Wilcox, Mark H. MD
From the Department of Microbiology, Leeds Teaching Hospitals & University of Leeds, Old Medical School, Leeds General Infirmary, Leeds, UK.
Correspondence to: Mark H. Wilcox, MD, Department of Microbiology, Leeds Teaching Hospitals & University of Leeds, Old Medical School, Leeds General Infirmary, Leeds LS1 3EX, UK. E-mail: firstname.lastname@example.org.
The author has no funding or conflicts of interest to disclose.
Prof. Wilcox is an advisory board member for Actelion, Astellas, Cerexa, J&J, MSD, Nabriva, Novacta, Optimer, Phico Therapeutics, The Medicines Company, and Viropharma. He is currently a consultant to Cerexa, Pfizer, Photopharmica, Summit, and Wyeth and has research collaborations with Actelion, Novacta, Summit, and The Medicines Company.
Clostridium difficile infection (CDI) has emerged from being primarily a nuisance disease causing diarrhea predominantly in the elderly, to a major cause of morbidity and mortality. This change in the epidemiology and clinical presentation of CDI has occurred during the last 8 years and coincides with the recognition and spread of a hitherto unrecognized C. difficile strain (referred to as NAP1, BI, and 027). The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have recently issued updated guidelines on the epidemiology, diagnosis, treatment, and infection control and environmental management of CDI in adults to reflect the current challenges.1 Notably, the previous (Society for Healthcare Epidemiology of America) guideline on CDI was published in 1995.2
The following are selected recommendations from the new guideline:
* Testing for C. difficile or its toxins should be performed only on diarrheal (unformed) stool, unless ileus due to C. difficile is suspected (B-II).
* Repeat testing during the same episode of diarrhea is of limited value and should be discouraged (B-II).
* Although stool culture is not clinically practical because of its slow turnaround time, the sensitivity and specificity of stool culture followed by identification of a toxigenic isolate (ie, toxigenic culture), as performed by an experienced laboratory, provide the standard against which other clinical test results should be compared (B-III).
* Enzyme immunoassay (EIA) testing for C. difficile toxins A and B is rapid but is less sensitive than the cell cytotoxin assay, and it is thus a suboptimal alternative approach for diagnosis (B-II).
* Toxin testing is most important clinically but is hampered by its lack of sensitivity. One potential strategy to overcome this problem is a 2-step method that uses EIA detection of glutamate dehydrogenase (GDH) as initial screening and then uses the cell cytotoxicity assay or toxigenic culture as the confirmatory test for GDH-positive stool specimens only. Results seem to differ based on the GDH kit used; therefore, until more data are available on the sensitivity of GDH testing, this approach remains an interim recommendation (B-II).
* Polymerase chain reaction (PCR) testing seems to be rapid, sensitive, and specific and may ultimately address testing concerns. More data on utility are necessary before this methodology can be recommended for routine testing (B-II).
With some irony, the timing of these long-awaited new recommendations means that there remains considerable uncertainty about the optimum approach to the laboratory diagnosis of CDI in the routine clinical setting. Clinicians need to be alert to the strengths and weaknesses of the CDI test options in place in their own diagnostic laboratories. Notably, the most prevalent (EIA) CDI diagnostic tests have both poor sensitivity and specificity.3,4 This has led to frequent retesting of fecal samples in some patients. Unfortunately, with poor specificity assays, use of multiple repeats tests risks generating false-positive results. Also, if these tests are used in low CDI prevalence settings, for example, community-associated CDI, the results have low positive predictive value. The guidelines offer some hope for clarity in the future based on either using combinations of tests (the algorithm approach) and/or using PCR.5,6 It should be remembered that the PCR tests, although having good sensitivity for the detection of C. difficile, do not actually detect toxin in feces. Thus, carriers of C. difficile who have diarrhea due to causes other than CDI will likely be flagged as positive by PCR tests. Also, patients with CDI experience symptomatic recurrence in 20% to 25% of cases; retesting of patients with new or continuing diarrhea by PCR may yield a positive result simply because a toxigenic strain is still present, even though it may not be causing the current symptoms. It is likely that the intensive ongoing research on the optimum diagnosis of CDI will yield much needed clarity. Until that point, judicious interpretation of test results is needed together with good clinical acumen for treating the patient (especially if severe CDI is suspected; see Treatment section) as opposed to the test result.
