 |
 |
 |
 |
 |
 |
 |
|
|
|
|||||||||
|
|||||||||||
Clinical Fellow, Division of Infectious Diseases, University of California, San Francisco - SFGH, Box 0811, 3rd and Parnassus Avenues, San Francisco, CA 94143, fax 415/648-8425, brian.schwartz{at}ucsf.edu.
Pediatric Clinical Pharmacist, Department of Pharmacy, University of California, San Francisco
Professor and Chair, Department of Clinical Pharmacy, University of California, San Francisco
Published Online, January 2, 2008. www.theannals.com, DOI 10.1345/aph.1K548
We report a case of a 70-year-old man hospitalized for repair of aortic dissection, complicated by hemodialysis-dependent renal failure, who developed vancomycin-resistant E. faecium mitral valve infective endocarditis.
Case Report. A 70-year-old man with vancomycin-resistant E. faecium bacteremia and infective endocarditis was originally treated with linezolid 600 mg every 12 hours (MIC 2 µg/mL) but remained bacteremic for 12 days on therapy. Treatment was then switched to daptomycin 6 mg/kg every 48 hours. The patient continued to be bacteremic on daptomycin 17 days into therapy. The daptomycin dose was increased to 8 mg/kg every 48 hours and gentamicin and doxycycline were added. Despite 10 days at this increased daptomycin dose and with 2 additional agents, 7 blood cultures became positive up to 24 hours after collection. The daptomycin MIC remained at 2 µg/mL throughout therapy (Laboratory Specialists, Inc.; Westlake, OH). Synergy was not present between any antibacterial combinations tested (Focus Diagnostics; Cypress, CA). On day 8 of high-dose daptomycin (8 mg/kg) therapy, a serum bactericidal assay determined at peak daptomycin concentration revealed that the concentration was neither lethal nor inhibitory at a dilution of 1:2.
After these results were obtained, daptomycin was discontinued and
quinupristin/dalfopristin (MIC 
0.5 µg/mL) therapy was initiated.
Forty-eight hours after the antibacterial change, 2 sets of blood cultures
were drawn; 1 of the 2 sets remained sterile, while the second set required 4
days to become positive. We were ultimately unable to sterilize the patient's
blood.
Discussion. Given the known high protein-binding of daptomycin, total and unbound serum daptomycin concentrations (Center for Anti-Infective Research and Development; Hartford, CT) were obtained revealing 27.57 µg/mL and 2.64 µg/mL, respectively, 65 hours after an 8 mg/kg dose. Considering that the daptomycin half-life is 30 hours in hemodialysis patients,4 the estimated total and unbound peak serum concentrations were 125 µg/mL and 12 µg/mL, respectively. In animal models, daptomycin unbound peak concentrations of 2.5-7 times the MIC are required to produce a bacteriostatic effect, and 7-25 times the MIC are required for bactericidal effect.5 It is therefore unlikely that the unbound peak serum concentrations achieved in this patient would have been effective for treatment of endocarditis. In addition, in an animal model, the AUC of daptomycin in a fibrin clot is only one-third to one-half of that observed in serum, further limiting its efficacy in the treatment of endocarditis.6
We conclude that inadequate unbound daptomycin concentrations in the serum and cardiac vegetation contributed to failure of daptomycin in this patient. The transient response observed with quinupristin/dalfopristin, a less highly protein-bound agent, supports the suggestion that protein binding may have been important in the daptomycin failure. Presently, daptomycin cannot be recommended for the treatment of severe infections due to vancomycin-resistant E. faecium, particularly with an associated MIC of greater than or equal to 2 µg/mL.
References
This article has been cited by other articles:
|
|
 |
|
  D. M. Livermore Future directions with daptomycin J. Antimicrob. Chemother., November 1, 2008; 62(suppl_3): iii41 - iii49. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
 |
 |
 |
 |
