disease associated with changes in gut flora,5 in whom early diagnosis of CDI and efficient treatment may influence the outcome in patients with inflammatory bowel disease.6 Reducing acid in the stomach may allow ingested vegetative cells as well as spores of C difficile to reach the small bowel and may lead to change in bile salts with secondary mucosal damage31 and inflammation,32 indirectly leading to bowel flora alterations33 and reduction in colonization resistance.34,35 Re-establishment of the colonic flora is essential for CDI recovery. Fidaxomicin and rifaximin are 2 drugs with inhibitory activity against C difficile strains that show relative sparing of gut flora,36,37 making them attractive as treatment options in CDI. The immune system is involved in the pathogenesis of and recovery from CDI. Patients chronically colonized before hospital admission by strains of C difficile show higher levels of serum IgG directed to toxin A and reduced rates of CDI,38 and

patients with CDI failing to mount an IgG response to toxin A show a higher rate of CDI recurrence39 influenced by the presence of a host interleukin-8 genetic polymorphism40 with high rates of CDI recurrence.41 Serum antitoxin A IgG2 and IgG3 classes of antibody have been shown to be reduced in patients with CDI recurrence.42

Treatment Specific treatment recommendations start with target 3 in Figure 1 after patients have been diagnosed with CDI. Therapeutic target 2 focuses on an enhanced immune response to C difficile toxins in preventing CDI recurrence. Target 1, which deals with improvements of the gut microbiome, is discussed later. The first phase of CDI treatment is to discontinue the antimicrobial agents that led to the development of CDI. In the mildest cases of CDI, the discontinuation of antimicrobial agents alone may be sufficient to manage clinical illness without further therapy. Not being able to do this will influence antimicrobial response to treatment and outcome for vancomycin22,43 but less so for fidaxomicin.43

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Table 2. Therapeutic Options for the First Bout of CDI Chemotherapeutic agents

Administration schedule

Metronidazole

Oral 500 mg 3 times/d for 10 d (can be given IV)

Vancomycin

125 mg 4 times/d orally for 10–14 d; for severe complicated disease 250–500 mg orally 4 times/d ⫾ 500 mg in 100 mL NS per rectum every 6 h by retention enema in presence of ileus

Fidaxomicin

200 mg orally 2 times/d for 10 d

Other antimicrobials with potential value: nitazoxanide, rifaximin, tigecycline, ramoplanin, surotomycin Colectomy

See available literature

Severely ill patient with increased serum lactate level ⱖ5 mmol/L and white blood cell count ⬎50,000 cells/mL

Comments The least expensive drug for CDI for use in milder forms of disease; pharmacokinetics are not ideal with ⬎95% of drug absorbed from the upper gut; not an approved therapy Standard therapy for more severe forms of CDI; capsule form is expensive, which can be reduced by working with compounding pharmacy to convert IV form for oral use Most recently approved therapy with high cost and lower rates of recurrence Small trials have been encouraging but further studies are needed

Colectomy should be considered in patients with progressive or fulminant colitis

IV, intravenously; NS, normal saline.

Antibiotic Therapy of the Initial Bout of Clostridium difficile Infection The 2 licensed drugs for treatment of CDI, vancomycin and fidaxomicin, both have cure rates of approximately 90%.44 Metronidazole, an unlicensed drug, is the preferred treatment for mild to moderate disease in a clinically stable patient based on expected effectiveness and low cost.45 Metronidazole has a pharmacokinetic limitation and should not be used in more severe CDI. The drug essentially is absorbed completely in the upper gut, resulting in very low drug levels in the colon, the major site of CDI. During a bout of CDI-induced diarrhea, fecal levels of metronidazole reach bactericidal concentrations against strains of C difficile46 owing to shorter than usual transit time from the small bowel to the colon and because of diffusion of drug into the inflamed gut from systemic circulation. Metronidazole levels decrease to essentially undetectable levels when diarrhea subsides.46,47 Metronidazole may be used intravenously in patients unable to take an oral drug, achieving similar low fecal levels. Oral vancomycin or fidaxomicin are preferred for severe clinical illness defined as the presence of important comorbidity, altered sensorium, unstable clinical course, confinement in an intensive care unit, renal failure (creatinine level ⱖ 1.5 times the upper limit of normal), reduced serum albumin level (⬍2.5 g/dL), hypotension, or leukocytosis with a white blood cell count greater than 15,000/mm3.45 Orally administered nonabsorbed vancomycin results in a mean fecal drug level of approximately 400 mg/L of drug after 4 days of anti-CDI therapy.48 Treatment of asymptomatic fecal excretion of C difficile is not effective and actually may be associated with a higher rate of colonization after treatment.47 In this review, currently approved drug dosage schedules are given (Table 2). It may be that duration of therapy normally given for CDI is not sufficiently long enough to eliminate C