* Discontinue therapy with the inciting antimicrobial agent(s) as soon as possible, as this may influence the risk of CDI recurrence (A-II).
* When severe or complicated CDI is suspected, initiate empirical treatment as soon as the diagnosis is suspected (C-III). If the stool toxin assay result is negative, the decision to initiate, stop, or continue treatment must be individualized (C-III).
* If possible, avoid use of antiperistaltic agents, as they may obscure symptoms and precipitate toxic megacolon (C-III).
* Metronidazole is the drug of choice for the initial episode of mild-to-moderate CDI (white blood cells ≤15,000/mL; serum creatinine <1.5 times premorbid level). The dosage is 500 mg orally 3 times per day for 10 to 14 days (A-I).
* Vancomycin is the drug of choice for an initial episode of severe CDI (white blood cells ≥15,000/mL or serum creatinine ≥1.5 times the premorbid level). The dosage is 125 mg orally 4 times per day for 10 to 14 days (B-I). Vancomycin administered orally (and per rectum, if ileus is present) with or without intravenously administered metronidazole is the regimen of choice for the treatment of severe, complicated CDI (hypotension or shock, ileus, megacolon). The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema, and the metronidazole dosage is 500 mg intravenously every 8 hours (C-III).
* Consider colectomy for severely ill patients. Monitoring the serum lactate level and the peripheral blood white blood cell count may be helpful in prompting a decision to operate, because a serum lactate level rising to 5 mmol/L and a white blood cell count rising to 50,000 cells per mL have been associated with greatly increased perioperative mortality. If surgical management is necessary, perform subtotal colectomy with preservation of the rectum (B-II).
* Treatment of the first recurrence of CDI is usually with the same regimen as for the initial episode (A-II) but should be stratified by disease severity (mild-to-moderate, severe, or severe complicated), as is recommended for treatment of the initial CDI episode (C-III).
* Treatment of the second or later recurrence of CDI with vancomycin therapy using a tapered and/or pulse regimen is the preferred next strategy (B-III).
* No recommendations can be made regarding prevention of recurrent CDI in patients who require continued antimicrobial therapy for the underlying infection (C-III).
The key treatment point emphasized in the guidelines is the need to determine and monitor closely the severity of CDI. The proposed severity markers for CDI, albeit currently based on retrospective studies, are white cell count, serum creatinine, temperature, and presence of colitis. It is clear that oral vancomycin is superior to oral metronidazole for severe CDI cases.7 Unfortunately, response to treatment with either metronidazole or vancomycin is inferior in CDI caused by C. difficile NAP1/BI/027strains.8 Options for treating life-threatening CDI remain poorly studied, but a multidisciplinary approach including early surgical assessment is crucial. It is likely that the proportion of patients treated with oral vancomycin for CDI will increase, assuming the guideline criteria are adopted. This predicted increase use and reliance on vancomycin, alongside the need for frequent repeat treatment courses in CDI because of symptomatic recurrence, highlights the need for new therapeutic options. Fidaxomicin proved superior to vancomycin in 2 recently completed phase 3 studies, in terms of the likelihood of recurrence9; decisions on the registration of fidaxomicin for CDI treatment are expected in the next 12 to 18 months. There are several other therapeutic options in the research pipeline, including monoclonal antibodies against C. difficile toxins.10 It is likely that, by the time of the next CDI guidelines, treatment options will have significantly expanded from the current limited choices.
INFECTION CONTROL AND PREVENTION, INCLUDING ENVIRONMENTAL CLEANING AND DISINFECTION
* Health care workers and visitors must use gloves (A-I) and gowns (B-III) on entry to a room of a patient with CDI.
* Emphasize compliance with the practice of hand hygiene (A-II).
* In a setting in which there is an outbreak or an increased CDI rate, instruct visitors and health care workers to wash hands with soap (or antimicrobial soap) and water after caring for or contacting patients with CDI (B-III).
* Accommodate patients with CDI in a private room with contact precautions (B-III). If single rooms are not available, cohort patients, providing a dedicated commode for each patient (C-III).
* Maintain contact precautions for the duration of diarrhea (C-III).
* Routine identification of asymptomatic carriers (patients or health care workers) for infection control purposes is not recommended (A-III), and treatment of such identified patients is not effective (B-I).
* Use chlorine-containing cleaning agents or other sporicidal agents to address environmental contamination in areas associated with increased rates of CDI (B-II).
* Routine environmental screening for C. difficile is not recommended (C-III).
