Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and ΔK767 (knockout strain). Efficacy (Δ log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (105 CFU/thigh) and high (107 CFU/thigh) inoculums. At 105 CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (−2.82, −1.88) and K767+ (−2.24, −2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (−2.74 and −2.19, respectively). Similar magnitudes of kill were observed at the 107 inocula. Except for ΔK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against ΔK767. ΔK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on β-lactam agents in vivo warrant further research.