Comparative antibacterial effects of moxifloxacin and levofloxacin on Streptococcus pneumoniae strains with defined mechanisms of resistance: impact of bacterial inoculum.

OBJECTIVES: We aim to further define the impact of the mechanism of fluoroquinolone resistance and inoculum load on the pharmacodynamic effects of levofloxacin and moxifloxacin on Streptococcus pneumoniae. METHODS: The antibacterial effects of and emergence of resistance (EoR) to moxifloxacin (400 mg once daily) or levofloxacin (750 mg once daily or 500 mg twice daily) were compared using five S. pneumoniae strains containing no known resistance mechanisms, efflux resistance mechanisms, a parC mutation or parC and gyrA mutations, at high (10(8) cfu/mL) and low (10(6) cfu/mL) inocula. An in vitro pharmacokinetic model was used and simulations were performed over 96 h. After drug exposure, isolates were tested for the presence of efflux pumps and mutations in the quinolone resistance-determining regions. RESULTS: A high inoculum diminished the antibacterial effect of moxifloxacin and levofloxacin. Levofloxacin at both dosages produced EoR with all strains. Levofloxacin regimens with AUC/MIC ratios <100 produced EoR. Moxifloxacin produced EoR with the parC strain only. CONCLUSIONS: Levofloxacin dosing regimens with low AUC/MIC ratios select for efflux pump overexpression, leading to fluoroquinolone resistance. Levofloxacin dosing may select for gyrA mutations, inducing moxifloxacin resistance. These data confirm that a fluoroquinolone AUC/MIC ratio of >100 is required for prevention of EoR.

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.