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

Abstract

e Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent-and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced >1-log 10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, >1-log 10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae. New Delhi metallo-␤-lactamase (NDM-1) is a novel carbapenemase that was first identified in a Klebsiella pneumoniae isolate in India in 2008 (1). Since then, it has disseminated at a high rate among Enterobacteriaceae isolates both within the Indian subcontinent and worldwide (2-4). The treatment options for infections caused by NDM-1-producing isolates are extremely limited, as these enzymes are known to hydrolyze penicillins, cephalosporins, and carbapenems while typically retaining susceptibility to only colistin and tigecycline (2), neither of which has been shown to be a dependable option on the basis of in vitro time-kill data and case reports (5-8). Aztreonam is not readily inactivated by metallo-␤-lactamases, including NDM-1, and may represent another potential option for therapy (1, 9). However, NDM-1-producing strains often coproduce other ␤-lactamases, such as CTX-M-and CMY-type enzymes, that possess the ability to hydrolyze aztreonam, further limiting the utility of all ␤-lactam antibiotics (1). Furthermore, in vivo efficacy data evaluating potential treatment options for NDM-1-producing isolates are sparse and clinical experience in treating inf...

Unexpected In Vivo Activity of Ceftazidime Alone and in Combination with Avibactam against New Delhi Metallo-β-Lactamase-Producing Enterobacteriaceae in a Murine Thigh Infection Model

“…A moderate reduction in bacterial density was demonstrated for ceftazidime alone against the isogenic NDM strain despite an fT ϾMIC (percentage of the dosing interval during which free drug concentrations exceed the MIC) of 0%. Similar to our previous studies, these data suggest that the in vivo effectiveness of this enzyme in reducing the antibacterial activity of the compound is discordant with the observations derived from in vitro MIC testing (8,9). However, against the four clinical NDM-producing strains, all of which were tested with in vitro ceftazidime MIC values of Ͼ128 g/ml, ceftazidime failed to show activity, likely due to the coproduction of other ␤-lactamases (e.g., ESBLs, OXAs), which is consistent with previously published in vivo observations of other NDM-producing clinical isolates (4,9).…”

“…While the novel non-␤-lactam ␤-lactamase inhibitor avibactam has been shown to restore the in vitro potency of ceftazidime against Ambler class A and C (and some class D) ␤-lactamases, the combination of ceftazidime and avibactam displays high MICs in vitro against Enterobacteriaceae isolates that produce metallo-␤-lactamases, such as NDM (5-7). Of note, previous work conducted by our group with carbapenems raised a question about the potencies of these NDM enzymes in vivo (8,9). Contrary to the observed in vitro resistance, human simulated doripenem and ertapenem regimens demonstrated in vivo efficacies against isogenic and clinical NDM-1-producing isolates in a murine thigh infection model.…”

Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance

“…Treatment regimens using carbapenems may be an option when the MICs of carbapenems are Յ8 mg/liter when a second antibiotic is added or when a prolonged intravenous infusion regimen is used (123,124). Encouraging results have been obtained with VIM and OXA-48 producers in humans and with NDM producers in animal models (106,125,126). Studies performed with an animal model of infection (i.e., mouse pneumonia) suggested that dual-carbapenem therapy (i.e., meropenem plus ertapenem) may be effective (126).…”

“…Encouraging results have been obtained with VIM and OXA-48 producers in humans and with NDM producers in animal models (106,125,126). Studies performed with an animal model of infection (i.e., mouse pneumonia) suggested that dual-carbapenem therapy (i.e., meropenem plus ertapenem) may be effective (126). Ertapenem most likely acts as a "suicide" molecule for carbapenemase activity, whereas the more active drug, meropenem, retains its efficacy.…”

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).…”