ACUTE HEMOLYSIS ANDRENAL FAILURE FOLLOWING DISCONTINUOUS USE OF R1FAMPIN Marc Levine,Kathleen Collin, and Barry O.Kassen
ABSlRACf:Rifampin is frequently used in the treatmentof mycobacterialinfections.Intermittentor discontinuoustherapy with rifampin has been associatedwith systemic symptoms referred to as the "flu syndrome" and, less frequently, acute hemolysis and acute renal failure. We report the case of a 73-year-oldwoman who experiencedacute hemolysis and renal failure while being treated with rifampin and ethambutol for a respiratoryinfectioncaused by Mycobacterium fortuitum and M. avium-intracellulare. This patient had interruptedher therapy for periods of one week or more due to a rash and flu-like symptoms, which she ascribed to her medications. A review of the literatureindicatedthat these adverse effects of rifampin appear to be immunologically mediated and that the symptoms of the flu syndrome may be due to mild intravascularhemolysis. Intermittenttherapy with rifampin should be avoidedand noncompliantpatients should be given alternativetreatmentwhen possible. DICP Ann Pharmacother 1991;25:743-4. RIFAMPIN IS A SEMISYNTHETIC ANTffiIOTIC frequently used in the treatment of tuberculosis and other mycobacterial infections. During the two decades since its release, a number of adverse effects have been associated with the intermittent or discontinuous (we use this term to denote interrupted therapy because of patient noncompliance) use of rifampin.' The most common of these is referred to as the "flu syndrome" and consists of episodes of fever, chills, and malaise, which may be accompanied by headache, dizziness, or bone pain. More rarely, cases of acute hemolysis or renal failure have occurred and in a few instances renal failure has directly followed an episode of acute hemolysis. There is evidence that these reactions are immunologically mediated, but their exact mechanism(s) and interrelationships are not known.P We report a case of acute hemolysis and nonoliguric renal failure following a dose of rifampin in a patient who had a prior history of discontinuous rifampin use and an associated flu syndrome.
CASE REPORT A 73-year-old woman, otherwise healthy, complained to her physician of fever, night sweats, weight loss, and morning sputum production.Chest X-rays taken intermittently during the previous seven years showed a density in a segment of the left upper lobe of the lung that had not changed significantly during this
MARC LEVINE. Ph.D., is an Associate Professor, Faculty of Pharmaceutical Sciences. University of British Columbia. and an associate member of the Departments of Pharmacy and Medicine; KATHLEEN COLLIN, B.Sc.(Pharm.), is a Clinical Pharmacist, Department of Pharmacy; and BARRY O. KASSEN, M.D., FRCP(C), is a Clinical Associate Professor, Department of Medicine, University Hospital (Shaughnessy Site), Vancouver, BC. Reprints: Marc Levine, Ph.D., Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
time. The woman had quit smoking 25 years previously. A spusample revealed acid-fastbacilli and the patient was initially prescribedisoniazidand rifampin.Subsequentcultures grew Mycobacterium fortuitum andM. avium-intracellulare susceptible to ethambutol and rifampin and the therapy was changed to a daily regimen of these two agents. The patient stated that she took the medications on and off during the next four months, interrupting therapy when she noticed an itchy rash and welts which she attributed to the medications. She also complainedof a "flu-like" feeling when taking her medications.The intervalsduring which she took no medication were a week or longer. One week prior to admission she again interruptedtherapy. On the morningof her hospitaladmissionthe patient took two rifampin 300-mg capsules.Within one-half hour she noticed the onset of flushing, nausea, vomiting, diaphoresis, feverishness, chills, and severe back pain. She came immediately to the emergency department and was noted to be hypotensive and diaphoretic. Catheterization yielded "black" urine. Laboratory tests revealedthe following (normal values in parentheses): 1. Elevated prothrombin time 14.5 s (10-12), activated partial thromboplastintime 38.6 s (22.5-32.6), lactate dehydrogenase 1671 U/L (297-537), plasma hemoglobin 1.95 gIL (0.Ql-0.06), reticulocyte count 128 x l(f/L (50-120), fibrin degradation products>160 but < 320 mgIL « 10), unconjugatedbilirubin 35.9 j.UIlollL (0-19). 2. At the time of admission, the patient's blood urea nitrogen (BUN) and creatinine were within nonnallimits but rose to 10.7 mmol/L (1.8-7.1) and I581lmollL (44-88), respectively, during the next eight hours. Urine samples on days I and II showed large amounts of hemoglobin. 3. Serum haptoglobinwas decreased and methemalbuminwas detected in the serum. The direct antiglobulintest was positive with complement (C3d) only. The patient's serum contained a hemolytic rifampin-dependent antibody demonstrable in an indirectantiglobulintest using the patient's serum, rifampin-treated red cells, and fresh (ABO compatible) serum as a source of complement. These serologic features are typical of immune complex-mediated hemolysis. Tests for hepatitis B surface antigen,myoglobinprecipitation, and glucose-6-phosphate dehydrogenasewere negative. Examination of the patient and other laboratory tests revealed no further abnormalities. The patient was admitted to the hospital and maintained on a low input of sodium, potassium,and protein.Her urine output began to fall and renal failure progressed.The patient's fluid intake was balancedwith her output and dialysiswas consideredbut not performed, as she was asymptomatic and her serum electrolytes remained within normal limits, During the hospital stay, the patient's serum creatinine rose to a maximum of 1024 umol/l, (44-88) on day 10 and her BUN rose to a maximum of 55.8 mmol/L (1.8-7.1) on day 14. Her urine output fell to a low of 786 mL/24 h on day 6 but was maintained for the most part between 1500 and 2000 mL/24 h. The patient was discharged on day 16, at which time her serum creatinine and BUN were 525 umol/l, and 49 mmol/L, respectively. From the time of admission, her antibiotictherapy was discontinuedand upon discharge tum
