Daptomycin dose-effect relationship against resistant gram-positive organisms

Abstract

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.

FIG. 1.

Pharmacodynamic time-kill analysis of MRSA-67. GC, growth control; D1 through D6, daptomycin at dose regimens ranging from 1 to 6 mg/kg every 24 h.

FIG. 2.

Pharmacodynamic time-kill analysis of GISA-992. GC, growth control; D2 through D8, daptomycin at dose regimens simulating 2 to 8 mg/kg every 24 h.

FIG. 3.

Pharmacodynamic time-kill analysis of VREF-12366. GC, growth control; D3 through D9, daptomycin at dose regimens simulating 3 to 9 mg/kg every 24 h.

FIG. 4.

Pharmacokinetic-pharmacodynamic dose modeling to effect for MRSA isolates. ED₅₀, dose correlating to 50% bacterial density reduction from growth control; ED₈₀, dose correlating to 80% bacterial density reduction from growth control. •, MRSA-67 bacterial densities at 48 h; ○, MRSA-R515 bacterial densities at 48 h.

FIG. 5.

Pharmacokinetic-pharmacodynamic dose modeling to effect for GISA isolates. ED₅₀, dose correlating to 50% bacterial density reduction from growth control; ED₈₀, dose correlating to 80% bacterial density reduction from growth control. •, GISA-992 bacterial densities at 48 h; ○, GISA-147398 bacterial densities at 48 h.

FIG. 6.

Pharmacokinetic-pharmacodynamic dose modeling to effect for VREF isolates. ED₅₀, dose correlating to 50% bacterial density reduction from growth control; ED₈₀, dose correlating to 80% bacterial density reduction from growth control. •, VREF-12366 bacterial densities at 48 h; ○, VREF-SF12047 bacterial densities at 48 h.