Inhibition of Daptomycin By Pulmonary Surfactant
Abstract and Commentary
By Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is associate editor of Infections Disease Alert
Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron and is on the speaker’s bureau of Pfizer/Agouron.
Synopsis: Daptomycin specifically interacts with pulmonary surfactant and its antimicrobial activity is inhibited in a dose-dependent fashion by surfactant.
Source: Silverman JA, et al. Inhibition of Daptomycin By Pulmonary Surfactant: In Vitro Modeling and Clinical Impact. J Infect Dis. 2005;191:2149-2152.
The FDA has recently approved daptomycin for use in skin and skin-structure infections, but this antibiotic failed the test of non-inferiority in a trial of severe community-acquired pneumonia. In addition, preclinical in vivo animal model studies of daptomycin conducted by the sponsor had shown disappointing results in bronchial-alveolar pneumonia, but displayed good activity in hematogenous staphylococcal pneumonia.
Silverman and colleagues demonstrate that the in vitro antistaphylococcal activity of daptomycin was inhibited by the inclusion of small amounts of bovine surfactant in broth media with > 100 fold increase in MIC observed with as little as 10% surfactant concentration. The activity of ceftriaxone was unaffected in these same experiments. Silverman et al, in a nice complementary experiment, demonstrated calcium-dependent insertion of daptomycin into surfactant aggregates in vitro, consistent with its in vitro antibacterial mechanism of action.
Commentary
Daptomycin is a new and important antibiotic in our arsenal to combat the emerging scourge of gram positive bacterial infections. Daptomycin is a lipopeptide antibiotic which exerts its bactericidal effect by a calcium-dependent insertion into and disruption of the functional integrity of the G+ plasma membrane, resulting in rapid loss of membrane potential, cessation of macromolecular synthesis, and cell death.1
The drug was approved by the FDA in 2003, for use in skin and skin-structure infections. Despite potent in vitro activity against Streptococcus pneumoniae (MIC90 0.06 ug/mL), a phase 3 clinical trial in severe community-acquired pneumonia failed to achieve statistical non-inferiority to the ceftriaxone comparator arm. Pulmonary surfactant is a complex mixture of dipalmitoylphosphatidylcholine, phosphatidylglycerol, minor phospholipids, neutral lipids, and cholesterol which acts within alveoli to reduce surface tension and prevent alveolar collapse.2 The experiments summarized above provide a nice explanation of these unexpected in vivo clinical trial results by demonstrating in vitro inhibition of the antibacterial effect of daptomycin by surfactant, and correlating this with calcium-dependent insertion of daptomycin into surfactant aggregates.
During the 4 decades I have been involved in clinical care of patients with infections and in drug development with several pharmaceutical companies, I never fail to be fascinated by the often poor correlation between in vitro activity of antimicrobials and in vivo activity. Some of the best-studied mechanisms of this discordance include bioavailability and metabolism which limit exposure of the pathogen to the drug, variable effects of protein binding (albumin, alpha-1-acid glycoprotein, etc.), physiochemical properties which limit diffusion of the drug into certain compartments, or ability of the drug to inhibit intraleukocytic pathogens. This paper adds another mechanism to this list.
Despite the limitation of daptomycin in treating patients with bronchial-alveolar pneumonia, I believe daptomycin will be an important antibiotic in the treatment of the ever-increasing numbers of patients with either Beta lactam-resistant or vancomycin-resistant pathogens. While not officially approved for indications other than skin and skin-structure infections at this time, daptomycin's bactericidal action makes it an attractive option for the treatment of bacteremia and endocarditis caused by antimicrobial resistant pathogens.
References
- Silverman JA, et al. Correlation of Daptomycin Bactericidal Activity and Membrane Depolarization in Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47:2538-2544.
- Goerke J. Pulmonary Surfactant: Functions and Molecular Composition. Biochem Biophys Acta. 1998; 1408:79-89.
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