C. difficile infection. Background and guidance for hospitals and clinical labs

infection Background and guidance for hospitals and clinical labs

infection is a serious public health concern First described in 1935 by Hall and O Toole, Clostridium difficile is the gram-positive, spore-forming bacterium behind the increasing number of infectious colitis cases in hospitals and care facilities in the US and elsewhere. When common intestinal flora is depleted (for example, following antibiotic treatment), bacteria can cause antibioticassociated diarrhea (AAD) and other intestinal disease [1,2]. Pathogenic produces a number of toxins in the infected individual. The primary virulence factors and the most characterized of these are toxin A and toxin B, both of which are responsible for the symptoms associated with C. difficile infection (CDI) [3]. Epidemiology In the United States the number of new cases of Clostridium difficile infection (CDI) has increased significantly [4,5]. It has been reported that approximately 500,000 cases occur annually, resulting in up to 20,000 fatalities [6]. Historically, C.difficile has been primarily seen as a hospital-acquired (HA) infection, though now the emergence of community-acquired (CA) infections associated with young healthy individuals without prior exposure to hospitals or antibiotics is increasing dramatically [7]. Symptoms The symptoms of CDI include: Watery diarrhea (at least three unformed bowel movements per day for two or more days) Fever Loss of appetite Nausea Abdominal pain/tenderness Clostridium bacteria The genus Clostridium comprises more than 150 distinct species, including those responsible for botulism poisoning, gas gangrene, and tetanus. Clostridium difficile causes a form of infectious colitis that is currently a serious health concern in the US and across the globe.

Far more could be done to stop the deadly bacteria USA Today, 8.16.2012 Infection control and prevention Citing hospital billing data, an article in USA Today puts the number of deaths due to C. diffi cile infection in the USA in 2010 at more than 30,000 much higher than the number reported by the CDC for the same period (CDC estimates are based on death certifi cates). In the article Far more could be done to stop the deadly bacteria C. diff, USA Today highlights several patients who died from C. diffi cile infections. Many of these people entered the hospital for routine procedures, contracted C. diffi cile, and died of the infection weeks or months later. CDI is not just a disease of the elderly or of severely ill patients. The article makes the case for more strict measures to be implemented to halt the spread of C. diffi cile infections in the US and across the globe. These include controlling the use of antibiotics, introducing patient isolation and accurate diagnostic testing procedures, and training staff on more effective cleaning protocols. A campaign to reduce C. diffi cile cases in England has shown considerable success, giving hope to governmental agencies and healthcare facilities that reduction in these infections is achievable. The faces of victims Charlee Ratliff, 8 months, contracted after heart surgery. Lucille Burns, 88, contracted after she was hospitalized for a bruised hip. C. diffi cile is transmitted from person to person by the fecaloral route. In hospital wards and intensive care units, C. diffi cile contamination was found in 49% of sites in rooms with CDI patients and 29% of sites in rooms with asymptomatic carriers. The most common sources of contamination were fl oors and bed rails. Other frequently contaminated sites were windowsills, toilets, bed sheets, call buttons, scales, blood pressure cuffs and feeding tube equipment [8]. Alcohol does not kill C. diffi cile spores, so the use of alcohol-based sanitizers should be discouraged as a method for eliminating C. diffi cile from the hands [8]. The most effective way to remove C. diffi cile spores is through handwashing with soap and water. The Society for Healthcare Epidemiology of America (SHEA) guidelines recommend all healthcare workers and visitors wear gloves and gowns when entering the room of a patient with CDI. CDI patients should be isolated in private rooms, if available. If not, they should be cohorted, and each patient should be provided with a dedicated commode. Contact precautions should be maintained throughout the duration of the diarrhea [9]. SHEA also recommends cleaning with a hypochlorite solution (a 1:10 dilution of concentrated bleach is shown to be effective) or other sporicidal agent to address environmental contamination. It is also important to properly disinfect common equipment such as stethoscopes, bed scales, IV poles, and pumps, and to use disposable thermometers [8,9]. The families of C. diffi cile patients are shouldering many emotional and fi nancial stresses and have had to bear the responsibility of educating themselves about this disease, its spread and possible treatments, as many hospitals and clinics are not yet profi cient in dealing with CDI. Richard Croke, 48, contracted after treatment for esophageal cancer. Isolate patient Wear gloves and gown Disinfect common equipment Keep patient rooms clean Inform other facilities In the US there are an estimated 500,000 cases annually, leading to up to 20,000 deaths. Heinlen L, Ballard JD (2010) Janice Malcom, 67, contracted after stomach surgery. Place patient in a private room if possible. If a private room is not available, cohort with CDI patients and provide each one with a dedicated commode. Caregivers should wear fresh gloves and gowns each time they enter the patient s room and dispose of them carefully. Alcohol-based sanitizers do not kill spores, washing with soap and water is recommended. Items such as stethoscopes, bed scales, IV poles, pumps, etc., should be disinfected. Consult the manufacturer of the equipment for the appropriate cleaning method for spores. 10% bleach and sporicidal cleaners are effective in neutralizing spores. The most contaminated surfaces in a patient s room include the floors, bed rails, windowsills, toilets, bed sheets, call buttons, scales, blood pressure cuffs, and feeding tube equipment. If you are transferring a CID patient to another hospital or care facility, inform the receiving facility of the status of the patient. 4 5

