Severe Rhabdomyolysis as a Consequence of the Interaction of Fusidic Acid and Atorvastatin
2010; Elsevier BV; Volume: 56; Issue: 5 Linguagem: Inglês
10.1053/j.ajkd.2010.07.011
ISSN1523-6838
AutoresCiara N. Magee, Samar Medani, Sean F. Leavey, Peter J. Conlon, Michael R. Clarkson,
Tópico(s)Muscle and Compartmental Disorders
ResumoRhabdomyolysis 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. 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. 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,1Shitara 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: 71-105Crossref PubMed Scopus (504) Google Scholar 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.2Hamilton-Craig I. Statin associated myopathy.Med J Aust. 2001; 175: 486-489PubMed Google Scholar, 3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar The reported incidence of rhabdomyolysis associated with the use of statins other than cerivastatin is 3.4 events/100,000 patient-years,4Law M. Rudnicka A.R. Statin safety: a systematic review.Am J Cardiol. 2006; 97: 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar and in most cases was triggered by the interaction of a statin with a second medication, particularly fibrates.3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar, 4Law M. Rudnicka A.R. Statin safety: a systematic review.Am J Cardiol. 2006; 97: 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar 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.3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar Fatal statin-induced rhabdomyolysis has a reported incidence of 0.15 deaths/million prescriptions5Staffa J.A. Chang J. Green L. Cerivastatin and reports of fatal rhabdomyolysis.N Engl J Med. 2002; 346: 539-540Crossref PubMed Scopus (552) Google Scholar and prompted the voluntary worldwide withdrawal of cerivastatin in 2001.6Charatan F. Bayer decides to withdraw cholesterol lowering drug.BMJ. 2001; 323: 359Crossref Scopus (5) Google ScholarFusidic 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 ReportsA summary of the clinical characteristics of the 4 patients with severe rhabdomyolysis who had received atorvastatin and fusidic acid is listed in Table 1.Table 1Clinical Characteristics of the 4 Cases DiscussedCase No.Age (y)/SexComorbid ConditionsBaseline Kidney FunctionAtorvastatinFusidic AcidCulture-Positive OrganismsOutcomeDose (mg/d)Duration of UseDose (g/d)Route of AdministrationIndication for UseTime to Onset of Rhabdomyolysis (wk)158/MT1DM, IHD, PVD, recurrent osteomyelitisSCr, 0.98 mg/dL40Years1.5IV & oralOsteomyelitis3-4Died273/MT2DM, ESRD, PVDESRD40Years1.5OralOsteomyelitis 30,000 IU/L, and serum creatinine level was 0.98 mg/dL (87 μmol/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 2A 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 3A 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 4A 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. Urine myoglobin was positive at 242 μg/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 μmol/L) and peaked at 1.56 mg/dL (138 μmol/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.DiscussionStatin-induced myopathy is a well-recognized entity, although it lacks a consensus definition.7Joy T.R. Hegele R.A. Narrative review: statin-related myopathy.Ann Intern Med. 2009; 150: 858-868Crossref PubMed Scopus (364) Google Scholar Reported incidence rates vary among studies; in clinical trials of statins, rates of associated myopathy are low (0.1%-0.2%),2Hamilton-Craig I. Statin associated myopathy.Med J Aust. 2001; 175: 486-489PubMed Google Scholar whereas a review of trials involving atorvastatin use reported a statin-associated 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).8Newman C.B. Palmer G. Silbershatz H. Szarek M. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients.Am J Cardiol. 2003; 92: 670-676Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar However, observational studies suggest that the incidence of statin-related 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.9Bruckert 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: 403-414Crossref Scopus (963) Google ScholarA 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.10Pasternak R.C. Smith S.C. Bairey-Merz C.N. Grundy S.M. Cleeman J.I. Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins.J Am Coll Cardiol. 2002; 40: 567-572Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar A review of statin-associated rhabdomyolysis showed that 58% of cases were associated with the coadministration of medications that interfered with statin metabolism.3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google ScholarThe 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.1Shitara 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: 71-105Crossref PubMed Scopus (504) Google Scholar, 3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar, 7Joy T.R. Hegele R.A. Narrative review: statin-related myopathy.Ann Intern Med. 2009; 150: 858-868Crossref PubMed Scopus (364) Google Scholar However, a decrease in cholesterol synthesis through inhibition of squalene synthase does not cause myotoxicity in vitro,11Flint O.P. Masters B.A. Gregg R.E. Durham S.K. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro.Toxicol Appl Pharmacol. 1997; 145: 91-98Crossref PubMed Scopus (115) Google Scholar 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 the synthesis of ubiquinone (coenzyme Q10), a steroid isoprenoid that participates in electron transport during mitochondrial oxidative phosphorylation.1Shitara 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: 71-105Crossref PubMed Scopus (504) Google Scholar, 3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar, 12De Pinieux G. Chariot P. Ammi-Said M. et al.Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio.Br J Clin Pharmacol. 1996; 42: 333-337Crossref PubMed Scopus (241) Google Scholar 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.12De Pinieux G. Chariot P. Ammi-Said M. et al.Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio.Br J Clin Pharmacol. 1996; 42: 333-337Crossref PubMed Scopus (241) Google Scholar Isoprenoid depletion also has caused apoptosis in vitro through a decrease in the prenylation of small GTP (guanosine triphosphate)-binding proteins,13Johnson T.E. Zhang X. Bleicher K.B. et al.Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone.Toxicol Appl Pharmacol. 2004; 200: 237-250Crossref PubMed Scopus (115) Google Scholar 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%.14Lennernäs H. Clinical pharmacokinetics of atorvastatin.Clin Pharmacokinet. 2003; 42: 1141-1160Crossref PubMed Scopus (450) Google Scholar 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)1Shitara 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: 71-105Crossref PubMed Scopus (504) Google Scholar, 14Lennernäs H. Clinical pharmacokinetics of atorvastatin.Clin Pharmacokinet. 2003; 42: 1141-1160Crossref PubMed Scopus (450) Google Scholar 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 hydroxy-acid forms of statins. The lactone form itself has a critical role in CYP3A4-catalyzed statin metabolism.15Prueksaritanont 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: 505-512Crossref PubMed Scopus (301) Google Scholar The fibrate gemfibrozil has been shown to inhibit this glucuronidation pathway,16Prueksaritanont T. Zhao J.J. Ma B. et al.Mechanistic studies on metabolic interactions between gemfibrozil and statins.J Pharmacol Exp Ther. 2002; 301: 1042-1051Crossref PubMed Scopus (261) Google Scholar 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.17Turnidge J. Fusidic acid pharmacology, pharmacokinetics and pharmacodynamics.Int J Antimicrob Agents. 1999; 12: S23-S34Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 18Greenwood D. Finch R. Davey P. Wilcox M. Inhibitors of bacterial protein synthesis.in: Antimicrobial Chemotherapy. 5th ed. Oxford University Press, Oxford, UK2007: 35-52Google Scholar The pharmacokinetics of fusidic acid in the setting of kidney failure therefore essentially is unchanged.19Brown N.M. Reeves D.S. McMullin C.M. 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: 803-809Crossref PubMed Scopus (13) Google Scholar 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 addition to our series, there have been isolated reports of rhabdomyolysis caused by the interaction of fusidic acid and atorvastatin.20Wenisch C. Krause R. Fladerer P. El Menjawi I. Pohanka E. Acute rhabdomyolysis after atorvastatin and fusidic acid therapy.Am J Med. 2000; 109: 78-80Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 21O'Mahony C. Campbell V.L. Al-Khayatt M.S. Brull D.J. Rhabdomyolysis with atorvastatin and fusidic acid.Postgrad Med J. 2008; 84: 325-327Crossref PubMed Scopus (21) Google Scholar There also are reports of rhabdomyolysis caused by the interaction of fusidic acid with other statins,22Kotanko P. Kirisits W. Skrabal F. Rhabdomyolysis and acute renal graft impairment in a patient treated with simvastatin, tacrolimus and fusidic acid.Nephron. 2002; 90: 234-235Crossref PubMed Scopus (29) Google Scholar, 23Yuen S.L. McGarity B. Rhabdomyolysis secondary to interaction of fusidic acid and simvastatin.Med J Aust. 2003; 179: 172-174PubMed Google Scholar 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.24Hospital Antimicrobial Consumption ReportConsumption of Antibiotics in Public Acute Hospitals in Ireland—2008 Data. Health Service Executive (HSE)—Health Protection Surveillance Centre (HPSC), Dublin, Ireland2009Google ScholarThe 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. 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,1Shitara 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: 71-105Crossref PubMed Scopus (504) Google Scholar 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.2Hamilton-Craig I. Statin associated myopathy.Med J Aust. 2001; 175: 486-489PubMed Google Scholar, 3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar The reported incidence of rhabdomyolysis associated with the use of statins other than cerivastatin is 3.4 events/100,000 patient-years,4Law M. Rudnicka A.R. Statin safety: a systematic review.Am J Cardiol. 2006; 97: 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar and in most cases was triggered by the interaction of a statin with a second medication, particularly fibrates.3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar, 4Law M. Rudnicka A.R. Statin safety: a systematic review.Am J Cardiol. 2006; 97: 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar 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.3Thompson P.D. Clarkson P. Karas R.H. Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1215) Google Scholar Fatal statin-induced rhabdomyolysis has a reported incidence of 0.15 deaths/million prescriptions5Staffa J.A. Chang J. Green L. Cerivastatin and reports of fatal rhabdomyolysis.N Engl J Med. 2002; 346: 539-540Crossref PubMed Scopus (552) Google Scholar and prompted the voluntary worldwide withdrawal of cerivastatin in 2001.6Charatan F. Bayer decides to withdraw cholesterol lowering drug.BMJ. 2001; 323: 359Crossref Scopus (5) Google Scholar 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 ReportsA summary of the clinical characteristics of the 4 patients with severe rhabdomyolysis who had received atorvastatin and fusidic acid is listed in Table 1.Table 1Clinical Characteristics of the 4 Cases DiscussedCase No.Age (y)/SexComorbid ConditionsBaseline Kidney FunctionAtorvastatinFusidic AcidCulture-Positive OrganismsOutcomeDose (mg/d)Duration of UseDose (g/d)Route of AdministrationIndication for UseTime to Onset of Rhabdomyolysis (wk)158/MT1DM, IHD, PVD, recurrent osteomyelitisSCr, 0.98 mg/dL40Years1.5IV & oralOsteomyelitis3-4Died273/MT2DM, ESRD, PVDESRD40Years1.5OralOsteomyelitis 30,000 IU/L, and serum creatinine level was 0.98 mg/dL (87 μmol/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 2A 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 3A 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 4A 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. Urine myoglobin was positive at 242 μg/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 μmol/L) and peaked at 1.56 mg/dL (138 μmol/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. 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. Note: Conversion factor for SCr in mg/dL to μmol/L, ×88.4. Abbreviations: E coli, Escherichia coli; ESRD, end-stage renal disease; IHD, ischemic heart di
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