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

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 2017-18. 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, defined as the presence of CDI-specific symptoms, a change in CDI therapy due to lack of patient response, and/or CDI-contributable mortality on or before day 6 of treatment, and other relevant clinical variables. Classification and regression tree (CART) analysis was used to identify the MTZ 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 a MTZ MIC ≥1 µg/mL above which patients had a higher rate of initial clinical failure. MTZ MICs ranged from 0.25-8 µg/mL (MIC50/90 = 0.25/2 µg/mL), and approximately 18% of isolates had MTZ MICs ≥1 µg/mL. In multivariable analysis, a MTZ MIC ≥1 µg/mL was an independent predictor of initial clinical failure in patients receiving a MTZ-based treatment regimen (OR, 2.27; 95% CI, 1.19-4.34). 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. These are the first data demonstrating poor clinical outcomes associated with reduced MTZ susceptibility in C. difficile.

Genetic Mechanisms of Vancomycin Resistance in Clostridioides difficile: A Systematic Review

“…Thus, vancomycin resistance in patients with CDI has not been studied in depth. However, resistance to other antibiotics used to treat CDI, namely metronidazole, has been identified, leading to the question of whether C. difficile may also evolve clinically meaningful resistance to vancomycin [ 6 , 7 , 8 ]. Prescription rates for oral vancomycin increased following the 2017 IDSA/SHEA recommendation of vancomycin as first-line therapy for CDI [ 9 ].…”

Decoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile

“…Isolates with heme-dependent MTZ resistance exhibited ≥4-fold higher MICs in BHI agars containing heme, compared to agars without heme. The line at 1 μg/ml indicates MTZ MIC found to associated with poor clinical outcomes 44 (the EUCAST breakpoint is 2 μg/ml). Inset illustrates selected RT027 epidemic and non-epidemic strains that are resistant or susceptible to MTZ in heme, respectively.…”

“…Over the last two decades, the global spread of epidemic C. difficile has been paralleled by declining response rates of metronidazole, culminating in major guidelines removing it as a recommended first-line option for CDI. We recently demonstrated that heme-dependent resistance to metronidazole, defined by an MIC breakpoint of ≥1 µg/mL, was associated with an increased risk of metronidazole clinical failure 44 . Fundamental to this finding was the revelation that heme is crucial for detecting metronidazole-resistant C. difficile 44 .…”

“…We conducted reference-guided assembly on 365 U.S. C. difficile isolates and 136 global, clade 2, 027/BI/NAP1 C. difficile isolates from He et al 22 Raw sequencing data were assembled using a reference-guided assembly pipeline (https://github.com/pepperell-lab/RGAPepPipe.git). Quality of the sequencing data was 44 (the EUCAST breakpoint is 2 g/ml). Inset illustrates selected RT027 epidemic and non-epidemic strains that are resistant or susceptible to MTZ in heme, respectively.…”

“…Homoplasy analysis was conducted using Treetime 74 to investigate gyrA and nimB SNPs for signs of selection. 44 (the EUCAST breakpoint is 2 g/ml). Inset illustrates selected RT027 epidemic and non-epidemic strains that are resistant or susceptible to MTZ in heme, respectively.…”