Question 1
What are the sensitivity, specificity, and predictive values of different methods for screening or diagnosis of CDI? a. Overall b. Do performance measures vary with sample characteristics?

Question 2
What are effective hospital prevention strategies? a. What is the effectiveness of current prevention strategies? b. What are the harms associated with prevention strategies? c. How sustainable are prevention practices in health care (outpatient, hospital inpatient, extended care) and community settings?

Question 3
What is the effectiveness of different antibiotic treatments? a. Does effectiveness vary by disease severity or strain? b. Does effectiveness vary by patient characteristics: age, gender, co-morbidity, hospital vs. community acquired setting?

Question 4
How do prevention and treatment of CDI affect resistance of other pathogens?

Question 5
What are the effectiveness and harms of non-antibiotic adjunctive interventions?

Question 6
Is it possible to distinguish how often CDI is a result of endogeneous activation of asymptomatic carriage of C. difficile or a result of acquisition of a new C. difficile strain?

Background

Clostridium difficile is a gram-positive, anaerobic bacterium that is generally acquired through ingestion. Various strains of the bacteria may produce enterotoxin A and cytotoxin B, as well as the lesser understood binary toxin. Clostridium difficile infection (CDI) symptoms can range from mild diarrhea to severe cases including pseudomembranous colitis and toxic megacolon. Mortality from CDI is estimated at 7 percent of cases.1

Distribution of CDI in the population is bimodal, with the largest incidence in elderly individuals, and a considerably smaller peak in children under age 10. The vast majority of severe morbidity and mortality is experienced in the elderly population.2-4 Residents of long term care facilities (LTC) are at high risk, with up to 26.2 cases per 10,000 resident days in LTC versus 6.5 cases per 10,000 patient days in hospitals.5,6 Incidence rates may increase by four or five fold during outbreaks.7 Community associated CDI rates are generally much lower, accounting for 27 percent of cases in a recent prevalence study,8 but is also on the rise. 7

New, more virulent strains have emerged since 2000 which affect a wider population often with a lack of standard risk profiles such as previous hospitalization or antibiotic use, including children, pregnant women, and other healthy adults.9 Characteristics associated with hypervirulent strains include increased toxin production, an additional “binary” toxin, hypersporulation, and high-level resistance to fluoroquinolone antibiotics.10 The time from symptom development to septic shock may be reduced in the hypervirulent strains, making quick diagnosis and proactive treatment regimens critical for positive outcomes. The hypervirulent strain accounts for 51 percent of CDI, compared to only 17 percent of historical isolates.11,12

Preventing the spread of C. difficile within institutional settings is dependent on staff compliance with national guidelines and standards13 and locally determined hygiene protocols. Unfortunately, protocols for targeted hospital acquired infections are not always congruent. For example, the availability of alcohol hand rubs improved physician compliance and reduced MRSA infections,14 yet C. difficile produces spores that can withstand hostile environments and are resistant to alcohol hand rubs and other routine antiseptics. Spores may be best removed by handwashing. Other institutional prevention strategies may be required as C. difficile transmission knowledge develops. For example, a recent study isolated C. difficile spores from air samples in a UK hospital, 4 to 7 weeks after the last confirmed CDI case in the ward, and successfully cultured bacterium.15

Once a patient has acquired C. difficile, the likelihood of developing CDI is dependent on a number of factors which allow colonization and toxin production, including failure of the immune defenses and use of antibiotics, particularly broad-spectrum or multiple antibiotics. In addition to eliminating, where possible, the offending antibiotic, and environmental and infection control strategies, recent prevention efforts at the patient level have also focused on improving immune defenses through healthy digestive function and gut flora, and nutritional status.16 Other risk factors include increasing age, female gender, comorbidities, and use of gastric acid suppressant medications (although this last is still controversial). Risk profiles for recurrent CDI are similar.17 One study which statistically modeled CDI within the hospital setting suggested that reducing patient susceptibility to infection is more effective in reducing CDI cases than lowering transmission rates.18

Community-acquired and community-onset CDI, where CDI occurs outside the institutional setting, complicates measuring the effectiveness of prevention within an institutional setting. The pathogenesis of CDI is complex and incompletely understood, and on-set may occur as late as several months after hospitalization or antibiotic use.