DICP,TheAnnalsofPharmacotherapy • 1991 July/August, Volume 25 •
743
she was advised not to take rifampin again. She had an uneventful recovery and at a follow-up visit approximately six months later, she remained well on no antibiotic therapy and had normal values for serum creatinine, BUN, unconjugated and conjugated bilirubin, and liver enzymes.
Acute hemolysis due to rifampin was first reported in 19713 and since then, fewer than 20 cases have appeared in the literature. In all of the reported cases, the patients had a history of either intermittent or discontinuous use of rifampin.P As in this case, symptoms usually appear within the first few hours after a rifampin dose and complete recovery occurs when the drug is withdrawn. Many patients develop antirifampin antibodies during therapy and acute hemolytic reactions are thought to be immunologically based. One case has been reported in which acute hemolysis was associated with antirifampin antibody of the immunoglobulin G (lgG) class.' It has been suggested that complement-fixing antibody of either the IgG or IgM type is responsible for rifampin-induced hemolysis.w' Acute renal failure caused by rifampin, although rare, appears to occur more frequently than hemolysis. In most cases, renal failure has occurred with intermittent or discontinuous use of rifampin and an immunologic mechanism is also suspected.Pe The typical symptoms at onset are fever, nausea, malaise, chills, and lumbar pain, followed rapidly by oliguria or anuria. In one review it was noted that 22 of 36 patients with rifampin-induced renal failure required dialysis and all but one went on to full recovery.s It is not known whether corticosteroids are of any value in the treatment of rifampin-induced renal failure. There have been only 11 other cases reported in which renal failure followed an acute hemolytic reaction to rifampin. In all of these cases, intermittent or discontinuous use of rifampin was noted. A significant factor in the present case was the patient's prior history of a flu-like reaction and pruritic rash. Cutaneous reactions have been reported in patients on daily or intermittent rifampin therapy. They tend to be mild and in most cases resolve without desensitization, allowing continuation of therapy. 1 The flu syndrome associated with rifampin therapy has been known since the early I970s. It is quite common and nearly always occurs in patients on intermittent or interrupted therapy, usually after three to six months of therapy. The onset of symptoms occurs one to two hours after a dose and they usually resolve within eight hours.' The syndrome may also be accompanied by a cutaneous reaction, as occurred in this case. Patients who have developed hemolysis or renal failure while taking rifampin have often reported prior symptoms characteristic of the flu syndrome. The evidence for an immunologic mechanism appears to be strongest for the flu syndrome as it has been more widely studied and is
well correlated with the presence of antirifampin antibodies. In one prospective study 16 patients with tuberculosis were prescribed intermittent rifampin as part of their regimens. Of these, three developed febrile reactions and other symptoms of the flu syndrome. These three patients continued to take isoniazid and ethambutol daily and were rechallenged in the laboratory with rifampin. Two developed symptoms within four hours and experienced a rise in both plasma hemoglobin and total bilirubin. The third patient had no increase in serum hemoglobin or bilirubin but had a persistent fever that subsequently resolved when isoniazid was withdrawn and did not recur when rifampin therapy was restarted. The authors suggested that the flu syndrome caused by rifampin is due to mild intravascular hemolysis and is only quantitatively different from more serious hemolytic reactions caused by the drug.' Summary
It is clear from the reported cases and prospective studies that intermittent or discontinuous use of rifampin substantially increases patients' risk of developing the flu syndrome, acute hemolysis, or renal failure. When rifampin is indicated, intermittent use should be avoided and patients with a prior history of rifampin therapy who again require the drug should be monitored carefully when therapy is restarted. Patients who are poor compliers should be given an alternative therapy when possible, particularly if they have experienced symptoms of the flu syndrome while taking rifampin. ~ The authors thank S. Krikler, M.B., Ch.B., FRCP(C), Hematopathologist, University Hospital (Shaughnessy site), for his assistance in the interpretation of this patient's hematologic data.
