In vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Staphylococcus aureus (SA) in the Murine Thigh Infection Model

Abstract

BackgroundOmadacycline is a novel aminomethylcycline antibiotic in development for acute bacterial skin and skin structure infection (ABSSSI) and community acquired bacterial pneumonia (CABP). The goal of the study was to determine the PK/PD targets in the murine thigh infection model against a diverse group of SA pathogens including MRSA.Methods10 SA strains (4 MSSA, 6 MRSA) were utilized. MICs were determined using CLSI methods. Single dose murine plasma PK was previously determined in our lab and used for PK/PD analyses. The neutropenic murine thigh infection model was utilized for all treatment studies and drug dosing was by subcutaneous route. Four-fold increasing doses of omadacycline (0.25–64 mg/kg) were administered q12h to groups of mice infected with each strain. Treatment outcome was measured by determining organism burden in the thighs (CFU) at the end of each experiment (24 hours). The Emax Hill equation was used to model the dose–response data to the PK/PD index AUC/MIC. The magnitude of the PK/PD index AUC/MIC associated with net stasis and 1-log kill were determined in the thigh model for all strains.ResultsMICs ranged from 0.25–0.5 mg/L. At the start of therapy, mice had 7.1 ± 0.3 log10 CFU/thigh. In control mice, the organism burden increased 2.3 ± 0.3 log10 CFU/thigh over 24 hours. There was a relatively steep dose–response relationship observed with escalating doses of omadacycline. Maximal organism reductions were 4–5 log10 CFU/thigh compared with untreated controls. Stasis and 1 log-kill (from start of therapy) was observed against each strain. The AUC/MIC magnitude associated with stasis and 1-log kill endpoints are shown in the table.SA Group (n = 10)24 hours Static Dose (mg/kg)Stasis AUC/ MIC24 hours 1 log kill Dose (mg/kg)1 log kill AUC/MICMean13.923.745.778.1Median13.021.939.857.7Std Dev4.310.631.479.5ConclusionOmadacycline demonstrated in vivo potency against a diverse group of SA pathogens including MRSA strains. Stasis 24 hours AUC/MIC targets were approximately 24. This is very similar to previous studies of omadacycline against S. pneumoniae (stasis AUC/MIC 18) and other PK/PD evaluations of tetracycline-class antibiotics. 1-log kill targets were only 2–3 fold more than stasis targets for each strain. This data should provide useful in the dose-regimen optimization of omadacycline.Disclosures D. R. Andes, Paratek: Grant Investigator, Research support