Statins are among the most frequently prescribed

CASE REPORT Severe Rhabdomyolysis as a Consequence of the Interaction of Fusidic Acid and Atorvastatin Ciara N. Magee, MB, MRCPI, 1,2 Samar A. Medani, MRCP(UK), 3 Sean F. Leavey, MD, MS, FRCPI, 3 Peter J. Conlon, FRCPI, 1 and Michael R. Clarkson, MD, FRCPI 2 Rhabdomyolysis is a known complication of statin therapy and may be triggered by a pharmacokinetic interaction between a statin and a second medication. Fatal statin-induced rhabdomyolysis has an incidence of 0.15 deaths/million prescriptions. We describe 4 cases of severe rhabdomyolysis with the common feature of atorvastatin use and coadministration of fusidic acid. All cases involved long-term therapy with atorvastatin; fusidic acid was introduced for treatment of osteomyelitis or septic arthritis. Three cases occurred in the setting of diabetes mellitus, with 2 in patients with end-stage renal disease, suggesting increased susceptibility to atorvastatin fusidic acid induced rhabdomyolysis in these patient populations. Of the 4 patients in this series, 3 died. Fusidic acid is a unique bacteriostatic antimicrobial agent with principal antistaphylococcal activity. There have been isolated reports of rhabdomyolysis attributed to the interaction of statins and fusidic acid, the cause of which is unclear. Fusidic acid does not inhibit the cytochrome P450 3A4 isoenzyme responsible for atorvastatin metabolism; increased atorvastatin levels due to inhibition of the glucuronidation pathway may be responsible. Considering the low frequency of fusidic acid use, the appearance of 4 such cases within a short time and in a small population suggests the probability that development of this potentially fatal complication may be relatively high. Am J Kidney Dis 56:e11-e15. 2010 by the National Kidney Foundation, Inc. INDEX WORDS: Rhabdomyolysis; fusidic acid and atorvastatin. Statins are among the most frequently prescribed medications, often used in patients with multiple comorbid conditions to decrease cholesterol levels and reduce the risk of cardiovascular events. Statins are metabolized by the cytochrome P450 system, 1 with the attendant risk of multiple potential drug interactions. Therapy is largely well tolerated, although associated with a spectrum of muscle disorders ranging from myalgia to rhabdomyolysis. 2,3 The reported incidence of rhabdomyolysis associated with the use of statins other than cerivastatin is 3.4 events/100,000 patient-years, 4 and in most cases was triggered by the interaction of a statin with a second medication, particularly fibrates. 3,4 The reported incidence of rhabdomyolysis requiring hospitalization with atorvastatin monotherapy is 0.54 events/10,000 patient-years, increasing to 22.45 events/10,000 patient-years when combined with a fibrate. 3 Fatal statin-induced rhabdomyolysis has a reported incidence of 0.15 deaths/ million prescriptions 5 and prompted the voluntary worldwide withdrawal of cerivastatin in 2001. 6 Fusidic acid is a unique bacteriostatic antimicrobial agent believed to act through inhibition of bacterial protein synthesis. Its principal activity is antistaphylococcal, and because it penetrates well into tissue and bone, it often is used for the treatment of staphylococcal osteomyelitis in conjunction with a second agent. There have been only isolated reports of rhabdomyolysis attributed to the interaction of statins and fusidic acid, the cause of which is unclear. CASE REPORTS A summary of the clinical characteristics of the 4 patients with severe rhabdomyolysis who had received atorvastatin and fusidic acid is listed in Table 1. From the 1 Department of Nephrology, Beaumont Hospital, Dublin; 2 Department of Renal Medicine, Cork University Hospital, Cork; and 3 Department of Nephrology, Waterford Regional Hospital, Waterford, Ireland. Received February 16, 2010. Accepted in revised form July 7, 2010. Originally published online as doi:10.1053/j. ajkd.2010.07.011 on October 1, 2010. Address correspondence to Michael R. Clarkson, MD, FRCPI, Department of Renal Medicine, Cork University Hospital, Wilton Rd, Cork, Ireland. E-mail: m.clarkson@ ucc.ie 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5605-0034$36.00/0 doi:10.1053/j.ajkd.2010.07.011 American Journal of Kidney Diseases, Vol 56, No 5 (November), 2010: e11-e15 e11

