Daptomycin: Safe at Higher Doses?
Abstract & Commentary
By Brian Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Blackburn reports no financial relationships relevant to this field of study.
Source: Figueroa DA, et al. Safety of High-Dose Intravenous Daptomycin Treatment: Three-Year Cumulative Experience in a Clinical Program. Clin Infect Dis. 2009;49:177-180.
Synopsis: A retrospective review of 61 patients treated with high-dose daptomycin (mean dose, 8 mg/kg/day) for various indications resulted in few major side effects; three patients experienced symptomatic CPK elevations necessitating drug discontinuation. Although these data are preliminary, high-dose daptomycin may be a safe alternative in patients with serious gram-positive infections.
Daptomycin is a lipopeptide antibiotic that exhibits concentration-dependent bactericidal activity against a wide array of gram-positive organisms. It is approved for the treatment of complicated skin and soft-tissue infections (SSTI) at a dose of 4 mg/kg/day, as well as for Staphylococcus aureus bloodstream infections at a dose of 6 mg/kg/day. At these doses, clinical trials have shown daptomycin to be non-inferior to comparator drugs, but demonstration of superiority has remained elusive; in addition, "MIC creep," while on therapy, has been observed in over 5% of patients in some trials.1 The drug's concentration-dependent killing makes it a tempting target for attempts at the use of increased doses, and in-vitro data suggest that higher doses can lead to more potent activity.2 In addition, endocarditis caused by highly resistant bacteria such as methicillin-resistant S. aureus (MRSA) or vancomycin-resistant Enterococcus (VRE), can be difficult to effectively treat, leading some clinicians to attempt higher doses. Figueroa et al, therefore, undertook a retrospective study to assess the safety of increased doses of this drug in clinical practice.
All patients who had received daptomycin from 2004-2007 at a single center in New York City were identified retrospectively through an electronic database; patients were then included in the study if they had received a dose above 6 mg/kg/day for two or more weeks. While on daptomycin, all patients had all concomitant 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA)-reductase inhibitors held. Daptomycin was dosed every 24 hours unless a patient's creatinine clearance was < 30 mL/min, in which case, it was dosed every 48 hours; dosing was based on actual body weight.
Sixty-one patients were included in the cohort, with a median age of 67 years. Infections by site included 43% with bloodstream infections, 23% with SSTIs, 15% with bone/joint infections, 10% with left-sided endocarditis, and 8% with intra-abdominal infections. Infecting organisms included methicillin-resistant S. aureus (26% of patients), methicillin-susceptible S. aureus (3%), methicillin-resistant Staphylococcus epidermidis (5%), Enterococcus faecium (15%), and Enterococcus faecalis (15%).
Patients received a mean dose of 8 mg/kg/day of daptomycin, for a median of 25 days (range 14-82 days). Baseline and follow-up laboratory testing of creatine phosphokinase (CPK) was not done systematically; three patients had no testing done and, of the remaining 58, most had some CPK testing done during therapy, though testing was often erratic and precise figures were not given.
Twenty-two (36%) patients experienced at least one mild adverse event (such as anemia, diarrhea, nausea, hypokalemia, or arthralgias). Three (5%) experienced CPK elevations above 1,000 U/L, with concomitant constitutional and/or musculoskeletal complaints. Daptomycin was stopped in all three with resolution of these abnormalities. Two of these three patients were obese (BMI "grade III").
Commentary
Daptomycin at a mean dose of 8 mg/kg/day was well tolerated in this cohort, one of the largest series of patients treated with high-dose daptomycin to date. Although historical safety data involving daptomycin at these doses are relatively limited, the use of high-dose daptomycin is not without precedent. A small cohort of healthy volunteers tolerated doses up to 12 mg/kg/day4 without any evidence of muscle toxicity. Other small clinical series and case reports have documented doses up to 10-12 mg/kg/day, most with minimal adverse effects.5-8 Although just under 5% experienced significant and symptomatic CPK elevations in the current study, this is only slightly higher than that seen in a key clinical trial involving standard-dose daptomycin.1 While this does mandate close CPK monitoring, it also suggests that with appropriate supervision, this adverse effect can be managed, and that this dose may not be significantly more toxic than standard-dose daptomycin.
Although efficacy data are not presented, this study represents an encouraging finding, as it paves the way for future studies to examine efficacy. It is particularly important given the rising MICs seen on standard-dose daptomycin therapy in a recent trial;1 perhaps the use of higher doses will mitigate this problem. In addition, although not licensed for this indication, daptomycin is frequently used for systemic enterococcal infections. Given that enterococci typically have higher MICs to daptomycin than S. aureus or other gram-positive organisms,3 it will be interesting to see if the use of higher doses makes a clinical difference in trials involving these organisms.
A particularly encouraging aspect of this study is the length of daptomycin therapy employed; all subjects received the drug for at least two weeks, and the median length of therapy was nearly four weeks. This may indicate that the use of high-dose daptomycin is safe, even for indications that require prolonged use, such as endocarditis and bone/joint infections. This will be a key aspect to monitor in future studies.
An intriguing finding of this study is that two of the three patients who experienced severe CPK elevations were obese; perhaps difficulty in accurately estimating dosing based on creatinine clearance and use of actual body weight in these cases led to inappropriately high dosing in these patients. This is another issue that should be examined closely in future studies. It is important to note that all patients in this study had concomitant HMG CoA-reductase therapy held during daptomycin treatment. Whether this is routinely necessary in patients treated with high-dose daptomycin is not clear, but the results from this paper may only be applicable in such a circumstance.
The limitations of this paper include the relatively small cohort and retrospective nature of the study. Several inherent biases result, such as the possibility of underreporting of adverse events, particularly given that not all patients in this cohort had CPK testing done at regular intervals. Nevertheless, these preliminary data are encouraging, and herald the next step of assessing the efficacy of high-dose daptomycin, as well as a careful assessment of adverse effects in a randomized, blinded trial.
References:
- Fowler VG, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665.
- Rose WE, et al. Evaluation of daptomycin pharmacodynamics and resistance at various dosage regimens against Staphylococcus aureus isolates with reduced susceptibilities to daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2008;52:3061-3067.
- Tedesco KL et. al. Daptomycin. Pharmacotherapy. 2004;24:41-57.
- Benvenuto M, et al. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006;50:3245-3249.
- Cunha BA, et al. Pacemaker-induced Staphylococcus aureus mitral valve acute bacterial endocarditis complicated by persistent bacteremia from a coronary stent: Cure with prolonged/ high-dose daptomycin without toxicity. Heart Lung. 2006;35:207-211.
- Cunha BA, et al. E. faecalis vancomycin-sensitive enterococcal bacteremia unresponsive to a vancomycin tolerant strain successfully treated with high-dose daptomycin. Heart Lung. 2007;36:456-461.
- Cunha BA, et al. Methicillin-resistant Staphylococcus aureus (MRSA) mitral valve acute bacterial endocarditis (ABE) in a patient with Job' syndrome (hyperimmunoglobulin E syndrome) successfully treated with linezolid and high-dose daptomycin. Heart Lung. 2008;37:72-75.
- Katz DE, et al. A pilot study of high-dose short duration daptomycin for the treatment of patients with complicated skin and skin structure infections caused by gram-positive bacteria. Int J Clin Pract. 2008;62:1455-1464.
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