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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

Efficacies of human-simulated regimens of 500 mg of DOR given every 8 hours and 2 g of DOR given every 8 hours as a 4-hour infusion (A) and 1 g of ETP given every 24 hours (B) in a neutropenic murine thigh infection model.Note: *Denote a statistically higher efficacy of the higher DOR dose as compared to the lower DOR dose. Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2014;58(3):1671–1677.50Abbreviations: CFU, colony-forming units; DOR, doripenem; EC, Escherichia coli; ETP, ertapenem; KP, Klebsiella pneumoniae.
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f4-idr-8-297: Efficacies of human-simulated regimens of 500 mg of DOR given every 8 hours and 2 g of DOR given every 8 hours as a 4-hour infusion (A) and 1 g of ETP given every 24 hours (B) in a neutropenic murine thigh infection model.Note: *Denote a statistically higher efficacy of the higher DOR dose as compared to the lower DOR dose. Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2014;58(3):1671–1677.50Abbreviations: CFU, colony-forming units; DOR, doripenem; EC, Escherichia coli; ETP, ertapenem; KP, Klebsiella pneumoniae.

Mentions: Carbapenems provide another example of discordance between in vitro data and in vivo data. A murine thigh infection model performed by Wiskirchen et al compared efficacy of humanized, high-dose, prolonged-infusion doripenem, and ertapenem against NDM-producing strains.49 An isogenic NDM-carrying K. pneumoniae strain as well as four clinical NDM-carrying strains all showed >1-log reduction in bacterial density with carbapenem therapy in an immunocompetent murine thigh infection model (Figure 3). The exception was one clinical strain with a doripenem MIC >32 µg/mL, which showed only a modest decrease in bacterial density. This successful reduction in bacterial density was shown again in the same study using two clinical strains in a neutropenic murine thigh infection model, and the effect was shown to be sustained out to 72 hours in an extended immunocompetent murine model. The efficacy of carbapenems against NDM producers was confirmed in a second study done by Wiskirchen et al in both immunocompetent and neutropenic murine thigh infection models (Figure 4).50 This second study also confirmed the need for higher doripenem doses; a dose providing the human exposure of 2 g every 8 hours infused over 4 hours consistently produced numerically higher bacterial reductions as compared to a standard dose of 500 mg given every 8 hours. This difference in bacterial reductions between the two regimens was statistically different in two of the four tested strains. Both studies also noted efficacy with carbapenems despite high MIC values and unmet pharmacokinetic/pharmacodynamic target for success (40% fT > MIC).49,50 NDM-producing organisms are not the first MBLs to demonstrate a mismatch between in vitro and in vivo efficacies. Enterobacteriaceae carrying the VIM MBL also show in vitro resistance to carbapenems, and yet, meropenem was able to produce a substantial reduction in bacterial density in a neutropenic murine thigh infection model (American Society for Microbiology, Washington, DC, data on file, 2015). Taken together, these studies suggest that carbapenems may make valuable contributions to fighting infections caused by NDM-producing organisms, and consideration should be given to utilizing these agents, especially when the organism fails to show susceptibility to other agents.


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

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

Efficacies of human-simulated regimens of 500 mg of DOR given every 8 hours and 2 g of DOR given every 8 hours as a 4-hour infusion (A) and 1 g of ETP given every 24 hours (B) in a neutropenic murine thigh infection model.Note: *Denote a statistically higher efficacy of the higher DOR dose as compared to the lower DOR dose. Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2014;58(3):1671–1677.50Abbreviations: CFU, colony-forming units; DOR, doripenem; EC, Escherichia coli; ETP, ertapenem; KP, Klebsiella pneumoniae.
© Copyright Policy
Related In: Results  -  Collection

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

f4-idr-8-297: Efficacies of human-simulated regimens of 500 mg of DOR given every 8 hours and 2 g of DOR given every 8 hours as a 4-hour infusion (A) and 1 g of ETP given every 24 hours (B) in a neutropenic murine thigh infection model.Note: *Denote a statistically higher efficacy of the higher DOR dose as compared to the lower DOR dose. Reproduced with permission from the American Society for Microbiology. Copyright © American Society for Microbiology. Wiskirchen DE, Nordmann P, Crandon JL, Nicolau DP. In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2014;58(3):1671–1677.50Abbreviations: CFU, colony-forming units; DOR, doripenem; EC, Escherichia coli; ETP, ertapenem; KP, Klebsiella pneumoniae.
Mentions: Carbapenems provide another example of discordance between in vitro data and in vivo data. A murine thigh infection model performed by Wiskirchen et al compared efficacy of humanized, high-dose, prolonged-infusion doripenem, and ertapenem against NDM-producing strains.49 An isogenic NDM-carrying K. pneumoniae strain as well as four clinical NDM-carrying strains all showed >1-log reduction in bacterial density with carbapenem therapy in an immunocompetent murine thigh infection model (Figure 3). The exception was one clinical strain with a doripenem MIC >32 µg/mL, which showed only a modest decrease in bacterial density. This successful reduction in bacterial density was shown again in the same study using two clinical strains in a neutropenic murine thigh infection model, and the effect was shown to be sustained out to 72 hours in an extended immunocompetent murine model. The efficacy of carbapenems against NDM producers was confirmed in a second study done by Wiskirchen et al in both immunocompetent and neutropenic murine thigh infection models (Figure 4).50 This second study also confirmed the need for higher doripenem doses; a dose providing the human exposure of 2 g every 8 hours infused over 4 hours consistently produced numerically higher bacterial reductions as compared to a standard dose of 500 mg given every 8 hours. This difference in bacterial reductions between the two regimens was statistically different in two of the four tested strains. Both studies also noted efficacy with carbapenems despite high MIC values and unmet pharmacokinetic/pharmacodynamic target for success (40% fT > MIC).49,50 NDM-producing organisms are not the first MBLs to demonstrate a mismatch between in vitro and in vivo efficacies. Enterobacteriaceae carrying the VIM MBL also show in vitro resistance to carbapenems, and yet, meropenem was able to produce a substantial reduction in bacterial density in a neutropenic murine thigh infection model (American Society for Microbiology, Washington, DC, data on file, 2015). Taken together, these studies suggest that carbapenems may make valuable contributions to fighting infections caused by NDM-producing organisms, and consideration should be given to utilizing these agents, especially when the organism fails to show susceptibility to other agents.

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