OII‐A‐3

BACKGROUND To predict the activity of various LZD dosage regimens for MRSA. The MIC 90 of LZD against MRSA is ∼4 mg/L. METHODS For 2 clinical MRSA isolates (MIC2, MIC4), 24h kill curve experiments were fit by a PD model: capacity limited replication inhibited by LZD via a Hill function, & 1 st order elimination. A mixture model described both strains as 2 populations: a predominant ‘sensitive’ population (EC 50 = 0.4 & 0.6xMIC) & a ‘resistant’ subpopulation (EC 50 of 3 & 5xMIC). LZD PK parameters derived from our previous population PK analysis were used to predict PD responses to 4 LZD regimens: 600mg PO q12h w/o (BID) or with (LBID) a loading dose (LD) of 900mg; 600mg PO q8h w/o (TID) or with (LTID) a LD of 1200mg. For verification, these regimens were studied against these MRSA isolates in an in vitro PK/PD infection model, over 96h. RESULTS All 4 regimens were effective against MIC2 (LBID≈ BID). In silico & in vitro , BID & LBID were ineffective, while TID & LTID were effective (with similar activity) against MIC4. For eg, in vitro at 48h, the log10(bacterial CFU) were decreased by 3.6 & 3.2, for MIC2, & by 1 & 2.6, for MIC4, with BID & TID regimens. CONCLUSIONS The BID regimen might not provide adequate activity at MIC ≥ 4 mg/L (though these studies did not include any effect due to the immune system). At MIC=4, a TID regimen may offer a substantial benefit over BID. With its ‘slow’ rate of kill & its shallow concentration‐effect curve, LZD appears to show only modest benefit for the evaluated loading doses. Clinical Pharmacology & Therapeutics (2005) 79 , P4–P4; doi: 10.1016/j.clpt.2005.12.012