Efficacy of Humanized Carbapenem Exposures against New Delhi Metallo-β-Lactamase (NDM-1)-Producing Enterobacteriaceae in a Murine Infection Model

Abstract

Enterobacteriaceae producing the novel carbapenemase New Delhi metallo-␤-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was <8 g/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing Enterobacteriaceae under certain conditions, and this warrants further in vivo exploration.

In VivoEfficacy of Human Simulated Regimens of Carbapenems and Comparator Agents against NDM-1-Producing Enterobacteriaceae

“…Unlike in vivo observations with isolates that produce the serine-carbapenemase KPC, carbapenem monotherapy has demonstrated reductions of NDM-1-producing bacterial isolates in a murine thigh infection model, even though the time that the concentration of an unbound antibiotic remains above the MIC during the dosing interval (ƒT ϾMIC ) needed for efficacy was not achieved for all of the isolates (10,11). Previous work by our group has demonstrated a reduction in bacterial density with human simulated monotherapy regimens of ertapenem and high-dose, prolonged infusion of doripenem against an isogenically constructed NDM-1-producing strain and four clinical NDM-1-producing strains in a murine thigh infection model (10).…”

“…Previous work by our group has demonstrated a reduction in bacterial density with human simulated monotherapy regimens of ertapenem and high-dose, prolonged infusion of doripenem against an isogenically constructed NDM-1-producing strain and four clinical NDM-1-producing strains in a murine thigh infection model (10). Since these results were both surprising and promising, it is essential to validate them with additional in vivo studies before determining the potential clinical utility of carbapenems for treating infections caused by NDM-1-producing organisms.…”

“…For experiments conducted in the neutropenic thigh infection model, efficacy was calculated as the change in bacterial density (in log 10 CFU) in treated mice after 24 h from the starting bacterial densities in 0-h control animals. In order to control for the effect of the host and associated variability of 0-h control bacterial density between isolates, efficacy in experiments conducted in the immunocompetent-mouse model was calculated as the change in bacterial density in treated mice after 24 h compared to that in the 24-h immunocompetent control mice (10,21). The efficacy of human simulated high-dose, prolonged infusion of doripenem and the standard regimen of ertapenem was evaluated previously for the isogenic pair, EC 389, EC393, and KP 425 and has been included to provide a complete comparison (10).…”

“…In order to control for the effect of the host and associated variability of 0-h control bacterial density between isolates, efficacy in experiments conducted in the immunocompetent-mouse model was calculated as the change in bacterial density in treated mice after 24 h compared to that in the 24-h immunocompetent control mice (10,21). The efficacy of human simulated high-dose, prolonged infusion of doripenem and the standard regimen of ertapenem was evaluated previously for the isogenic pair, EC 389, EC393, and KP 425 and has been included to provide a complete comparison (10). The observed efficacies of the two doripenem regimens and the ertapenem regimen were compared for each isolate by one-way repeatedmeasures analysis of variance.…”

Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

“…Most interestingly, animal studies (mouse thigh infection) showed that both doripenem and ertapenem were effective against the metallo-b-lactamase (MBL) NDM-producing but not against KPC-producing K. pneumoniae isolates exhibiting similar levels of resistance to the latter drug (Wiskirchen et al, 2013(Wiskirchen et al, , 2014. Moreover, using the same animal model, increased doses of imipenem exhibited measurable bactericidal activity against K. pneumoniae resistant to the latter drug owing to production of another clinically important MBL, VIM-1 (Daikos et al, 2007).…”