Antimicrob Agents Chemother. 2016 May 23. pii: AAC.00647-16. [Epub ahead of print]

In vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus,Streptococcus pneumoniae, and Klebsiella pneumoniae in the Murine Lung Infection Model.

Lepak AJ1, Andes DR2.

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Abstract

BACKGROUND:

Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the PK/PD targets in the murine lung infection model for S. aureus, S. pneumoniae, and K. pneumoniae.

METHODS:

Four isolates of each species were utilized for in vivo studies: S. aureus (1 methicillin-susceptible, 3 methicillin-resistant), S. pneumoniae (2 penicillin-susceptible, 2 penicillin-resistant), K. pneumoniae (3 extended spectrum beta-lactamase producing, 1 wild-type). Minimum inhibitory concentrations (MICs) were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies and drug dosing was by subcutaneous route. Single dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40 and 160 mg/kg. For in vivo studies, four-fold increasing doses of delafloxacin (range 0.03 to 160 mg/kg) were administered q6h to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU) at the end of each experiment (24 h). The Emax Hill equation was used to model the dose-response data. The magnitude of the PK/PD index AUC/MIC associated with net stasis and 1-log kill were determined in the lung model for all isolates.

RESULTS:

MICs ranged from 0.004-1 mg/L. Single dose PK parameter ranges include: Cmax 2-70.7 mg/L, AUC0-∞ 2.8-152 mg*h/L, T1/2 0.7-1 h. At the start of therapy mice had 6.3 ± 0.09 log10 CFU/lung. In control mice the organism burden increased 2.1 ± 0.44 log10 CFU/lung over the study period. There was a relatively steep dose-response relationship observed with escalating doses of delafloxacin. Maximal organism reductions ranged from 2- to more than 4-log10 The median free drug AUC/MIC magnitude associated with net stasis for each species group was 1.45, 0.56, and 40.3 for S. aureus, S. pneumoniae, and K. pneumoniae, respectively. 1-log kill AUC/MIC targets were 2- to 5-fold higher.

CONCLUSION:

Delafloxacin demonstrated in vitro and in vivo potency against a diverse group of pathogens including those with phenotypic drug-resistance to other classes. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints for delafloxacin for the treatment of lower respiratory tract infections involving these pathogens.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

PMID: 27216072 [PubMed - as supplied by publisher]