Pharmacodynamics of colistin resistance in carbapenemase-producing Klebsiella pneumoniae: the double-edged sword of heteroresistance and adaptive resistance.

Introduction. The presence of heteroresistant subpopulations and the development of resistance during drug exposure (adaptive resistance) limits colistin's efficacy against carbapenemase-producing Klebsiella pneumoniae (CP-Kp) isolates.Hypothesis/Gap statement. The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of both types of colistin resistance against CP-Kp are unknown.Aim. We therefore studied the PK/PD characteristics of colistin resistance in an in vitro PK/PD model simulating clinical colistin exposures.Methods. Two K. pneumoniae clinical isolates, one non-CP-Kp and one CP-Kp, with colistin MICs of 0.5-1 mg l-1 at a final inoculum of 107 c.f.u. ml-1 were used in an in vitro PK/PD dialysis/diffusion closed model simulating 4.5 MU q12h and 3 MU q8h clinical dosing regimens. Heteroresistant (HRS, bacteria with stable high-level resistance present before drug exposure) and adaptive resistant (ARS, bacteria with reversible low-level resistance emerging after drug exposure) subpopulations were measured and optimal PK/PD targets for reducing both ARS and HRS were determined. Cumulative fractional response (CFR) was calculated with Monte Carlo simulation for 9 MU q24h, 4.5 MU q12h and 3 MU q8h clinical dosing regimens.Results. A 2-5 log10c.f.u. ml-1 decrease of the total bacterial population was observed within the first 2 h of exposure, followed by regrowth at 12 h. Colistin exposure was positively and negatively correlated with HRS and ARS 24-0 h c.f.u. ml-1 changes, respectively. An optimal PK/PD (~0.5log10 increase) target of 35 fAUC/MIC (the ratio of the area under the unbound concentration-time curve to the MIC) was found for reducing both HRS and ARS of high-level resistance (MIC >16 mg l-1). The 4.5 MU q12h regimen had slightly higher CFR (74 %) compared to the other dosing regimens.Conclusions. High colistin exposures reduced high-level adaptive resistance at the expense of selection of heteroresistant subpopulations.