Issue: February 2018
December 31, 2017
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Extended dosing with Dificid improves cure rates for C. difficile

Issue: February 2018
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Dale Gerding
Dale N. Gerding

Extended-pulsed dosing with Dificid was more effective than standard-dose vancomycin for achieving and maintaining clinical cure of Clostridium difficile infection, according to results of the EXTEND study published in The Lancet Infectious Diseases.

Extended dosing with Dificid (fidaxomicin, Merck) also resulted in the lowest rates of recurrent infection seen in a clinical trial of antibiotic therapy for C. difficile infection, according to the findings.

The FDA approved fidaxomicin in 2011. A standard regimen comprises twice-daily 200-mg tablets for 10 days.

“Evidence from a validated in vitro human gut model suggests that an extended-pulsed fidaxomicin regimen, which extends 20 fidaxomicin doses over a longer time period after initial daily dosing, might allow persistence of fidaxomicin at above inhibitory concentrations, thus prolonging suppression of C. difficile and simultaneously facilitating microbiota recovery,” the researchers wrote. “We aimed to assess clinical outcomes of extended-pulsed fidaxomicin compared with vancomycin, with a primary efficacy endpoint of sustained clinical cure of C. difficile infection 30 days after the end of treatment, in a microbiota-sparing strategy.”

Benoit Geury, MD, of the infectious diseases service in the department of medicine at the University Hospital and University of Lausanne, Switzerland, and colleagues conducted a randomized, controlled, open-label superiority study in adults aged 60 years and older with established cases of C. difficile. The trial included 364 patients from 86 hospitals in 21 European countries.

Patients were randomly assigned, in a 1:1 fashion, to receive extended-pulsed fidaxomicin or vancomycin. Fidaxomicin was administered as 200-mg oral tablets twice daily on days 1 through 5 and then once daily on alternate days for days 7 through 25. Vancomycin was given as 125-mg oral capsules four times per day on days 1 through 10. Patients were grouped according to the severity of baseline C. difficile infection, the presence or absence of cancer, age ( 75 years vs. < 75 years) and the number of prior incidences of C. difficile infection.

The primary endpoint of continued clinical cure, which was classified as clinical response at the test-of-cure visit and no recurrence, was evaluated 30 days after the conclusion of treatment (day 40 for vancomycin and day 55 for fidaxomicin) and on day 90, at the end of follow-up. All cases that did not meet these criteria were considered treatment failures for continued clinical cure.

From November 2014 to May 2016, 362 patients, or 181 patients in each treatment arm, were treated with at least one dose of medication. The modified full analysis set included 177 patients who were treated with fidaxomicin and 179 patients who were treated with vancomycin. More patients in this analysis who were treated with fidaxomicin (n = 124; 70%) achieved and maintained clinical cure 30 days after treatment ended compared with patients treated with vancomycin (n = 106; 59%). This made for a difference between groups of 11% (95% CI, 1-20.7; P = .03) and an OR of 1.62 (95% CI, 1.04-2.54).

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The number of treatment-related adverse events did not significantly vary between patients treated with fidaxomicin (67%) and patients treated with vancomycin (71%). One death in the vancomycin arm was categorized by the investigator as related to the study drug.

In a related editorial, Dale N. Gerding, MD, professor of medicine in the division of infectious diseases at Loyola University Chicago Stritch School of Medicine, noted that several investigations, including the EXTEND study, “suggest that extended-pulsed dosing is a crucial element in improving prevention of recurrent C. difficile infection.” Such dosing can be used for initial or recurrent infections, according to Gerding, and it is useful for both fidaxomicin and vancomycin.

Gerding also highlighted the importance of determining the appropriate dose and length of therapy for pulsed dosing, as well as additional measures — including the use of monoclonal antibodies and fecal microbiota transplants — that can help decrease the rate of recurrent C. difficile infections.

“Ultimately, the goal of C. difficile infection management is to achieve recurrence prevention and primary prevention of C. difficile infection, but further research into vaccines and biotherapeutics is needed,” Gerding wrote. “In the meantime, further exploration of pulsed dosing of antibiotic treatment for C. difficile infection is certainly warranted.” – by Julia Ernst, MS

Disclosures: The authors report no relevant financial disclosures. Gerding reports receiving grants and other fees from Seres Therapeutics; personal fees from Actelion, Da Volterra, Merck, MGB Biopharma, Pfizer, Rebiotix, Sanofi Pasteur and Summit outside the submitted work; and issuing a patent for nontoxigenic Clostridium difficile for prevention of C. difficile infection.