Activity of Meropenem-Vaborbactam Against Enterobacteriaceae Isolates Carrying bla _KPC Collected Worldwide

Abstract

Background

Meropenem-vaborbactam (MER-VAB) is a carbapenem-β-lactamase inhibitor combination with enhanced activity against KPC-producing Enterobacteriaceae recently evaluated in a phase 3 clinical trials for cUTIs and infections due to CRE. We analyzed the activity of MER-VAB against 517 isolates carrying bla _KPC collected worldwide during 2014–16.

Methods

Enterobacteriaceae isolates ( n = 34,069) from 34 countries were susceptibility (S) tested by reference broth microdilution method for MER-VAB (at fixed 8 µg/mL) and comparators. Carbapenem-resistant Enterobacteriaceae (CRE; CLSI criteria) were submitted to PCR/Sanger sequencing or next-generation sequencing for bla _KPC screening.

Results

A total of 517 (1.5%) carried bla _KPC and 6 variants were observed: 293 bla _KPC-3, 218 bla _KPC-2, 2 bla _KPC-4, 2 bla _KPC-17, and 1 each of bla _KPC-2-like and bla _KPC-12. Isolates were mainly K. pneumoniae (437), but also 32 E. cloacae, 13 K. oxytoca, 12 E. coli, 12 S. marcescens, and 4 other species. Isolates carrying bla _KPC were detected in 17 countries. The occurrence ranged from <0.1% to 11.3%, being higher in Brazil, Italy (9.3%), Poland (5.6%), and Argentina (5.2%). MER-VAB inhibited 514/517 (99.4%) isolates carrying bla _KPC at ≤8 µg/mL and this compound was the most active agent tested against these isolates (MIC _50/90, 0.12/1 µg/mL). Three isolates displaying elevated MER-VAB MIC values (>8 µg/mL) co-harbored bla _NDM-1 or bla _OXA-48-like in addition to bla _KPC or had a missense mutation on OmpK35. MER alone (MIC _50/90, 32/>32 µg/mL), imipenem (MIC _50/90, >8/>8 µg/mL), and doripenem (MIC _50/90, >4/>4 µg/mL) were not active against isolates harboring bla _KPC. Amikacin (MIC _50/90, 16/>32 µg/mL) and gentamicin (MIC _50/90, 2/>8) µg/mL inhibited only 54.9% and 57.3% of the isolates (CLSI breakpoint). Colistin (MIC _50/90, ≤0.5/>8 µg/mL; 70.4% S/EUCAST breakpoint) and tigecycline (MIC _50/90, 0.5/1 µg/mL; 99.4% S/US FDA criteria) were the most active comparators.

Conclusion

The occurrence of bla _KPC is still low overall, but can be as high as 5–10% in a few countries and occur in species other than Klebsiella. KPC-producers are highly resistant to available antimicrobial agents and MER-VAB will be a useful alternative to treat infections caused by these organisms.

Disclosures

M. Castanheira, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. E. Mendes, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. R. Duncan, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. N. Woosley, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. K. Flamm, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant