1 Pharmacy Service, South Texas Veterans Healthcare System, 2 Department of Medicine, The University of Texas Health Science Center, 3 Pharmacy Service, University Health System, 4 Departments of Clinical Pharmacy & Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA
Keywords: anti-infective agents , adverse reactions , lipopeptide antibiotics
Sir,
A 52-year-old male with a history of intravenous drug abuse, idiopathic thrombocytopenia, hyperlipidaemia and hepatitis C was admitted to hospital with low back pain, fevers and chills. MRI findings were compatible with L3L4 discitis and osteomyelitis. The patient underwent an open biopsy where Gram-positive cocci were observed on Gram stain, but cultures were negative. The patient was started on vancomycin, but this was discontinued and daptomycin was initiated after the patient developed a generalized erythematous rash with facial angiooedema. Daptomycin was begun at 500 mg (6.5 mg/kg) intravenously as a single daily dose. The patient was also on simvastatin, which was discontinued upon initiation of daptomycin, in accordance with the manufacturer's recommendations. The baseline creatinine phosphokinase (CPK) level was 102 U/L (normal, 25220 U/L) and liver function tests were within normal limits. Nine days into his course (5 days after discharge) he developed generalized muscle pain and weakness, progressing to the point where he could not get out of bed. Physical examination revealed generalized tenderness and decreased muscle strength in both upper (4/5) and lower (3/5) extremities. No sensory deficits were present and deep tendon reflexes were 2+ bilaterally. His admission CPK level was 20 771 U/L, urinalysis was negative for blood and serum creatinine was 0.9 mg/L. A serum myoglobin was not performed. Alkaline phosphatase was elevated at 118 U/L, as were aspartase aminotransferase and alanine aminotransferase at 239 U/L and 48 U/L. Serum bilirubin was 0.5 mg/dL. A urine toxicology screen was negative for illicit drugs, and the patient denied resuming his simvastatin or taking any other new medications, including over-the-counter medications. Daptomycin was discontinued and the patient was admitted to the intensive care unit for close monitoring and hydration. The patient gradually recovered his muscle strength over the following 48 h, with resolution of pain, although CPK levels were still 2700 U/L 5 days after admission. His renal function remained normal throughout the hospitalization. He was discharged on linezolid with close monitoring to complete 6 weeks of antibiotic therapy. Two weeks later the CPK and liver enzymes had normalized and all muscular symptoms had resolved.
Daptomycin is a cyclic lipopeptide antibiotic approved by the FDA in 2003. It is rapidly bactericidal against most Gram-positive organisms including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. It has been shown to be efficacious for skin and soft tissue infections at a dose of 4 mg/kg daily and is currently being studied for serious Gram-positive infections, such as endocarditis, at a dose of 6 mg/kg daily.1
Daptomycin is well tolerated by most patients.1,2 As with all new drugs, however, uncommon adverse events may become apparent during post-marketing surveillance. Skeletal muscle toxicity was recognized in Phase I clinical studies when two of five patients receiving a dose of 4 mg/kg every 12 h developed marked elevations of CPK with associated muscle weakness and myalgias.3 Several recent pharmacokinetic, efficacy and safety studies have supported the safety of single daily doses of 48 mg/kg for up to 14 days.1,2 A recent animal model provides insight into the skeletal muscle toxicity of daptomycin in dogs; it found that toxicity was closely related to dosing frequency.4 In this study, dividing the total dose of daptomycin every 8 h was associated with significantly greater elevations in CPK and more marked skeletal muscle changes (primarily degeneration of myofibres with minimal inflammation) than a large single daily dose. Some muscle fibres were in a state of regeneration and it was postulated that the longer time between doses allowed for greater repair before additional damage occurred due to the next dose of drug. Our patient shows once-daily dosing may not be completely protective, despite monitoring as recommended in the product information. Although statins could theoretically increase the risk of daptomycin myopathy via additive effects, 34 patients in clinical trials received concomitant statin or fibrate therapy along with daptomycin without evidence of musculoskeletal adverse events (Cubist Pharmaceuticals, Inc., data on file). Another case of daptomycin-induced myalgia at 6 mg/kg daily has recently appeared in the literature, but the peak CPK elevation in this case was only a small fraction of that seen in our patient.5
The elevation of liver enzymes with myopathy is also concerning, as it has not been described previously. Despite a history of hepatitis C, the patient's liver enzymes during the past year were normal. No other hepatotoxic medications or substances were identified. The enzymes also increased and resolved temporally with the CPK elevation, suggesting a common mechanism.
We conclude that daptomycin was the likely cause of our patient's myopathy and possible hepatotoxicity. To our knowledge, this is the only case of daptomycin myopathy with associated liver function abnormalities. We recommend close monitoring of CPK and symptoms of myopathy in all patients started on this drug, and discontinuation of concurrent statin therapy.
Acknowledgements
No specific financial support was obtained for the preparation of this article. The authors have no potential conflicts of interest to declare with respect to this paper.
References
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Veligandla, S. R., Louie, K. R., Malesker, M. A. et al. (2004). Muscle pain associated with daptomycin. Annals of Pharmacotherapy 38, 18602.