Pharmacy & Therapeutics - May 2008 - (Page 287) Drug Utilization Evaluation: Daptomycin continued on page 284 resulted partly because of the site of concern; for example, the usual dose of 4 mg/kg was not prescribed for a UTI, based on the extensive renal excretion of daptomycin. Pai et al. noted that administering daptomycin based on total body weight in morbidly obese patients correlated best to the volume of distribution.11 They also reported a case in which vancomycin serum concentrations were used to estimate a dosing interval for daptomycin in a morbidly obese patient with renal insufficiency.12 They found that using vancomycin serum concentrations was more accurate, compared with using common CrCl equations, for estimating CrCl. Daptomycin has been studied in healthy volunteers at doses exceeding the current FDA-approved dosages. The pharmacokinetics and tolerability of daptomycin at 10 mg/kg once daily for 14 days, 12 mg/kg once daily for 14 days, or 6 or 8 mg/kg once daily for four days were evaluated in 12 participants.13 All of the patients had BMIs ranging from 24 to 27 kg/m2 and weights ranging from 53 to 72 kg. No electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity was noted, and none of the patients experienced myalgia. The most common adverse events were headache (27.8%), adenoviral upper respiratory infection (22%), aphthous stomatitis (11.1%), constipation (11.1%), arthralgia (11.1%), and UTIs (11.1%). All of these events, except arthralgia and UTI, were also observed in one or more patients who received placebo. Although one patient receiving daptomycin 10 mg/kg on the third day of therapy had mild numbness in the hands, this event did not recur despite continuation of therapy. One patient receiving 12 mg/kg experienced mild paresthesia on the fourth day, but this event subsequently resolved seven days later, even with continued therapy.13 We did not observe any creatinine phosphokinase (CPK) elevations in our audit, but we recognize that myopathy can occur. Because CPK elevations were more frequent in the phase 1 and 2 trials, when daptomycin was given more often than once daily, this agent should not be administered more than once per day. In the phase 3 skin and skin structure trial, CPK elevations were reported in 15 of 534 patients (2.8%) at a dose of 4 mg/kg every 24 hours. In the bacteremia/endocarditis trial, Fowler et al. reported CPK elevations in eight of 120 patients (6.7%) who received 6 mg/kg every 24 hours.7 In one case report, a 26-year-old patient receiving daptomycin 6 mg/kg per day for 14 days experienced muscle pain with a creatine kinase (CK) increase to 492 units/liter.14 Rhabdomyolysis was also reported in a 45-year-old woman with refractory acute myeloid leukemia who received 6 mg/kg every 24 hours.15 The most recent daptomycin package insert (from 2007) recommends that patients be monitored for symptoms of muscle pain or weakness, especially in the distal extremities.16 CPK levels should be monitored weekly or more often in patients who have recently received other drugs or who are taking statin drugs concomitantly. For patients with renal insufficiency, CPK levels and renal function should be monitored more often. Daptomycin should be discontinued if patients have myopathy as well as CPK elevations above 1,000 units/liter (about five times the upper limit of normal [ULN]) or if asymptomatic patients have CPK levels above 2,000 units/liter (10,000 times the ULN or greater).16 In addition to concerns about adverse drug events, reduced susceptibility to daptomycin has been associated with less susceptibility to vancomycin (i.e., vancomycin minimum inhibitor y concentrations [MICs] of 4 to 16 mcg/mL) in S. aureus isolates. The S. aureus isolates submitted to the Centers for Disease Control and Prevention (CDC) revealed an association of vancomycin MICs of 4 mcg/mL or 8 mcg/mL with daptomycin MICs of 2 mcg/mL or greater.17 According to the Clinical and Laboratory Standards Institute (CLSI), daptomycin MICs of 1 mcg/mL or lower in Staphylococcus isolates are considered to be susceptible.18 In another report, resistance occurred in a patient with vancomycin-resistant E. faecalis infection.19 The initial three isolates of E. faecalis had daptomycin MICs of 1 mcg/mL before the patient started daptomycin therapy. A fourth isolate obtained during therapy had an increased daptomycin MIC of 16 mcg/mL.19 Decreased susceptibility or treatment failure has also been reported in other cases of S. aureus infection.20–22 We presented the results of our evaluation to the P&T committee, and vancomycin remains the empirical antibiotic of choice for S. aureus infections at our institution. When culture and sensitivity data are available, de-escalation to a narrowerspectrum antibiotic is recommended (e.g., nafcillin for MSSA). The P&T committee recommended that the hospital’s daptomycin guidelines be reworded as follows: Revised Daptomycin Drug Usage Guidelines: Daptomycin requires ID consultation and approval by the Antimicrobial Management Team. Daptomycin is indicated for: • treatment of resistant gram-positive infection (e.g., MRSA, VRE) in patients who are allergic to vancomycin or linezolid. • treatment of resistant gram-positive infection (e.g., MRSA, VRE) that is intermediate or resistant to vancomycin and resistant or intermediate to linezolid. • treatment of resistant gram-positive infection (e.g., MRSA, VRE) in patients who develop thrombocytopenia thought to be secondary to linezolid or patients with existing thrombocytopenia where use of linezolid would be concerning (clinical judgment must be used). • treatment of gram-positive infection in patients who have not responded to treatment with vancomycin. Daptomycin should not be used for: treatment of pneumonia, surgical prophylaxis, or empirical coverage. CONCLUSION Guidelines for daptomycin usage, along with a requirement of consultation with an infectious-disease specialist, have succeeded in ensuring that prescribing is appropriate at our hospital. Although daptomycin use increased during the audit period, the overall use of vancomycin and linezolid remained constant. It is anticipated that reserving daptomycin as an alternative agent for serious gram-positive infections will limit continued on page 302 Vol. 33 No. 5 • May 2008 • P&T® 287
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