Activity of Imipenem-Relebactam (MK-7655) Against Enterobacteriaceae and Pseudomonas aeruginosa from Intraabdominal Infections in North America - SMART 2015

 

Background: Relebactam (formerly MK-7655) (REL) is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases.  REL restores the in vitro activity of imipenem (IMI) against Enterobacteriaceae, including those producing KPC, and Pseudomonas aeruginosa (PA). In this study we evaluated the ability of REL to restore IMI susceptibility to a collection of gram-negative isolates from intraabdominal infections (IAI) from North America collected as part of the 2015 SMART surveillance program.

Methods: 26 hospitals in the US (19) and Canada (7) collected up to 100 consecutive gram-negative pathogens from IAI.  MICs were determined for 189 PA and 1,607 non-Proteae Enterobacteriaceae (NPE) using CLSI broth microdilution. Proteae were excluded due to intrinsic non-susceptibility to IMI. REL was tested at a fixed concentration of 4 µg/mL in combination with IMI.  The percent susceptible (S) was assessed using CLSI breakpoints.  IMI S breakpoints of ≤1 µg/mL (NPE) and ≤2 µg/mL (PA) were applied to IMI/REL.  

Results:  The cumulative percent of isolates at each IMI and IMI/REL MIC is shown in the table.

Organism	N	Drug	MIC (µg/mL)
			≤0.5	1	2	4	8	16	32	>32
P. aeruginosa	189	IMI	16.4	70.4	78.8	81	87.3	96.3	99.5	100
P. aeruginosa		IMI/REL	79.9	89.4	95.8	98.4	100
P. aeruginosa, IMI NS	40	IMI				10.0	40.0	82.5	97.5	100
P. aeruginosa, IMI NS		IMI/REL	12.5	50.0	80.0	92.5	100
NPE	1607	IMI	92.2	97.9	98.7	99.3	99.6	99.6	99.9	100
NPE		IMI/REL	97.5	99.4	99.8	99.9				100
NPE, IMI NS	34	IMI			38.2	67.6	79.4	82.4	94.1	100
NPE, IMI NS		IMI/REL	44.1	70.6	88.2	97.1	0	0	0	100

Shaded area indicates susceptible by CLSI 2016 imipenem breakpoint; MIC₉₀ bolded; NPE, non-Proteae Enterobacteriaceae; IMI, imipenem; REL, relebactam; NS, non-susceptible

Among 189 PA, 78% (149) were S to IMI; of the 40 non-susceptible (NS) isolates, 32 (80%) were rendered S by the addition of REL, for a final 96% S. Among 1,607 NPE, 98% (1,573) were S to IMI; of the 34 NS isolates, 24 (71%) were rendered S by the addition of REL, for a final 99% S. 

Conclusion: Relebactam exhibited strong potential for restoring the in vitro activity of IMI against many IAI pathogens otherwise NS to carbapenems.  Further development of this compound could provide a valuable therapeutic option for treating infections caused by resistant Gram-negative bacilli.