difficile spores from the gut. Studies in the early 1980s establishing a short 10-day course of therapy were performed with small numbers of subjects.49,50 Recommended therapy for another spore-forming organism, anthrax, is for 2 months. Two treatment observations support the idea that 10 days is an insufficient duration of therapy in CDI. First, recurrences do not generally represent infection by resistant organisms and for the first recurrence the same drug used initially can be used in re-treatment.51 Second, it has been shown that giving a second antibiotic, rifaximin, after completion of initial therapy successfully prevented subsequent infection,52,53 supporting the concept that prolonged treatment is needed in CDI to prevent recurrence. Before recommending longer durations of therapy studies are needed to prove this concept.

Colectomy Colectomy is being performed with increasing frequency in patients with severe or fulminant CDI54 and may be lifesaving in patients showing clinical deterioration or fulminant infection.55 An alternative to colectomy in severe CDI is the creation of a diverting loop ileostomy with colonic lavage with vancomycin.56

Treatment of Recurrent Clostridium difficile Infection A unique feature of CDI is the very high recurrence rate seen in 25% of patients treated with equivalent frequency with either metronidazole or vancomycin,57,58 typically beginning 7 to 14 days after therapy is completed for the first bout. Primary treatment of CDI with fidaxomicin reduces the rate of recurrence to 15% for infection caused by non-NAP1 strains.44 The options for treatment of recurrent CDI detailed in Table 3 include administration of tapering doses of vanco-

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Table 3. Treatment Options for Patients With Recurrent CDI Chemotherapeutic agents

Administration schedule

Comments Preferentially use oral vancomycin with severe CDI

Fidaxomicin

Metronidazole 500 mg 3 times/d, vancomycin 125 mg 4 times/d or fidaxomicin 200 mg twice a day for 10 d Week 1: 125 mg 4 times/d Week 2: 125 mg twice a day Week 3: 125 mg once a day Week 4: 125 mg every other day Weeks 5 and 6: 125 mg every 3 d 125 mg every 2 d or 500 mg every 3 d for 3 wks 200 mg twice a day for 10–20 d

Rifaximin

550 mg twice a day for 20 d

Vancomycin high dose followed by S boulardii

250–500 mg vancomycin 4 times/d for 10 d followed by S boulardii 500 mg (2 capsules) twice a day for 28 d Single treatment of ⱖ50 g of donor stool diluted in saline and filtered by nasoduodenal tube, colonoscopy, or retention enema; occasionally needs to be repeated 200–400 mg/kg, can be repeated

First recurrence, reuse drug already given Vancomycin, tapered dose

Vancomycin pulse therapy

Fecal bacteriotherapy from a healthy donor

Intravenous immunoglobulin

Monoclonal antibodies to toxins A/B

Single infusion

mycin or intermittent vancomycin in an unproven attempt to preserve gut flora, fidaxomicin, and other antibiotic approaches.

Bacteriotherapy Although bacteriotherapy is useful for poorly responsive initial infections, the most important use is for therapy of recurrent CDI. Two approaches have been used to improve colonization resistance by repopulating the colonic flora with healthy bacteria, fecal transplantation, or oral administration of one or more probiotics, defined as living bacterial or fungal strains with health benefits. Fecal transplantation. Fecal microbiota transplantation has been used increasingly for management of severe primary CDI59 or CDI recurrence.60,61 Although family member stool donors have been used, the current movement is toward volunteer donor pools with screening of the donors for health before they provide their stools for transplantation.61 In one center a volunteer donor bank provided stools that were frozen in aliquots for transplanting into multiple patients with CDI.62 One investigator performed safety screening in family donors and patients and provided instructions for in-home self-administration of a fecal suspension by an enema bag kit.63 A follow-up study of 77 patients having undergone fecal transplant was performed after an average of 17 months showing most had experienced an excellent clinical response.64 Bacteriotherapy centers should be developed in large urban centers for patient referrals. It was found in Houston that there was a need for a center after surveying local gastroenterologists and infectious diseases specialists.65 Bacteriotherapy centers will

