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Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Oct 19; Vol. 60 (1), pp. 180-9. Date of Electronic Publication: 2015 Oct 19 (Print Publication: 2016). - Publication Year :
- 2015
-
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 with Streptococcus 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 with both models showed slightly higher-than-dose-proportional exposure, with 3-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 AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 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.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Amidohydrolases antagonists & inhibitors
Amidohydrolases metabolism
Animals
Anti-Bacterial Agents blood
Anti-Bacterial Agents pharmacology
Area Under Curve
Bacterial Proteins antagonists & inhibitors
Bacterial Proteins metabolism
Bridged Bicyclo Compounds, Heterocyclic blood
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Enzyme Inhibitors blood
Enzyme Inhibitors pharmacology
Haemophilus Infections blood
Haemophilus Infections microbiology
Haemophilus influenzae drug effects
Haemophilus influenzae enzymology
Haemophilus influenzae growth & development
Hydroxamic Acids blood
Hydroxamic Acids pharmacology
Lung drug effects
Lung microbiology
Male
Mice
Microbial Sensitivity Tests
Pneumonia, Pneumococcal blood
Pneumonia, Pneumococcal microbiology
Rats
Rats, Sprague-Dawley
Staphylococcal Infections blood
Staphylococcal Infections microbiology
Staphylococcus aureus drug effects
Staphylococcus aureus enzymology
Staphylococcus aureus growth & development
Streptococcus pneumoniae drug effects
Streptococcus pneumoniae enzymology
Streptococcus pneumoniae growth & development
Anti-Bacterial Agents pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics
Enzyme Inhibitors pharmacokinetics
Haemophilus Infections drug therapy
Hydroxamic Acids pharmacokinetics
Pneumonia, Pneumococcal drug therapy
Staphylococcal Infections drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 60
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 26482300
- Full Text :
- https://doi.org/10.1128/AAC.01842-15