Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City

Abstract

Imipenem with relebactam was active against Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp., including K. pneumoniae carbapenemase (KPC)-producing isolates. Loss of OmpK36 in KPC-producing K. pneumoniae isolates affected the susceptibility of this combination. Enhanced activity was evident against Pseudomonas aeruginosa, including isolates with depressed oprD and increased ampC expression. However, the addition of relebactam to imipenem did not provide added benefit against Acinetobacter baumannii. The combination of imipenem with relebactam demonstrated activity against KPC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa. The spread of carbapenemases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii has created therapeutic dilemmas for clinicians. In particular, the acquisition of metallo-␤-lactamases and the class A enzyme Klebsiella pneumoniae carbapenemase (KPC) affords protection against virtually all ␤-lactam therapeutic agents (1). The worldwide dissemination of bacteria possessing bla KPC has been especially striking (2). First reported in the northeastern United States in the 1990s, pathogens harboring this ␤-lactamase are now endemic in countries in Asia, South America, and Europe (2).Novel ␤-lactamase inhibitors are being developed to restore the utility of ␤-lactam antibiotics against carbapenemase-producing pathogens (3, 4). Avibactam and relebactam are diazabicyclooctane inhibitors with activity against a wide spectrum of ␤-lactamases, including class A (extended-spectrum ␤-lactamases [ESBLs] and KPC) and class C (AmpC) enzymes (3,4). In this study, we determined the activity of imipenem with relebactam against Gram-negative pathogens from medical centers in New York City.Between November 2013 and January 2014, single patient isolates of Escherichia coli, K. pneumoniae, Enterobacter spp., P. aeruginosa, and A. baumannii were collected from 11 hospitals in Brooklyn and Queens, New York. Susceptibility tests were performed in a central research laboratory using the agar dilution method, and results were interpreted according to CLSI guidelines (5). Isolates of E. coli and K. pneumoniae were presumed to harbor ESBLs if they were not susceptible to ceftazidime and/or ceftriaxone and did not have bla KPC . Imipenem was tested both with and without the presence of relebactam (fixed concentration of 4 g/ ml). For the purposes of this study, imipenem breakpoints were used to interpret susceptibility to imipenem plus relebactam.Cephalosporin-resistant isolates were tested by PCR for the presence of bla KPC , bla OXA-23-type , bla OXA-24-type , bla VIM , bla IMP , and bla NDM using previously described primers (6-9). Isolates of K. pneumoniae with bla KPC and isolates of A. baumannii with bla OXA23-type underwent genetic fingerprinting by the repetitive element palindromic PCR (rep-PCR) method with the ERIC-2 primer, as described previously (6).Susceptibility testing of imipenem with and without relebactam was also performed with a collection of prev...

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae

“…Second, imipenem-relebactam was ac- OmpK36 mutations also showed a trend toward an independent association with higher ceftazidime-avibactam MICs. Overall, imipenem-relebactam and ceftazidimeavibactam are promising additions to the current antibiotic armamentarium, providing broad activity against CRE, including Klebsiella spp., Enterobacter spp., and E. coli (18,20). The drugs have overlapping spectra of activity, as well as niches in which each is superior.…”

“…In a recent phase 2 dose-ranging study of patients with complicated intraabdominal infections (13% of whom were infected with imipenem-resistant Gramnegative organisms), clinical response rates for imipenem-relebactam were Ͼ96% (16). An earlier study established the in vitro efficacy of imipenem-relebactam against Gram-negative pathogens from New York City, including KPC-producing organisms (20). However, not all the isolates were CRE, and whole-genome-sequencing (WGS) data were available for only a minority of isolates.…”

Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1

“…Relebactam, currently in clinical development in conjunction with imipenem-cilastatin, and its closely related counterpart, avibactam, can both inactivate P. aeruginosa AmpC but generally do not improve the activity of ␤-lactams against most class B and D enzymes (87,93,(101)(102)(103)(104). The concern about the use of such inhibitors is that inactivation of AmpC by avibactam-or relebactam-like compounds in the presence of carbapenems could select for carbapenem-nonsusceptible strains that overproduce a carbapenemase.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…Therefore, considerable efforts have been made to esto e the a ti a te ial a ti it of β-lactams against Gramnegative pathogens through inhibition of β-lactamases or of efflux pumps. While marketed β-lactamase inhibitors utilize a -lactam motif themselves for suicide inhibition, chemists have recently identified and optimized novel structural templates: 1,6-diazabicyclo[3.2.1]octane-2-carboxamide-based, reversible β-lactamase inhibitors such as avibactam 13, relebactam 14 and OPO595 15 (Scheme 9) have been advanced to clinical trials as additive in combination therapies with different β-lactam antibiotics (Hirsch et al 2012;Livermore et al 2013;Lapuebla et al 2015a;Livermore et al 2015;Paris 2015;Toussaint and Gallagher 2015). Avibactam has already been approved for combination therapy with ceftazidime and is in clinical t ials fo o i atio the ap ith se e al othe β-lactams (Zetts 2014;Paris 2015).…”