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American Society of Health-System Pharmacists Summer 2013

Update in Infectious Diseases: Treatment of Clostridium difficile Infection

Clostridium difficile infection (CDI) is a common hospital-acquired infection that is associated with a high clinical and economic burden. Because of this management of CDI is quickly becoming a part of institutional quality measures.
Douglas Slain, PharmD, BCPS, FASHP, a clinical assistant professor of infectious disease at West Virginia University, discussed Clostridium difficile infection (CDI), including current treatment options and the most appropriate situations for use of current therapies. Dr Slain also presented a summary of the studies involved in the approval of a newer antibiotic option, fidaxomicin.

To engage the audience, Dr Slain began with 3 clinical questions that challenged the audience’s ability to identify proper infection control procedures and differentiate between situations when vancomycin is preferential to metronidazole. Dr Slain then described the pathogen that these antibiotics are intended to kill—Clostridium difficile. This gram-positive spore-forming bacillus can live for up to 70 days in a dormant form on virtually any surface. Furthermore, alcohol-based hand cleansers do not effectively kill the pathogen; soap and water hand washing is still the best method for disinfecting.

Bacterial spores that cause CDI may enter the digestive tract via the mouth, germinate and grow in the intestinal tract, and produce toxins. These toxins, termed toxin A and toxin B, may damage the colon and lead to membranous stool. The growth of CDI organisms requires an intestinal tract that contains altered bacterial flora. Broad-spectrum oral antibiotics may diminish normal levels of beneficial bacteria in the gut, providing the right conditions for CDI to occur.

Dr Slain described the symptoms of the pathogenic process, including diarrhea, and also described methods clinicians use to achieve diagnostic confirmation. This confirmation may come from a stool sample with verified presence of C difficile, or a colonoscopy that verifies damage to intestinal membranes caused by pseudomembranous colitis. Citing a 2010 paper from Infection Control and Hospital Epidemiology, Dr Slain described findings associated with severe disease including high white blood cell count, high serum creatinine, and low blood albumin levels. Patients at higher risk for severe infection include those with compromised immunity or people over the age of 65 years.

Using a scoring system called ATLAS described by Chopra et al at a meeting of the Infectious Disease Society of America, Dr Slain explained how physicians classify CDI severity by a scoring system involving age, body temperature, serum albumin level, and the number of antibiotics used. Among patients with the highest ATLAS score, 56% die as a result of CDI. Dr Slain explained that megacolon, ileus, hypotension, and shock caused by CDI may be the ultimate cause of death in these patients.

Not only is CDI dangerous, but it is also common, causing over 165,000 cases of hospital-acquired infections in 2008. Infections that began in the hospital incurred about $1.3 billion in healthcare expenses. In the 50,000 annual cases that occur in the community setting after a hospital stay, the cost of treatment is $300 million. Cases that occur in the nursing home setting cost $2.2 billion. CDI is also associated with substantial mortality—annually about 9000 people in the hospital, 3000 people in the community, and 16,500 people in nursing homes die of CDI. Because of this burden, the prevalence and management of CDI are being included in institutional quality measures.

Dr Slain emphasized that receiving definitive results of tests for CDI is a 2-step process that is being used in more institutions across the United States. Guidelines recommend an initial test for glutamate dehydrogenase, followed by confirmation with a test for presence of toxin such as a tissue culture cytotoxicity assay. It was also noted that because of this change in methodology, the prevalence of CDI would appear to increase once this 2-step process is implemented. Due to the lengthiness of the process involved in confirming a diagnosis of CDI, treatment is empiric. Clinical response often determines therapy.

It was explained that vancomycin and metronidazole have limitations. Between 20% and 30% of cases of CDI will recur within 60 days of antibiotic use. Some evidence suggests that treatment for more than 10 days may be more effective in eliminating the spores that cause reinfection. Some clinicians have studied regimens with tapered dosing of vancomycin or periodic dosing of vancomycin. Serum markers can help identify patients at high risk for reinfection. For instance, patients who do not develop IgG antibodies to toxin A are more likely to experience reinfection.

By 2012, a newer strain of C difficile emerged, termed BI/NAP 1. This strain requires higher concentrations of metronidazole for effective treatment, leads to greater morbidity and mortality in infected patients, forms more spores than previous strains, and demonstrates greater resistance to antibiotics in the fluoroquinolone class.

