Daptomycin for Treatment of Gram-Positive Infections
Daptomycin for Treatment of Gram-Positive Infections
Study Objective. To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections.
Design. Multicenter, retrospective, observational, case series analysis.
Setting. Five academic medical centers in four major United States cities.
Patients. Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated grampositive infections between January 1, 2005, and March 1, 2010.
Measurements and Main Results. Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0–10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5–16 days) and 13 days (IQR 6–18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26–67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level.
Conclusion. Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.
Infections with resistant strains of Staphylococcusaureus and Enterococcus species have been steadily increasing over the past decade. These highly adaptable organisms were recently reported as two of the six bacteria—Enterococcusfaecium, S. aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE pathogens)—that are the leading pathogens causing nosocomial infections. Given the scarcity of novel antimicrobials with activity against these bacteria, it is evident that multidrug resistance poses a major challenge when it comes to managing infections with these pathogens.
Daptomycin is a cyclic lipopeptide that binds to the bacterial membrane through calcium-dependent insertion of its lipophilic tail and, through membrane depolarization, exerts rapid concentration-dependent bactericidal activity against drug-resistant gram-positive pathogens. Daptomycin has been generally well tolerated, but concerns for clinical or biochemical myositis warrant weekly creatine phosphokinase (CPK) measurements during therapy.
Daptomycin is approved by the United States Food and Drug Administration at 4 mg/kg/day for the treatment of skin and soft structure infections and 6 mg/kg/day for S. aureus bacteremia including right-sided endocarditis. However, based on its concentration-dependent activity, higher doses of daptomycin may increase the degree and rapidity of bacterial killing, and reduce the emergence of resistance. The potential clinical response to higher doses is supported in an animal model of infective endocarditis against strains with reduced daptomycin susceptibility. Finally, case reports and postmarketing surveillance data suggest that higher doses may be safe and efficacious.
In an attempt to confirm these preliminary observations, we evaluated the clinical response and safety of high-dose daptomycin therapy, defined as 8 mg/kg/day or greater, in patients confirmed or suspected to have S. aureus and/or enterococcal infections, in a multicenter evaluation.
Abstract and Introduction
Abstract
Study Objective. To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections.
Design. Multicenter, retrospective, observational, case series analysis.
Setting. Five academic medical centers in four major United States cities.
Patients. Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated grampositive infections between January 1, 2005, and March 1, 2010.
Measurements and Main Results. Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0–10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5–16 days) and 13 days (IQR 6–18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26–67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level.
Conclusion. Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.
Introduction
Infections with resistant strains of Staphylococcusaureus and Enterococcus species have been steadily increasing over the past decade. These highly adaptable organisms were recently reported as two of the six bacteria—Enterococcusfaecium, S. aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE pathogens)—that are the leading pathogens causing nosocomial infections. Given the scarcity of novel antimicrobials with activity against these bacteria, it is evident that multidrug resistance poses a major challenge when it comes to managing infections with these pathogens.
Daptomycin is a cyclic lipopeptide that binds to the bacterial membrane through calcium-dependent insertion of its lipophilic tail and, through membrane depolarization, exerts rapid concentration-dependent bactericidal activity against drug-resistant gram-positive pathogens. Daptomycin has been generally well tolerated, but concerns for clinical or biochemical myositis warrant weekly creatine phosphokinase (CPK) measurements during therapy.
Daptomycin is approved by the United States Food and Drug Administration at 4 mg/kg/day for the treatment of skin and soft structure infections and 6 mg/kg/day for S. aureus bacteremia including right-sided endocarditis. However, based on its concentration-dependent activity, higher doses of daptomycin may increase the degree and rapidity of bacterial killing, and reduce the emergence of resistance. The potential clinical response to higher doses is supported in an animal model of infective endocarditis against strains with reduced daptomycin susceptibility. Finally, case reports and postmarketing surveillance data suggest that higher doses may be safe and efficacious.
In an attempt to confirm these preliminary observations, we evaluated the clinical response and safety of high-dose daptomycin therapy, defined as 8 mg/kg/day or greater, in patients confirmed or suspected to have S. aureus and/or enterococcal infections, in a multicenter evaluation.
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