THE WESTERN JOURNAL OF MEDICINE *
FEBRUARY 1991
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154 * 2
sive investigation and has been called the anticardiolipin syndrome. II Phlegmasia cerulea dolens is a life-threatening disorder that requires aggressive intervention to combat the high frequency of morbidity and mortality."'4',5 The treatment of PCD includes anticoagulation, thrombolytic therapy, and surgical thrombectomy used alone or in combination. 41,5 A recent review of the therapeutic options for PCD suggests that surgical intervention is needed when patients fail to respond to heparin therapy within 6 to 12 hours.15 The discovery of the lupus anticoagulant in our patient led to the institution of thrombolytic therapy that proved to be successful. It has been suggested that all patients with hypercoagulable clotting abnormalities are at high risk for the development of PCD.2 This case supports that suggestion. Cohen and colleagues have recently described six cases of PCD in patients who had associated hypercoagulable states, including heparin-induced thrombocytopenia, congenital protein C deficiency, and antithrombin III deficiency.2 The authors commented that recognition of an underlying coagulopathy is essential for the proper management of PCD. We agree and think the lupus anticoagulant should be included as another coagulopathy associated with PCD. Our patient had no evidence of an underlying collagen vascular disease or occult malignant neoplasm. The lupus anticoagulant contributed to the development of PCD, although she had morbid obesity and a previous deep vein
Rhabdomyolysis Associated With Lovastatin and Erythromycin Use DAVID H. SPACH, MD J. ERIC BAUWENS, MD CHRISTINE D. CLARK, MD WYLIE G. BURKE, MD, PhD
Seattle, Washington
LOVASTATIN,
a
hydroxymethylglutaryl-coenzyme A reduc-
tase inhibitor used to treat patients with hypercholesterole-
mia, has become a commonly administered drug. Its use has been associated with a low incidence of side effects that include elevated aminotransferase levels, skin rash, gastrointestinal symptoms, and skeletal muscle abnormalities.12 Clinically, the most important of these side effects is the skeletal muscle abnormalities that can manifest as asymptomatic creatine kinase elevations; muscle aches, tenderness, and weakness; and rhabdomyolysis.2 Patients at greatest risk of muscle abnormalities developing include those with an underlying illness or concurrently taking medication such as cyclosporine, gemfibrozil, or niacin. I We present a case of rhabdomyolysis associated with lovastatin use that occurred shortly after a course of erythromycin. In addition, we re(Spach DH, Bauwens JE, Clark CD, Burke WG: Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med 1991 Feb; 154:213215) From the Departments of Internal Medicine (Drs Spach, Bauwens, and Burke) and Pathology (Dr Clark), University of Washington School of Medicine, Seattle. Reprint requests to David H. Spach, MD, Harborview Medical Center, ZA-89, 325 9th Ave, Seattle, WA 98104.
213
thrombosis as additional risk factors. She will require anticoagulation therapy indefinitely. REFERENCES 1. Brockman SK, Vasko JS: Phlegmasia cerulea dolens. Surg Gynecol Obstet 1965; 121:1347-1356 2. Cohen DJ, Briggs R, Heard HD, Acher CW: Phlegmasia cerulea dolens and its association with hypercoagulable states: Case reports. Angiology 1989; 40:498-508 3. Chalmers N, Campbell 1: Phlegmasia coerulia dolens revisited. Practitioner 1987; 231:1520-1521 4. Coddington CC, Drake TS: Phlegmasia cerulea dolens as a complication of short-course oral contraceptives for dysfunctional bleeding. South Med J 1982; 75:377-378 5. Wilson B, Hawkins ML, Mansberger AR: Posttraumatic phlegmasia cerulea dolens: An indication for the Greenfield filter. South Med J 1989; 82:780-782 6. Conley CL, Hartman RC: A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 62 1-622 7. Mueh JR, Herbst KD, Rapaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intem Med 1980; 92:150-159 8. Elias M, Eldor A: Thromboembolism in patients with the 'lupus'-type circulating anticoagulant. Arch Intern Med 1984; 144:510-515 9. Gastineau DA, Kazmler FJ, Nichols WL, Bowie EJW: Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19:265-275 10. Triplett DA, Brandt JT, Mass RL: The laboratory heterogeneity of lupus anticoagulants. Arch Pathol Lab Med 1985; 109:446-451 11. Freyssinet JM, Cazenave JP: Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 1987; 58:679-681 12. Schleider MA, Nachman RL, Jaffe EA, Coleman MA: A clinical study of the lupus anticoagulant. Blood 1976; 48:499-509 13. Hughes GRV, Harris NN, Gharavi AE: The anticardiolipin syndrome (Editorial). J Rheumatol 1986; 13:486-489 14. Elliot MS, Immelman EJ, Jeffery P, et al: The role of thrombolytic therapy in the management of phlegmasia caerulea dolens. Br J Surg 1979; 66:422-424 15. Weaver FA, Meacham PW, Adkins RB, Dean RH: Phlegmasia cerulea dolens: Therapeutic considerations. South Med J 1988; 81:306-312
view two previously reported cases of rhabdomyolysis that occurred after the concomitant use of lovastatin and erythromycin and conclude that erythromycin should be added to the known list of drugs associated with lovastatin-induced rhabdomyolysis.
Report of a Case The patient, a 68-year-old woman with diabetes mellitus, coronary artery disease, congestive heart failure, and chronic renal insufficiency, was admitted to the hospital for the evaluation of dyspnea and pulmonary infiltrates. Seven months before admission, a regimen of lovastatin, 20 mg twice a day, was started for hypercholesterolemia. The patient's baseline-total cholesterol level of 7.34 mmol per liter (282 mg per dl) decreased to 4.45 mmol per liter (171 mg per dl) after six months oflovastatin therapy. Nine days before the current admission, the patient had been admitted to the hospital with dyspnea, fever, and pulmonary infiltrates. During this previous hospital admission, she received a combination drug containing ampicillin sodium and sulbactam sodium intravenously for three days, followed by a combination of amoxicillin and clavulanate potassium orally for three days. She responded well and was discharged on the oral antibiotic regimen but was readmitted to the hospital four days later with a recurrence of her symptoms. Her medications on admission included lovastatin, 20 mg twice a day; amoxicillinclavulanate; furosemide; sucralfate; ranitidine; allopurinol; insulin; isosorbide dinitrate; enalapril; and digoxin. Pertinent physical examination findings included rales at the bases of both lung fields, a holosystolic murmur heard best at the mitral region, and an absence of hepatosplenomegaly. Laboratory studies on admission elicited the follow-
214
214
ing values: serum potassium, 4.2 mmol per liter; serum creatinine, 309.1 Amol per liter (3.5 mg per dl); serum creatine kinase, 35 U per liter; and total bilirubin, 8.6 ,tmol per liter (0.5 mg per dl). While the patient was breathing room air, a specimen of arterial blood showed that the pH was 7.45, the Pao2 was 7.1 kPa (53 mm of mercury), and the Paco2 was 4.4 kPa (33 mm of mercury). An echocardiogram was obtained two days after admission and revealed severe mitral regurgitation, mild aortic regurgitation, and moderately decreased left ventricular function. Three days after admission, the amoxicillin-clavulanate therapy was changed to erythromycin. On the seventh day after admission, the patient underwent a bronchoscopic examination, and tests were negative for acid-fast bacilli, bacteria, and legionella direct fluorescent antibody. Biopsy findings were consistent with idiopathic pulmonary fibrosis, and a course of prednisone, 60 mg a day, was started. About 24 hours after receiving her first dose of prednisone, the patient's dyspnea decreased, and over the following 72 hours the pulmonary infiltrates present on chest radiograph resolved considerably. Five days after completing the ten-day course of erythromycin, the patient complained of muscle weakness and tenderness. At this time, her pulmonary and cardiac states were stable andjaundice had not developed. The following day her urine turned dark, and laboratory studies revealed a serum creatine kinase level of 26,400 U per liter, serum aldolase 243.2 U per liter, serum potassium 6.6 mmol per liter, and serum phosphate 2.3 mmol per liter (7.1 mg per dl). The patient received vigorous alkaline fluid and diuretic therapy; the lovastatin therapy was discontinued. Her urine output became fixed at 10 ml per hour, and her serum creatinine level of 309.1 4mol per liter (3.5 mg per dl) increased to 371.3 Amol per liter (4.2 mg per dl). Dialysis was recommended but was refused by the patient in repeated discussions throughout this period. She died two days later of progressive renal failure and pulmonary edema. Additional laboratory tests revealed normal thyroid function and a lovastatin concentration of 48 ng equivalents per milliliter. The lovastatin concentration, from a specimen drawn 2½/2 hours after the patient's last dose, represents an almost threefold elevation above the expected value derived from pharmacokinetic studies (J.A. Tobert, MD, PhD, written communication, March 1989). At autopsy, both quadriceps muscle specimens showed edema and necrosis of individual muscle fibers in a patchy distribution; occasional macrophages and rare lymphocytes were seen. There were no regenerating fibers (Figure 1). Discussion We report the third case of lovastatin-associated rhabdomyolysis occurring after the completion of a course of erythromycin. Several pieces of information lead us to conclude that lovastatin was the specific etiologic agent causing this patient's rhabdomyolysis: there was no evidence of any other known cause of rhabdomyolysis, the patient's serum lovastatin level was elevated nearly threefold above the expected level, and postmortem quadriceps muscle biopsy findings were consistent with a toxic injury or drug-induced rhabdomyolysis. The muscle biopsy in this case was most useful for excluding polymyositis which, if present, should have revealed regenerating muscle fibers or an interstitial inflammatory
ALERTS, NOTICES, AND CASE REPORTS
ALERTS,
Figure 1.-The biopsy specimen of the right quadriceps muscle shows patchy myocyte necrosis (arrows); no significant inflammation is present (trichrome, original magnification x 400).
infiltrate. In addition, no direct evidence of an infectious cause was seen. Degenerative changes on a muscle biopsy specimen similar to those seen in our patient can occur with an acquired myopathy associated with hyperthyroidism, but the results of thyroid function tests were normal in our patient. Three previous muscle biopsy reports from patients with lovastatin-associated rhabdomyolysis were limited but noted cell necrosis without inflammation,3 nonspecific abnormalities without inflammation or necrosis,4 and type II atrophy with scattered muscle fiber degeneration.5 The efficacy and adverse effects of lovastatin use have recently been reviewed.2 Cases of myopathy were reported in 17 patients, with myopathy being defined as a combination of muscle pain or weakness plus a tenfold or greater elevation in creatine kinase values .2 Plasma levels of lovastatin were measured in 6 of the 17 patients, and all were elevated severalfold or more. Patients particularly at risk of having muscle injury were those concomitantly taking cyclosporine, niacin, or gemfibrozil. In this series, all patients recovered after discontinuing lovastatin use, including two patients with rhabdomyolysis-induced renal failure. The patient we present is the second patient to require hemodialysis,3 and had she not refused hemodialysis, she may have recovered from the acute episode of lovastatin-associated rhabdomyolysis. In a recent report of a patient taking lovastatin, rhabdomyolysis was noted to develop shortly after the patient completed a 13-day course of erythromycin.6 The patient, a 65year-old man with coronary artery disease and chronic renal failure, received erythromycin for the treatment of pneumonia. At the end of the antibiotic course, weakness, myalgias, and a pronounced elevation in the creatine kinase level developed, similar to the findings in our patient. An additional reported case of rhabdomyolysis may have been associated with concurrent lovastatin and erythromycin use.7 This occurred in a 46-year-old man with a heart transplant who took prednisone, cyclosporine, and lovastatin for more than a year, without any muscle abnormalities. Acute rhabdomyolysis developed shortly after he completed a course of erythromycin. Rhabdomyolysis in this case was attributed to the combination of cyclosporine and lovastatin. Because of his previous stable course, we suspect that erythromycin may have triggered the episode of rhabdomyolysis. For several reasons, we strongly suspect that erythromycin use contributed to our patient's lovastatin-associated
THE WESTERN JOURNAL OF MEDICINE
*
FEBRUARY 1991
*
154 *
rhabdomyolysis. Before receiving the course of erythromycin, our patient had taken lovastatin for more than six months without any muscle difficulties. Prednisone therapy, which was started shortly after the erythromycin, could possibly have played a role in the rhabdomyolysis, but it has not been previously associated with lovastatin-induced rhabdomyolysis. Our patient's course of rhabdomyolysis was similar to that of the other two cases described involving erythromycin. Specifically, in all three cases the rhabdomyolysis occurred after the course of erythromycin was completed. The mechanism of the lovastatin-erythromycin interaction is unknown, but it has been proposed that erythromycin inactivation of hepatic microsomes alters the metabolism and excretion of lovastatin. An alternative explanation involves erythromycin displacing protein-bound lovastatin.6 We therefore speculate that initiating erythromycin therapy increases lovastatin concentrations, muscle injury begins on a low-grade level, and clinical symptoms and signs of overt rhabdomyolysis develop at a later point. The apparent association of erythromycin and lovastatin use with rhabdomyolysis is an important one. As the use of lovastatin continues to rise, the chance of its concomitant use with erythromycin, which is frequently prescribed for respi-
