Model-based Drug Development for KPC- or OXA48- produced Klebsiella pneumoniae: using PK/PD Model to Predict an Efficacious Dose for Meropenem combination regimen

Background: Carbapenemase-produced Enterobacteriaceae (CPE) are an important and increasing threat to global health. Carbapenem is still irreplaceable in terms of safety and efficacy. How to use carbapenem judiciously in the context of advocating carbapenem-sparing strategies remains largely undetermined. Methods: Five Klebsiella pneumoniae (KP) strains carrying different single carbapenem enzyme (three KPC and two OXA48) were collected. The genome sequence, drug resistance phenotype, and synergistic effect of different meropenem-based antimicrobial combinations were tested. Dynamics in vitro pharmacokinetic/pharmacodynamic (PK/PD) model was used to optimize the dosage. The selected combination regimens were verified in murine model of peritoneal sepsis. Results: OXA48-KP, minimum inhibitory concentration (MIC) ≤ 2mg/L, were more sensitive to meropenem than KPC-KP (MIC ≥ 64mg/L). The combination of meropenem and fosfomycin barely has synergism effect. For KPC-KP, maximum dose regimen of colistin 2mg/L + meropenem 2.75 q6h can ensure the colony-form units (CFU) below the detection limit within 24 hours for highly meropenem resistant strains. However, colistin heterogeneous drug resistance was induced with MIC increased more than 128 times. For OXA48-KP, colistin 2mg/L + meropenem 1g q8h were sufficient to maintain the CFU below the detection limit more than 24h even after the discontinuation of meropenem without inducing colistin heterogeneity resistance. Conclusions: Meropenem in combination with colistin was an effective choice for KPC-KP and OXA48-KP with low risk of induced colistin heterogeneity resistance. High-dose meropenem and colistin is necessary to achieve bactericidal goals in highly meropenem resistant of KPC-KP strains.