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Impact of the New Delhi metallo-beta-lactamase on beta-lactam antibiotics.

Zmarlicka MT, Nailor MD, Nicolau DP - Infect Drug Resist (2015)

Bottom Line: It is thus surprising that the literature examining clinical experiences with NDM does not report corresponding poor clinical outcomes.However, animal studies do begin to shed more light on this phenomenon.They imply that the in vivo expression of NDM may not confer clinical resistance to all cephalosporin and carbapenem antibiotics as predicted by in vitro testing but other resistance mechanisms need to be present to generate a resistant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Hartford Hospital, Hartford, CT, USA.

ABSTRACT
Since the first New Delhi metallo-beta-lactamase (NDM) report in 2009, NDM has spread globally causing various types of infections. NDM-positive organisms produce in vitro resistance phenotypes to carbapenems and many other antimicrobials. It is thus surprising that the literature examining clinical experiences with NDM does not report corresponding poor clinical outcomes. There are many instances where good clinical outcomes are described, despite a mismatch between administered antimicrobials and resistant in vitro susceptibilities. Available in vitro data for either monotherapy or combination therapy does not provide an explanation for these observations. However, animal studies do begin to shed more light on this phenomenon. They imply that the in vivo expression of NDM may not confer clinical resistance to all cephalosporin and carbapenem antibiotics as predicted by in vitro testing but other resistance mechanisms need to be present to generate a resistant phenotype. As such, previously abandoned therapies, particularly carbapenems and beta-lactamase inhibitor combinations, may retain utility against infections caused by NDM producers.

No MeSH data available.


Related in: MedlinePlus

Comparative efficacies of human-simulated regimens of CAZ-AVI and CAZ alone against NDM-carrying EC and KP, and an isogenic NDM-1 pair in the neutropenic murine thigh infection model.Note: Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. Efficacy of humanized carbapenem exposures against New Delhi metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae in a murine infection model. Antimicrob Agents Chemother. 2013;57(8):3936–3940.49Abbreviations: CAZ, ceftazidime; CAZ-AVI, ceftazidime-avibactam; CFU, colony-forming units; EC, Escherichia coli; KP, Klebsiella pneumoniae; NDM, New Delhi metallo-beta-lactamase.
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f2-idr-8-297: Comparative efficacies of human-simulated regimens of CAZ-AVI and CAZ alone against NDM-carrying EC and KP, and an isogenic NDM-1 pair in the neutropenic murine thigh infection model.Note: Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. Efficacy of humanized carbapenem exposures against New Delhi metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae in a murine infection model. Antimicrob Agents Chemother. 2013;57(8):3936–3940.49Abbreviations: CAZ, ceftazidime; CAZ-AVI, ceftazidime-avibactam; CFU, colony-forming units; EC, Escherichia coli; KP, Klebsiella pneumoniae; NDM, New Delhi metallo-beta-lactamase.

Mentions: Despite the grim outlook on therapy provided by in vitro data, in vivo data from animal studies paints a different picture in terms of antimicrobial options and potentially explains the discordant results of human clinical data. One study compared humanized doses of ceftazidime versus ceftazidime with avibactam against isolates producing NDM, as well as other beta-lactamases.48 In vitro susceptibility testing to ceftazidime, avibactam, and the combination of ceftazidime/avibactam showed that all NDM-producing isolates were resistant to the tested compounds. Therefore, it was unexpected when humanized exposures of both ceftazidime alone and ceftazidime in combination with avibactam had activity against NDM-producing isolates in a murine thigh infection model (Figure 2). Ceftazidime alone showed a 1.4-log reduction against an isogenic strain harboring NDM-1, whereas only modest to no activity was noted against clinical strains. The addition of avibactam to ceftazidime restored activity against all the tested strains, showing 0.61–1.42-log reductions in bacterial growth. Since ceftazidime was active against the isogenic NDM harboring the single enzyme, it was not surprising that the addition of avibactam essentially eliminated the impact of other beta-lactamases, preserving ceftazidime’s activity against the clinical isolates. These data suggest that the magnitude of the in vivo expression of NDM beta-lactamase is not large enough in the context of conventional exposure to ceftazidime as used in the clinical setting. It also highlights that genotypic testing only for NDM may not be sufficient for determining clinical response to therapy.


