Inhibition of Daptomycin by Pulmonary Surfactant: In Vitro Modeling and Clinical Impact

TLDR

Daptomycin, approved for skin infections, did not meet noninferiority criteria in a severe community‑acquired pneumonia trial. In pulmonary models, daptomycin was active against Staphylococcus aureus hematogenous pneumonia and inhalation anthrax but inactive against Streptococcus pneumoniae, and its antibacterial effect was inhibited in vitro by pulmonary surfactant—a specific, organ‑specific inhibition not seen with other antibiotics, marking the first such example.

Abstract

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.