Attempting to inhibit vegetative cells of C difficile but preserve colonic flora

Attempting to inhibit vegetative cells of C difficile but preserve colonic flora Fidaxomicin spares colonic flora and is well tolerated Rifaximin spares colonic flora and is well tolerated This regimen has been shown to be effective in treating recurrent disease Most effective approach for multiple recurrent disease, attempting to repopulate the colon with healthy flora; limitation is lack of availability of treatment centers; mechanism of efficacy needs study Effective in recurrent disease in case reports but small clinical trials have failed to show efficacy Effective when used after standard therapy to prevent later recurrence (in development; not currently available)

provide therapy to the increasing numbers of patients with complicated or recurrent CDI and will allow metagenomic research to better understand mechanisms of successful reconstitution of microflora. Probiotics. Recognizing the importance of colonization resistance induced by gut flora single bacterial and fungal probiotics have been evaluated in studies as a means of preventing and treating CDI.66 Saccharomyces boulardii with colonizing and anti-inflammatory effects67 has been used alone or with vancomycin to prevent or to treat CDI.68 This fungal probiotic is not currently adequate by itself for therapy of CDI and has been inconsistent in preventing CDI.69,70 A mixture of strains of Lactobacillus was shown to effectively control diarrhea associated with antibiotics and to reduce the risk of acquiring CDI in hospitalized patients on antibiotics.71,72 One of the concerns of widespread use of probiotics is that many of the patients who experience CDI are elderly and infirm and susceptible to systemic infection by bacterial or fungal strains.73–75 Because metagenomics show the important constituents of the normal flora and the bacterial elements needed to recover from CDI, it may be possible to provide patients with single strains or a mixture of intestinal bacteria after antimicrobial therapy.76 In a recent report, 33 bacterial isolates from a single stool sample derived from a healthy donor were administered by colonoscopy to 2 refractory cases of CDI with excellent clinical resolution and C difficile–free stools.77 More studies such as this one need to be performed comparing intestinal instillation of characterized bacteria with that seen after standard fecal transplantation.

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Immunotherapy Passive immunization approaches also are being considered by some authorities in CDI therapy because of the importance of IgG antitoxin antibodies. Favorable results from the administration of intravenous immunoglobulin have been reported in an uncontrolled therapeutic study of recurrent CDI78 and in case reports of treatment of primary CDI.79,80 In small controlled clinical trials, no clinical response was seen when intravenous immunoglobulin was added to standard treatment of severe cases of primary CDI.81,82 A humanized monoclonal antibody preparation of antitoxins A and B in commercial development successfully prevented recurrence after conventional antimicrobial therapy for primary CDI or recurrent CDI.83 How this costly preparation will be used when licensed is uncertain but it is likely to be important in the management of patients with recurrent CDI refractory to other treatments. Recognizing the importance of antitoxin antibodies in the prevention of first and recurrent cases of CDI supports the idea that a toxin-/toxoid-based vaccine should be pursued in disease control.84 Vaccine efficacy was higher when a vaccine included both toxin A and toxin B compared with toxin A alone.85 C difficile toxoid vaccines are in development and have been shown to stimulate serum levels of antitoxin A IgG antibodies in patients with recurrent CDI.86 A variety of vaccines are under development including bacterial and toxoid preparations that, if protective, should represent a cost-effective approach to preventing CDI.87

Research Questions and the Future Important new research is needed in this field. A validated and sensitive assay for CDI is needed to eliminate concern about important numbers of false-negative and false-positive results. Better treatment approaches are needed for therapy of primary and recurrent CDI. Longer treatments and treatment combinations might be pursued. The most exciting area in therapy and prevention of CDI is reconstitution of flora through bacteriotherapy. At a workshop sponsored by the FDA and NIH, held May 1 and 2, 2013, it was decided by the FDA that because fecal microbial transplantation is not approved for any therapeutic purposes, an investigational new drug application is needed for the use of fecal microbial transplantation to treat any disease, including CDI. Improved probiotics will have advantages and this is where the field will move. It will be necessary to test individual strains of a probiotic flora mixture in animal models and in human beings with CDI to show that each strain provides value. This line of research will not be sorted out quickly but the rewards are likely to be important. Although therapy will be the major focus in the near future in the CDI field, studies directed toward immunotherapy should be pursued actively. An effective vaccine with durable levels of immunity could be the breakthrough in this field that is needed. Who would be vaccinated will require debate, but it certainly would include debilitated and infirm people and those of an advanced age likely to receive antimicrobial drugs. References 1. Khan MY, Hall WH. Staphylococcal enterocolitis–treatment with oral vancomycin. Ann Intern Med 1966;65:1– 8.

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Reprint requests Address requests for reprints to: Herbert L. DuPont, MD, MACP, University of Texas School of Public Health, 1200 Herman Pressler, Suite 733, Houston, Texas 77030. e-mail: herbert.l.dupont@uth. tmc.edu; fax: (713) 500-9359. Conflicts of interest The author discloses the following: The author received a consulting fee in 2011 from Salix Pharmaceuticals for the topic of antibiotic resistance in rifaximin treatment of hepatic encephalopathy.