Clostridioides difficile: Reduced Susceptibility to Vancomycin?
January 30, 2025
By Carol A. Kemper, MD, FIDSA, FACP
Source: Eubank TA, Dureja C, Garey KW, et al. Reduced vancomycin susceptibility in Clostridioides difficile is associated with lower rates of initial cure and sustained clinical response. Clin Infect Dis. 2024;79(1):15-21.
Many sites have been reluctant to prescribe fidaxomicin as the first-line agent, despite fairly robust evidence indicating its efficacy relative to vancomycin in preventing recurrences. We still cannot predict who will do well with vancomycin and which patients are likely to relapse or to do more poorly. The gradual emergence of Clostridioides difficile (CD) with reduced vancomycin susceptibility may contribute to adverse outcomes when using this agent.
A Houston-based multicenter cohort study, performed from 2016 to 2021, examined CD susceptibility to vancomycin, ribotype identification, and sequence variation of the vanR gene, compared with clinical outcomes at 14 and 30 days. Reduced susceptibility was defined as a minimum inhibitory concentration (MIC) > 2 mcg/mL based on Clinical and Laboratory Standards Institute (CLSI) epidemiological cutoff values. The primary study outcome was 30-day sustained clinical response, and secondary outcomes were 14-day clinical response, 30-day recurrence, and 30-day mortality. Samples were prospectively collected, although the clinical portion of the study was based on retrospective database analysis. The study included adults (≥ 18 years of age) testing positive for CD (either nucleic acid amplification testing or toxin testing) who were treated with orally administered vancomycin monotherapy (metronidazole was not permitted beyond the first 48 hours of treatment). The average duration of vancomycin therapy was ~ 15 days.
Three hundred stool samples were analyzed, of which 102 (34%) demonstrated reduced vancomycin susceptibility (none demonstrated high-level resistance with MIC ≥ 32 mcg/mL). Fifty-three isolates were identified as the “hypervirulent” ribotype NAP1/B1/027 strain, 41 (77.4%) of which exhibited reduced vancomycin susceptibility. Sustained clinical response was observed at 30 days in 249 patients (83%), including 171/198 (86%) of patients with vancomycin-susceptible strains and 78/102 (76%) with reduced vancomycin susceptibility (P = 0.031). Clinical cure at 14 days also was significantly associated with vancomycin susceptibility vs. reduced susceptibility (96% vs. 89%, respectively) (P = 0.04). Of the 51 patients who did not achieve a sustained clinical response at 30 days, 20 (39%) had continued diarrhea at day 14, nine (18%) relapsed by 30 days, and 22 (43%) died within 30 days of their CD infection diagnosis.
In preliminary analysis, failing to achieve a 30-day sustained clinical response was significantly associated with ribotype 027 and a worse Charlson Comorbidity Index (CCI). However, in multivariate analysis, only reduced vancomycin susceptibility and a higher CCI score remained independent predictors of 30-day sustained clinical response.
Reduced vancomycin susceptibility was observed in 34% of clinical isolates and was associated with a reduced clinical response at 14 and 30 days. Despite evidence of reduced vancomycin susceptibility, 76% of such patients achieved a 30-day sustained clinical response with this agent. This is believed to be the result of extremely high concentrations of vancomycin within the gut lumen (ranging from 500 mcg/mL to 2,000 mcg/mL), which may “overcome” modest reductions in susceptibility. It also is possible that vancomycin may not be evenly distributed throughout the gut lumen.
Relapses in patients receiving vancomycin may occur in up to 20% to 25% of patients, and many are re-treated with the same agent, perhaps for longer durations or with an extended taper. This study provides several useful clues to clinical management. Firstly, while CD cultures are labor intensive, outcomes for patients with CD, especially hospitalized patients, are critical enough to justify the use of MIC as a therapeutic marker. Patients with continued diarrhea or who failed to achieve clinical cure at 14 days of treatment are unlikely to achieve a clinical response with vancomycin and experience higher rates of mortality, suggesting these patients should be switched to an alternate agent. A majority of ribotype 027 isolates (77.4%) exhibited reduced vancomycin susceptibility, and consideration could be given to preemptively treating patients with recognized 027 infection with an alternate agent. The Xpert gene test (Cepheid) detects both toxigenic genes and also presumptively identifies the 027 strain, providing a rapid diagnostic tool for differentiating these isolates.
This study has several limitations, including a lack of information on whether continued antibacterial therapy was used in some patients; the dose of vancomycin monotherapy was not specified; some patients were identified based on a positive nucleic acid amplification test result and may not have had active CD infection; and the duration of follow-up for clinical cure and relapse was only 30 days, although the usual definition of relapse is within eight weeks.
Carol A. Kemper, MD, FIDSA, is Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation.
Many sites have been reluctant to prescribe fidaxomicin as the first-line agent, despite fairly robust evidence indicating its efficacy relative to vancomycin in preventing recurrences. We still cannot predict who will do well with vancomycin and which patients are likely to relapse or to do more poorly. The gradual emergence of Clostridioides difficile with reduced vancomycin susceptibility may contribute to adverse outcomes when using this agent.
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