Effective prevention and treatment of CDI is dependent on swift and accurate diagnosis. There are increasing numbers of diagnostic tests with a variety of sensitivities, specificities, predictive values, biotechnologies used, costs, and time-to-results. No single commercial test offers both sufficient sensitivity and specificity together with fast turn-around time.19,20 Greater than 90 percent of labs in the United States use enzyme immunoassay because it is fast, inexpensive, and technically easy to perform.19 Physicians may not always be sufficiently educated as to which diagnostic test is best to use and how best to resolve a suspected false negative result (e.g. evidence suggests retesting with the same test is common practice, yet not recommended).

There are a number of treatment algorithms available in the literature.7,21-23 Treatment for mild to moderate CDI appears to have a fairly good clinical consensus for the use of metrozanidole, in part because of the concern that overuse of vancomycin may contribute to increasing pathogen resistance. Consensus also exists for treatment of severe initial incident CDI with vancomycin. Surgery may be life-saving in patients with fulminant, or acute severe, colitis. Pepin24 suggests that both vancomycin and metrozanidole are implicated in increased frequency of vancomycin-resistant enterococci. Surgery may be life-saving in patients with fulminant, or acute severe, colitis.

Treatment for relapsed or recurrent CDI, however, is much more problematic. CDI recurs in 15-35 percent of patients with one previous episode and 33-65 percent of patients who have had more than two episodes.22 Currently, clinicians choose from a number of antibiotics and dosing protocols and adjunctive treatments such as the use of antimicrobials, probiotics, fecal transplant, toxin-binding agents, and immune-system enhancing agents.25-27

CDI rates in the United States (and globally) have increased in the last decade, along with associated morbidity and mortality, particularly among elderly persons. Increasing morbidity and mortality, the limited therapeutic options and difficulty treating recurrent cases, and the associated economic costs all argue for increased attention to hospital acquired infections. CMS is considering adding CDI to the inpatient prospective payment system, and reimbursing hospitals at a lower rate for CDI if it is acquired during the hospital stay.

Population(s)

• KQ1-6: Adults with clinical indicators of CDI
• KQ1: Adult hospitalized patients
• KQ1-5: Adult nursing home/extended care residents

Interventions

• Diagnostic tests: cell cytotoxicity assay, enzyme immunoassays for toxins, enzyme immunoassays for specific antigens, enzyme-linked immunosorbent assay, stool culture, polymerase chain reaction, immunochromatography assay,
• Antibiotics: vancomycin, metronidazole, rifampicin, rifaxamin
• Non-antibiotic adjunctive treatments: probiotics, immunoglobulin, steroids, fecal transplant, colestipol, cholestyramine
• Prevention: education, handwashing, patient isolation, contact barriers, environmental cleaning, dedicated medical equipment, antibiotic stewardship

Outcomes

Prevention and Treatment Outcomes

1. Mortality rate
2. Recurrence rate
3. Clearance rate
4. Complications
5. CDI-related colectomy rate
6. Symptom resolution

Intermediate Prevention Outcomes

1. Appropriate antibiotic usage
2. Positive environmental cultures
3. Days to resolution of symptoms
4. Carriage/CDI rates

Timing

• Diagnostic testing: time to test
• Prevention and treatment: variable.

Setting

• Diagnostic testing: Health care facilities: outpatient, inpatient, extended care
• Treatment: inpatient and extended care
• Prevention: inpatient and extended care

References

1. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005 Dec 8;353(23):2442-9.

2. Brandt LJ, Kosche KA, Greenwald DA, Berkman D. Clostridium difficile-associated diarrhea in the elderly. Am J Gastroenterol. 1999 Nov;94(11):3263-6.

