Myopathy Associated with Daptomycin Use

Special Feature

By Heather Baker, Jennifer Murphy, Jessica C. Song, Heather Baker is PharmD Candidate, University of the Pacific School of Pharmacy, Stockton, CA, Jennifer Murphy is California Polytechnic University Student, San Luis Obispo, CA, and Jessica C. Song, PharmD, is Pharmacy Residency Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

Heather Baker, Jennifer Murphy, and Jessica C. Song report no financial relationships relevant to this field of study.

Introduction

Daptomycin is a cyclic lipopeptide antibiotic which was initially approved by the Food and Drug Administration (FDA) for the treatment of complicated skin and skin-skin structure infections in September 2003.1 More recently, the FDA issued an approval letter to Cubist Pharmaceuticals for the indication of the treatment of Staphylococcus aureus bacteremia, including right-sided endocarditis caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus.2

Of note, earlier phase-1 and phase-2 clinical trials in the 1980s and early 1990s utilized multiple daily dosing regimens of daptomycin. However, because of the apparent propensity of daptomycin to cause myopathy, Eli Lilly voluntarily discontinued clinical development of this agent in 1991.3 However, because of the relative lack of treatment options for life-threatening Gram-positive infections, the renewed clinical development of daptomycin was licensed to Cubist Pharmaceuticals in 1997.3 Subsequent animal studies indicated that increasing the dosing interval appeared to minimize the frequency and severity of myotoxic effects of this drug.3,4

This article will: 1) review the mechanism of myopathy induction by daptomycin; 2) review the literature reports of myopathy associated with daptomycin; and 3) review the potential interaction between daptomycin and statins (HMG CoA Reductase Inhibitors).

Pathophysiology for Daptomycin-Induced Myotoxicity

Several clinical studies and case reports have examined the possible causes and options for controlling myopathy. Unlike other causes of myopathy, daptomycin-associated myotoxicity appears to be specific for skeletal muscle.4 No myofiber lesions were detected during microscopic evaluation of canine cardiac muscle at doses as high as 75mg/kg daily.4 Moreover, studies in animals, as well as humans have shown that muscle-related adverse effects associated with daptomycin are readily reversible, with no resulting fibrosis of the skeletal muscle.4,5

Creatine phosphokinase (CPK) is an important marker for both the diagnosis, as well as in monitoring the course of myopathy. When skeletal muscle is injured, CPK leaks into the blood and is commonly associated with muscle weakness.6 CPK release by skeletal muscle has been attributed to numerous events, including surgical trauma, IM injections, physical activity, and bacterial or viral infection.5 Consistent with daptomycin's characteristics and mechanism of action, membrane disturbances can lead to cellular release of CPK, with corresponding elevations of CPK in plasma. Clinical studies have shown that 2.8% of patients experience CPK elevations,7 and some case reports have described CPK elevations as high as 21,243 U/L (normal 0-200).8

Dosing Frequency of Daptomycin

The dosing frequency of daptomycin has been implicated in the development of myopathy and CPK elevations. In Phase I studies, 2 of 5 subjects dosed at 4mg/kg q12h experienced myopathy, with CPK levels 10 times the upper limit of normal.5 In contrast, Oleson and colleagues demonstrated in animals that once-daily dosing of daptomycin resulted in significantly fewer skeletal muscle effects, with 5 times more muscle degeneration seen in dogs dosed at intervals of 8h compared to every 24h (see Chart A).4

Oleson et al evaluated fractionated versus once-daily dosing regimens and the subsequent effects on skeletal muscle, along with serum CPK levels. The highest elevations in CPK were observed in animals that received fractionated regimens. Similar CPK values were seen in both the high-dose and low-dose once-daily regimens, despite the 3-fold increase in daily dose. However, a 4-fold increase in CPK was seen in the fractionated regimen versus once-daily regimen, despite the same total overall dose. Of further significance, muscle fiber lesions seen upon microscopic evaluation were higher in the fractionated regimens of daptomycin compared to the once-daily regimen. Chart A illustrates these results.

The dosing regimen of 75 mg/kg q24h resulted in plasma daptomycin concentrations well below the trough achieved with fractionated dosing for 12 hours prior to the next dose administration. It was postulated by researchers that this could allow for repair of myofibers damaged during previous dosing.4

Although the dosing interval plays a major role in the development of myopathy, the Cmax is unlikely to be responsible for the acquisition of this adverse effect. In the study conducted by Oleson et al, a dosing regimen of 25 mg/kg q8h resulted in a CPK value of 3996 U/L, whereas dosing once daily at 75 mg/kg yielded a CPK value of 991 U/L, even though the Cmax was twice that of the fractionated regimen.4

Case Studies in Specific Patient Populations

In a Phase I study conducted by Cubist Pharmaceuticals, 2 subjects experienced elevations in CPK to values no more than 2.5 times the upper limit of normal. The subject who experienced the highest CPK elevation (477 U/L) had engaged in significant physical activity the day prior to serum sampling, to which the elevation was attributed. In both subjects, CPK levels returned to normal within 2 days, despite continued therapy with daptomycin. However, this study population consisted solely of those with normal hepatic and renal function and those who were free from prescription medication use for at least 30 days prior to initiation of the study.5

