Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact.
The lipopeptide daptomycin has been approved for use in skin and skin-structure infections but has failed to meet statistical noninferiority criteria in a clinical trial for severe community-acquired pneumonia. Daptomycin exhibited an unusual pattern of activity in pulmonary animal models: efficacy in Staphylococcus aureus hematogenous pneumonia and inhalation anthrax but no activity against Streptococcus pneumoniae in simple bronchial-alveolar pneumonia. Daptomycin was shown to interact in vitro with pulmonary surfactant, resulting in inhibition of antibacterial activity. This effect was specific to daptomycin and consistent with its known mechanism of action. This represents the first example of organ-specific inhibition of an antibiotic.
Silverman
Jared A
JA
Cubist Pharmaceuticals, Lexington, Massachusetts 02421, USA. jared.silverman@cubist.com
Mortin
Lawrence I
LI
Vanpraagh
Andrew D G
AD
Li
Tongchuan
T
Alder
Jeff
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D017576:Daptomycin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D008168:Lung / Q000502:physiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011008:Pneumococcal Infections / Q000188:drug therapy; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy
D000900:Anti-Bacterial Agents; D011663:Pulmonary Surfactants; D017576:Daptomycin