Frequent Emergence of Resistance in Clostridium difficile during Treatment of C. difficile -Associated Diarrhea with Fusidic Acid

Abstract

Samples from patients with Clostridium difficile-associated diarrhea (CDAD) that were randomized to fusidic acid (n ‫؍‬ 59) or metronidazole (n ‫؍‬ 55) therapy for 7 days were cultured for Clostridium difficile in feces on days 1, 8 to 13, and 35 to 40. Of the patients who were culture positive only before treatment, 77% (36/47) were permanently cured (no treatment failure and no clinical recurrence), compared to 54% (22/41) of those with persistence of C. difficile at one or both follow-ups (P ‫؍‬ 0.03). A similar association between bacterial persistence and a worse outcome of therapy was seen in both treatment groups. Resistance to fusidic acid was found in 1 of 88 pretherapy isolates available, plus in at least 1 subsequent isolate from 55% (11/20) of patients who remained culture-positive after fusidic acid therapy. In 10 of these 11 patients, the resistant follow-up isolate(s) belonged to the same PCR ribotype as the susceptible day 1 isolate, confirming frequent emergence of resistance to fusidic acid during treatment. Despite this, 5 of these 11 patients were permanently cured with fusidic acid, relative to 5 of 9 patients with susceptible C. difficile at follow-up (P ‫؍‬ 1.0). None of the 36 PCR ribotypes of C. difficile identified was associated with any particular clinical outcome or emergence of fusidic acid resistance. In conclusion, culture positivity for C. difficile was common after both fusidic acid and metronidazole therapy and was associated with treatment failure or recurrence of CDAD. Development of resistance in C. difficile was frequent in patients given fusidic acid, but it was without apparent negative impact on therapeutic efficacy in the actual CDAD episode.

Antibacterials Developed to Target a Single Organism: Mechanisms and Frequencies of Reduced Susceptibility to the Novel Anti-Clostridium difficileCompounds Fidaxomicin and LFF571

“…Although not approved for use, other drugs, such as rifaximin and fusidic acid, against which high-frequency single-step resistance can be selected in C. difficile, are occasionally used to treat CDI. Attempts to understand the impact of mutants with reduced susceptibility to these agents on therapeutic outcome have been reported (Noren et al 2006;Mattila et al 2013). For example, a study comparing fusidic acid with metronidazole for the treatment of CDI showed that although all isolates from patients randomized to fusidic acid were susceptible at baseline, 55% (11/20) of posttreatment isolates were resistant to fusidic acid (median MIC .256 mg/mL) (Noren et al 2006).…”

Mutations in fusA Associated with Posttherapy Fusidic Acid Resistance in Clostridium difficile

“…Of 44 patients treated with fusidic acid in our previous study (16), 20 (45%) had C. difficile persisting at follow-up, and 11 (55%) of these patients carried fusidic acidresistant C. difficile isolates (n ϭ 12) ( Table 1). These isolates were selected for study, together with the resistant isolates recovered both pre-and posttherapy from one patient randomized to metronidazole (Table 1, patient 12) but who had received fusidic acid 2 weeks before inclusion in the study.…”

“…The in vitro susceptibility of C. difficile to fusidic acid is generally excellent (4,11), and like for metronidazole, the high fusidic acid absorption (98%) (24) presumably results in sufficient therapeutic concentrations in feces from an inflammatory mucosa. However, we recently found that 55% of the fusidic acid-treated CDAD patients with posttherapy persistent C. difficile carried fusidic acid-resistant isolates of identical PCR ribotypes at follow-up (16). Our aims were to identify fusA of C. difficile, to explore the heterogeneity of the gene, and to find mutations associated with the emergence of fusidic acid resistance.…”

“…Thus, the putative fusA genes of 27 paired C. difficile isolates from 12 patients were sequenced. Culture, MIC determination, and PCR ribotyping of the isolates were performed as described previously (16,17).…”

MBX-500, a Hybrid Antibiotic with In Vitro and In Vivo Efficacy against Toxigenic Clostridium difficile

“…Based on PCR analysis, the epidemic strain was designated ribotype 27 or NAP1/027 (19), which is distinguished from other strains by increased production of toxins, fluoroquinolone resistance, and production of binary toxin CDT, a third C. difficile toxin that has been associated with increased disease severity (12). Additionally, resistance development to several C. difficile agents has further complicated treatment (9,21,23).…”