Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis

ABSTRACT Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if MIC ≤ 8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem princeps (AstraZeneca), and four different generic products (Actavis, Kabi, Mylan, Panpharma), in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 x MICs. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of KPC-99YC (meropenem MIC, 4 mg/L; colistin MIC, 1 mg/L). Treatment started 14 days after inoculation, for 7 days, in 7 groups of >10 rabbits: control group, colistin, and one group for each meropenem product (i.e., the princeps, and the 4 generics), in combination with colistin. In vitro, meropenem + colistin were bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the princeps when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem princeps (n=3), and generics (n=3). In conclusion, the efficacy of four generics of meropenem was not different from the princeps in vitro, and in an experimental model of KPC-producing K. pneumoniae osteomyelitis in rabbits, in terms of bactericidal activity, and emergence of resistance.