Heteroresistance to cefepime- taniborbactam in metallo-& beta;-lactamase- encoding Enterobacterales

We read with great interest the Correspondence by Christophe Le Terrier and colleagues1Le Terrier C Gruenig V Fournier C Nordmann P Poirel L NDM-9 resistance to taniborbactam.Lancet Infect Dis. 2023; 23: 401-402Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar regarding NDM-9-mediated resistance to cefepime–taniborbactam in an engineered Escherichia coli strain. Metallo-β-lactamases (MBLs), including the New Delhi MBL (NDM) group, pose a substantial threat to the efficacy of β-lactams due to their broad-spectrum ability to hydrolyse these antibiotics and the poor clinical availability of β-lactamase inhibitors with strong activity against them.2Bush K Bradford PA Interplay between β-lactamases and new β-lactamase inhibitors.Nat Rev Microbiol. 2019; 17: 295-306Crossref PubMed Scopus (263) Google Scholar There is excitement around taniborbactam, a novel β-lactamase inhibitor with activity against NDMs and Verona integron-encoded MBLs (VIMs).3Karlowsky JA Hackel MA Wise MG et al.In vitro activity of cefepime–taniborbactam and comparators against clinical isolates of gram-negative bacilli from 2018 to 2020: results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.Antimicrob Agents Chemother. 2023; 67: e0128122Crossref PubMed Scopus (4) Google Scholar, 4Krajnc A Brem J Hinchliffe P et al.Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases.J Med Chem. 2019; 62: 8544-8556Crossref PubMed Scopus (114) Google Scholar However, previous studies have not investigated the potential presence of heteroresistance to cefepime–taniborbactam among MBL isolates. Heteroresistance is a form of antibiotic resistance that occurs when a minor subpopulation of resistant cells coexists with a majority susceptible population. The resistant cells are selected for when a strain is treated with a given antibiotic and thus can cause treatment failure, as has been observed in murine infection models.5Band VI Crispell EK Napier BA et al.Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae.Nat Microbiol. 2016; 1: 16053Crossref PubMed Scopus (129) Google Scholar The rate of heteroresistance to the β-lactam cefiderocol was also closely correlated with the rate of mortality in recent (2016–19) clinical trials.6Choby JE Ozturk T Satola SW Jacob JT Weiss DS Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?.Lancet Microbe. 2021; 2: e648-e649Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Due to the low frequency of resistant cells (as low as 1 in 1 million), heteroresistance is often undetected by antimicrobial susceptibility testing, such as broth microdilution.5Band VI Crispell EK Napier BA et al.Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae.Nat Microbiol. 2016; 1: 16053Crossref PubMed Scopus (129) Google Scholar, 6Choby JE Ozturk T Satola SW Jacob JT Weiss DS Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?.Lancet Microbe. 2021; 2: e648-e649Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar We tested a panel of MBL-encoding Enterobacterales isolates from the Centers for Disease Control and Prevention and US Food and Drug Administration Antibiotic Resistance Isolate Bank (appendix p 10) for their susceptibility status to cefepime–taniborbactam using population analysis profile, the gold standard method to identify and differentiate heteroresistance from resistance and susceptibility (appendix p 3). We observed a high occurrence of heteroresistance to cefepime–taniborbactam (29 of 34 isolates, 85%), but little resistance (4 of 34, 12%) and susceptibility (1 of 34, 3%) (table; appendix p 4). These data reveal that heteroresistance to cefepime–taniborbactam is the predominant phenotype among this collection of MBL isolates and that almost all isolates (33 of 34, 97%) exhibited cefepime–taniborbactam non-susceptibility (ie, heteroresistance or resistance). In contrast, broth microdilution, which has no designation for heteroresistance, classified only 10 of 34 isolates (29%) as resistant, highlighting that standard tests do not detect most heteroresistance to cefepime–taniborbactam (appendix p 5). This low rate of resistance to cefepime–taniborbactam according to broth microdilution is in keeping with a previous study of MBL isolates in which a minority were classified as resistant (13·6%, n=235).3Karlowsky JA Hackel MA Wise MG et al.In vitro activity of cefepime–taniborbactam and comparators against clinical isolates of gram-negative bacilli from 2018 to 2020: results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.Antimicrob Agents Chemother. 2023; 67: e0128122Crossref PubMed Scopus (4) Google ScholarTableFrequency of heteroresistance to cefepime–taniborbactam among MBL-encoding Enterobacterales isolates from the CDC and FDA Antibiotic Resistance BankPopulation analysis profileBroth microdilutionSusceptibleHeteroresistantResistantSusceptibleResistantNDM (n=29)3·6% (1)82·8% (24)13·8% (4)65·5% (19)34·5% (10)VIM (n=5)0% (0)100% (5)0% (0)100% (5)0% (0)Data are % (n). The criteria for population analysis profile classifications are explained in the appendix (p 3). For broth microdilution, isolates with a minimum inhibitory concentration (MIC) lower than or equal to 16/4 ug/mL were deemed susceptible, whereas isolates with an MIC higher than or equal to 32/4 ug/mL were classified as resistant.3Karlowsky JA Hackel MA Wise MG et al.In vitro activity of cefepime–taniborbactam and comparators against clinical isolates of gram-negative bacilli from 2018 to 2020: results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.Antimicrob Agents Chemother. 2023; 67: e0128122Crossref PubMed Scopus (4) Google Scholar CDC=Centers for Disease Control and Prevention. FDA=US Food and Drug Administration. MBL=metallo-β-lactamase. NDM=New Delhi MBL. VIM=Verona integron-encoded MBL. Open table in a new tab Data are % (n). The criteria for population analysis profile classifications are explained in the appendix (p 3). For broth microdilution, isolates with a minimum inhibitory concentration (MIC) lower than or equal to 16/4 ug/mL were deemed susceptible, whereas isolates with an MIC higher than or equal to 32/4 ug/mL were classified as resistant.3Karlowsky JA Hackel MA Wise MG et al.In vitro activity of cefepime–taniborbactam and comparators against clinical isolates of gram-negative bacilli from 2018 to 2020: results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program.Antimicrob Agents Chemother. 2023; 67: e0128122Crossref PubMed Scopus (4) Google Scholar CDC=Centers for Disease Control and Prevention. FDA=US Food and Drug Administration. MBL=metallo-β-lactamase. NDM=New Delhi MBL. VIM=Verona integron-encoded MBL. To our knowledge, these data provide the first description of heteroresistance to cefepime–taniborbactam. The isolates did not encode NDM-9, which was characterised by Le Terrier and colleagues as causing resistance to cefepime–taniborbactam.1Le Terrier C Gruenig V Fournier C Nordmann P Poirel L NDM-9 resistance to taniborbactam.Lancet Infect Dis. 2023; 23: 401-402Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar NDM-9 is an uncommon MBL that has thus far been restricted to a few geographic regions, most prominently in east Asia.7Acman M Wang R van Dorp L et al.Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM.Nat Commun. 2022; 13: 1131Crossref PubMed Scopus (31) Google Scholar In contrast, the majority of isolates in the present study were heteroresistant to cefepime–taniborbactam and, as a group, encoded a diversity of MBLs with NDM-1 being the most frequent among all isolates (23 of 34 isolates, 68%; appendix p 10). This observation is in line with NDM-1 being the most common and globally distributed NDM.7Acman M Wang R van Dorp L et al.Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM.Nat Commun. 2022; 13: 1131Crossref PubMed Scopus (31) Google Scholar These data, therefore, suggest that compared with resistance, heteroresistance to cefepime–taniborbactam might be much more prevalent, geographically widespread, and often undetected. The data demonstrate a concerning occurrence of heteroresistance to cefepime–taniborbactam among MBL-encoding Enterobacterales and indicate that further investigation is needed to assess the potential effect of this phenomenon on the clinical efficacy of this novel combination antibiotic. CA and DSW conceived the study and CA performed all experiments. CA, SWS, and DSW conferred on study design and data analysis. CA wrote the manuscript with assistance from SWS and DSW. This Correspondence was funded by NIH grants (grant number AI158080 to SWS and DSW and grant number AI148661 to DSW). DSW was also funded by a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award. The funders had no role in the study. DSW has pending patents related to heteroresistance. All other authors declare no competing interests. Download .pdf (.52 MB) Help with pdf files Supplementary appendix