Molecular Epidemiology and Mechanisms of Carbapenem Resistance in Acinetobacter baumannii Endemic in New York City

Abstract Background The combination of cefepime and zidebactam (WCK5222), a novel β-lactam enhancer, has demonstrated activity against a wide variety of Gram-negative pathogens and is currently under clinical evaluation. Objectives To examine the activity of cefepime/zidebactam against: (i) a contemporary collection of Gram-negative isolates from New York City; (ii) a collection of carbapenem-resistant clinical isolates; and (iii) a collection of isolates with characterized resistance mechanisms. Methods Susceptibility tests were performed using broth microdilution for cefepime, zidebactam and cefepime/zidebactam (1:1). Results More than 99% of a contemporary collection of Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. had cefepime/zidebactam MICs ≤2 mg/L, the susceptibility breakpoint for cefepime. For K. pneumoniae, the acquisition of blaKPC resulted in increased MICs, although MICs remained ≤2 mg/L for 90% of KPC-possessing isolates. Overall for Pseudomonas aeruginosa, 98% of isolates had MICs ≤8 mg/L and MICs were affected by increased expression of ampC. For carbapenem-resistant P. aeruginosa, 78% of isolates had cefepime/zidebactam MICs ≤8 mg/L. The activity of cefepime/zidebactam against Acinetobacter baumannii was lower, with 85% of all isolates and 34% of carbapenem-resistant isolates with MICs ≤8 mg/L (cefepime interpretative criteria). Conclusions Cefepime/zidebactam demonstrated excellent activity against Enterobacteriaceae and P. aeruginosa, although activity was reduced in carbapenem-non-susceptible isolates. The activity against A. baumannii was reduced and studies examining the therapeutic efficacy in strains with high cefepime/zidebactam MICs are warranted.

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334Emergence of OXA-23-possessing Acinetobacter baumannii in Hospitals in New York City

Open Forum Infectious Diseases ◽

10.1093/ofid/ofu052.200 ◽

2014 ◽

Vol 1 (suppl_1) ◽

pp. S134-S135

Author(s):

Marie Abdallah ◽

Olawole Olafisoye ◽

Christopher Cortes ◽

Carl Urban ◽

Clayton Charles ◽

...

Keyword(s):

New York ◽

New York City ◽

Acinetobacter Baumannii ◽

York City

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Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04809-14 ◽

2014 ◽

Vol 59 (3) ◽

pp. 1802-1805 ◽

Cited By ~ 61

Author(s):

Marie Abdallah ◽

Olawole Olafisoye ◽

Christopher Cortes ◽

Carl Urban ◽

David Landman ◽

...

Keyword(s):

New York ◽

New York City ◽

Acinetobacter Baumannii ◽

York City ◽

Enterobacter Aerogenes ◽

Enterobacter Cloacae ◽

Multidrug Resistant ◽

Gram Negative ◽

Content Type

ABSTRACTEravacycline demonstratedin vitroactivity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC50/MIC90values, respectively, forEscherichia coliof 0.12/0.5 μg/ml,Klebsiella pneumoniaeof 0.25/1 μg/ml,Enterobacter aerogenesof 0.25/1 μg/ml,Enterobacter cloacae0.5/1 μg/ml, andAcinetobacter baumanniiof 0.5/1 μg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. ForA. baumannii, eravacycline MICs correlated with increased expression of theadeBgene.

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High-Level Carbapenem Resistance in a Klebsiella pneumoniae Clinical Isolate Is Due to the Combination of blaACT-1 β-Lactamase Production, Porin OmpK35/36 Insertional Inactivation, and Down-Regulation of the Phosphate Transport Porin PhoE

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00285-06 ◽

2006 ◽

Vol 50 (10) ◽

pp. 3396-3406 ◽

Cited By ~ 141

Author(s):

Frank M. Kaczmarek ◽

Fadia Dib-Hajj ◽

Wenchi Shang ◽

Thomas D. Gootz

Keyword(s):

New York ◽

New York City ◽

Klebsiella Pneumoniae ◽

York City ◽

Carbapenem Resistance ◽

Clinical Isolates ◽

Wild Type ◽

Down Regulation ◽

Carbapenem Resistant ◽

Insertional Inactivation

ABSTRACT Clinical isolates of Klebsiella pneumoniae resistant to carbapenems and essentially all other antibiotics (multidrug resistant) are being isolated from some hospitals in New York City with increasing frequency. A highly related pair of K. pneumoniae strains isolated on the same day from one patient in a hospital in New York City were studied for antibiotic resistance. One (KP-2) was resistant to imipenem, meropenem, and sulopenem (MICs of 16 to 32 μg/ml) while the other (KP-1) was susceptible (MIC of 0.5 μg/ml); both contained the bla ACT-1, bla SHV-1, and bla TEM-1 β-lactamases. bla ACT-1 in both strains was encoded on a large ∼150-kb plasmid. Both isolates contained an identical class 1 integron encoding resistance to aminoglycosides and chloramphenicol. They each had identical insertions in ompK35 and ompK36, resulting in disruption of these key porin genes. The carbapenem-resistant and -susceptible isolates were extensively studied for differences in the structural and regulatory genes for the operons acrRAB, marORAB, romA-ramA, soxRS, micF, micC, phoE, phoBR, rpoS, and hfq. No changes were detected between the isolates except for a significant down-regulation of ompK37, phoB, and phoE in KP-2 as deduced from reverse transcription-PCR analysis of mRNA and polyacrylamide gel electrophoresis separation of outer membrane proteins. Backcross analysis was conducted using the wild-type phoE gene cloned into the vector pGEM under regulation of its native promoter as well as the lacZ promoter following transformation into the resistant KP-2 isolate. The wild-type gene reversed carbapenem resistance only when under control of the heterologous lacZ promoter. In the background of ompK35-ompK36 gene disruption, the up-regulation of phoE in KP-1 apparently compensated for porin loss and conferred carbapenem susceptibility. Down-regulation of phoE in KP-2 may represent the normal state of this gene, or it may have been selected from KP-1 in vivo under antibiotic pressure, generating the carbapenem-resistant clone. This is the first study in the Enterobacteriaceae where expression of the phosphate-regulated PhoE porin has been associated with resistance to antimicrobials. Our results with this pair of Klebsiella clinical isolates highlight the complex and evolving nature of multiple drug resistance in this species.

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