Fidaxomicin

Antibiotics for All but Very Mild C difficile.

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On October 29, the European Society of Clinical Microbiology and Infection (ESCMID) issued updated guidelines for Clostridium difficile infection (CDI), reviewing treatment options of antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, and fecal or bacterial intestinal transplantation. The new recommendations, published online October 5 in Clinical Microbiology and Infection, advise antibiotic treatment for all but very mild cases of CDI.

CDI, which is potentially fatal, is now the leading cause of healthcare-acquired infections in hospitals, having surpassed methicillin-resistant Staphylococcus aureus.

“[A]fter the recent development of new alternative drugs for the treatment of CDI (e.g. fidaxomicin) in US and Europe, there has been an increasing need for an update on the comparative effectiveness of the currently available antibiotic agents in the treatment of CDI, thereby providing evidence-based recommendations on this issue,” write Sylvia B. Debast, from the Centre for Infectious Diseases, Leiden University Medical Center The Netherlands, and colleagues from the ESCMID Committee.

The new guideline, which updates the 2009 ESCMID recommendations now used widely in clinical practice, summarizes currently available CDI treatment options and offers updated treatment recommendations on the basis of a literature search of randomized and nonrandomized trials.

The ESCMID and an international team of experts from 11 European countries developed recommendations for different patient subgroups, including initial nonsevere disease, severe CDI, first recurrence or risk for recurrent disease, multiple recurrences, and treatment of CDI when patients cannot receive oral antibiotics.

Antibiotic Recommended in Most Cases

Specific recommendations include the following:

·         For nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop the inducing antibiotic and observe the clinical response for 48 hours. However, patients must be monitored very closely and treated immediately for any signs of clinical deterioration.

·         Antibiotic treatment is recommended for all cases of CDI except for very mild CDI, which is actually triggered by antibiotic use. Suitable antibiotics include metronidazole, vancomycin, and fidaxomicin, a newer antibiotic that can be given by mouth.

·         For mild/moderate disease, metronidazole is recommended as oral antibiotic treatment of initial CDI (500 mg 3 times daily for 10 days).

·         Fidaxomicin may be used in all CDI patients for whom oral antibiotic treatment is appropriate. Specific indications for fidaxomicin may include first-line treatment in patients with first CDI recurrence or at risk for recurrent disease, in patients with multiple recurrences of CDI, and in patients with severe disease and nonsevere CDI.

These recommendations were based on 2 large phase 3 clinical studies that compared 400 mg/day oral fidaxomicin with 500 mg/day oral vancomycin, the standard of care. The rate of CDI recurrence was lower with fidaxomicin, but the cure rate was similar for both treatments.

·         For severe CDI, suitable oral antibiotic regimens are vancomycin 125 mg 4 times daily (may be increased to 500 mg 4 times daily) for 10 days, or fidaxomicin 200 mg twice daily for 10 days.

·         In life-threatening CDI, there is no evidence supporting the use of fidaxomicin.

·         In severe CDI or life-threatening disease, the use of oral metronidazole is strongly discouraged.

·         For multiple recurrent CDI, fecal transplantation is strongly recommended.

·         Total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended for CDI with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment.

·         Additional measures for CDI management include discontinuing unnecessary antimicrobial therapy, adequate fluid and electrolyte replacement, avoiding antimotility medications, and reviewing proton pump inhibitor use.

Recurrent Clostridium difficile Infection: Enter Fidaxomicin.

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 Fidaxomicin significantly reduced the recurrence rate in patients infected with non-NAP1/BI/027 strains.

Recurrence of Clostridium difficile infection (CDI) is common, whether metronidazole or vancomycin is used as initial therapy. Fidaxomicin, a new macrocyclic antibiotic that has no cross-resistance with other antibiotics, is more active in vitro than vancomycin against clinical C. difficile isolates; in a phase II trial, it was associated with good clinical response and a low CDI recurrence rate. Now, in a manufacturer-sponsored, multicenter, double-blind, phase III trial, researchers have compared this agent with oral vancomycin in 629 adults with CDI.

Participants were randomized to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg 4 times daily) orally for 10 days. The primary endpoint was clinical cure (resolution of diarrhea; no need for additional CDI therapy as of posttreatment day 2). Secondary endpoints included CDI recurrence during the 4-week period after the end of therapy.

The clinical cure rates with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat (MITT) population (88.2% and 85.8%, respectively) and the per-protocol (PP) population (92.1% and 89.8%). Among patients infected with the NAP1/BI/027 strain, the recurrence rates were similar between treatment arms in the two populations. However, among those infected with non-NAP1/BI/027 strains, the recurrence rates differed dramatically between vancomycin and fidaxomicin in both the MITT population (28.1% vs. 10.3%; P<0.001) and the PP population (25.5% vs. 7.8%; P<0.001). The rates of adverse events and serious adverse events were similar between treatment arms.

Comment: On the basis of the findings from this investigation, an editorialist wrote that fidaxomicin appeared to be “an important advance.” I hope that this is the case — new, more-effective treatments for CDI are badly needed.

Source: Journal Watch Infectious Diseases.

 

Fidaxomicin versus vancomycin for Clostridium difficile infection

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Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection.
METHODS: Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence).
RESULTS: A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non-North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies.
CONCLUSIONS: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non-North American Pulsed Field type 1 strains.

source: NEJM