Pharmacy & Therapeutics - May 2008 - (Page 284) Drug Utilization Evaluation: Daptomycin tible and methicillin-resistant isolates.6 Subsequently, the S. aureus Endocarditis and Bacteremia Study Group published the data for IV daptomycin 6 mg/kg daily, compared with standard therapy for bacteremia and endocarditis caused by S. aureus.7 Standard therapy consisted of vancomycin 1 g every 12 hours with appropriate dose adjustments or an anti-staphylococcal penicillin, such as nafcillin (Unipen, Wyeth), oxacillin, or flucloxacillin (Floxapen, Fluclox) at 2 g every four hours. A successful outcome was documented in 44.2% (53 of 120 patients) in the daptomycin group compared with 41.7% (48 of 115 patients) receiving standard therapy (absolute difference, 2.4%; 95% confidence interval [CI], –10.2% to 15.1%). Daptomycin was associated with a higher rate of microbiologic failure (19 patients) compared with standard therapy (in 11 patients) (P = 0.17). Fowler et al. thus concluded that daptomycin was not inferior to standard therapy for S. aureus bacteremia or right-sided endocarditis.7 In the Cubicin Outcomes Registry and Experience (CORE) 2004 database, 126 of 168 patients who had bacteremia and were clinically evaluable received daptomycin. The median initial dose was 4 mg/kg (range, 2.5–9.2 mg/kg).8 The overall clinical success rate was 89%. For patients with endocarditis (n = 49), the median initial dose was 6 mg/kg (range, 4–7 mg/kg). Levine and Lamp concluded that daptomycin should be considered a possible therapy for patients with right-sided S. aureus endocarditis, although further investigation was needed for those patients with left-sided or enterococcal endocarditis.9 In our audit, microbiological or clinical cure rates were not available from all patients, primarily because these patients were frequently discharged to the outpatient setting on daptomycin and data were not available when therapy was finally completed. In the CORE 2004 database, 67 patients were treated for osteomyelitis and were clinically evaluable at the end of therapy.10 The median initial dose was 5.6 mg/kg (range, 3.2–7.5 mg/kg). The clinical success rate was higher with an initial daptomycin dose of more than 4 mg/kg, compared with an initial dose of 4 mg/kg or less (88% vs. 65%; P = 0.013).10 In our evaluation, three of the four patients received a dose of 4 mg/kg, and one patient received 6 mg/kg. All four patients completed daptomycin therapy as outpatients. For most of our patients, the daptomycin dosage interval was adjusted appropriately for patients with renal insufficiency. Of note, the dosage based on weight (mg/kg) varied widely, but it did not exceed 6 mg/kg per dose. The package insert for daptomycin describes pharmacokinetic data for six moderately obese patients with a body mass index (BMI) of 25 to 39.9 kg/m2 and six extremely obese patients with a BMI of 40 kg/m2 or greater.6 After a dose of 4 mg/kg IV based on total body weight, daptomycin plasma clearance was approximately 15% lower in the moderately obese subjects and 23% lower in the extremely obese subjects, compared with non-obese controls. The area-under-the-curve (AUC0-∞) concentration increased by approximately 30% in the moderately obese subjects and by 31% in the extremely obese subjects. Thus, no dosage adjustment is warranted in obese patients, according to this package insert.6 The variety of dosages in our evaluation might have continued on page 287 75 DDD 50 25 0 62.5 66.1 50.3 64.3 65.1 60.4 6.1 0.0 Jul–Sep 2003 2.7 0.4 4.5 0.5 6.5 5.7 Apr–Jun 2004 4.9 5.1 Jul–Sep 2004 5.7 6.4 Oct–Dec 2004 Oct–Dec Jan–Mar 2003 2004 Vancomycin IV Linezolid Daptomycin Figure 2 Defined daily doses (DDD) per 1,000 patientdays: comparison of daptomycin and intravenous vancomycin versus linezolid. DDDs per the World Health Organization, where vancomycin IV DDD = 2 g; linezolid DDD = 1.2 g; and daptomycin DDD = 0.28 g.2 1,000 patient days and 6.1 DDDs per 1,000 patient-days for linezolid (IV and oral routes). In the first two quarters in which daptomycin was available, usage was low (0.4 DDDs per 1,000 patient-days and 0.5 DDDs per 1,000 patient-days). Subsequently, daptomycin usage increased to 5.7 DDDs per 1,000 patient-days from April to June 2004, to 5.1 DDDs per 1,000 patient-days from July to September 2004, and to 6.4 DDDs per 1,000 patient-days from October to December 2004. Although daptomycin usage increased during the audit period, the use of parenteral vancomycin and linezolid was not altered to a major degree, compared with the baseline quarter (Figure 2). DISCUSSION Overall, the use of daptomycin met most of our institution’s drug-usage guidelines; it was used primarily for treating multidrug-resistant, gram-positive infections. Because of its in vitro activity against resistant gram-positive infections such as VRE and MRSA, daptomycin has been described in the literature as a welcome addition for antibiotics with gram-positive activity.3,4 Daptomycin was also prescribed for other off-label infections (e.g., for endocarditis at the time of the evaluation), which prompted a dose higher than 4 mg/kg. Sakoulas et al. compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis resulting from MRSA in Sprague-Dawley rats.5 This in vivo experimental model of MRSA endocarditis demonstrated that daptomycin, when given at a dose corresponding to a human dose of 4 to 6 mg/kg every 24 hours, was comparable to or better than therapy with vancomycin; the combination of rifampin with daptomycin was also superior to daptomycin alone. At the time of our data collection, ongoing studies were under way at a dose of 6 mg/kg per day in humans. On May 25, 2006, the FDA granted approval for daptomycin 6 mg/kg per day for the treatment of S. aureus bacteremia, including right-sided infective endocarditis, caused by methicillin-suscep- 284 P&T® • May 2008 • Vol. 33 No. 5
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