2
215
ratory tract and skin infections, will certainly increase. We therefore recommend caution when simultaneously administering lovastatin and erythromycin. In addition, physicians should consider temporarily discontinuing lovastatin during periods of acute illness because ofthe potential for alterations in drug metabolism, the increased susceptibility to drug toxicity, and the frequent use of multiple medications that may interact adversely. REFERENCES 1. Grundy SM: HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988; 319:24-33 2. Tobert JA: Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62:28J-34J 3. Norman DJ, Illingworth DR, Munson J, Hosenpud J: Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin (Letter). N Engl J Med 1988;
318:46-47 4. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA: Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation (Letter). N Engl J Med 1988; 318:4748 5. Goldman JA, Fishman AB, Lee JE, Johnson RJ: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis (Letter). Arthritis Rheum 1989; 32:358-359 6. Ayanian JZ, Fuchs CS, Stone RM: Lovastatin and rhabdomyolysis (Letter). Ann Intern Med 1988; 109:682-683 7. Corpier CL, Jones PH, Suki WN, et al: Rhabdomyolysis and renal injury with lovastatin use-Report of two cases in cardiac transplant recipients. JAMA 1988; 260:239-241
FEBRUARY 1991
*
154 * 2
sive investigation and has been called the anticardiolipin syndrome. II Phlegmasia cerulea dolens is a life-threatening disorder that requires aggressive intervention to combat the high frequency of morbidity and mortality."'4',5 The treatment of PCD includes anticoagulation, thrombolytic therapy, and surgical thrombectomy used alone or in combination. 41,5 A recent review of the therapeutic options for PCD suggests that surgical intervention is needed when patients fail to respond to heparin therapy within 6 to 12 hours.15 The discovery of the lupus anticoagulant in our patient led to the institution of thrombolytic therapy that proved to be successful. It has been suggested that all patients with hypercoagulable clotting abnormalities are at high risk for the development of PCD.2 This case supports that suggestion. Cohen and colleagues have recently described six cases of PCD in patients who had associated hypercoagulable states, including heparin-induced thrombocytopenia, congenital protein C deficiency, and antithrombin III deficiency.2 The authors commented that recognition of an underlying coagulopathy is essential for the proper management of PCD. We agree and think the lupus anticoagulant should be included as another coagulopathy associated with PCD. Our patient had no evidence of an underlying collagen vascular disease or occult malignant neoplasm. The lupus anticoagulant contributed to the development of PCD, although she had morbid obesity and a previous deep vein
Rhabdomyolysis Associated With Lovastatin and Erythromycin Use DAVID H. SPACH, MD J. ERIC BAUWENS, MD CHRISTINE D. CLARK, MD WYLIE G. BURKE, MD, PhD
Seattle, Washington
LOVASTATIN,
a
hydroxymethylglutaryl-coenzyme A reduc-
tase inhibitor used to treat patients with hypercholesterole-
mia, has become a commonly administered drug. Its use has been associated with a low incidence of side effects that include elevated aminotransferase levels, skin rash, gastrointestinal symptoms, and skeletal muscle abnormalities.12 Clinically, the most important of these side effects is the skeletal muscle abnormalities that can manifest as asymptomatic creatine kinase elevations; muscle aches, tenderness, and weakness; and rhabdomyolysis.2 Patients at greatest risk of muscle abnormalities developing include those with an underlying illness or concurrently taking medication such as cyclosporine, gemfibrozil, or niacin. I We present a case of rhabdomyolysis associated with lovastatin use that occurred shortly after a course of erythromycin. In addition, we re(Spach DH, Bauwens JE, Clark CD, Burke WG: Rhabdomyolysis associated with lovastatin and erythromycin use. West J Med 1991 Feb; 154:213215) From the Departments of Internal Medicine (Drs Spach, Bauwens, and Burke) and Pathology (Dr Clark), University of Washington School of Medicine, Seattle. Reprint requests to David H. Spach, MD, Harborview Medical Center, ZA-89, 325 9th Ave, Seattle, WA 98104.
