1620. Response to imipenem plus MK-7655, a novel beta-lactamase inhibitor, among 212 recent clinical isolates of P. aeruginosa
Session: Poster Abstract Session: Novel Antimicrobial Agents
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H

Carbapenems have been a vital option used to treat multi-drug-resistant gram-negative pathogens; however, resistance to carbapenems does occur in Pseudomonas aeruginosa (Pa) and is increasingly seen in Enterobacteriaceae.  MK-7655 is a Class A and C b-lactamase (BL) inhibitor that can restore susceptibility to imipenem (IPM) both in vitro and in vivo for isolates producing such enzymes.  The present study determined susceptibility to the IPM+MK-7655 (IMK) combination in a population of 212 recent clinical isolates of Pa.


The Pa isolates were chosen for geographic distribution (25% ea. USA, EU, SA, and Asia) and MIC distribution (susceptible, intermediate, and non-susceptible).  Isolates non-susceptible (NS) to IMK were analyzed by outer membrane preparations/SDS-PAGE and multiplex PCR for presence of BLs including Class A KPC, GES, PER, SHV, TEM and VEB; Class B IMP, NDM SPM and VIM; and Class D Oxa24/40. AmpC single-PCR was used as confirmation of identification of Pa isolates.   Those isolates without a class B BL were subjected to PFGE and BL inhibitor profiling.


82% of the panel was NS to IPM.  Of the isolates with MICs of 8, 16, 32, 64, 128, or >128 mg/L IPM, MK-7655 at 4 mg/L restored susceptibility to IPM at the then breakpoint of 4 mg/L for 100, 95, 69, 7, 0, and 0 percent, respectively.  All tested IPM NS isolates lacked or had lowered expression of IPM entry porin OprD except one, which contained a VIM MBL.  Of 18 isolates requiring ≥ 16 mg/L MK-7655 to restore IPM-S, 11 contained a class B MBL.  All of the 7 isolates NS to IMK and not producing an MBL were from Mexico in 2009.  PFGE showed 4 of 7 were identical and 2 were highly related to each other and the four identical isolates.


IMK demonstrates an added advantage to IPM alone in vitro against a recent clinical population of Pa.  The in vitro profile of MK-7655 among clinical isolates reflects the enzyme activity profile against Class A and C enzymes.  Only 7 highly IMK NS isolates without a Class B enzyme were found.  PFGE indicates there may be a clonal relationship between them.

Katherine Young, MS1, Meredith Hackel, PhD, MPH2, Christine Lascols, MS2, Samuel Bouchillon, MD2, Robert Badal, B.S.2, Luis Martínez-Martínez3, Chris Pillar, PhD4, Dean Shinabarger, PhD4, Jennifer Deane5 and Dan Sahm5, (1)Antibacterials/Antifungals, Merck Research Laboratories, Kenilworth, NJ, (2)IHMA, Inc., Schaumburg, IL, (3)Hosp. Univ. Marqués de Valdecilla, Santander, Spain, (4)Micromyx, Kalamazoo, MI, (5)Eurofins, Global Infectious Disease Services, Chantilly, VA


K. Young, Merck Research Laboratories: Employee and Shareholder, Salary

M. Hackel, None

C. Lascols, None

S. Bouchillon, None

R. Badal, Merck Research Laboratories: Research Contractor, fee for service

L. Martínez-Martínez, None

C. Pillar, None

D. Shinabarger, Merck Research Laboratories: Research Contractor, fee for service

J. Deane, None

D. Sahm, Merck Research Laboratories: Research Contractor, fee for service

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