Antimicrob Agents Chemother. 2016 Apr 4. pii: AAC.00363-16. [Epub ahead of print]

In vivo Pharmacodynamic Target Investigation of Two Bacterial Topoisomerase inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus.

Lepak AJ1, Seiler P2, Surivet JP2, Ritz D2, Kohl C2, Andes DR3.

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Abstract

ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad spectrum activity against gram-positive and -negative bacteria including methicillin-resistant Staphylococcus aureus(SA) and penicillin- and fluoroquinolone-resistantStreptococcus pneumonia(SP). We used the neutropenic murine thigh infection model to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of these investigational compounds against a group of 10 SA and SP isolates with phenotypic resistance to beta-lactams and fluoroquinolones. In vitro activity was very similar between the two compounds (MIC range 0.03 - 0.125 mg/L). Plasma pharmacokinetics were determined for each compound using four escalating doses administered by subcutaneous route. In treatment studies, mice had 107.4- 108CFU/thigh at the start of therapy for ACT-387042 and 106.7to 108.3for ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3-4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC and therapeutic efficacy in the model (R20.63-0.82). The 24 h free drug AUC/MIC associated with net stasis for ACT-387042 against SA and SP was 43 and 10, respectively. The 24 h free drug AUC/MIC associated with net stasis for ACT-292706 against SA and SP was 69 and 25, respectively. The stasis PD targets were significantly lower for SP (p< 0.05) for both compounds. The 1-log kill AUC/MIC targets were approximately 2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. The results should be helpful in design of clinical trials for topoisomerase inhibitors.

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PMID: 27044547 [PubMed - as supplied by publisher]