Daptomycin: the role of high-dose and combination therapy for Gram-positive infections

Daptomycin, a cyclic lipopeptide with rapid bactericidal activity, is approved at doses of 4 mg/kg and 6 mg/kg for the treatment of its respective indications [i.e. complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria; and Staphylococcus aureus bacteraemia associated with right-sided infective endocarditis (RIE) or cSSTIs, or RIE due to S. aureus]. Higher doses and combination therapy strategies have been investigated in some difficult-to-treat infections in order to: enhance clinical success rates; treat pathogens that may be non-susceptible to standard doses; and minimise the risk of resistance development in patients, particularly those who may need an extended treatment duration, who may have had suboptimal surgical management and/or who may have not responded to prior antibiotic therapy. Although clinical trial data of daptomycin doses >6 mg/kg and of daptomycin in combination with other antibiotics are limited, clinical experience reported to date suggests that daptomycin is effective and well tolerated at higher doses and in combination. In this review, the rationale both for high-dose and combination therapy strategies with daptomycin is explored and the available evidence is presented by indication and evaluated from a clinical perspective. Safety and efficacy are discussed from prospective and retrospective clinical studies, together with case reports for a variety of infections, including bacteraemia, endocarditis, cSSTIs and osteomyelitis, and expert recommendations are provided in summary of the evidence. The use of high-dose daptomycin, alone or in combination, may be useful for difficult-to-treat Gram-positive infections and further evaluation of these strategies is warranted.