Rhabdomyolysis and acute renal failure associated with the co-administration of daptomycin and an HMG-CoA reductase inhibitor

Sir, Daptomycin is a lipopeptide antibiotic approved for the treatment of complicated skin and skin structure infections (cSSSIs) due to specified organisms and the treatment of Staphylococcus aureus bloodstream infections, including right-sided endocarditis, caused by methicillin-susceptible S. aureus and methicillin-resistant S. aureus.1 Although well tolerated in clinical trials and use, there have been reports of elevations in serum creatine phosphokinase (CPK) concentrations, occasionally with accompanying rhabdomyolysis and acute renal failure.2–5 Here, we report this first case of CPK elevation with rhabdomyolysis and acute renal failure that developed during the co-administration of daptomycin and an HMG-CoA reductase inhibitor. Symptoms resolved after discontinuation of daptomycin. A patient suffered a fall injury with a resulting fracture of the femoral bone at the site of previous total hip arthroplasty. Irrigation and debridement and removal of the prosthesis were performed. Intravenous (iv) vancomycin (1 g every 24 h) and cefepime (1 g every 12 h) were given post-operatively. Copious amounts of purulence had been encountered at the arthroplasty site, but no organisms grew from intraoperative cultures. For the next 2 weeks, there was no fever, but the white blood cell (WBC) count remained elevated (18 000–23 000 WBC/mm3). Vancomycin was discontinued and iv daptomycin was begun (7.2 mg/kg daily). Serum creatinine was noted to be 1.5 mg/dL, with a calculated creatinine clearance of 24.6 mL/min. Four days later, the daptomycin dose was changed to 7.2 mg/kg every 48 h. On the 16th day of daptomycin treatment, the patient complained of weakness and diffuse aches in the proximal thighs and arms. Serum CPK concentration was found to be 8995 IU/L (normal 38–234 IU/L). No prior CPK value was available. Antibiotics were changed to oral linezolid 600 mg and ciprofloxacin 500 mg, both twice daily. Vigorous iv fluids were administered. The serum creatinine reached a peak of 3.4 mg/dL. Urinalysis revealed 1+ albumin and a urine Hansel stain showed eosinophils. The patient’s usual medications included simvastatin (80 mg each evening), extended-release niacin (500 mg each evening) and esomeprazole (20 mg daily) and were continued throughout her hospitalization. Six days after stopping daptomycin, the serum creatinine returned to baseline. Seven days after stopping daptomycin, the CPK concentration had decreased to 125 IU/L. A 4 week course of linezolid was completed, followed by oral minocycline 100 mg twice daily. The arthroplasty was successfully revised and the patient was discharged on long-term suppressive minocycline therapy, continuing to do well after 1 year with no evidence of recurrent infection. Few cases of daptomycin-induced rhabdomyolysis have been described in the literature.2–5 In clinical trials, up to 6.7% of subjects experienced an increase in CPK concentrations.6 In Phase 3 cSSSI studies, 0.2% of patients treated with daptomycin had symptoms of muscle pain or weakness associated with CPK elevations greater than four times the upper limits of normal.7 Dosing frequency appears to have a more direct relationship on skeletal muscle than do peak plasma concentrations of daptomycin.8 The mechanism behind adverse skeletal muscle effects may involve leakage of intracellular CPK from affected myocytes in a manner similar to the drug’s ability to cause release of intracellular ions from bacterial cells. It is thought that less frequent administration of the drug allows additional repair time for damaged myocytes. In most prior reports of daptomycin toxicity, complaints usually began within 1 week, occasionally after a single dose.2–5 This patient developed symptoms on the 16th day of treatment. The patient was also receiving niacin and an HMG-CoA reductase inhibitor, drugs that are known to increase the risk of rhabdomyolysis when used alone or in combination.9,10 Both niacin and simvastatin were continued, and the rhabdomyolysis resolved after discontinuation of daptomycin. The temporal occurrence of rhabdomyolysis seems to implicate daptomycin as the causative agent rather than simvastatin and/or niacin, both of which had been well tolerated before and after the course of daptomycin and episode of rhabdomyolysis. Speculatively, any of these three agents could have contributed to, or potentiated, the actions of the other agent or agents in causing the rhabdomyolysis. Previous reports have not included the co-administration of HMG-CoA reductase inhibitors with daptomycin.2–5 A literature search at www.pubmed.com performed using the keywords ‘daptomycin’, ‘statin’, ‘rhabdomyolysis’ and/or ‘reductase inhibitor’ did not reveal a previous report of rhabdomyolysis in a patient receiving daptomycin and concomitant statin therapy. The eosinophiluria may have been due to interstitial nephritis. While a number of medications, including cephalosporins and proton pump inhibitors, can be associated with interstitial nephritis, the other drugs have not been frequently implicated in the literature as causes of rhabdomyolysis. The elevation in the CPK concentration was sufficient enough to potentially have had a detrimental effect on renal function. The complaints of myalgias and weakness were consistent with a clinical impression of myopathy. The initial dose and frequency of daptomycin used in this patient were based on estimates by the prescribing physicians and were higher than those recommended by the manufacturer.7 This may have led to an increased risk of elevated CPK and associated problems. In conclusion, this is the first case reporting reversible rhabdomyolysis and renal failure after the co-administration of daptomycin and an HMG-CoA reductase inhibitor. According to the package insert for daptomycin, experience with co-administration with HMG-CoA reductase inhibitors is limited, and their use might need to be suspended during therapy with daptomycin.7 Consistent with earlier experiences, this patient’s renal dysfunction improved within 10 days after stopping daptomycin.2,7 Additional clues to impending adverse effects of daptomycin may be obtained by monitoring renal and hepatic function tests. The current recommendation is to monitor the serum CPK concentration at least weekly, and more frequently if clinical conditions warrant.7 No financial support was received for this work. None to declare.