213
thrombosis as additional risk factors. She will require anticoagulation therapy indefinitely. REFERENCES 1. Brockman SK, Vasko JS: Phlegmasia cerulea dolens. Surg Gynecol Obstet 1965; 121:1347-1356 2. Cohen DJ, Briggs R, Heard HD, Acher CW: Phlegmasia cerulea dolens and its association with hypercoagulable states: Case reports. Angiology 1989; 40:498-508 3. Chalmers N, Campbell 1: Phlegmasia coerulia dolens revisited. Practitioner 1987; 231:1520-1521 4. Coddington CC, Drake TS: Phlegmasia cerulea dolens as a complication of short-course oral contraceptives for dysfunctional bleeding. South Med J 1982; 75:377-378 5. Wilson B, Hawkins ML, Mansberger AR: Posttraumatic phlegmasia cerulea dolens: An indication for the Greenfield filter. South Med J 1989; 82:780-782 6. Conley CL, Hartman RC: A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 62 1-622 7. Mueh JR, Herbst KD, Rapaport SI: Thrombosis in patients with the lupus anticoagulant. Ann Intem Med 1980; 92:150-159 8. Elias M, Eldor A: Thromboembolism in patients with the 'lupus'-type circulating anticoagulant. Arch Intern Med 1984; 144:510-515 9. Gastineau DA, Kazmler FJ, Nichols WL, Bowie EJW: Lupus anticoagulant: An analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19:265-275 10. Triplett DA, Brandt JT, Mass RL: The laboratory heterogeneity of lupus anticoagulants. Arch Pathol Lab Med 1985; 109:446-451 11. Freyssinet JM, Cazenave JP: Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 1987; 58:679-681 12. Schleider MA, Nachman RL, Jaffe EA, Coleman MA: A clinical study of the lupus anticoagulant. Blood 1976; 48:499-509 13. Hughes GRV, Harris NN, Gharavi AE: The anticardiolipin syndrome (Editorial). J Rheumatol 1986; 13:486-489 14. Elliot MS, Immelman EJ, Jeffery P, et al: The role of thrombolytic therapy in the management of phlegmasia caerulea dolens. Br J Surg 1979; 66:422-424 15. Weaver FA, Meacham PW, Adkins RB, Dean RH: Phlegmasia cerulea dolens: Therapeutic considerations. South Med J 1988; 81:306-312
view two previously reported cases of rhabdomyolysis that occurred after the concomitant use of lovastatin and erythromycin and conclude that erythromycin should be added to the known list of drugs associated with lovastatin-induced rhabdomyolysis.
