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. 2021 Jul 8;8(8):ofab365.
doi: 10.1093/ofid/ofab365. eCollection 2021 Aug.

Reduced Susceptibility to Metronidazole Is Associated With Initial Clinical Failure in Clostridioides difficile Infection

Anne J Gonzales-Luna  1 , Abiola O Olaitan  2 , Wan-Jou Shen  2 , Aditi Deshpande  2 , Travis J Carlson  3 , Kierra M Dotson  4 , Chris Lancaster  1 , Khurshida Begum  1 , M Jahangir Alam  1 , Julian G Hurdle  2 , Kevin W Garey  1
Affiliations

Reduced Susceptibility to Metronidazole Is Associated With Initial Clinical Failure in Clostridioides difficile Infection

Anne J Gonzales-Luna et al. Open Forum Infect Dis. .

Abstract

Background: Clinical studies have demonstrated inferior cure rates when metronidazole (MTZ) is used to treat Clostridioides difficile infection (CDI). We hypothesized that a newly identified, heme-inducible form of reduced MTZ susceptibility in C. difficile leads to higher odds of initial clinical failure in patients with CDI treated with MTZ.

Methods: This multicenter cohort study included adults diagnosed with CDI between 2017 and 2018. C. difficile isolated from stool samples underwent agar dilution MTZ susceptibility testing with incorporation of fresh heme. Blinded investigators reviewed medical records for initial clinical failure and other relevant clinical variables. Classification and regression tree (CART) analysis was used to identify the MTZ minimum inhibitory concentration (MIC) breakpoint that was predictive of initial clinical failure. Results were confirmed using univariate and multivariable logistic regression analyses to account for potential confounders.

Results: Of the 356 patients included, 72% received MTZ-based therapy and 27% experienced initial clinical failure. CART analysis identified an MTZ MIC ≥1 µg/mL above which patients had a higher rate of initial clinical failure. MTZ MICs ranged from 0.25 to 8 µg/mL (MIC50/90 = 0.25/2 µg/mL), and approximately 18% of isolates had MTZ MICs ≥1 µg/mL. In multivariable analysis, an MTZ MIC ≥1 µg/mL was an independent predictor of initial clinical failure in patients receiving an MTZ-based treatment regimen (odds ratio, 2.27 [95% confidence interval, 1.18-4.34]).

Conclusions: Using a reproducible method to determine C. difficile MICs to MTZ, a breakpoint of ≥1 µg/mL identified patients at higher risk of initial clinical failure.

Keywords: Clostridium difficile; antibiotic resistance; antimicrobial resistance; heme; susceptibility testing.

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Figures

Figure 1.
Figure 1.
Clostridioides difficile metronidazole minimum inhibitory concentration (MIC) distribution measured using the agar dilution method with incorporation of fresh heme.
Figure 2.
Figure 2.
Classification and regression tree (CART) analysis for initial clinical failure stratified by metronidazole (MTZ) minimum inhibitory concentration (MIC). The primary node, based on initial clinical failure, indicates that the MIC above which therapy fails is ≥1.0 µg/mL.
See this image and copyright information in PMC

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