2005. Effect of Imipenem-Relebactam on sub-types of KPC in Klebsiella pneumoniae
Session: Poster Abstract Session: Antimicrobial Resistance Mechanisms
Saturday, October 29, 2016
Room: Poster Hall
Background: Antibiotic resistance is a crisis world-wide. Beta-lactamases (BLs) remain the most important mechanism of beta-lactam non-susceptibility in Gram-negatives. Carbapenem-resistant Enterobacteriaceae (CRE) include Klebsiella pneumoniae carbapenemase (KPC) expressing isolates which have spread worldwide since initial discovery. There have been 15 sequence sub-types of KPC identified to date. Relebactam (REL) is a diazobicyclo-octane b-lactamase inhibitor with class A/C activity currently in phase 3 clinical development in combination with imipenem/cilastatin (IMI/CIL). An analysis of the in vitroefficacy for the KPC-3 sub-type vs. KPC-2 was undertaken for IMI/REL.

Methods: SMART is an on-going world-wide surveillance study that collects and tests consecutive clinical isolates from intra-abdominal, urinary, and lower respiratory tract sources since 2002. A total of 145 sequenced Kp KPC isolates were studied, 98 from SMART and an additional 47 isolates received as referrals from clinical laboratories. Susceptibility to IMI in the presence and absence of REL at a fixed concentration of 4 µg/mL was determined and the KPC sequence sub-type determined by PCR. Susceptibility results were analysed by KPC sub-type with an unpaired t-test using PRISM 6.04.

Results: Among 145 KPC-expressing Kp the % S increased from 9.9% to 98 % in the presence of REL. The IMI MIC geometric mean in µg/mL for KPC-2 (N=89), KPC-3 (N=56), and KPC-11 (N=4) was 15.26/17.70/9.51, respectively, while that for IMI/REL was 0.41/0.29/0.25. There was a statistically significantdifference between the effect of REL on the IMI MIC for KPC-2 vs. KPC-3, P=0.0153; however, the difference in MIC geometric mean ratio was less than 2-fold, KPC-3/KPC-2 of 0.71 (90% CI: 0.56, 0.89), which is within normal variability in microbroth assays.

Conclusion: REL restored activity to 98 % of KPC-expressing Kp. Although the geometric mean MIC of KPC-2 vs. KPC-3 producers comparison was statistically significant, the variability was within a microbroth 2-fold dilution (0.41 vs. 0.29), and the mean MICs were less than 2-fold below the CLSI MIC for IMI (1 µg/mL). Since most clinical labs do not have simple systems to determine KPC sub-type it is important that a new therapy cover equally the most widely circulating isolates. Therefore, IMI/REL represents a distinct advantage in antibacterial therapy.

Katherine Young, MS1, Mary Motyl, PhD1 and Daniel Tatosian, PhD2, (1)Infectious Disease, Merck & Co., Inc., Kenilworth, NJ, (2)Ppdm, Merck & Co., Inc., Kenilworth, NJ


K. Young, Merck & Co., Inc.: Employee and Shareholder , Salary

M. Motyl, Merck & Co., Inc.: Employee , Salary

D. Tatosian, Merck & Co., Inc.: Employee and Shareholder , Salary

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