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Daptomycin
General information
Daptomycin is a novel lipopeptide antibiotic, an inhibitor of lipoteichoic acid synthesis, with potent bactericidal activity against most clinically important Gram-positive bacteria, including resistant strains [ , ], such as meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci and was the first inhibitor of lipoteichoic acid synthesis.
Daptomycin was initially developed in the late 1980s and early 1990s [ ] but was ultimately shelved owing to concerns regarding adverse effects, in particular drug-induced myopathy [ , ]. In clinical trials, the most common adverse effects included gastrointestinal disorders, for example constipation (6%), nausea (6%), and diarrhea (5%), injection site reactions (6%), headache (5%), and rash (4%) [ ]. Most of the reported adverse effects of daptomycin have been mild to moderate in intensity.
Phase III study results have suggested no difference in efficacy or tolerability between daptomycin 4 mg/kg/day intravenously and vancomycin or semisynthetic penicillins for complicated skin and skin–structure infections; however, specific adverse effects were not discussed [ ].
Daptomycin has linear pharmacokinetics at doses of 0.5–6 mg/kg, but in 20% of adults given 8 mg/kg intravenously there is non-linear accumulation. Daptomycin is highly protein-bound and is distributed mainly in the extracellular fluid. In a study of daptomycin concentrations collected from serum and inflammatory blisters, the mean concentrations at 1 and 2 hours were 9.4 and 14.5 μg/ml respectively [ ].
When daptomycin 4 mg/kg was given intravenously to seven healthy men the mean peak concentrations in plasma and inflammatory fluid were 78 and 28 μg/ml respectively; the mean half-lives were 7.7 and 13 hours respectively; the overall penetration of total drug into the inflammatory fluid was 68% and the mean urinary recovery over 24 hours was 60% [ ].
Drug studies
Placebo-controlled studies
Three cohorts of 12 healthy subjects each were given daptomycin 10 mg/kg or placebo once daily for 14 days, daptomycin 12 mg/kg or placebo once daily for 14 days, or daptomycin 6 or 8 mg/kg once daily for 4 days. Daptomycin did not cause electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity [ ].
Organs and systems
Respiratory
Because of known cephalosporin sensitivity, a 60-year-old man was given intravenous daptomycin for Staphylococcus aureus endocarditis and 2 weeks later developed a fever, rigors, profound sweating, and raised CRP concentrations. A CT scan of the lung showed diffuse patchy areas [ ]. A transbronchial lung biopsy showed alveolar and interstitial eosinophils. Daptomycin was stopped for 8 days, but within 4 hours of reintroduction he spiked a fever, sweated profusely, and required intubation for respiratory failure. Daptomycin was withdrawn and he was given intravenous methylprednisolone. There was significant improvement within 24 hours.
Nervous system
Daptomycin has been associated with neuropathy in a few cases in phase 2 clinical studies [ ]. The dose in these studies (3 mg/kg bd) was higher than in phase 3 studies. Pooled laboratory data showed no differences in hematological measurements, blood chemistry, or hepatobiliary function between daptomycin and comparative antibiotics.
In a randomized trial, 120 patients with Staphylococcus aureus bacteremia with or without endocarditis received daptomycin 6 mg/kg/day intravenously and 115 received initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin [ ]. Eleven of the 120 patients who received daptomycin (9.2%) had adverse events related to the peripheral nervous system (e.g. paresthesia, dysesthesia, and peripheral neuropathies) compared with two of 116 patients (1.7%) who received standard therapy. All of the events were classified as mild to moderate in intensity; most were short-lived and resolved during continued treatment.
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