Daptomycin Tested in an In Vitro Model of Endocarditis Due to MRSA, GISA, and VREF
Abstract & Commentary
Synopsis: Daptomycin given at high doses has good bactericidal activity against glycopeptide-intermediate susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium in an in vitro model of endocarditis.
Source: Akins RL, Rybak MJ. Antimicrob Agents Chemother. 2001;45:454-459.
The bactericidal activity of 2 daptomycin dosing regimens against strains of glycopeptide-intermediate susceptible Staphylococcus aureus (GISA), vancomycin-resistant Enterococcus faecium (VREF), and methicillin-resistant Staphylococcus aureus (MRSA) was evaluated in an experimental in vitro model of endocarditis.
Simulated endocarditis vegetations were prepared by mixing a suspension of the microorganism to be studied with human donor cryoprecipitate and platelet suspension, to which bovine thrombin in the presence of a monofilament was added. This is a process that results in the formation of bacteria embedded in platelet-fibrin matrix, the typical components of in vivo endocardial vegetations.
The simulated vegetations were subsequently placed in a 250-mL container containing nutrient broth. The antibiotics were added to the broth at regular intervals, and antibiotic-containing broth was removed from the container with a peristaltic pump and replaced with antibiotic-free broth at a rate designed to simulate the in vivo peak and trough concentrations, as well as the half-lives of the antibiotics at specific dosages. Experiments were performed by simulating endocarditis with GISA, VREF, and MRSA, and quantitative cultures of the simulated vegetations were performed at regular intervals for a period of 72 hours, simulating therapy with no antibiotic (growth control), daptomycin 6 mg/kg/d, daptomycin 10 mg/kg/d, and vancomycin 1 g every 12 hours.
The results of serial quantitative cultures of the simulated vegetations showed that daptomycin 10 mg/kg/d resulted in an undetectable bacterial content within 72 hours in all 3 sets of experiments (GISA, VREF, and MRSA). Undetectability was achieved most rapidly (within 8 hours) and most consistently (throughout the 72-hour period) in the GISA experiment. Daptomycin 6 mg/kg/d did not achieve undetectability in any of the 3 experiments; however, it resulted in significantly more bacterial killing than vancomycin in all experiments, including the MRSA (vancomycin-susceptible) experiment.
The above results indicate that daptomycin exhibits a significant dose-dependent killing of MRSA, GISA, and VREF in an experimental in vitro model of endocarditis.
Comment by Joseph F. John, MD, & Imad H. Durra, MD
The management and containment of antibiotic-resistant bacteria has become a major concern of health care professionals almost since the introduction of antibiotics several decades ago.1 Historically, most of the efforts were made to contain the emergence of resistant Gram-negative organisms, and little efforts were made for the development of newer antimicrobial agents for use against resistant Gram-positive organisms. Although the emergence of MRSA had been at least partially controlled with the escalating use of vancomycin, the emergence of VREF2 and GISA3 left the medical community facing potentially dreadful organisms with no adequate antibiotics available in their pharmacologic armamentarium.
There are currently 2 antibiotics available for the treatment of infection due to VREF or GISA: linezolid, an oxazolidinone, and quinupristin/dalfopristin (Q/D), a combination of 2 different streptogramins. There are no publications in the medical literature concerning the usefulness of linezolid in the treatment of endovascular infections. Most of the evidence for the use of Q/D in the treatment of endocarditis comes from isolated case reports4 or from experimental endocarditis in animals. Animal model experiments showed that Q/D is adequately bactericidal against MRSA-infected vegetations and demonstrated an even penetration into the tissue of the vegetations.5
Daptomycin (Cubist Pharmaceuticals) is an investigational lipopeptide antibiotic in phase III trials. Trials with earlier lipopeptide agents were interrupted because of their side effects, but the interest in this class of antibiotics is now being renewed. Daptomycin was shown to be adequately effective in experimental VREF endocarditis, but only at extremely high dosages (12 mg/kg q 8 hours), especially when given in combination with an aminoglycoside.6
In the current article, Akins and Rybak showed that daptomycin may eventually prove to be an adequate antibiotic choice for GISA and VREF endocarditis at an even lower dose, 10 mg/kg/d. Several issues, however, limit the ability to draw conclusions from their findings. One issue is the dosage of daptomycin suggested: 10 mg/kg/d has never been a dose used in any of the human trials of the antibiotic, and the currently used dose of 6 mg/kg/d has already been associated with a significant amount of side effects, especially myositis, though to a lesser extent than earlier lipopeptides.
The second major issue is finding how close the in vitro endocarditis model is to the real human endocarditis, both in terms of the pathophysiology of the vegetation and the pharmacodynamics of the body, which rarely behaves like a test tube.
Although more experiments need to be done on the animal model of endocarditis using the higher dosing regimen of daptomycin before drawing any conclusions, it is probably encouraging to have a long-awaited and definitively bactericidal antibiotic that can be used for GISA and VREF endocarditis. We will have to wait to see if the use of daptomycin may be mitigated by unwelcome side effects, although reports from early clinical trials suggest that serious side effects are rare. (Dr. Durra is an Infectious Diseases Fellow at Robert Wood Johnson Medical School, New Brunswick, NJ.)
References
1. Murray BE. N Engl J Med. 1994;330:1229-1230.
2. Uttley AH, et al. Lancet. 1988;1:57-58.
3. Hiramatsu K, et al. J Antimicrob Chemother. 1997;40:
135-136.
4. Furlong WB, Rakowski TA. Clin Infect Dis. 1997;25: 163-164.
5. Fantin B, et al. Antimicrob Agents Chemother. 1994; 38:432-437.
6. Caron F, et al. Antimicrob Agents Chemother. 1992; 36:2611-2616.
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