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
Background:

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.

Methods:

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.

Results:

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.

Conclusion:

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

Disclosures:

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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