Introduction

1. A1-1271 49th ICAAC Meeting San Francisco, CA September 12-15, 2009 The Relationship between Daptomycin (DAP) Free drug AUC/MIC, Antibacterial effect (ABE) and Emergence of Resistance (EoR) in S.aureus.KE Bowker, AR Noel, AP MacGowanBCARE, Department of Microbiology, North Bristol NHS Trust, Bristol, UK Corresponding author karen.bowker@nbt.nhs.uk Results cont’d • Introduction • Animal studies indicate that for daptomycin (DAP) AUC/MIC is the main pharmacodynamic index for S. aureus,S. pneumoniae and Enterococcus spp. • Extrapolated animal data has shown that a free drug (f)AUC/MIC between 12 and 62 is required for a static effect. DAP is 92% protein bound. The DAP EUCAST/CLSI breakpoint for staphylococci (1mg/L) based on 4mg/kg dosing confers a mean target AUC/MIC of 438 equating to fAUC/MIC of 35. • The objectives of this study were: determine the DAP fAUC/MIC ratio required for a static, 1, 2 and 3 log reduction in viable count against UKEMRSA15, UKEMRSA16 strains and a VISA strain with raised DAP MIC and, to relate these targets to the DAP clinical breakpoint and the relative risk of emergence of resistance (EoR). • Results • The relationship between DAP fAUC/MIC and log reduction in count at 24h for the individual strains and the meaned data is shown on Table 1. • The combined DAP fAUC/MIC ratios for the six strains were plotted against log change in viable count at 24h using a sigmoid Emax model (r2 =0.80) (Figure1). • A static effect, 1 log and 3 log reduction in count were achieved at ratios of 37.2  16.5, 40.6 17.8 and 49.8  19.2 respectively. • A good correlation was also demonstrated for the six strains between AUC/MIC and AUBKC24 (r2 =0.78) (Figure 2). • The EoR assessed by growth on plates containing x2 and x4 DAP MIC, associated with fAUC/MIC ratio is shown on Table 2. • The relative risk of EoR increased from 17% at fAUC/MIC>40, to 67 (x2MIC) or 73% (x4MIC) at fAUC/MIC <10. Table 1 Relationship between DAP fAUC/MIC and ABE • Materials and methods • An in vitro pharmacokinetic (pK) model was used to perform DAP dose ranging studies simulating free drug pK concentrations based on DAP 6 mg/kg 24 hrly: Cmax 6.4 mg/L, T1/2 8h for 48h. • Five strains UKEMRSA-15 (SMH15841 & SMH40289) and 16 (SMH40275, SMH33922 & SMH33024) a VRSA (SMH19898) from the collection of BCAREwere used. • 10% Mueller Hinton broth supplemented with 50 mg/L calcium, inoculum of 106cfu/mL were used and aliquots taken throughout the simulations were plated onto nutrient agar plates for viable count determination. • Antibacterial effect (ABE) was assessed by area-under-the bacterial kill curve 0–24 h (AUBKC24) and 0–48 (AUBKC48; log CFU/ml.h); and log reduction in viable count at 24 and 48 h (d24) (48h data not shown) • Dose ranging A sigmoid dose-response variable slope Emax model was used to relate ABE to fAUC/MIC. • EoR was determined by plating aliquots of the bacterial suspensions onto nutrient agar plates containing x2, x4 and x8 the DAP MIC. The risk of EoR as measured by growth on x2MIC and x4MIC plates was related to fAUC/MIC. • Conclusions • The EoR data in this study validates the existing AUC/MIC targets: DAP fAUC/MICs of >40 are associated with 1-3 log drop in MRSA bacterial counts and a minimum risk of EoR, fAUC/MICs of <30 have an increased risk of emergence of resistance. • Dose ranging experiments indicate that the fAUC/MIC associated with a 24h bacteriostatic to 1 log reduction in count is compatible with a clinical breakpoint of 0.5-1mg/L for a DAP dose of 6mg/kg. Table 2 Relationship between fAUC/MIC and EoR