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Antimicrobial Agents and Chemotherapy, May 2003, p. 1598-1603, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1598-1603.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Daptomycin Dose-Effect Relationship against Resistant Gram-Positive Organisms

Raymond Cha,1 Richard G. Grucz Jr.,1 and Michael J. Rybak1,2*

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences,1 School of Medicine, Wayne State University, Detroit, Michigan 482012

Received 12 February 2002/ Returned for modification 8 September 2002/ Accepted 30 January 2003

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 log10 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% (ED50) and 80% (ED80) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 µg/ml. Model fitting resulted in an r2 of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log10 CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED50 and ED80 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 ED50 and ED80 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 ED80 values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED80) against these multidrug-resistant S. aureus and E. faecium isolates.

* Corresponding author. Mailing address: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. Phone: (313) 577-4376. Fax: (313) 577-8915. E-mail: m.rybak{at}wayne.edu.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1598-1603, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1598-1603.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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