In contrast, several case reports have described substantial elevations in CPK with severe corresponding myopathy. A 45-year-old female with refractory AML (acute myeloid leukemia) received 6 mg/kg daptomycin daily after failing both vancomycin and linezolid therapy for E. faecium bacteremia. Her CPK values increased from 108 U/L to 996 U/L within 10 days of initiating daptomycin, and she subsequently developed rhabdomyolysis. Of note, this patient was also taking Amphotericin B lipid complex and had developed bacterial sepsis, both of which are known to be precipitating factors for the development of rhabdomyolysis.1

In another case report, a patient with diabetes, hypertension, and peripheral vascular disease experienced rhabdomyolysis while on 6 mg/kg daptomycin once daily. After experiencing severe muscle weakness with a CPK level of 21,243 U/L (10 days after start of therapy), daptomycin therapy was withdrawn and a diagnosis of acute renal failure secondary to rhabdomyolysis was made. In this case, no other medications or disease states thought to cause rhabdomyolysis were involved.8

In addition to renal dysfunction and rhabdomyolysis, a case report of possible hepatotoxicity associated with daptomycin has been filed. This patient was also taking simvastatin, which was discontinued upon initiation of daptomycin, per the manufacturer's recommendations. Even without concomitant use of medications known to cause myopathy, this patient's CPK value rose to 20,771 U/L after 9 days of treatment with 6.5 mg/kg daptomycin once daily.9

Finally, a 26-year-old SLE (systemic lupus erythematosus) patient who failed quinupristin/dalfopristin due to severe myalgia, also experienced myopathy while on daptomycin, with a CPK elevation of 492 U/L (day 15 of therapy). This patient continued treatment with a normalization of her CPK level within 3 days of the end of therapy. Although this patient also had SLE, the inflammation and release of CPK was attributed solely to daptomycin.10

FDA Briefing Document on Daptomycin

In the FDA-reviewed document prepared by the manufacturer, the incidence of significant CPK elevations was examined between daptomycin and comparator regimens (nafcillin/oxacillin, vancomycin).11 Also examined was the relationship between CPK elevations and prior or concomitant therapy with statins, a medication class known to cause myotoxicity. Below is a summary of the manufacturer's findings (see Chart B).

In the daptomycin-treated patients who experienced CPK elevations (n = 11), 4 had prior or current treatment with statins, namely simvastatin and atorvastatin. Of the 11 patients who developed CPK elevations, 6 required discontinuation of daptomycin therapy, but it is unclear if this included patients who were also being treated with statins.11

Of interest is the dose of statin therapy that led to elevations in CPK. While not reported in the FDA briefing document, the manufacturer has stated in the package insert that patients stable on 40mg of simvastatin while taking 4mg/kg daptomycin did not show an increase in adverse muscle effects.12

Recommendations for Appropriate Use of Daptomycin

Current manufacturing recommendations include weekly CPK monitoring, as well as discontinuing daptomycin therapy if CPK levels exceed 10 times the normal level, or if myopathy symptoms are present with a CPK level above 1,000U/L.12

The manufacturer also recommends consideration be given to holding medications known to cause myopathy while on daptomycin therapy, including statins.

Post-marketing case reports have led to recommendations for patient-specific monitoring, including obtaining more frequent CPK levels for critically ill patients and those patients who are also taking myopathy-causing drugs.1

References

  1. Papadopoulos S, et al. Rhabdomyolysis During Therapy with Daptomycin. Clin Infect Dis. 2006;42:e108-e110.
  2. FDA Approves Expanded Label for IV Antibiotic Cubicin. Cubist Pharmaceuticals News Bulletin. Website accessed on August 15, 2006. www.cubist.com/about/news/27/fda_approves_expanded_label_foriv_antibiotic_cubicin/
  3. Tedesco KL, Rybak MJ. Daptomycin. Pharmacotherapy. 2004;24:41-57.
  4. Oleson FB Jr., et al. Once-Daily Dosing in Dogs Optimizes Daptomycin Safety. Antimicrob Agents Chemother. 2000;44:2948-2953.
  5. Dvorchik BH, et al. Daptomycin Pharmacokinetics and Safety Following Administration of Escalating Doses Once Daily to Healthy Subjects. Antimicrob Agents Chemother. 2003;47:1318-1323.
  6. Goldman L, Ausiello D. Cecil Textbook of Medicine. 22nd edition. Saunders Pennsylvania.
  7. Arbeit RD, et al. The Safety and Efficacy of Daptomycin for the Treatment of Complicated Skin and Skin-Structure Infections. Clin Infect Dis. 2004;38:1673-1681.
  8. Kazory A, et al. Rhabdomyolysis and Acute Renal Failure in a Patient Treated with Daptomycin. J Antimicrob Chemother. 2006;57:578-579.
  9. Echevarria K, et al. Severe Myopathy and Possible Hepatotoxicity Related to Daptomycin. J Antimicrob Chemother. 2005;55:599-600.
  10. Veligandla SR, et al. Muscle Pain Associated with Daptomycin. Ann Pharmacother. 2004;38:1860-1862.
  11. FDA Briefing Document for Anti-infective Drug Advisory Committee Meeting, March 6, 2006. Cubicin (Daptomycin for Injection) for the Treatment of Staphylococcus aureus Bacteremia, Including Those with Known or Suspected Infective Endocarditis.
  12. Cubicin (Daptomycin) Injection [Package Insert]. Lexington, MA: Cubist Pharmaceuticals, 2005.