3. Hebuterne X. Gut changes attributed to ageing: effects on intestinal microflora. Curr Opin Clin Nutr Metab Care. 2003 Jan;6(1):49-54.

4. Kim J, Smathers SA, Prasad P, Leckerman KH, Coffin S, Zaoutis T. Epidemiological features of Clostridium difficile-associated disease among inpatients at children's hospitals in the United States, 2001-2006. Pediatrics. 2008 Dec;122(6):1266-70.

5. Laffan AM, Bellantoni MF, Greenough WB, 3rd, Zenilman JM. Burden of Clostridium difficile-associated diarrhea in a long-term care facility. J Am Geriatr Soc. 2006 Jul;54(7):1068-73.

6. Gravel D, Miller M, Simor A, Taylor G, Gardam M, McGeer A, et al. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis. 2009 Mar 1;48(5):568-76.

7. McFarland LV. Renewed interest in a difficult disease: Clostridium difficile infections--epidemiology and current treatment strategies. Curr. 2009 Jan;25(1):24-35.

8. Jarvis WR, Scholsser J, Jarvis AA, Chinn RY. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. 2009 May;37(4): 263-70.

9. MMRW Weekly. 2005, Dec 2:54(47)1201-1205 accessed on-line May 18, 2009. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55447a1.htm

10. Gerding DN, Muto CA, Owens RC, Jr. Measures to control and prevent Clostridium difficile infection. Clin Infect Dis. 2008a Jan 15;46 Suppl 1:S43-9.

11. Hubert B, Loo VG, Bourgault A-M, Poirier L, Dascal A, Fortin E, et al. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin Infect Dis. 2007 Jan 15;44(2):238-44.

12. Karpa KD. Probiotics for Clostridium difficile diarrhea: putting it into perspective. Ann Pharmacother. 2007 Jul;41(7):1284-7.

13. Dubberke ER, Gerding DN, Classen D, Arias KM, Podgorny K, Anderson DJ, et al. Strategies to prevent clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008 Oct;29 Suppl 1:S81-92.

14. Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. 2005 Jul;26(7):650-3

15. Roberts K, Smith CF, Snelling AM, Kerr KG, Banfield KR, Sleigh PA, et al. Aerial dissemination of Clostridium difficile spores. BMC Infect Dis. 2008;8:7.

16. Owens RC, Jr., Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S19-31.

17. Garey KW, Sethi S, Yadav Y, DuPont HL. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008 Dec;70(4):298-304.

18. Starr JM, Campbell A, Renshaw E, Poxton IR, Gibson GJ. Spatio-temporal stochastic modelling of Clostridium difficile. J Hosp Infect. 2009 Jan;71(1):49-56.

19. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S12-8.

20. Planche T, Aghaizu A, Holliman R, Riley P, Poloniecki J, Breathnach A, et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis. 2008 Dec;8(12):777-84.

21. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 1997 May;92(5):739-50.

22. Gerding DN, Muto CA, Owens RC, Jr. Treatment of Clostridium difficile infection. Clin Infect Dis. 2008b Jan 15;46 Suppl 1:S32-42.

23. Jaber MR, Olafsson S, Fung WL, Reeves ME. Clinical review of the management of fulminant clostridium difficile infection. Am J Gastroenterol. 2008 Dec;103(12):3195-203.

24. Pepin J. Vancomycin for the treatment of Clostridium difficile Infection: for whom is this expensive bullet really magic? Clin Infect Dis. 2008 May 15;46(10):1493-8.

25. Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. 2006 Dec;40(12):2164-9.

26. Stepan C, Surawicz CM. Treatment strategies for C. difficile associated diarrhea. Acta Gastroenterol Latinoam. 2007 Sep;37(3):183-91.

27. Halsey J. Current and future treatment modalities for Clostridium difficile-associated disease. Am J Health-Syst Pharm. 2008 Apr 15;65(8):705-15.