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

Figures & data

Figure 1 Plasma daptomycin concentration–time curves at steady state (day 4).

Notes: Antimicrob Agents Chemother, 2006;50(10):3245–3249. DOI: 10.1128/AAC.00247-06,⁸ reproduced with permission from American Society for Microbiology.

Table 1 Pharmacokinetics of daptomycin in special populations

Authors	Patients	Daptomycin (dose, treatment duration)	Findings
Dvorchik^Citation11	N=19 with moderate hepatic failure; aged ≥18 years	6 mg/kg once	No statistically significant differences in Cmax or AUC were found as compared to healthy volunteers. Adjustment in daptomycin dose or dose regimen was not required
Dvorchik and Damphousse^Citation18	N=25 patients with morbid obesity; aged ≥18 years	4 mg/kg once	Cmax and AUC increased by 25% and 35%, respectively. There was no effect on half-life and no change in fraction of daptomycin excreted unchanged in the urine
Di Paolo et al^Citation17	N=58 with severe Gram-positive infections; aged ≥18 years	4–12 mg/kg/day, 18 days	Daptomycin plasma concentrations lower than that described for healthy volunteers
Corti et al^Citation19	N=9 with continuous renal replacement therapy; aged ≥18 years	6 mg/kg/day, 5 days	PK of daptomycin similar to healthy volunteers
Khadzhynov et al^Citation20	N=8 with continuous renal replacement therapy; aged ≥18 years	8 mg/kg loading dose followed by 4 mg/kg every 48 hours*	PK of daptomycin similar to healthy volunteers
Kullar et al^Citation21	N=160 with renal impairment (23.8% on hemodialysis); aged ≥18 years	5.8–7.8 mg/kg/day, 13.5 days	Successful outcome observed in 128 (80%) patients at the end of daptomycin therapy. Daptomycin was considered as a safe and effective therapeutic option in patients with renal insufficiency

Note:

* Treatment duration is missing.

Abbreviations: AUC, area under plasma concentration–time curve; C_max, maximum plasma concentration; PK, pharmacokinetics.

Table 2 Characteristics of the main efficacy and safety studies for daptomycin

Authors	Patients	Daptomycin (dose, treatment duration)	Comparator (type, dose, treatment duration)	Efficacy results	Safety results
Aikawa et al^Citation22	N=101 patients with cSSTIs; aged ≥20 years	4 mg/kg/day over 30 minutes, 7–14 days	Vancomycin 1 g over at least 60 minutes, twice daily, 7–14 days	Clinical success rate: 81.8% (95% CI: 69.1%, 90.9%) with daptomycin and 84.2% (95% CI: 60.4%, 96.6%) with vancomycin	AEs related to the study drug: 21.6% with daptomycin and 27.3% with vancomycin. Elevation of CPK >500 U/L found in one patient in each group. None of these CPK elevations led to study discontinuation or was serious
Konychev et al^Citation23	N=120 patients with cSSTIs; aged ≥65 years	4 or 6 mg/kg/day over 30 minutes, 5–14 or 10–28 days with bacteremia	Semisynthetic penicillin 2 g every 6 hours or every 4 hours for patients with bacteremia; vancomycin 1 g every 12 hours, 5–14 or 10–28 days with bacteremia	Clinical success rate: 89.0% with daptomycin and 83.3% with pooled comparators; odds ratio 1.65 (95% CI: 0.49, 5.54)	Rates of AEs were similar between treatment groups: 62.5% with daptomycin and 65.0% with pooled comparators. AEs related to the study drug: 13.8% and 12.5%, respectively. Elevation of CPK was found in one patient in the daptomycin group and two patients in the pooled comparator group
Quist et al^Citation24	N=194 patients with cSSTIs; aged ≥18 years	4 mg/kg/day, 4–10 days	Vancomycin 1 g twice daily; teicoplanin 400 mg once daily	Clinical success rate: 91.4% with daptomycin and 87.2% with the comparator	Similar incidences of AEs and serious AEs across treatment groups. Severe AEs: 7.2% with daptomycin and 16.3% with comparators. Discontinuation due to AEs or death: 3.1% and 9.8%, respectively. Elevation of CPK was found in one patient in the daptomycin group (no discontinuation) and in five patients in the pooled comparator group (one discontinued)
Pertel et al^Citation25	N=103 patients with cellulitis or erysipelas; aged ≥18 years	4 mg/kg/day, 7–14 days	Vancomycin 1 g every 12 hours, 7–14 days	Clinical success rate: 94.0% with daptomycin and 90.2% with vancomycin (95% CI for the difference: 6.7%, 14.3%)	Similar incidences of AEs: 16.0% with daptomycin and 15.7% with vancomycin. AEs related to the study drug: three patients with daptomycin and one patient with vancomycin. No elevation of CPK was found
Katz et al^Citation26	N=100 patients with cSSTIs; aged ≥18 years	10 mg/kg/day, 4 days	Vancomycin 1 g every 12 hours, up to 14 days	Clinical success rate: 75.0% with daptomycin and 87.5% with vancomycin (95% CI for the difference: −27.9%, 2.9%)	Similar incidences of AEs: 56.3% with daptomycin and 52.1% with vancomycin. AEs related to the study drug: 41.7% and 22.9%, respectively. Three patients had CPK elevations (>500 U/L)
Fowler et al^Citation27	N=246 patients with Staphylococcus aureus bacteremia with or without endocarditis; aged 21–91 years	6 mg/kg/day, 14–15 days	Standard therapy: vancomycin 1 g every 12 hours with appropriate dose adjustment, or an anti-staphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin) 2 g every 4 hours	Clinical success rate: 44.2% with daptomycin and 41.7% with standard therapy; absolute difference: 2.4% (95% CI for the difference: −10.2%, 15.1%)	Similar overall incidence of AEs in the two treatment groups. AEs related to the study drug: 42 (35.0%) with daptomycin and 49 (42.2%) with standard therapy. CPK elevations (>500 U/L): 9.5% and 1.5%, respectively, P=0.02
Arbeit et al^Citation28	N=1,092 patients with cSSTIs; aged 18–85 years	4 mg/kg/day, 7–14 days	Penicillinase-resistant penicillin 4–12 g four times a day or vancomycin 1 g every 12 hours by 60-minute infusion	Clinical success rate: 83.4% with daptomycin and 84.2% with comparators. No differences according to infection type (abscess, wound, ulcer) and infecting agent	Similar incidences of AEs between treatment groups. AEs related to the study drug: 94 (18%) with daptomycin and 119 (21%) with comparators. Discontinuation rates: 2.8% in both groups. CPK levels reported as drug-related AEs: 11 (2.1%) patients in the daptomycin and eight (1.4%) patients in the comparator group

