Medicolegal Issues

C. Difficile Infection: Are We Doing Enough?


 

The worst of the nationwide Clostri-dium difficile epidemic is yet to come. The current, highly virulent NAP1/027 strain has reached all 50 states and Canada, with a total burden estimated at more than 500,000 annual cases.1

The economic burden associated with managing C. difficile-associated disease (CDAD) in Massachusetts hospitals over a two-year period was estimated at $51.2 million and associated with 55,380 inpatient days.2 A retrospective review (n=3,692) identified a mean cost per stay for a first hospitalization with a primary CDAD diagnosis at $10,212. This was associated with a mean length of stay (LOS) of 6.4 days. For patients with a secondary CDAD diagnosis, the LOS was estimated at 15.7 days, most likely due to time spent in the intensive-care unit (ICU) and not likely related to CDAD management. The CDAD-related increased LOS in these patients was estimated to be an additional 2.95 days, with an additional cost of $13,675.

More recently, CDAD-associated costs were noted to be more than $7,000 per case, according to data from 439 cases evaluated by two statistical methods.3

Bacillus Background

C. difficile is a spore-forming, gram-positive, anaerobic bacillus that has become one of the most significant causes of hospitalization-associated diarrhea in adults.4 The number of infections occurring with the more virulent strain is disquieting. It is associated with a spectrum of illnesses, which include uncomplicated diarrhea presenting as mild, watery stools, life-threatening pseudomembranous colitis, and toxic megacolon, leading to sepsis and death.

CDAD might be an unrecognized and under-reported cause of death in the U.S.5 From 1999 to 2004, CDAD was reported as a cause of death for 24,642 people and an underlying cause of death for an additional 12,264 people.6 The median patient age was 82.

As an aside, CDAD is the older terminology for what is now being referred to as C. difficile infection (CDI).

CDI is predominantly seen as a nosocomial or long-term-care facility concern, although community-acquired infections have been reported.7 Risk factors include previous antimicrobial use, particularly with clindamycin, fluoroquinolones, cephalosporins, ampicillin, or ß-lactams. Other risk factors include use of immunosuppressants or chemotherapeutic agents, advanced age, surgery, exposure to gastric acid suppressants, host immunity, and serious underlying illnesses or comorbidities.8,9 Gastric acid suppressant use outside a healthcare facility might be a significant risk factor for outpatient CDI.

Prevention

Healthcare-facility-based CDI prevention strategies include discontinuing any suspected antibiotic, as this alone has been known to resolve CDI in up to 25% of patients. C. difficile spores are resistant to bactericidal effects of alcohol and most hospital disinfectants. Therefore, additional prevention measures should include:

  • Meticulous and proper hand hygiene for healthcare workers, patients, and visitors;
  • Utilizing soap and water and avoiding alcohol-based rubs that are not sporicidal;
  • Environmental cleaning with sporicidal cleaning agents;
  • Placing patients under contact isolation infection control procedures until resolution of the diarrhea; and
  • Adopting antibiotic restriction policies to limit excessive antimicrobial use.

Two additional principles include not giving prophylactic antimicrobials for patients at high risk of developing CDI and not treating or attempting to decolonize asymptomatic C. difficile carriers. The Centers for Disease Control recently developed a patient-safety initiative to assist healthcare facilities in dealing with multidrug-resistant organisms (MDRO) and CDAD.10

Management

General management strategies for CDI patients include:

  • Discontinuing all unnecessary antimicrobials or utilizing lower-risk agents when able;
  • Monitoring volume status and electrolytes and appropriately replete when necessary;
  • Avoiding anti-diarrheal agents, such as loperamide, atropine, or diphenoxylate, as these agents do not allow the toxin to be excreted and can worsen symptoms and lead to serious complications;
  • Encouraging patient hand hygiene through use of soap and water;
  • Possibly avoiding the use of lactose-containing foods;
  • Possibly discontinuing proton pump inhibitors and other acid suppressants; and
  • Administering specific anti-Clostridial antibiotics, if necessary, based on infection severity.

Severe CDI causes volume depletion, electrolyte imbalances, and hypotension, as well as renal impairment, hemodynamic instability, leukocytosis, toxic megacolon, and death. Severe diarrhea associated with this form of CDI might include 10 or more loose stools per day. A surgical consultation should be obtained for a complete evaluation in the most severe cases, as patients may require colectomy.

