High Rate of Metronidazole Resistance Seen in C difficile Infection

A potentially high rate of antibiotic resistance to imidazole agents may promote a higher rate of infection recurrence among patients given first-line therapy for Clostridium difficile infection (CDI), according to a new study by Jodie A. Barkin, MD, from the Division of Gastroenterology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Florida, and colleagues, published in Digestive Diseases and Sciences.¹

Patterns of antibiotic resistance to the 2 most commonly used agents for CDI (metronidazole and vancomycin) have been largely unknown, and the selection of antibiotic therapy is primarily determined by the clinical severity of the infection on presentation. Current treatment guidelines by the American College of Gastroenterology recommend initiating therapy with oral metronidazole for clinically mild to moderate CDI, oral vancomycin for severe CDI, and combination therapy with oral vancomycin and intravenous metronidazole (with the possible addition of liquid vancomycin by enema) for CDI cases that are determined to have complications.²

In the current study, investigators from the University of Miami identified 2 patterns of resistance to vancomycin (vanA and vanB), and 1 to imidazole, a drug class that includes metronidazole (nimA), and tested for their presence in 282 CD-positive stool samples collected from a single laboratory during a 6-month period. The researchers reported that 134 (47.5%) of the 282 samples were positive for imidazole resistance compared with 17 (6.1%) of 279 specimens that were positive for either type of vancomycin resistance.

Metronidazole treatment, in particular, has been associated with substantial rates of treatment failure. A previous study by Musher et al (2005) found a 50% failure rate when combining nonresponders (22%) with CDI recurrence occurring within 90 days of treatment (28%).³ In 2008, Baines et al demonstrated a 24.4% reduced susceptibility to only the 001 strain of CDI.⁴ Dr Barkin and colleagues suggested that such a pattern of resistance to metronidazole may emerge over time, or as a result of prior metronidazole exposure, which could not be determined in their study population.

They also showed a geographical influence to patterns of antimicrobial resistance by mapping occurrences. Cases of vancomycin-treatment resistance appeared to cluster in eastern, and particularly northeastern, regions of the United States compared with imidazole resistance, which more generally followed patterns of CD positivity.

CDI has risen sharply and suddenly since 2000, with the emergence of more virulent strains and high mortality, which are largely associated with gastroenteritis.^5-7 Dr Barkin and coauthors suggested that the many factors identified in the current study pointed strongly toward using new treatment algorithms that rely on testing for antibiotic resistance to improve both the efficacy and cost-effectiveness of current treatment models, in addition to markers of clinical severity.

References

1. Barkin JA, Sussman DA, Fifadara N, Barkin JS. Clostridium difficile infection and patient-specific antimicrobial resistance testing reveals a high metronidazole resistance rate [published online January 23, 2107]. Dig Dis Sci. doi: 10.1007/s10620-017-4462-9
2. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498. doi: 10.1038/ajg.2013.4
3. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590. doi: 10.1086/430311
4. Baines SD, O’Connor R, Freeman J, et al. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J Antimicrob Chemother 2008;62:1046-1052. doi: 10.1093/jac/dkn313
5. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58:1394-1400. doi: 10.1093/cid/ciu125
6. Rao K, Micic D, Natarajan M, et al. Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality. Clin Infect Dis. 2015;61:233-241. doi: 10.1093/cid/civ254
7. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372:825-834.