With this new strain of C difficile, investigators have questioned whether metronidazole is still effective enough in treating CDI to be used first line. Although metronidazole never received an indication for treating CDI, studies dating back to 1982 demonstrate a 90% to 98% cure rate with metronidazole. However, as Dr Slain explained, studies conducted after 2004 showed lower response rates of 62% to 84%. Also noted were concerns about the effectiveness of metronidazole at the site of action (the intestinal lumen), which may potentially be lowered as a result of reduced intestinal absorption due to bowel inflammation. In rare strains of C difficile, the minimum inhibitory concentration (MIC) of metronidazole measured in vitro far exceeds the concentrations of metronidazole found in the intestinal lumen.

Dr Slain cited a 1995 study by Wilcox that showed a significantly faster time to resolution of diarrhea with use of vancomycin than with metronidazole (3 days vs 4.6 days; P <.01). In US hospitals, use of metronidazole instead of vancomycin was also associated with an increased length of stay, increased mortality, and a longer stay in the intensive care unit. Although these data may seem to universally support the use of vancomycin, Dr Slain presented the results of a trial of vancomycin (125 mg taken 4 times daily) versus metronidazole (250 mg taken 4 times daily). The trial showed that use of a rating scale of the severity of CDI allowed selection of patients that might benefit most from treatment with vancomycin. In patients with the most severe forms of disease, vancomycin did show a significantly higher response rate than metronidazole. However, in patients with mild disease, the difference in effectiveness was not statistically significant.

The high cost of oral vancomycin limits its broader use; insurance plans often require prior approval for vancomycin. However, hospital pharmacies and compounding pharmacies often produce an oral solution of vancomycin to replace the expensive premade capsules. Hospitals and pharmacies compounding the medication may meet resistance from insurance plans that will not cover compounded medications.

Guidelines published jointly by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America in 2010 indicate a high quality of evidence supporting use of metronidazole for the initial episode of a mild to moderate case of CDI. Severe infection requires use of vancomycin, a recommendation supported by moderate-quality evidence. Other dosage regimens are supported by moderate- or poor-quality evidence, mostly based on expert opinion. These recommendations involve tapered or pulsed dosing of vancomycin for secondary episodes of CDI. For complicated cases of CDI that occur in a hospital setting, expert opinion supports use of a combination of vancomycin, metronidazole, and rectal vancomycin enemas.

A recently approved antibiotic for treatment of CDI, fidaxomicin, works by inhibiting RNA polymerase, thereby reducing bacterial protein synthesis. Its narrow spectrum of activity against CDI, long postantibiotic effect, low bioavailability, high fecal concentration, and low MIC for bactericidal efficacy against C difficile make this drug highly desirable for treatment of CDI. The biggest drawback of fidaxomicin is the cost. Without insurance, 10 days of therapy costs about $2800.

A phase III trial evaluated the efficacy of fidaxomicin versus vancomycin in 629 patients. The 2 end points were resolution of diarrhea, defined as a cure, and resolution of diarrhea without recurrence, defined as a global cure. Although both agents were tolerated with minimal adverse events, a small but statistically significant increase in laboratory abnormalities occurred in patients treated with fidaxomicin, including 3 cases of elevated transaminases. Clinical cure rates were not significantly different between fidaxomicin and vancomycin, but the global cure rate approached 80% with fidaxomicin versus just under 70% with vancomycin. The lower rate of recurrence of CDI was statistically significant. In a subanalysis of patients with CDI caused by a resistant strain of C difficile (BI/NAP 1 strain), the recurrence rate was not significantly changed, and was numerically higher with fidaxomicin treatment than with vancomycin treatment. In a further subanalysis, patients receiving antibiotics to treat a separate infection while receiving fidaxomicin experienced a significantly lower risk of recurrence than those treated with vancomycin.

Dr Slain discussed several adjunctive therapies including rifaximin, IVIg, tigecycline, nitazoxanide, cholestyramine, and probiotics. A small study of rifaximin involving 68 patients showed effectiveness in treating the first episode of CDI, but did not show a reduction in the rate of CDI recurrence. Unfortunately, rifaximin was ineffective against the highly resistant BI/NAP 1 strain. Dr Slain also discussed the role of probiotics such as those found in yogurt cultures, as well as the role of bacteriotherapy. Bacteriotherapy, also known as fecal transplant, showed improved outcomes over vancomycin in 1 trial. The fecal transplant was so effective that the trial was stopped early. The results of the trial were published in a 2013 issue of the New England Journal of Medicine.

In closing, Dr Slain discussed the importance of antimicrobial stewardship in reducing hospital CDI rates. Strategies such as limiting the use of antibiotics known to cause CDI at a higher rate than other treatments and multidisciplinary management of antimicrobial use can help achieve this outcome.

 
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