The strength of evidence associated with many of these recommendations reflects the uncertainties and difficulties in providing proof of concept in this field. However, it is clear from experiences of large outbreaks that the principles outlined here do represent feasible and effective controls mechanisms for CDI. The key for many of these points is achieving high compliance, given the high potential for cross-transmission of C. difficile and the ubiquity of the organism in endemic settings. The potential for widespread environmental contamination by C. difficile, including dissemination by air (new data not included in the guidelines),11 emphasizes the need for early isolation of symptomatic patients suspected of having CDI. Health care institutions seem generally to have become more successful at promoting hand hygiene. Importantly, however, the prevalent alcohol-based gels and liquid preparations are ineffective at removing C. difficile from hands.12 There is no evidence that the use of these agents is associated with increases in the incidence of CDI,13 but health care workers need to be alert to the need to switch to use of soap-based hand hygiene, as opposed to alcohol hand gels/liquids, when managing suspected or proven CDI cases.
ANTIMICROBIAL USE RESTRICTIONS
* Minimize the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed, to reduce CDI risk (A-II).
* Implement an antimicrobial stewardship program (A-II). Antimicrobials to be targeted should be based on the local epidemiology and the C. difficile strains present, but restricting the use of cephalosporin and clindamycin (except for surgical antibiotic prophylaxis) may be particularly useful (C-III).
The evidence for the effectiveness of optimizing antibiotic use in reducing CDI risk is good. Where the evidence base struggles is determining which agents (apart from cephalosporins and clindamycin) are high versus lower risk for CDI.14 This reflects poor study design, typically before-and-after studies carried out in response to outbreaks of CDI. Typically, in such settings, there are multiple interventions, including antimicrobial restriction, with inadequate study control for exposure to C. difficile. Hence, there are reports with conflicting findings implicating or exonerating individual antibiotics or classes of antimicrobials.15,16 The key message in controlling CDI is first and foremost to limit C. difficile transmission. Avoiding high CDI risk agents (taking into account the above points about evidence quality) in high-risk patients makes clear sense. However, minimizing the frequency, duration, and number of antimicrobial agents prescribed should be part of general good antimicrobial husbandry and will also contribute to reduced CDI risk.
1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Health care Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
2. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995;16:459-477.
3. Planche T, Aghaizu A, Holliman R, et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis. 2008;8:777-784.
4. Eastwood K, Else P, Charlett A, et al. Comparison of nine commercially available C. difficile toxin detection assays, a real time PCR assay for C. difficile tcdB and a GDH detection assay, with cytotoxin testing and cytotoxigenic culture. J Clin Microbiol. 2009;47:3211-3217.
5. Sloan LM, Duresko BJ, Gustafson DR, et al. Comparison of real-time PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection. J Clin Microbiol. 2008;46:1996-2001.
6. Novak-Weekley SM, Marlowe EM, Miller JM, et al. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol. 2010;48:889-893.
7. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.
8. Pepin J, Valiquette L, Gagnon S, et al. Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP 1/027. Am J Gastroenterol. 2007;102:2781-2788.
9. Crook D, Weiss K, Cornely OA, et al. Randomized clinical trial in Clostridium difficile infection confirms equivalent cure rate and lower recurrence rate of fidaxomicin vs. vancomycin. 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, 2010. Abstract LB 2401.
10. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. NEJM. 2010;362:197-205.
11. Best EI, Fawley WN, Parnell P, et al. The potential for airborne dispersal of Clostridium difficile from symptomatic patients. Clin Infect Dis. 2010;50:1450-1457.
12. Jabbar U, Leischner J, Kasper D, et al. Effectiveness of alcohol-based hand rubs for removal of Clostridium difficile spores from hands. Infect Control Hosp Epidemiol. 2010;31:565-570.
13. Gordin FM, Schultz ME, Huber RA, et al. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol based handrub. Infect Control Hosp Epidemiol. 2005;26:650-653.
14. Davey P, Brown E, Fenelon L, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2005;19:CD003543.
15. Valiquette L, Cossette B, Garant MP, et al. Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain. Clin Infect Dis. 2007;45(suppl 2):S112-S121.
16. Biller P, Shank B, Lind L, et al. Moxifloxacin therapy as a risk factor for Clostridium difficile-associated disease during an outbreak: attempts to control a new epidemic strain. Infect Control Hosp Epidemiol. 2007;28:198-201.
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