Nitazoxanide is active against Clostridium difficile strains with reduced susceptibility to metronidazole

Sir,

Treatment strategies for Clostridium difficile infection (CDI) have changed little over the past two decades. Metronidazole and vancomycin continue to be the first-line antimicrobial treatments for CDI.¹ While the drugs were thought to be similar in terms of response and recurrence rates, recent reports suggest that metronidazole efficacy may be reducing.^2,3 A study of 52 patients by Al-Nassir et al.³ showed that while diarrhoea resolved in a majority of patients (>90%) treated with either metronidazole or vancomycin, the former was associated with a slower and less consistent microbiological response. In addition, poor gut levels of metronidazole and emerging evidence of reduced susceptibility in epidemic C. difficile strains, particularly among epidemic C. difficile PCR ribotypes,⁴ may play a role in reduced antibiotic efficacy. These issues highlight the need for effective new treatments for CDI.

Nitazoxanide is a 5-nitrothiazole compound showing good antimicrobial activity against a range of helminthic and protozoal parasites, as well as anaerobic bacteria. We evaluated nitazoxanide efficacy against a panel of 127 C. difficile strains isolated from patients in the Leeds Teaching Hospitals and CDI cases referred to the national C. difficile Ribotyping Network (CDRN). These included epidemic strains (PCR ribotypes 001, 027 and 106) with and without reduced susceptibility to metronidazole. The strains comprised 39 epidemic isolates (2005 and 2008) with reduced susceptibility to metronidazole (MIC 4–8 mg/L) (CD-RM), 57 epidemic isolates (2005 and 2008) susceptible to metronidazole (MIC ≤2 mg/L) and 31 isolates from the remainder of the top 10 most common C. difficile PCR ribotypes, including PCR ribotype 010 (non-toxigenic), which shows reduced metronidazole susceptibility. MICs were determined by agar incorporation. Briefly, following culture in pre-reduced Schaedler's anaerobic broth at 37°C for 48 h, strains were multipoint inoculated (10⁴ cfu/spot) onto Wilkins–Chalgren agar containing nitazoxanide (a gift from Romark) and cultured anaerobically for 48 h. Bacteroides fragilis NCTC 6343 and Staphylococcus aureus NCTC 6571 were used as control organisms.

In agreement with previous reports, we found nitazoxanide to be very active against all C. difficile isolates tested (MIC range 0.03–0.5 mg/L) (Table 1).⁵ Geometric mean MICs of nitazoxanide appeared to be unaffected by metronidazole susceptibility and there was little variation among CD-RM epidemic PCR ribotypes or between isolation dates. Nitazoxanide is moderately well absorbed, with 67% of the dose eliminated in faeces, mainly as the desacetyl-metabolite tizoxanide.⁵ Tizoxanide activity was not investigated in the present study, but previous studies have shown good activity against C. difficile.⁵ The promising in vitro activity of nitazoxanide has been borne out by recent reports of its clinical use in CDI treatment.⁶ A recent prospective, double-blind study of nitazoxanide and vancomycin in hospitalized patients with CDI found no difference in outcome, although patient numbers were small (27 received vancomycin and 23 received nitazoxanide).⁶

In light of the recent emergence of reduced metronidazole susceptibility among epidemic C. difficile PCR ribotypes, the good activity (range 0.03–0.5 mg/L) of nitazoxanide against epidemic CD-RM is encouraging, and indicates that the mechanism underlying reduced metronidazole susceptibility does not affect the activity of nitazoxanide. The mechanism underlying reduced metronidazole susceptibility among C. difficile has not yet been elucidated.⁴ Both metronidazole and nitazoxanide are thought to affect the pyruvate ferredoxin oxidoreductase (PFOR) pathway in anaerobic bacteria. However, nitazoxanide does not require nitroreduction to become active and has recently been postulated to affect PFOR activity at an earlier stage than metronidazole.⁷ This may explain why C. difficile strains with reduced susceptibility to metronidazole remain fully susceptible to nitazoxanide. Non-toxigenic C. difficile PCR ribotype 010 (metronidazole MIC 8–16 mg/L) was marginally less susceptible to nitazoxanide (0.5 mg/L) than the other isolates we examined, but this result is within the accepted variance of MIC studies.

In conclusion, nitazoxanide showed excellent activity against all C. difficile isolates tested in this study, regardless of metronidazole susceptibility or epidemic type. The results display the potential of nitazoxanide as a treatment option in CDI and highlight the value of further clinical assessment of this agent.

Funding

This study was supported by internal funding.

Transparency declarations

J. F. has received financial support to attend meetings from Bayer and Wyeth. S. D. B. has received financial support to attend meetings from Bayer and Targanta Therapeutics. M. H. W. has received honoraria for consultancy work, financial support to attend meetings and research funding from Astellas, Astra-Zeneca, Bayer, bioMérieux, Cerexa, Nabriva, Novacta, Pfizer, Summit, The Medicines Company and Viropharma. S. L. T. and G. S. H.: none to declare.

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