Prevalence and associated cost Evolution of diagnostic tests accounts for 20 30% of cases of antibiotic-associated diarrhea and is the most commonly recognized cause of infectious diarrhea in healthcare settings. Infections in the United States have tripled from 2000 to 2005, and disease mortality has increased, particularly among the elderly [8]. The New York State Department of Health estimated that the marginal cost associated with each hospital-acquired CDI in the period from 2007 to 2008 was approximately $29,000, and the estimated annual cost of CDI in New York State was approximately $55 million, with nearly 23,000 additional hospital days [10]. For the United States as a whole, it was estimated that the annual excess hospital costs associated with CDI were $3.2 billion per year between 2000 and 2002 [9]. With the prevalence of asymptomatic carriage reported as high as 51 85%, authors of a 2012 report suggest that screening every hospital admission for and implementing rigorous contact isolation procedures (i.e., the use of gloves and gowns for each patient contact) for those with a positive result would reduce the number of CDI cases and, consequently, reduce the large economic burden currently being shouldered by the nation s healthcare system [11]. Disease mortality has increased, particularly among the elderly. Gerding et al. (2008) In patients who develop diarrhea within 72 hours of being admitted to the hospital and who also received antibiotics within the 3-month period preceding hospitalization, testing should be ordered as there is a strong likelihood of hospital-acquired CDI [12]. Several different methods are available for the detection of toxigenic. There are, however, considerable differences in the performance and the assay methodologies used to definitively diagnose toxigenic from other nontoxic strains. Factors to consider when investigating different methods include the antigen or target detected by the assay, sample types consistent with CDI, disease prevalence, performance criteria used in the studies and comparisons to relevant predicate assays. 6 7

Commonly used CDI test methods NAAT is emerging as the detection assay of choice GDH antigen screening Glutamate dehydrogenase (GDH) antigen screening is a common frontline test method used to detect C. diffi cile, but it is not specifi c for the toxigenic strain. Product inserts for commercially available GDH tests (as well as some independent reports) indicate the sensitivity of this test is as high as 94%. Several other investigators, however, report sensitivities as low as 84% [13 18]. Labs relying on GDH screening may be dramatically underestimating the incidence of C. diffi cile, and underreporting the incidence of such a highly infectious bacterial strain poses a serious risk to the patients and the community at large. EIA to detect toxin A and B Enzyme immunoassay (EIA) tests for toxins A and B have demonstrated very poor sensitivity even when combined with GDH antigen detection methods. In some studies the overall sensitivity has been reported to be as low as 48 67% [13 18]. Despite good specifi city, this test, the GDH test, or the combination of the two cannot be used as a standalone assay according to guidance from the American Society for Microbiology [19]. Toxigenic culture of and cell culture cytotoxin neutralization assays Toxigenic culture and cell culture cytotoxin neutralization assays have traditionally been held as the standard for C. diffi cile detection, but the skill level involved in their use is signifi cant. Toxigenic culture involves the successful culture and identifi cation of the C. diffi cile organism from stool; the cytotoxin neutralization assay relies on the technician s ability to identify the C. diffi cile toxin present in a stool sample through its effect on cultured cells. These tests are not widely available and are also timeconsuming, taking from 2 to 5 days depending on the method selected, making them inappropriate for patient management. NAAT Nucleic acid amplifi cation tests (NAATs) have delivered very specifi c and very sensitive results when detecting toxigenic C. diffi cile. These assays target the toxin genes in disease-causing C. diffi cile strains, making them consistent and reliable testing methodologies. Although PCRbased NAATs may not be accessible to every hospital lab due to the lack of space, budget, and trained staff, the clinical need for better and more defi nitive diagnosis is met by the molecular methods now available. The most widely used detection assay is the EIA assay to detect GDH, but according to the American Society for Microbiology, GDH assay results alone are not suffi cient for C. diffi cile identifi cation. A Practical Guidance Document for the Laboratory Detection of Toxigenic Clostridium diffi cile states, GDH assay results must be confi rmed. A GDH positive result along with a positive toxin A/B EIA, a positive cytotoxin neutralization or a positive nucleic acid amplifi cation test (NAAT) result may be reported as positive C. diffi cile. If the A/B EIA or cytotoxin neutralization assay is used and is negative, specimens should be further tested by either NAAT or toxigenic culture [see assay workfl ow diagrams]. Laboratories can also use a NAAT to detect C. diffi cile toxin genes as a stand alone diagnostic test. [19]. The high sensitivity, specifi city, and rapid time-to-results of the molecular NAATs makes them ideal for the detection of CDI [20], and the CDC, in guidance released in March 2012, advises that patients who have had three or more unformed bowel movements in 24 hours should be tested for C. diffi cile, preferably using NAAT [21]. 1 2 3 GDH Assay Toxin A/B Assay or Cytotoxin Neutralization Assay NAAT Assay or Toxigenic Culture GDH + Toxin A/B Combination Lateral Flow Assay Both tests positive One test positive One test negative NAAT or Toxigenic Culture Both tests negative NAAT as stand alone test (to date PCR is the most sensitive and specific) 8 9

