TY - JOUR
AU1 - Darkoh, Charles
AU2 - DuPont, Herbert L
AU3 - Arias, 
Cesar A.
AU4 - Oyaro, Micah
AU5 - Brown, Eric L
AU6 - Hanson, Blake M
AB - To the Editor—We appreciate the letter by Lutgring et al focusing on the clinical significance of our study in which we report the common occurrence of vancomycin nonsusceptibility among Clostridioides difficile isolates in Houston, Texas, and Nairobi. The authors indicate that the methodology for antimicrobial susceptibility testing should be expanded and questioned the clinical relevance of vancomycin nonsusceptibility in C. difficile. Our robust clinical experience with patients infected with C. difficile indicates that clinical treatment failures are in the ascendency. Indeed, the volume of patients being referred to our fecal microbiota transplantation program for treatment of vancomycin nonresponsive disease is evidence of the overall lack of efficacy of vancomycin in treating the infection. Further, vancomycin was removed as the preferred agent in recent guidelines. Although we agree that nonsusceptibility to the antibiotic may not be the only cause of failures, and this phenomenon may relate to the damaging effect of vancomycin on the gut microbiome and failure of the drug to eradicate spores, the reduced susceptibility of infecting strains is likely to play a role. Our studies suggest that rising minimum inhibitory concentrations (MICs) of infecting C. difficile strains may be more common than previously thought and should be considered in patients who fail vancomycin treatment. Lutgring et al indicate that because the rate of nonsusceptibility that we found exceeded rates reported in the literature, the validity of our data and our methods should be questioned. Since in vitro susceptibility for strict anaerobes is not routinely performed and surveys of susceptibility are few, the existing data in the published literature on vancomycin susceptibility of C. difficile strains performed in recent years are limited. However, an increase in the vancomycin MICs of C. difficile isolates has been reported by other groups [1–4]. In our article, we call for more studies of susceptibility of C. difficile strains to help define the extent of antibiotic resistance. Lutgring et al cite limitations of our laboratory methods, where agar dilution methods are standard to determine susceptibility to these anaerobic bacteria. While the agar dilution method is the method recommended by the Clinical and Laboratory Standards Institute (CLSI), it was not a practical method for us as we had to study more than 3000 isolates. We do not feel that this is a deficiency in our experiments. We used both E-test and broth dilution methods, which have compared favorably with agar dilution methods in other studies [5, 6]. Furthermore, we were reassured about our methods after finding that results with broth dilution and E-test methods resulted in similar patterns of susceptibility of C. difficile isolates. The in vitro correlation with drug concentrations in the stool is very poor (see point below); therefore, the MIC value may be less relevant for therapeutic purposes, regardless of the methodology used. We clearly showed that by using a standard methodology, we can identify increased MICs in clinical isolates. Lutgring et al indicate that because there is an inadequate correlation between in vitro susceptibility and outcome, CLSI has not established clinical outcome breakpoints. The reason breakpoints have not been established for vancomycin in C. difficile infections is not related to the expected clinical outcomes of the infection. Breakpoints are used for systemic infections where MICs of an infecting organism can be compared with expected serum concentrations of antibiotics. Breakpoints have not been established for any enteric infection for poorly absorbed antibiotics (eg, neomycin, rifaximin, vancomycin) and are considered irrelevant in these settings where the MICs are expected to be far below the levels of intraintestinal drug [7]. Lutgring et al remark that our study offers no clinical correlation to determine the significance of our findings. The authors also questioned the significance of the in vivo data. We agree with this point and strongly support studies correlating MICs of C. difficile strains with clinical outcome of vancomycin treatment. We have currently embarked on a Texas Medical Center–wide program to follow patients with C. difficile infections treated with vancomycin in order to identify the clinical significance of our laboratory findings. We agree that mice are not humans, but our in vivo data clearly show a difference in the in vivo response to treatment when the vancomycin MICs increased. These findings support our main point that rising MICs may compromise the therapeutic efficacy of vancomycin. Note Potential conflicts of interest. C. A. A. reports grants from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics outside of the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1 Adler A , Miller-Roll T, Bradenstein R, et al. A national survey of the molecular epidemiology of Clostridium difficile in Israel: the dissemination of the ribotype 027 strain with reduced susceptibility to vancomycin and metronidazole . Diagn Microbiol Infect Dis 2015 ; 83 : 21 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Snydman DR , McDermott LA, Jacobus NV, et al. U.S.-based National Sentinel Surveillance Study for the epidemiology of Clostridium difficile-associated diarrheal isolates and their susceptibility to fidaxomicin . Antimicrob Agents Chemother 2015 ; 59 : 6437 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Baghani A , Mesdaghinia A, Kuijper EJ, Aliramezani A, Talebi M, Douraghi M. High prevalence of Clostridiodes difficile PCR ribotypes 001 and 126 in Iran . Sci Rep 2020 ; 10 : 4658 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Saldanha GZ , Pires RN, Rauber AP, et al. Genetic relatedness, virulence factors and antimicrobial resistance of C. difficile strains from hospitalized patients in a multicentric study in Brazil . J Glob Antimicrob Resist 2020 ; 22 : 117 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Igawa G , Casey M, Sawabe E, et al. Comparison of agar dilution and broth microdilution methods for Clostridium difficile antimicrobial susceptibility testing . J Glob Antimicrob Resist 2016 ; 7 : 43 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Erikstrup LT , Danielsen TK, Hall V, et al. Antimicrobial susceptibility testing of Clostridium difficile using EUCAST epidemiological cut-off values and disk diffusion correlates . Clin Microbiol Infect 2012 ; 18 : E266 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Calanni F , Renzulli C, Barbanti M, Viscomi GC. Rifaximin: beyond the traditional antibiotic activity . J Antibiot (Tokyo) 2014 ; 67 : 667 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
TI - Reply to Lutgring et al 
JF - Clinical Infectious Diseases
DO - 10.1093/cid/ciac376
DA - 2022-07-12
UR - https://www.deepdyve.com/lp/oxford-university-press/reply-to-lutgring-et-al-rd4tJvvVLf
SP - 1678
EP - 1679
VL - 75
IS - 9
DP - DeepDyve
ER -