e12 Magee et al Table 1. Clinical Characteristics of the 4 Cases Discussed Atorvastatin Fusidic Acid Culture-Positive Organisms Outcome Time to Onset of Rhabdomyolysis (wk) Indication for Use Route of Administration Dose (g/d) Duration of Use Dose (mg/d) Baseline Kidney Function Age (y)/sex Comorbid Conditions Case No. SCr, 0.98 mg/dl 40 Years 1.5 IV & oral Osteomyelitis 3-4 Died 1 58/M T1DM, IHD, PVD, recurrent osteomyelitis Died 2 73/M T2DM, ESRD, PVD ESRD 40 Years 1.5 Oral Osteomyelitis 3 Enterococcus spp (ankle swab); E coli (bone biopsy) 3 71/M T2DM, IHD, ESRD ESRD 20 Years 1.5 Oral Osteomyelitis 3-4 Died 4 48/M Hyperlipidemia SCr, 0.98 mg/dl 40 18 mo 1.5 Oral Septic arthritis 3 MRSA Recovered with normal kidney function Note: Conversion factor for SCr in mg/dl to mol/l, 88.4. Abbreviations: E coli, Escherichia coli; ESRD, end-stage renal disease; IHD, ischemic heart disease; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; PVD, peripheral vascular disease; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; SCr, serum creatinine. Case 1 A 58-year-old man with a history of type 1 diabetes mellitus (DM), ischemic heart disease, and recurrent osteomyelitis who was on long-term atorvastatin therapy was admitted with osteomyelitis. This was treated with flucloxacillin and fusidic acid; treatment with both agents was continued on discharge. He was readmitted 1 week later with malaise and generalized myalgia. His creatinine kinase (CK) level was increased at 30,000 IU/L, and serum creatinine level was 0.98 mg/dl (87 mol/l). Atorvastatin therapy was withheld, and he was managed conservatively with intravenous normal saline solution. During the following days, CK level peaked at 500,000 IU/L and he developed severe acute kidney injury (RIFLE grade F), requiring transfer to a tertiary referral center and the start of hemodialysis therapy. He subsequently developed necrotizing fasciitis and underwent emergent radical debridement and fasciectomy. Despite aggressive measures, he developed profound septic shock and experienced a fatal cardiac arrest after a myocardial infarction. Case 2 A 73-year-old man with complicated type 2 DM and end-stage renal disease (on hemodialysis therapy) was admitted with an infected malleolar ulcer. Baseline medications included atorvastatin. He was treated with benzylpenicillin, flucloxacillin, and metronidazole; fusidic acid was added after the diagnosis of osteomyelitis. Approximately 3 weeks later, he developed a progressive painless myopathy. CK level was increased at 2,266 IU/L, and atorvastatin therapy was withdrawn. Nevertheless, his CK level continued to increase, peaking at 120,000 IU/L. His clinical condition deteriorated, requiring transfer to the intensive therapy unit for mechanical ventilation. After several episodes of ventricular arrhythmia in conjunction with declining clinical status, active treatment was withdrawn and he died. Case 3 A 71-year-old man with type 2 DM, ischemic heart disease, and end-stage renal disease (on hemodialysis therapy) was admitted with metatarsal osteomyelitis. Maintenance medications included atorvastatin. He underwent surgical debridement and was treated with flucloxacillin, benzylpenicillin, and fusidic acid, all of which were maintained on discharge. One week later, he was readmitted with generalized weakness. The admission CK level was increased at 19,772 IU/L, and atorvastatin therapy was stopped. However, his CK level increased further, peaking at 147,000 IU/L. His clinical condition deteriorated, and notwithstanding maximal supportive intensive therapy unit care, he died of multiorgan dysfunction syndrome. Case 4 A 48-year-old man with a history of hyperlipidemia and recent knee arthroscopy complicated by methicillin-resistant Staphylococcal aureus septic arthritis (treated with linezolid and fusidic acid) presented with malaise and generalized myalgia. Admission medications included atorvastatin. Urinalysis showed cola-colored urine without red blood cells.

