Antimicrob Agents Chemother. 2015 Oct 19. pii: AAC.01842-15. [Epub ahead of print]

Pharmacokinetics/Pharmacodynamics (PK/PD) of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in rodent models of infection.

Hoover J1, Lewandowski T2, Straub RJ2, Novick SJ2, DeMarsh P2, Aubart K2, Rittenhouse S2, Zalacain M2.

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Abstract

GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection withStreptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model), and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies in both models showed slightly higher than dose-proportional exposure, with three-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free (f)AUC/MIC index in S. pneumoniae (R2, 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R2, 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis or a 1-log reduction in bacterial burden were 8.1 and 14.4 for eleven S. pneumoniae isolates (R2, 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R2, 0.93). The data showed that for eight S. aureus isolates fAUC correlated better with efficacy than fAUC/MIC (R2, 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range 0.5-4 μg/mL). Median fAUCs of 2.1 and 6.3 μg.h/mL were associated with stasis and 1-log10 reductions, respectively, for S. aureus.

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PMID: 26482300 [PubMed - as supplied by publisher]