Report of a Case The patient, a 68-year-old woman with diabetes mellitus, coronary artery disease, congestive heart failure, and chronic renal insufficiency, was admitted to the hospital for the evaluation of dyspnea and pulmonary infiltrates. Seven months before admission, a regimen of lovastatin, 20 mg twice a day, was started for hypercholesterolemia. The patient's baseline-total cholesterol level of 7.34 mmol per liter (282 mg per dl) decreased to 4.45 mmol per liter (171 mg per dl) after six months oflovastatin therapy. Nine days before the current admission, the patient had been admitted to the hospital with dyspnea, fever, and pulmonary infiltrates. During this previous hospital admission, she received a combination drug containing ampicillin sodium and sulbactam sodium intravenously for three days, followed by a combination of amoxicillin and clavulanate potassium orally for three days. She responded well and was discharged on the oral antibiotic regimen but was readmitted to the hospital four days later with a recurrence of her symptoms. Her medications on admission included lovastatin, 20 mg twice a day; amoxicillinclavulanate; furosemide; sucralfate; ranitidine; allopurinol; insulin; isosorbide dinitrate; enalapril; and digoxin. Pertinent physical examination findings included rales at the bases of both lung fields, a holosystolic murmur heard best at the mitral region, and an absence of hepatosplenomegaly. Laboratory studies on admission elicited the follow-
214
214
ing values: serum potassium, 4.2 mmol per liter; serum creatinine, 309.1 Amol per liter (3.5 mg per dl); serum creatine kinase, 35 U per liter; and total bilirubin, 8.6 ,tmol per liter (0.5 mg per dl). While the patient was breathing room air, a specimen of arterial blood showed that the pH was 7.45, the Pao2 was 7.1 kPa (53 mm of mercury), and the Paco2 was 4.4 kPa (33 mm of mercury). An echocardiogram was obtained two days after admission and revealed severe mitral regurgitation, mild aortic regurgitation, and moderately decreased left ventricular function. Three days after admission, the amoxicillin-clavulanate therapy was changed to erythromycin. On the seventh day after admission, the patient underwent a bronchoscopic examination, and tests were negative for acid-fast bacilli, bacteria, and legionella direct fluorescent antibody. Biopsy findings were consistent with idiopathic pulmonary fibrosis, and a course of prednisone, 60 mg a day, was started. About 24 hours after receiving her first dose of prednisone, the patient's dyspnea decreased, and over the following 72 hours the pulmonary infiltrates present on chest radiograph resolved considerably. Five days after completing the ten-day course of erythromycin, the patient complained of muscle weakness and tenderness. At this time, her pulmonary and cardiac states were stable andjaundice had not developed. The following day her urine turned dark, and laboratory studies revealed a serum creatine kinase level of 26,400 U per liter, serum aldolase 243.2 U per liter, serum potassium 6.6 mmol per liter, and serum phosphate 2.3 mmol per liter (7.1 mg per dl). The patient received vigorous alkaline fluid and diuretic therapy; the lovastatin therapy was discontinued. Her urine output became fixed at 10 ml per hour, and her serum creatinine level of 309.1 4mol per liter (3.5 mg per dl) increased to 371.3 Amol per liter (4.2 mg per dl). Dialysis was recommended but was refused by the patient in repeated discussions throughout this period. She died two days later of progressive renal failure and pulmonary edema. Additional laboratory tests revealed normal thyroid function and a lovastatin concentration of 48 ng equivalents per milliliter. The lovastatin concentration, from a specimen drawn 2½/2 hours after the patient's last dose, represents an almost threefold elevation above the expected value derived from pharmacokinetic studies (J.A. Tobert, MD, PhD, written communication, March 1989). At autopsy, both quadriceps muscle specimens showed edema and necrosis of individual muscle fibers in a patchy distribution; occasional macrophages and rare lymphocytes were seen. There were no regenerating fibers (Figure 1). Discussion We report the third case of lovastatin-associated rhabdomyolysis occurring after the completion of a course of erythromycin. Several pieces of information lead us to conclude that lovastatin was the specific etiologic agent causing this patient's rhabdomyolysis: there was no evidence of any other known cause of rhabdomyolysis, the patient's serum lovastatin level was elevated nearly threefold above the expected level, and postmortem quadriceps muscle biopsy findings were consistent with a toxic injury or drug-induced rhabdomyolysis. The muscle biopsy in this case was most useful for excluding polymyositis which, if present, should have revealed regenerating muscle fibers or an interstitial inflammatory
ALERTS, NOTICES, AND CASE REPORTS
ALERTS,
Figure 1.-The biopsy specimen of the right quadriceps muscle shows patchy myocyte necrosis (arrows); no significant inflammation is present (trichrome, original magnification x 400).