Rhabdomyolysis, Fusidic Acid, and Atorvastatin Urine myoglobin was positive at 242 g/l. CK level was grossly increased at 133,327 IU/L and peaked at 300,000 IU/L 3 days later. Serum creatinine level on admission was 0.98 mg/dl (87 mol/l) and peaked at 1.56 mg/dl (138 mol/l). Atorvastatin therapy was stopped and an aggressive regimen of intravenous fluids was implemented, along with urinary alkalinization. Kidney function subsequently improved without the need for renal replacement therapy. DISCUSSION Statin-induced myopathy is a well-recognized entity, although it lacks a consensus definition. 7 Reported incidence rates vary among studies; in clinical trials of statins, rates of associated myopathy are low (0.1%-0.2%), 2 whereas a review of trials involving atorvastatin use reported a statinassociated myalgia rate of 1.9%, requiring discontinuation of therapy in 0.4% of patients. These rates were similar to those seen with other statins (3% and 0.7%, respectively). 8 However, observational studies suggest that the incidence of statinrelated muscle disorders may be significantly higher. The PRIMO (Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Chronic Kidney Disease Stage 3/4) Study, which reviewed high-dose statin therapy, reported an incidence of myalgia of 10.5%; the highest rates (18.2%) were seen with high-dose simvastatin therapy. 9 A number of factors associated with an increased risk of statin-associated myopathy have been identified, including advanced age, female sex, multisystem disease (including chronic kidney and liver disease, hypothyroidism, and DM), heavy alcohol consumption, and medications that interfere with the cytochrome P450 system. 10 A review of statin-associated rhabdomyolysis showed that 58% of cases were associated with the coadministration of medications that interfered with statin metabolism. 3 The exact mechanism of statin-induced myopathy is uncertain, although several theories have been proposed. The decrease in cholesterol synthesis is believed to decrease cholesterol levels in skeletal muscle cell membranes, causing instability. 1,3,7 However, a decrease in cholesterol synthesis through inhibition of squalene synthase does not cause myotoxicity in vitro, 11 suggesting an alternative cause. Inhibition of HMG- CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase leads to decreased synthesis of farnesyl pyrophosphate, an intermediate compound in e13 the synthesis of ubiquinone (coenzyme Q10), a steroid isoprenoid that participates in electron transport during mitochondrial oxidative phosphorylation. 1,3,12 Serum ubiquinone levels are lower in patients on statin therapy, whereas significantly higher ratios of lactate to pyruvate have been found in statin-treated patients, indicating mitochondrial dysfunction. 12 Isoprenoid depletion also has caused apoptosis in vitro through a decrease in the prenylation of small GTP (guanosine triphosphate)-binding proteins, 13 which may be an additional mechanism in the development of statin myopathy. Atorvastatin administered in its acid form is highly soluble and is completely absorbed after oral administration. It is subject to extensive first-pass metabolism in the gut and liver. Plasma protein binding is 98%. 14 Along with lovastatin and simvastatin, it is metabolized predominantly by cytochrome P450 3A4 (CYP3A4; ie, family 3, subfamily A, polypeptide 4; encoded by the CYP3A4 gene) 1,14 and has been shown to undergo glucuronidation, which leads to lactonization of the open acid forms, thought to be a common metabolic pathway for the hydroxyacid forms of statins. The lactone form itself has a critical role in CYP3A4-catalyzed statin metabolism. 15 The fibrate gemfibrozil has been shown to inhibit this glucuronidation pathway, 16 leading to increased statin levels. Fusidic acid is a unique bacteriostatic antimicrobial agent believed to act through inhibition of bacterial protein synthesis. Its principal activity is antistaphylococcal, and because it penetrates well into tissue and bone, it often is used for the treatment of staphylococcal osteomyelitis in conjunction with a second agent. Although not US Food and Drug Administration approved in the United States, fusidic acid use is common in Europe and Australasia. Limited data exist about its metabolism, but it is near-exclusively hepatically metabolized with biliary excretion; its main metabolite is a glucuronide conjugate. 17,18 The pharmacokinetics of fusidic acid in the setting of kidney failure therefore essentially is unchanged. 19 It does not interfere with the CYP3A4 system (which is principally responsible for atorvastatin metabolism), but interference with the glucuronidation pathway may lead to mutual inhibition and increased drug levels, thereby increasing the risk of rhabdomyolysis. In addi-

