By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Growth inhibition of Clostridioides difficile isolates from patients in Houston and Nairobi is requiring increasing concentrations of vancomycin, raising concerns about reduced therapeutic efficacy.
SOURCE: Darkoh C, Keita K, Odo C, et al. Emergence of clinical Clostridioides difficile isolates with decreased susceptibility to vancomycin. Clin Infect Dis 2022;74:120-126.
The reasons for the frequent failure of vancomycin in the treatment of diarrhea due to Clostridioides difficile infection (CDI) have remained unexplained. One possibility is reduced susceptibility to vancomycin, a possibility that Darkoh and colleagues have addressed. They evaluated the prevalence of this phenomenon by examining more than 500 clinical isolates collected from patients on two continents.
Although there are no relevant Clinical and Laboratory Standards Institute (CLSI) breakpoints, nonsusceptibility was defined as the presence of growth on agar plates containing 4 mcg/mL of vancomycin and, separately, 8 mcg/mL of metronidazole. Of 438 C. difficile isolates obtained during 2012-2017 in Houston, 114 (26%) grew on vancomycin-containing plates, 128 (29%) grew on plates containing metronidazole, and 97 (22%) grew on both. The proportions with growth were higher among the 98 isolates from Nairobi: 67% on vancomycin, 85% on metronidazole, and 58% grew on both plates. The vancomycin minimal inhibitory concentrations (MICs) ranged from 4 mcg/mL to > 32 mcg/mL, and all isolates with MIC > 32 mcg/mL also were resistant to teicoplanin.
The proportion of Houston isolates that were vancomycin nonsusceptible increased from zero in 2012 to 35% in 2017. Nonsusceptibility was inducible, and the vanA gene cluster was not detected using whole genome sequencing. Vancomycin therapy in a murine model failed to eliminate infection with a vancomycin nonsusceptible isolate of C. difficile.
COMMENTARY
The results of this study in Houston and Nairobi appear to differ from those recently reported in other geographic areas. Thus, examination of 414 isolates from 13 Asia-Pacific countries found that all were susceptible to metronidazole, vancomycin, and fidaxomicin.1 Similarly, all 1,091 isolates in Australia were susceptible to metronidazole and fidaxomicin, while 62 (5.7%) were deemed to be vancomycin resistant.2
However, the lack of an accepted breakpoint for nonsususceptibility of C. difficile to vancomycin makes all these results, including those of Darkoh et al, difficult to interpret. Nonetheless, the evidence of a significant increase in MIC over time in both Houston and Nairobi seems an unequivocal signal that reduced susceptibility is occurring. The mechanism of resistance of C. difficile, which Darkoh and colleagues found to be inducible, remains unknown, but it was not the result of the presence of a vanA gene cluster.
Based on the study reviewed here, it appears that the phenomenon of a reduction in susceptibility of C. difficile to vancomycin appears real, and the clinical significance is yet to be determined. Although, in contrast, resistance to fidaxomicin appears to continue to be rare, clinical trials comparing its use to that of vancomycin have not detected significant differences in outcomes of the acute infection (in contrast to the reduction of recurrences in fidaxomicin recipients). Furthermore, the concentrations of vancomycin considered nonsusceptible generally are trivial compared to the enormous concentration of vancomycin reached in the fecal stream after oral administration, although it is possible that the fecal milieu may interfere with its antibacterial activity. In the meantime, the problem is resolved if the current Infectious Diseases Society of America guideline recommendation for use of fidaxomicin as the preferred therapy for CDI is followed.
REFERENCES
- Lew T, Putsathit P, Sohn KM, et al. Antimicrobial susceptibilities of Clostridium difficile isolates from 12 Asia-Pacific countries in 2014 and 2015. Antimicrob Agents Chemother 2020;64:e00296-20.
- Putsathit P, Hong S, George N, et al. Antimicrobial resistance surveillance of Clostridioides difficile in Australia, 2015-18. J Antimicrob Chemother 2021;76:1815-1821.
Growth inhibition of Clostridioides difficile isolates from patients in Houston and Nairobi is requiring increasing concentrations of vancomycin, raising concerns about therapeutic efficacy.
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