Abbreviations: AEs, adverse events; CI, confidence interval; CPK, creatine phosphokinase; cSSTIs, complicated skin and soft tissue infections.

Table 3 Clinical outcome and safety in high-dose daptomycin studies

Authors	Patients	Daptomycin (dose, treatment duration)	Comparator (type, dose, treatment duration)	Efficacy results	Safety results
Katz et al^Citation26	N=100 patients with cSSTIs; aged ≥18 years	10 mg/kg/day, 4 days	Vancomycin 1 g every 12 hours, up to 14 days	Clinical success rate: 75.0% with daptomycin and 87.5% with comparator (95% CI for the difference: −27.9%, 2.9%)	Similar incidences of AEs: 56.3% with daptomycin group and 52.1% with vancomycin. AEs related to the study drug: 41.7% and 22.9%, respectively. Three patients had CPK elevations (>500 U/L)
Moise et al^Citation38	N=94 patients mainly with bacteremia, osteomyelitis, and endocarditis; aged ≥18 years	8–10 mg/kg/day, 15 days	None	Overall clinical success rate was 89%, with the lowest success rate seen in patients with endocarditis	29.8% of patients reported at least one AE or exhibited at least one abnormal laboratory result, and 6.4% of patients reported AEs as possibly related to daptomycin
Seaton et al^Citation43	N=1,097 patients mainly with osteomyelitis, foreign body/prosthetic infection, and endocarditis; aged ≥18 years	>6 mg/kg/day, 13–14 days	None	Overall clinical success rate was 81.9%	Daptomycin was well tolerated with no new or unexpected safety findings. Increased CPK was reported in 27 patients
Byren et al^Citation58	N=75 patients with osteomyelitis; aged ≥18 years	6 and 8 mg/kg/day, 42 days	Standard-of-care antibiotics (vancomycin, teicoplanin, or semisynthetic penicillin), 40 days	Clinical success rates were 58.3% for 6 mg/kg/day daptomycin, 60.9% for 8 mg/kg daptomycin, and 38.1% for the comparator	No differences in the incidence of serious AEs across groups. CPK elevation of >500 U/L with daptomycin occurred in four (6 mg/kg/day) and five patients (8 mg/kg/day), and with comparator in two patients
Carugati et al^Citation59	N=178 patients with left-sided infective endocarditis; aged ≥18 years	7.7–10 mg/kg/day, 39 days	Standard-of-care antibiotics (anti-staphylococcal penicillins, vancomycin, or ampicillin plus an aminoglycoside)	In-hospital mortality (primary outcome) was similar in both groups. Median time to clearance of methicillin-resistant Staphylococcus aureus bacteremia was 1.0 and 5.0 days (P<0.01) with daptomycin and standard-of-care antibiotics, respectively	Regimens with higher daptomycin doses were not associated with increased incidence of AEs
Casapao et al^Citation60	N=245 patients with enterococcal infections; aged ≥18 years	7.7–9.7 mg/kg/day, 10 days	None	Overall clinical success rate was 89%	No patients experienced AEs attributed to high- dose daptomycin therapy. Seven patients had CPK elevations, yet no high-dose daptomycin regimen was discontinued due to an elevated CPK

Abbreviations: AEs, adverse events; CI, confidence interval; CPK, creatine phosphokinase; cSSTIs, complicated skin and soft tissue infections.

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