Applied Evidence

It’s time to rethink your approach to C diff infection

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First-line treatment? Drug of choice has changed

In 2018, the IDSA published new treatment guidelines that provide important updates from the 2010 guidelines.11 Chief among these was the elimination of metronidazole as a first-line therapy. Vancomycin or fidaxomicin are now recommended as first-line treatment options because of superior eradication of C difficile when compared with metronidazole.11 In the opinion of the authors, vancomycin should be considered the drug of choice because of cost. (See “The case for vancomycin.”)

The case for vancomycin

The majority of studies conducted prior to publication of the 2010 Infectious Diseases Society of America guidelines described numerically worse eradication rates of Clostridioides difficile infection (CDI) with metronidazole compared with vancomycin for all severities of infection, but statistical significance was not achieved. These studies also showed a nonsignificant increase in CDI recurrence with metronidazole.17,40,41

A 2005 systematic review demonstrated increased treatment failure rates with metronidazole.42 The rates of metronidazole discontinuation and transition to alternative options more than doubled in 2003-2004, to 25.7% of patients compared with 9.6% in earlier years.42 Metronidazole efficacy was further questioned in a prospective observational study conducted in 2005, in which only 50% of patients were cured after an initial course of treatment, while 28% had recurrence within 90 days.43

Vancomycin was found to be the superior treatment option to metronidazole and tolevamer in a 2014 randomized controlled trial.18 This study also demonstrated that vancomycin was the superior therapy when comparing treatment-naïve vs experienced patients and severity of CDI.18 A 2017 retrospective cohort study demonstrated decreased 30-day all-cause mortality for patients taking vancomycin vs metronidazole (adjusted relative risk = 0.86; 95% confidence interval, 0.74-0.98), although it should be noted that this difference was driven by those with severe CDI, and there was no statistically significant difference in mortality for patients with mild-to-moderate CDI.44

The results of these studies led to the recommendation of vancomycin over metronidazole as first-line pharmacotherapy for CDI in practice, despite the historical perspective that overutilization of oral vancomycin could potentially increase rates of vancomycinresistant Enterococcus.11

Metronidazole should only be used in the treatment of CDI as a lastresort medication because of cost or insurance coverage. Although the price of oral vancomycin is higher, favorable patient outcomes are substantially greater, and recent analyses have shown that vancomycin is actually more cost-effective than metronidazole as a result.24 Adverse effects for metronidazole include neurotoxicity, gastrointestinal discomfort, and disulfiram-like reaction.

Vancomycin does not harbor as many adverse effects because of extremely low systemic absorption when taken orally, but patients may experience gastrointestinal discomfort.45 While systemic exposure with oral administration of vancomycin is very low (< 1%), there have been case reports of nephrotoxicity and “red man syndrome” that are more typically seen with intravenous vancomycin.44

Given the low rate of systemic exposure, routine monitoring of renal function and serum drug levels is not usually necessary during oral vancomycin therapy. However, it may be appropriate to monitor renal function and serum levels of vancomycin in patients who have renal failure, have altered intestinal integrity, are age ≥ 65 years, or are receiving high doses of vancomycin.46

10-day vs 14-day treatment of CDI. Most studies for the treatment of CDI have used a 10-day regimen rather than increasing the duration to a 14-day regimen, and nearly all studies conducted have displayed high rates of symptom resolution at the end of 10 days of treatment.17,18 Thus, treatment duration beyond 10 days should only be considered for patients who continue to have symptoms or complications with CDI on Day 10 of treatment.

First recurrence. Metronidazole is no longer the recommended treatment for first recurrence of CDI treated initially with metronidazole; instead, a 10-day course of vancomycin should be used.11 For recurrent cases in patients initially treated with vancomycin, a tapered and pulsed regimen of vancomycin is recommended11:

  • vancomycin PO 125 mg four times daily for 10 to 14 days followed by
  • vancomycin PO 125 mg twice daily for 7 days, then
  • vancomycin PO 125 mg once daily for 7 days, then
  • vancomycin PO 125 mg every 2 to 3 days for 2 to 8 weeks.

Pediatric patients. The IDSA guidelines recommend use of metronidazole or vancomycin to treat an initial case or first recurrence of mild-to-moderate CDI in this population.11 Due to a lack of quality evidence, the drug of choice for initial treatment is inconclusive, so patient-specific factors and cost should be considered when choosing an agent.11 If not cost prohibitive, vancomycin should be the drug of choice for most cases of pediatric CDI, and for severe cases or multiple recurrences of CDI, vancomycin is clearly the drug of choice.

Recommended agents: A closer look

Oral vancomycin products. Vancocin, a capsule, and Firvanq, an oral solution, are 2 vancomycin products currently on the market for CDI. Although the capsules are a readily available treatment option, the cost of the full course of treatment can be a barrier for patients without insurance, or with high copays or deductibles (brand name, $4000; generic, $1252).19

Continue to: Historically, in an effort to keep costs down...

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