Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections

Abstract

Infections caused by Gram-positive pathogens remain a major public health burden and are associated with high morbidity and mortality. Increasing rates of infection with Gram-positive bacteria and the emergence of resistance to commonly used antibiotics have led to the need for novel antibiotics. Daptomycin, a cyclic lipopeptide with rapid bactericidal activity against a wide range of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, has been shown to be effective and has a good safety profile for the approved indications of complicated skin and soft tissue infections (4 mg/kg/day), right-sided infective endocarditis caused by S. aureus, and bacteremia associated with complicated skin and soft tissue infections or right-sided infective endocarditis (6 mg/kg/day). Based on its pharmacokinetic profile and concentration-dependent bactericidal activity, high-dose (>6 mg/kg/day) daptomycin is considered an important treatment option in the management of various difficult-to-treat Gram-positive infections. Although daptomycin resistance has been documented, it remains uncommon despite the increasing use of daptomycin. To enhance activity and to minimize resistance, daptomycin in combination with other antibiotics has also been explored and found to be beneficial in certain severe infections. The availability of daptomycin via a 2-minute intravenous bolus facilitates its outpatient administration, providing an opportunity to reduce risk of health care-associated infections, improve patient satisfaction, and minimize health care costs. Daptomycin, not currently approved for use in the pediatric population, has been shown to be widely used for treating Gram-positive infections in children.

Peptidomimetic therapeutics: scientific approaches and opportunities

“…The peptide binds to the bacterial cell membrane, causing rapid disruption because of calcium efflux and inhibiting the synthesis of DNA, RNA, protein, and lipoteichoic acid. This results in rapid concentration-dependent bacterial cell death with a prolonged postantibiotic effect (Table 2) [17]. …”

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

“…In light of vigorous research into mechanisms of S. aureus virulence, important avenues have been investigated with regard to emerging alternative therapies for treating S. aureus infections. In spite of the fact that antibiotic research and development has steadily decreased in the last twenty years, with only seven new antibiotics launched from 2009–2012, a range of approved antibiotics to treat MRSA infections have been implemented only recently [47–49]. These include established classes such as fluoroquinolones and cephalosporins, but also novel compound classes such as peptide mimics, oxadiazoles, and diaminopyrimidines [49–51].…”

“…In spite of the fact that antibiotic research and development has steadily decreased in the last twenty years, with only seven new antibiotics launched from 2009–2012, a range of approved antibiotics to treat MRSA infections have been implemented only recently [47–49]. These include established classes such as fluoroquinolones and cephalosporins, but also novel compound classes such as peptide mimics, oxadiazoles, and diaminopyrimidines [49–51]. Additionally, owing to the widespread knowledge of multi-drug resistance in global rates of S. aureus infections, efforts to develop non-drug alternatives to combat MRSA have been emerging.…”

Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

“…It has been approved for adult patients with complicated skin and soft tissue infections (cSSTI) and right-sided endocarditis (RIE) due to S. aureus, as well as S. aureus bacteremia when associated with RIE or cSSTI. It has also been approved for treatment of pediatric (1 to 17 yrs old) patients with cSSTI by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (1).…”

“…The pharmacokinetic/pharmacodynamic (PK/PD) parameters best correlating with daptomycin efficacy in vivo are AUC/MIC and C max /MIC ratios. The mean AUC 0 -24 /MIC values associated with static, 1-log killing, and 2-log killing effects against S. aureus are 438 Ϯ 67, 666 Ϯ 87, and 1,061 Ϯ 296, respectively (1,8). Daptomycin exhibits linear pharmacokinetics when administered at doses up to 12 mg/kg QD in healthy adults (12).…”