e14 tion to our series, there have been isolated reports of rhabdomyolysis caused by the interaction of fusidic acid and atorvastatin. 20,21 There also are reports of rhabdomyolysis caused by the interaction of fusidic acid with other statins, 22,23 supporting the proposed mechanism of glucuronidation inhibition. Although fusidic acid has relatively narrow therapeutic indications, prescribed courses usually are of several weeks duration, such that potential cumulative exposure to the drug is significant. Community use of fusidic acid in Ireland in 2000-2008 represented approximately 0.1% of total community antibiotic use. In 2008, approximately 93% of fusidic acid dispensed was for inpatient hospital use; overall hospital fusidic acid use represented approximately 0.35% of total antibiotic use or 0.3 defined daily doses (1.5 g of fusidic acid) per 100 bed-days used. Use in larger (tertiary/regional) hospitals was higher, representing approximately 0.6% of total antibiotic use. 24 The appearance of 4 cases of such severity in a population of fewer than 4.5 million people during a 3-year period, when considered with the low frequency of fusidic acid use, suggests that the probability of developing this potentially fatal complication of treatment may be relatively high. We strongly recommend that statin therapy be withheld if starting treatment with fusidic acid. ACKNOWLEDGEMENTS The authors gratefully acknowledge the contribution of Ajay Oza, Health Service Executive, Health Protection Surveillance Centre, Dublin, Ireland. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. REFERENCES 1. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112(1): 71-105. 2. Hamilton-Craig I. Statin associated myopathy. Med J Aust. 2001;175(9):486-489. 3. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289(13):1681-1690. Magee et al 4. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C-60C. 5. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346(7):539-540. 6. Charatan F. Bayer decides to withdraw cholesterol lowering drug. BMJ. 2001;323(7309):359. 7. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150(12):858-868. 8. Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients. Am J Cardiol. 2003;92(6):670-676. 9. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients the PRIMO Study. Cardiovasc Drugs Ther. 2006;19(6):403-414. 10. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40(3):567-572. 11. Flint OP, Masters BA, Gregg RE, Durham SK. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol. 1997;145(1):91-98. 12. De Pinieux G, Chariot P, Ammi-Said M, et al. Lipidlowering drugs and mitochondrial function: effects of HMG- CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol. 1996;42(3):333-337. 13. Johnson TE, Zhang X, Bleicher KB, et al. Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol. 2004;200(3):237-250. 14. Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141-1160. 15. Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30(5):505-512. 16. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002;301(3):1042-1051. 17. Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 1999;12(suppl 2):S23-34. 18. Greenwood D, Finch R, Davey P, Wilcox M. Inhibitors of bacterial protein synthesis. In: Antimicrobial Chemotherapy. 5th ed. Oxford, UK: Oxford University Press; 2007:35-52. 19. Brown NM, Reeves DS, McMullin CM. The pharmacokinetics and protein-binding of fusidic acid in patients with severe renal failure requiring either haemodialysis or continuous ambulatory peritoneal dialysis. J Antimicrob Chemother. 1997;39(6):803-809. 20. Wenisch C, Krause R, Fladerer P, El Menjawi I, Pohanka E. Acute rhabdomyolysis after atorvastatin and fusidic acid therapy. Am J Med. 2000;109(1):78-80.

Rhabdomyolysis, Fusidic Acid, and Atorvastatin 21. O Mahony C, Campbell VL, Al-Khayatt MS, Brull DJ. Rhabdomyolysis with atorvastatin and fusidic acid. Postgrad Med J. 2008;84(992):325-327. 22. Kotanko P, Kirisits W, Skrabal F. Rhabdomyolysis and acute renal graft impairment in a patient treated with simvastatin, tacrolimus and fusidic acid. Nephron. 2002; 90(2):234-235. e15 23. Yuen SL, McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin. Med J Aust. 2003;179(3):172-174. 24. HospitalAntimicrobial Consumption Report. Consumption of Antibiotics in Public Acute Hospitals in Ireland 2008 Data. Dublin, Ireland: Health Service Executive (HSE) Health Protection Surveillance Centre (HPSC); 2009.