Treatments and some new options References Patients with confirmed CDI are usually managed by first discontinuing antibiotics that could be contributing to the infection. Depending on how severe the illness is and whether it is a first or a recurrent infection, antibiotic treatment (metronidazole, vancomycin, or fidaxomicin), probiotic supplementation, and the application of toxin-binding resins can be employed [6,22]. Some physicians are turning to fecal microbiota transplantation, which has a response time of hours (compared to days with antibiotic treatment), results in an approximately 90% cure rate, and appears to have negligible adverse effects [23]. A clinical trial is currently underway to test synthetic stool pure cultures of probiotic intestinal bacteria as a treatment for recurrent and refractory CDI [24]. 1. Kelly CP, LaMont JT (2008) Clostridium difficile more difficult than ever. N Engl J Med 359(18):1932 1940. 2. Noren T (2010) Clostridium difficile and the disease it causes. Methods Mol Biol 646:9 35. 3. Voth DE, Ballard JD (2005) Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18(2):247 263. 4. McDonald LC, Owings M, Jernigan DB (2006) Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis 12(3):409 415. 5. Lessa FC, Gould CV, McDonald LC (2012) Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 55 Suppl 2:S65 70. 6. Heinlen L, Ballard JD (2010) Clostridium difficile infection. Am J Med Sci 340(3):247 252. 7. Brandt LJ, Feuerstadt P (2011) Clostridium difficile: epidemiology, transmission, and treatment. Pharmacy Practice News, Oct 2011. 8. Gerding DN, Muto CA, Owens RC (2008) Measures to control and prevent Clostridium difficile infection. Hines Veterans Affairs Hospital, IL. Clin Infect Dis 46(Suppl 1):S43 49. 9. Cohen SH, Gerding DN, Johnson S et al. (2010) Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 31(5):431 455. 10. Lipp MJ, Nero DC, Callahan MA (2012) Impact of hospital-acquired Clostridium difficile. J Gastroenterol Hepatol 27(11):1733 1737. 12. McFarland LV, Mulligan ME, Kwok RY et al. (1989) Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 320(4):204 210. 13. Chapin KC, Dickenson RA, Wu F et al. (2011) Comparison of five assays for detection of Clostridium difficile toxin. J Mol Diagn 13(4):395 400. 14. Eastwood K, Else P, Charlett A et al. (2009) Comparison of nine commercially available Clostridium difficile toxin detection assays, a real-time PCR assay for tcdb, and a glutamate dehydrogenase detection assay to cytotoxin testing and cytotoxigenic culture methods. J Clin Microbiol 47(10):3211 3217. 15. Peterson L, Robicsek A (2009) Does my patient have Clostridium difficile infection? Ann Intern Med 151(3):176 179. 16. Novak-Weekley SM, Marlowe EM, Miller JM et al. (2010) Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol 48(3):889 893. 17. Tenover FC, Novak-Weekley SM, Woods CW et al. (2010) Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. J Clin Microbiol 48(10):3719 3724. 18. Sharp SE, Ruden LO, Pohl JC et al. (2010) Evaluation of the C. Diff Quik Chek complete assay, a new glutamate dehydrogenase and A/B toxin combination lateral flow assay for use in rapid, simple diagnosis of Clostridium difficile disease. J Clin Microbiol 48(6):2082 2086. 19. A Practical Guidance Document for the Laboratory Detection of Toxigenic Clostridium difficile. American Society for Microbiology, September 21, 2010, available online at http://www.asm.org/images/pdf/clinical/ clostridiumdifficile9-21.pdf infection: a meta-analysis. Clin Infect Dis 53(7):81 90. 21. Making health care safer: stopping infections. CDC Vital Signs, March 2012. http://www.cdc.gov/vitalsigns/hai 22. Golan Y, Epstein L (2012) Safety and efficacy of fidaxomicin in the treatment of Clostridium difficile associated diarrhea. Therap Adv Gastroenterol 5(6):395 402. 23. Bakken JS, Borody T, Brandt LJ et al. (2011) Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 9:1044 1049. 24. Harnessing the Healthy Gut Microbiota to Cure Patients With Recurrent C. Difficile Infection. Clinical trial principal investigator Dr. Elaine Petrof, Department of Medicine, Queen s University, Ontario, Canada; clinicaltrials.gov identifier: NCT01372943. Note: The summary above outlining various treatment options is for informational purposes only and is not intended to be used to guide patient treatment. 11. Bartsch SM, Curry SR, Harrison LH et al. (2012) The potential economic value of screening hospital admissions for Clostridium difficile. Eur J Clin Microbiol Infect Dis 31(11):3163 3171. 20. Deshpande A, Pasupuleti V, Rolston DD et al. (2011) Diagnostic accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile 10 11

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