Once-Daily Dosing in Dogs Optimizes Daptomycin Safety

Abstract

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

Liposomal co-delivery of daptomycin and clarithromycin at an optimized ratio for treatment of methicillin-resistantStaphylococcus aureusinfection

“…This demonstrated that the quantity of daptomycin used may be decreased substantially in the presence of clarithromycin, with the same clinical effect. Although there are only scattered case reports, the reported side-effects of intravenous administration of daptomycin, including rhabdomyolysis, should not be ignored (Oleson et al, 2000;Kazory et al, 2006). The findings of the present study indicated that liposomal co-delivery of daptomycin with clarithromycin had significant benefits over single drug formulation in potential clinical application.…”

“…For histological analysis, tissue samples were collected from all groups on the third day after treatment, fixed in 10% phosphate-buffered formalin, stained with hematoxylin-eosin (HE) and viewed through a light microscope. A preliminary safety assessment of the co-delivery treatment was conducted by studying tissue sections and serum biochemical parameters, including alanine aminotransferase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, creatinine, uric acid and creatinine phosphokinase, using a fully automated biochemistry analyzer (TMS-1024i; BOEKI; Tokyo; Japan) (Oleson et al, 2000;Dopazo et al, 2009). …”

The action mechanism of daptomycin

“…They found that the myopathic side effects could be minimized by altering the dose regimen. 20 These successful tests resulted in approval for clinical use beginning in 2003 (see next section).…”

Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia

“…In general, however, lower AUC/MIC exposures are required to achieve static or 80% maximum effects for enterococci compared with staphylococci [68]. Over a 24 h period, free daptomycin concentrations averaging 1-2 times the MIC are needed for a bacteriostatic effect and 2-4 times the MIC for >99% killing [69,70].…”