Safety of High‐Dose Intravenous Daptomycin Treatment: Three‐Year Cumulative Experience in a Clinical Program

Figueroa, Deborah A.; Mangini, Ed; Amodio-Groton, Maria; Vardianos, B.; Melchert, Alex F.; Fana, C.; Wehbeh, W.; Urban, Carl; Segal‐Maurer, Sorana

doi:10.1086/600039

Cited by 147 publications

(117 citation statements)

References 18 publications

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“…Although the increases in CPK observed with both the 6-and 8-mg/kg doses of daptomycin in this study were numerically higher than those seen with the comparator group, they are consistent with other clinical trials of daptomycin at Ն6 mg/kg, where 2.5% to 8.3% of patients experienced CPK elevations (6,9,11,14). Most CPK elevations in our study were of short duration and did not result in musculoskeletal symptoms.…”

Section: Discussionsupporting

confidence: 88%

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

Byren

Rege

Campanaro

et al. 2012

Antimicrob Agents Chemother

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The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2-to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients. Prosthetic joint infection (PJI) occurs in 0.5% to 1.0% and 0.5% to 2% of hip and knee replacements, respectively (5,20,24,25). PJI is predominantly caused by Staphylococcus aureus (28%) and coagulase-negative staphylococci (CoNS) (25%) (23). PJI is associated with mortality (up to 2.5%) and significant morbidity, and outcomes are poor (8). There are no prospective, randomized controlled trials to guide treatment in this area (16,21). Conducting trials is challenging due to the difficulty of identifying patients and confounding outcomes by prior use of antibiotics.The ideal antimicrobial agent should be bactericidal, with activity against biofilm-producing microorganisms (26). Daptomycin exhibits rapid, concentration-dependent bactericidal activity in vitro against Gram-positive organisms, including S. aureus (regardless of methicillin susceptibility), Staphylococcus haemolyticus, and Staphylococcus epidermidis (4). Clinical outcomes in osteomyelitis from a retrospective, noncomparative registry showed that daptomycin doses of Ͼ4 mg/kg of body weight were more effective than doses of Յ4 mg/kg (88% versus 65%; P ϭ 0.013) (15).This study assessed the safety and efficacy of 6 and 8 mg/kg daptomycin compared with standard-of-care therapy in patients with hip or knee PJI c...

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Section: Discussionsupporting

confidence: 88%

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

Byren

Rege

Campanaro

et al. 2012

Antimicrob Agents Chemother

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“…The optimal therapy for the treatment of infections caused by DNS S. aureus infections is therefore currently unknown (19,35). Since the area under the concentration-time curve (AUC)/ MIC or peak/MIC ratio is the pharmacodynamic parameter that best predicts efficacy, a "high dose" of DAP of 8 to 12 mg/kg/day has been evaluated clinically, showing both efficacy and a favorable safety profile (11,22,24). For this reason, high-dose DAP (10 mg/kg/day) is included in the recent MRSA guidelines to treat a variety of infections (19).…”

Section: Daptomycin (Dap)-nonsusceptible (Dns)mentioning

confidence: 99%

Evaluation of Ceftaroline Activity versus Daptomycin (DAP) against DAP-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Steed

Vidaillac

Rybak

2011

Antimicrob Agents Chemother

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The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin- ], 2.3 h), daptomycin at 6 mg/kg q24h (fC max , 7.9 g/ml; t 1/2 , 8 h), and daptomycin at 10 mg/kg q24h (fC max , 15.2 g/ml; t 1/2 , 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a >3-log 10 CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 g/ml, and the daptomycin MIC values were 2, 2, 4, and 4 g/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, ؊3.1 log 10 CFU/ml; R5563, ؊2.5 log 10 CFU/ml; R5996, ؊5.77 log 10 CFU/ml; R5995, ؊6.38 log 10 CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains, P < 0.008) and daptomycin at 10 mg/kg q24 h (3 strains, P < 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.

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“…Third, daptomycin shows an antimicrobial activity in an in vivo model of acute osteomyelitis (13) and penetrates rapidly into biofilms (14,15); also, due to its unique mechanism of action on cell membrane, daptomycin retains antimicrobial activity against both stationary-phase cultures of staphylococci within the biofilm and bacteria in the multiplication phase (16)(17)(18)(19)(20). Finally, the safety and tolerability of daptomycin have been established (21)(22)(23). Therefore, daptomycin could be a relevant treatment for bone and joint infection, provided that its penetration into bone is satisfactory.…”

mentioning

confidence: 99%

Penetration of Daptomycin into Bone and Synovial Fluid in Joint Replacement

Montange

Berthier

Leclerc

et al. 2014

Antimicrob Agents Chemother

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Safety of High‐Dose Intravenous Daptomycin Treatment: Three‐Year Cumulative Experience in a Clinical Program

Abstract: Daptomycin treatment was well tolerated at a mean dose of 8 mg/kg for a median duration of 25 days. The incidence of symptomatic CPK level elevation was within the range reported with lower doses of daptomycin and/or for shorter treatment durations.

Cited by 147 publications

References 18 publications

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

Evaluation of Ceftaroline Activity versus Daptomycin (DAP) against DAP-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Penetration of Daptomycin into Bone and Synovial Fluid in Joint Replacement

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