Impact of the New Delhi metallo-beta-lactamase on beta-lactam antibiotics.

Zmarlicka MT, Nailor MD, Nicolau DP - Infect Drug Resist (2015)

Comparative efficacies of human-simulated regimens of CAZ-AVI and CAZ alone against NDM-carrying EC and KP, and an isogenic NDM-1 pair in the neutropenic murine thigh infection model.Note: Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. Efficacy of humanized carbapenem exposures against New Delhi metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae in a murine infection model. Antimicrob Agents Chemother. 2013;57(8):3936–3940.49Abbreviations: CAZ, ceftazidime; CAZ-AVI, ceftazidime-avibactam; CFU, colony-forming units; EC, Escherichia coli; KP, Klebsiella pneumoniae; NDM, New Delhi metallo-beta-lactamase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554481&req=5

f2-idr-8-297: Comparative efficacies of human-simulated regimens of CAZ-AVI and CAZ alone against NDM-carrying EC and KP, and an isogenic NDM-1 pair in the neutropenic murine thigh infection model.Note: Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. Efficacy of humanized carbapenem exposures against New Delhi metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae in a murine infection model. Antimicrob Agents Chemother. 2013;57(8):3936–3940.49Abbreviations: CAZ, ceftazidime; CAZ-AVI, ceftazidime-avibactam; CFU, colony-forming units; EC, Escherichia coli; KP, Klebsiella pneumoniae; NDM, New Delhi metallo-beta-lactamase.
Mentions: Despite the grim outlook on therapy provided by in vitro data, in vivo data from animal studies paints a different picture in terms of antimicrobial options and potentially explains the discordant results of human clinical data. One study compared humanized doses of ceftazidime versus ceftazidime with avibactam against isolates producing NDM, as well as other beta-lactamases.48 In vitro susceptibility testing to ceftazidime, avibactam, and the combination of ceftazidime/avibactam showed that all NDM-producing isolates were resistant to the tested compounds. Therefore, it was unexpected when humanized exposures of both ceftazidime alone and ceftazidime in combination with avibactam had activity against NDM-producing isolates in a murine thigh infection model (Figure 2). Ceftazidime alone showed a 1.4-log reduction against an isogenic strain harboring NDM-1, whereas only modest to no activity was noted against clinical strains. The addition of avibactam to ceftazidime restored activity against all the tested strains, showing 0.61–1.42-log reductions in bacterial growth. Since ceftazidime was active against the isogenic NDM harboring the single enzyme, it was not surprising that the addition of avibactam essentially eliminated the impact of other beta-lactamases, preserving ceftazidime’s activity against the clinical isolates. These data suggest that the magnitude of the in vivo expression of NDM beta-lactamase is not large enough in the context of conventional exposure to ceftazidime as used in the clinical setting. It also highlights that genotypic testing only for NDM may not be sufficient for determining clinical response to therapy.

Bottom Line: It is thus surprising that the literature examining clinical experiences with NDM does not report corresponding poor clinical outcomes.However, animal studies do begin to shed more light on this phenomenon.They imply that the in vivo expression of NDM may not confer clinical resistance to all cephalosporin and carbapenem antibiotics as predicted by in vitro testing but other resistance mechanisms need to be present to generate a resistant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Hartford Hospital, Hartford, CT, USA.

ABSTRACT
Since the first New Delhi metallo-beta-lactamase (NDM) report in 2009, NDM has spread globally causing various types of infections. NDM-positive organisms produce in vitro resistance phenotypes to carbapenems and many other antimicrobials. It is thus surprising that the literature examining clinical experiences with NDM does not report corresponding poor clinical outcomes. There are many instances where good clinical outcomes are described, despite a mismatch between administered antimicrobials and resistant in vitro susceptibilities. Available in vitro data for either monotherapy or combination therapy does not provide an explanation for these observations. However, animal studies do begin to shed more light on this phenomenon. They imply that the in vivo expression of NDM may not confer clinical resistance to all cephalosporin and carbapenem antibiotics as predicted by in vitro testing but other resistance mechanisms need to be present to generate a resistant phenotype. As such, previously abandoned therapies, particularly carbapenems and beta-lactamase inhibitor combinations, may retain utility against infections caused by NDM producers.

No MeSH data available.


Related in: MedlinePlus