Safety of daptomycin in patients completing more than 14 days of therapy: results from the Cubicin® Outcomes Registry and experience.

Patients with complicated infections may receive daptomycin for extended periods. This retrospective analysis was conducted to describe the safety profile of daptomycin in patients completing >14 days of therapy. In the Cubicin(®) Outcomes Registry and Experience (CORE(®)) 2005-2009, a retrospective, multicentre, observational registry, patients completing >14 days of daptomycin were studied. Investigators assessed adverse events (AEs) using ICH-E2A definitions of seriousness/severity ≤30 days after completing daptomycin. AEs were grouped by onset at ≤14, 15-28 and >28 days after starting daptomycin. In total, 2263 patients received >14 days of daptomycin. The most common indications were complicated skin and skin-structure infection (25.5%) and osteomyelitis (21.7%). Regarding AEs, 205 patients (9.1%) experienced AEs with an onset ≤14 days of therapy, 168 (7.4%) between 15-28 days and 108 (4.8%) >28 days; a total of 389/2263 patients experienced 814 AEs. The most common AE was increased blood creatine phosphokinase (CPK), occurring in 49 patients (2.2%) during ≤14 days of therapy, 32 (1.4%) between 15-28 days and 10 (0.4%) >28 days. In 183/2263 patients (8.1%), 264 AEs were possibly related to daptomycin. Serious AEs occurred in 153/2263 patients (6.8%). Eighty-nine (3.9%) of 2263 patients had daptomycin discontinued due to AEs, with 36 discontinued due to increased CPK. The overall mortality rate was 63/2263 (2.8%); 4 patients died of a possibly related AE. The most common AEs with onset <14 days were similar to those occurring between 15-28 days and >28 days. Daptomycin appears to be safe in patients treated for >14 days.

Clinical outcomes of patients receiving daptomycin for the treatment of Staphylococcus aureus infections and assessment of clinical factors for daptomycin failure: a retrospective cohort study utilizing the Cubicin Outcomes Registry and Experience.

BACKGROUND: Daptomycin is most commonly used as a second-line treatment. Previous studies have not differentiated the effect of prior antibiotic therapy on daptomycin clinical outcomes. OBJECTIVES: The primary objective of this study was to compare clinical outcomes of patients treated with daptomycin as first-line therapy versus after prior antibiotic therapy (specifically, vancomycin). A secondary objective was to identify other factors associated with the clinical failure of daptomycin therapy. METHODS: This was a retrospective cohort study using data from a postlabeling registry database. The effects of relevant patient characteristics on the clinical outcome of individuals treated for Staphylococcus aureus infections with daptomycin were examined in an unblinded approach using univariate and multivariate analyses. Only patients with an evaluable clinical outcome (ie, cure, improvement, failure) and culture-confirmed S aureus infection were included in the analysis cohort. RESULTS: Of 1227 clinically evaluable patients, 250 (20%) received daptomycin as first-line therapy and 977 (80%) received daptomycin after other prior antibiotic therapy. Overall, 53% of patients were male; 64% were aged 31 to 65 years and 26% were aged >or=66 years. Race information was collected beginning in 2007; of the patients studied, 71% were white and 18% were black. The initial daptomycin dose (mean [SD]) overall was 5.1 (1.1) mg/kg and was highest for patients with endocarditis (5.9 [1.2] mg/kg) and lowest for those with uncomplicated skin and skin structure infections (4.4 [0.9] mg/kg). Clinical success, defined as an outcome of cured or improved at the end of daptomycin therapy, was reported for 1140 (93%) of the 1227 evaluable patients. The clinical success rates for first-line therapy with daptomycin and after prior antibiotics were both 93%. Using univariate analysis, 8 variables were associated with clinical failure (receipt of daptomycin in an intensive care unit setting, severe renal dysfunction [creatinine clearance <30 mL/min], dialysis, diabetes mellitus (DM), concomitant antibiotics, bacteremia, endocarditis, and failure of prior vancomycin therapy) and 3 with clinical success (outpatient daptomycin therapy and complicated and uncomplicated skin and skin structure infections). Using the stepwise multivariate regression analysis, only the presence of endocarditis (odds ratio [OR] = 2.56; 95% CI, 1.18-5.54; P = 0.017), bacteremia (OR = 1.77; 95% CI, 1.04-3.02; P = 0.037), severe renal dysfunction (OR = 1.78; 95% CI, 1.05-3.03; P = 0.034), and DM (OR = 1.79; 95% CI, 1.10-2.93; P = 0.02) were identified as factors independently associated with clinical failure of daptomycin therapy. Of the remaining patients, 9% were aged 18 to 30 years and 0.7% were aged 12 to 17 years. CONCLUSIONS: In this retrospective study, after controlling for clinical factors that are associated with suboptimal outcomes, clinical outcomes with daptomycin did not differ whether it was used as first-line therapy or after other antibiotics. Endocarditis, bacteremia, severe renal dysfunction, and DM were associated with higher rates of clinical failure of daptomycin treatment.

Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results.

A cluster of patients experiencing elevations of International Normalized Ratio without clinical bleeding in temporal association with daptomycin therapy was identified during postmarketing safety surveillance. A common element was the thromboplastin reagent used for the laboratory assay. The present study evaluated the effect of daptomycin on measured prothrombin time using commercially available thromboplastin reagent kits commonly used in the United States. Thirty reagent kits were obtained. Daptomycin was added to pooled normal human plasma samples to achieve final concentrations of 0-200 microg/ml. Quality control ranges were established for each reagent kit using normal and abnormal control plasmas. Triplicate assays of the prothrombin time were performed on the daptomycin-spiked plasma samples using each of the 30 kits. The activated partial thromboplastin time and thrombin time were also assessed. Statistical comparisons of interest were performed using analysis of variance with the Bonferroni t-test for multiple comparisons; alpha = 0.05 was used. Addition of daptomycin to human plasma samples dose-dependently prolonged measured prothrombin times when two recombinant thromboplastin reagents were utilized. The findings were statistically and clinically significant. No clinically meaningful effect was observed with the other reagents. The activated partial thromboplastin time and thrombin time were not affected. Prolonged International Normalized Ratio patient values were an artifact caused by the interaction of daptomycin with the in-vitro prothrombin time test reagent; an in-vivo anticoagulant effect was not observed. Healthcare providers should consider a possible drug-laboratory test interaction if prolonged prothrombin time or elevated International Normalized Ratio values are observed in patients receiving daptomycin.