infiltrate. In addition, no direct evidence of an infectious cause was seen. Degenerative changes on a muscle biopsy specimen similar to those seen in our patient can occur with an acquired myopathy associated with hyperthyroidism, but the results of thyroid function tests were normal in our patient. Three previous muscle biopsy reports from patients with lovastatin-associated rhabdomyolysis were limited but noted cell necrosis without inflammation,3 nonspecific abnormalities without inflammation or necrosis,4 and type II atrophy with scattered muscle fiber degeneration.5 The efficacy and adverse effects of lovastatin use have recently been reviewed.2 Cases of myopathy were reported in 17 patients, with myopathy being defined as a combination of muscle pain or weakness plus a tenfold or greater elevation in creatine kinase values .2 Plasma levels of lovastatin were measured in 6 of the 17 patients, and all were elevated severalfold or more. Patients particularly at risk of having muscle injury were those concomitantly taking cyclosporine, niacin, or gemfibrozil. In this series, all patients recovered after discontinuing lovastatin use, including two patients with rhabdomyolysis-induced renal failure. The patient we present is the second patient to require hemodialysis,3 and had she not refused hemodialysis, she may have recovered from the acute episode of lovastatin-associated rhabdomyolysis. In a recent report of a patient taking lovastatin, rhabdomyolysis was noted to develop shortly after the patient completed a 13-day course of erythromycin.6 The patient, a 65year-old man with coronary artery disease and chronic renal failure, received erythromycin for the treatment of pneumonia. At the end of the antibiotic course, weakness, myalgias, and a pronounced elevation in the creatine kinase level developed, similar to the findings in our patient. An additional reported case of rhabdomyolysis may have been associated with concurrent lovastatin and erythromycin use.7 This occurred in a 46-year-old man with a heart transplant who took prednisone, cyclosporine, and lovastatin for more than a year, without any muscle abnormalities. Acute rhabdomyolysis developed shortly after he completed a course of erythromycin. Rhabdomyolysis in this case was attributed to the combination of cyclosporine and lovastatin. Because of his previous stable course, we suspect that erythromycin may have triggered the episode of rhabdomyolysis. For several reasons, we strongly suspect that erythromycin use contributed to our patient's lovastatin-associated
THE WESTERN JOURNAL OF MEDICINE
*
FEBRUARY 1991
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rhabdomyolysis. Before receiving the course of erythromycin, our patient had taken lovastatin for more than six months without any muscle difficulties. Prednisone therapy, which was started shortly after the erythromycin, could possibly have played a role in the rhabdomyolysis, but it has not been previously associated with lovastatin-induced rhabdomyolysis. Our patient's course of rhabdomyolysis was similar to that of the other two cases described involving erythromycin. Specifically, in all three cases the rhabdomyolysis occurred after the course of erythromycin was completed. The mechanism of the lovastatin-erythromycin interaction is unknown, but it has been proposed that erythromycin inactivation of hepatic microsomes alters the metabolism and excretion of lovastatin. An alternative explanation involves erythromycin displacing protein-bound lovastatin.6 We therefore speculate that initiating erythromycin therapy increases lovastatin concentrations, muscle injury begins on a low-grade level, and clinical symptoms and signs of overt rhabdomyolysis develop at a later point. The apparent association of erythromycin and lovastatin use with rhabdomyolysis is an important one. As the use of lovastatin continues to rise, the chance of its concomitant use with erythromycin, which is frequently prescribed for respi-
2
215
ratory tract and skin infections, will certainly increase. We therefore recommend caution when simultaneously administering lovastatin and erythromycin. In addition, physicians should consider temporarily discontinuing lovastatin during periods of acute illness because ofthe potential for alterations in drug metabolism, the increased susceptibility to drug toxicity, and the frequent use of multiple medications that may interact adversely. REFERENCES 1. Grundy SM: HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J Med 1988; 319:24-33 2. Tobert JA: Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62:28J-34J 3. Norman DJ, Illingworth DR, Munson J, Hosenpud J: Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin (Letter). N Engl J Med 1988;
318:46-47 4. East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA: Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation (Letter). N Engl J Med 1988; 318:4748 5. Goldman JA, Fishman AB, Lee JE, Johnson RJ: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis (Letter). Arthritis Rheum 1989; 32:358-359 6. Ayanian JZ, Fuchs CS, Stone RM: Lovastatin and rhabdomyolysis (Letter). Ann Intern Med 1988; 109:682-683 7. Corpier CL, Jones PH, Suki WN, et al: Rhabdomyolysis and renal injury with lovastatin use-Report of two cases in cardiac transplant recipients. JAMA 1988; 260:239-241
