Daptomycin: a novel agent for Gram-positive infections

Abstract

The alarming increase in the incidence of Gram-positive infections, including those caused by resistant bacteria, has sparked renewed interest in novel antibiotics. One such agent is daptomycin, a novel lipopeptide antibiotic with proven bactericidal activity in vitro against all clinically relevant Gram-positive bacteria. These include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediately susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS) and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. Daptomycin provides rapid, concentration-dependent killing and a relatively prolonged concentration-dependent post-antibiotic effect in vitro. Spontaneous acquisition of resistance to daptomycin occurs rarely. Daptomycin exhibits linear pharmacokinetics, minimal accumulation with once-daily dosing, and low plasma clearance and volume of distribution. Phase II clinical trials indicate that daptomycin at doses of 2 mg/kg q24 h and 3 mg/kg q12 h is efficacious against skin and soft tissue infections and bacteremia, respectively. In addition, results in endocarditis suggested potential efficacy with higher doses. On the basis of clinical trials to date, it appears that daptomycin has an excellent safety profile, with the incidence and nature of serious adverse events comparable to those observed with conventional therapy. Adverse events associated with other classes of antimicrobials (nephrotoxicity, local irritation, ototoxicity, hypersensitivity, and gastrointestinal effects) were uncommon with daptomycin. Minimal skeletal muscle toxicity was seen at only the highest dose tested (4 mg/kg q12 h), predicted by elevations in serum creatinine phosphokinase, and readily reversible upon discontinuation of treatment. There were no signs of toxicity in cardiac or smooth muscle. Phase II and III clinical trials are underway to evaluate daptomycin for the treatment of Gram-positive bacteremia and complicated skin and soft tissue infections, respectively. Daptomycin holds promise as a rapidly acting and highly effective antibiotic for Gram-positive infections.

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

“…Due to daptomycin's concentration dependence, a once-daily dosing regimen has been proposed to optimize its pharmacodynamic properties and has demonstrated an improved safety profile compared with that of the initially evaluated twice-daily regimen [71][72][73][74][75]. A Monte Carlo prediction model analysis was conducted to determine if AUC/MIC targets could be achieved in a clinical setting [74].…”

Daptomycin exerts rapid bactericidal activity against Bacillus anthracis without disrupting membrane integrity

“…This drug exerts strong bactericidal activities in vitro against most clinically relevant, gram-positive pathogens [12] . Its unique mode of action [13] , ie, inserting into bacterial membrane and perturbing membrane function, makes it a useful alternate therapeutic for B anthracis infection if resistant isolates emerged.…”

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections

“…Daptomycin has attractive properties for treating osteoarticular infections, because of its rapid bactericidal activity against susceptible as well as multi-resistant, Gram-positive isolates. Emergence of daptomycin resistance remains a rare event in staphylococci and is limited to individual case reports [9,10]. While recent clinical data assessed the efficacy and safety of high-dose daptomycin in Gram-positive osteoarticular infections [2][3][4][5][6], no specific study evaluated the combined regimen of high-dose daptomycin (8 mg/kg/day) and rifampicin (600 mg/day) in this context.…”

“…Daptomycin is a lipopeptide antibiotic that has a rapid bactericidal activity in vitro and in vivo, but this bactericidal activity is concentration-dependent and its optimal expression may require plasma levels equivalent to eight times the lipopeptide minimum inhibitory concentration (MIC) for some strains [9,10]. The relatively high protein binding and low volume of distribution of daptomycin recorded in healthy volunteers [11] represent a difficult challenge for defining a dosing schedule exerting optimal activity against various categories of deep-seated bacterial infections.…”

“…Subsequently, daptomycin was found effective for therapy of S. aureus bacteremia and right-sided endocarditis at a once-daily dosing regimen of 6 mg/kg/day [13]. While early clinical studies with twice-daily regimens of daptomycin raised concerns about potential myopathy characterised by high elevations (>10-fold) in serum creatine phosphokinase [9,14], further pharmacokinetic studies demonstrated the safety of higher doses of daptomycin, such as 8 mg/kg/day, when they were administered once daily for 14 days in healthy volunteers [11].…”