Recent reports suggest oral (OP) vancomycin be considered as first-line therapy for severe CDI. Intravenous (IV) vancomycin should not be used, because it does not reach high enough stool levels to treat the infection. Vancomycin should be dosed at 500 mg four times daily for 10 to 14 days (severe CDI) and 125 mg four times daily for 10 to 14 days in cases of mild to moderate CDI; alternatively, the duration of treatment can be extended for several days after the diarrhea resolves. This usually occurs within a few days after commencing treatment.

The treatment of choice for mild to moderate CDI is metronidazole. It is dosed at either 500 mg PO three times daily or 250 mg PO four times daily. Oral metronidazole achieves higher stool concentrations than IV metronidazole, so it is the preferred route for CDI management.

Metronidazole can cause nausea and a metallic taste. It also interacts with warfarin, so the international normalized ratio (INR) must be followed. Concomitant administration of alcohol can lead to a reaction similar to that associated with use of Antabuse. The drug should not be used in pregnant women or children. Metronidazole and vancomycin usually are equally effective for treating mild to moderate CDI, but some resistance has been noted. Vancomycin PO currently is available only as a branded drug with a high cost, but this may soon change.11

Recurrence

Recurrence can occur in approximately 20% of patients within 60 days, and these patients can be treated with the same antibiotics as were previously utilized. Subsequent recurrences can be managed with pulse dosing, or by tapering the dose at the end of therapy. Due to a lack of controlled studies, the use of probiotics, such as Lactobacillus, in the prevention of CDI cannot be routinely recommended.12 However, Lactobacillus-containing products generally are considered safe in immunocompetent individuals.

The Future

Generic oral vancomycin is on the horizon and a number of agents are currently undergoing phase 3 clinical trials for CDI management. These include rifaximin, nitazoxanide, and rifampin in combination with current agents.13-16 For now, prevention is key. Utilize some of the measures noted above to prevent this potentially serious, nosocomial infection. For infected patients, current treatments are effective and new ones will be here soon. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

1.Walker EP. ICAAC-IDSA: C. difficile epidemic continues to worsen. MedPage Web site. Available at: www.medpagetoday.com/MeetingCoverage/ ICAAC/11518. Accessed Jan. 13, 2009.

2.O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28:1219-1227.

3.Dubberke ER, Reske RA, Olsen MA, McDonald C, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-associated disease in nonsurgical patients. Clin Infect Dis. 2008;46:497-504.

4.Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. 2006;40:2164-2169.

5.Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis. 2007;13:1417-1419.

6.The national healthcare safety network protocol multi-drug-resistant organism and Clostridium difficile-associated disease module version 4.1. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/ pdf/nhsn/MDRO_CDADprotocolv41Dec08final.pdf. Accessed Jan. 14, 2009.

7.Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. CDC Web site. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm. Accessed Jan. 14, 2009.

8.Lawrence SJ. Contemporary management of Clostridium difficile-associated disease. IDSE Web site. Available at: www.idse.net/download/079idse0907WM.pdf. Accessed Jan. 14, 2009.

9.Dubberke ER, Gerding DN, Classen D, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S81-S92.

10.Multidrug-resistant organisms (MDRO) and Clostridium difficile-associated disease (CDAD) module. CDC Web site. Available at: www.cdc.gov/ncidod/dhqp/nhsn_MDRO_CDAD.html. Accessed Jan. 14, 2009.

11.ViroPharma files FOIA complaint seeking administrative record for vancocin. ViroPharma Inc. Web site. Available at: phx.corporateir.net/phoenix.zhtml?c=92320&p=irol-newsArticle&ID=1237649. Published Dec. 18, 2008. Accessed Jan. 14, 2009.

12.Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;6. Available at: www.bmj.com/cgi/reprint/bmj.39231.599815.55v1. Accessed Jan. 14, 2009.

13. A trial to compare xifaxan to vancomycin for the treatment of Clostridium difficile-associated diarrhea (CDAD). National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/ NCT00269399?term=rifaximin+and+clostridium&rank=1. Accessed Jan. 10, 2009.

14. Efficacy of metronidazole versus metronidazole and rifampin in CDAD treatment. National Institutes of Health Web site. Available at www.clinicaltrials.gov/ct2/show/NCT00182429?term=rifampin+and+cdad&rank=1. Accessed Jan. 10, 2009.

15. Compassionate use of nitazoxanide for the treatment of Clostridium difficile infection. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304356?term=Nitazoxanide+and+clostridium&rank=2. Accessed Jan. 10, 2009.

16. Vancomycin vs. nitazoxanide to treat recurrent C. difficile colitis. National Institutes of Health Web site. Available at: www.clinicaltrials.gov/ct2/show/NCT00304889?term=Nitazoxanide+and+vancomycin&rank=2. Accessed Jan. 10, 2009.

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