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...

Multidrug-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are endemic to hospitals in New York City and other regions. RPX7009 is a novel ␤-lactamase inhibitor with activity against serine carbapenemases. We tested the activity of meropenem plus RPX7009 against 4,500 recent Gram-negative clinical isolates from 11 New York City hospitals. The meropenem-RPX7009 combination was found to have excellent in vitro activity against Escherichia coli, K. pneumoniae, and Enterobacter spp., including multidrug-resistant (MDR) KPC-producing strains. Overall, 131/133 (98.5%) KPCproducing Enterobacteriaceae strains were inhibited by meropenem (<1 g/ml) plus RPX7009 (8 g/ml). In a limited number of strains, the combination appeared to have reduced activity against KPC-producing K. pneumoniae isolates with diminished ompK35 and ompK36 expression. The addition of RPX7009 did not affect the activity of meropenem against Acinetobacter baumannii and Pseudomonas aeruginosa. The meropenem-RPX7009 combination shows promise as a novel agent against KPCproducing Enterobacteriaceae and deserves further study. Other approaches will be needed to address multidrug-resistant A. baumannii and P. aeruginosa, which typically possess different mechanisms of carbapenem resistance.

Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC 50 /MIC 90 values, respectively, for Escherichia coli of 0.12/0.5 g/ml, Klebsiella pneumoniae of 0.25/1 g/ml, Enterobacter aerogenes of 0.25/1 g/ml, Enterobacter cloacae 0.5/1 g/ml, and Acinetobacter baumannii of 0.5/1 g/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of the adeB gene.

Measurable improvement has occurred in reducing the spread of KPC-possessing K. pneumoniae, and reducing the average length of stay may augment infection control efforts. However, the problem of carbapenem-resistant A. baumannii and P. aeruginosa lingers. New approaches, including respiratory isolation and environmental cleaning, need to be examined to control the spread of A. baumannii and P. aeruginosa.

Over the past decade there has been a steady decline in KPC-producing K. pneumoniae in most New York City hospitals. The reason for the decline is probably multifactorial, involving a reduction in device (catheter) utilization and possibly an improvement in infection control practices.