Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.
J Antimicrob Chemother
; 78(12): 2869-2877, 2023 12 01.
Article
in En
| MEDLINE
| ID: mdl-37837411
ABSTRACT
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 (Tâ>â25 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-4191Tâ>â0.5-0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacinâ+âEPIs. 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 Tâ>âthreshold 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 ciprofloxacinâ+âEPIs, however, mutations in gyrA, gyrB and marR were detected.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chlorpromazine
/
Escherichia coli
Language:
En
Journal:
J Antimicrob Chemother
Year:
2023
Document type:
Article
Affiliation country:
United kingdom