Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.

BACKGROUND: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown. METHODS: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine ß naphthylamide (PAßN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS. RESULTS: The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAßN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5-1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaßN with CIP AUC, 0.6 mg·h/L PaßN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5-0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA, gyrB or marR. CONCLUSIONS: AUC was the pharmacodynamic driver for chlorpromazine and PAßN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAßN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA, gyrB and marR were detected.

Pharmacodynamics of minocycline against Acinetobacter baumannii studied in a pharmacokinetic model of infection.

Minocycline (MNO) is an old antibiotic that may have an important role in the treatment of multidrug-resistant Gram-negative bacterial infections as the burden of such infections increases. In this study, a single-compartment dilutional pharmacokinetic model was used to determine the relationship between MNO exposure and antibacterial effect, including the risk of resistance emergence, against strains of Acinetobacter baumannii. The mean ± standard deviation area under the unbound drug concentration-time curve to minimum inhibitory concentration ratio (fAUC/MIC) associated with a 24-h bacteriostatic effect was 16.4 ± 2.6 and with a -1 log reduction in bacterial load at 24 h was 23.3 ± 3.7. None of the strains reached a -2 log reduction over 48 h. Changes in population profiles were noted for two of the three strains studied, especially at fAUC/MIC ratios of >5-15. A reasonable translational pharmacodynamic target for MNO against A. baumannii could be an fAUC/MIC of 20-25. However, if maximum standard 24-h doses of intravenous MNO are used (400 mg/day), many strains would be exposed to MNO concentrations likely to change population profiles and associated with the emergence of resistance. Either MNO combination therapy or an increased MNO dose (>400 mg/day) should be considered when treating A. baumannii infections.