References 1. GIRLING DJ. Adversereactions 10 rifampinin antituberculosis regimens. J
Antimicrob Chemother 1977;3:115-32. 2. TAHAN SR. DIAMOND JR, BLANK JM, HORAN RF.Acute hemolysisand renal failure with rifampicin-dependent antibodiesafter discontinuous administration. Transfusion 1985;25:124-7. 3. HASSE W, POHLE HD, WARNECKE F. WIEK K. Hamolytische krise durch rifampicin. Prax Pneunwl1971;25:466-8. 4. LAKSHMINARAYAN S, SAHN SA, HUDSON LD. Massive hemolysis causedby rifampicin. Br Med J 1973;2:282-3. 5. NESSI R. BONOLDI GL, REDAELLI B. or FILLIPO G. Acuterenalfailure after rifampicin: a case reportand surveyof the literature. Nephron 1976; 16:148-59. 6. ADLER SG, COHEN AH, BORDER WA. Hypersensitivityphenomenaand the kidney: role of drugs and environmentalagents. Am J KidneyDis 1985;5:75-96. 7. MATTSON K. JANNE J. Mild intravasa\ hemolysis associated withflu-syndrome duringintermittent rifampicin treatment. Eur J RespirDis 1982; 63:68-72.
744 • DICP,The Annalsof Pharmacotherapy • 1991 July/August, Volume 25
ABSlRACf:Rifampin is frequently used in the treatmentof mycobacterialinfections.Intermittentor discontinuoustherapy with rifampin has been associatedwith systemic symptoms referred to as the "flu syndrome" and, less frequently, acute hemolysis and acute renal failure. We report the case of a 73-year-oldwoman who experiencedacute hemolysis and renal failure while being treated with rifampin and ethambutol for a respiratoryinfectioncaused by Mycobacterium fortuitum and M. avium-intracellulare. This patient had interruptedher therapy for periods of one week or more due to a rash and flu-like symptoms, which she ascribed to her medications. A review of the literatureindicatedthat these adverse effects of rifampin appear to be immunologically mediated and that the symptoms of the flu syndrome may be due to mild intravascularhemolysis. Intermittenttherapy with rifampin should be avoidedand noncompliantpatients should be given alternativetreatmentwhen possible. DICP Ann Pharmacother 1991;25:743-4. RIFAMPIN IS A SEMISYNTHETIC ANTffiIOTIC frequently used in the treatment of tuberculosis and other mycobacterial infections. During the two decades since its release, a number of adverse effects have been associated with the intermittent or discontinuous (we use this term to denote interrupted therapy because of patient noncompliance) use of rifampin.' The most common of these is referred to as the "flu syndrome" and consists of episodes of fever, chills, and malaise, which may be accompanied by headache, dizziness, or bone pain. More rarely, cases of acute hemolysis or renal failure have occurred and in a few instances renal failure has directly followed an episode of acute hemolysis. There is evidence that these reactions are immunologically mediated, but their exact mechanism(s) and interrelationships are not known.P We report a case of acute hemolysis and nonoliguric renal failure following a dose of rifampin in a patient who had a prior history of discontinuous rifampin use and an associated flu syndrome.
CASE REPORT A 73-year-old woman, otherwise healthy, complained to her physician of fever, night sweats, weight loss, and morning sputum production.Chest X-rays taken intermittently during the previous seven years showed a density in a segment of the left upper lobe of the lung that had not changed significantly during this
MARC LEVINE. Ph.D., is an Associate Professor, Faculty of Pharmaceutical Sciences. University of British Columbia. and an associate member of the Departments of Pharmacy and Medicine; KATHLEEN COLLIN, B.Sc.(Pharm.), is a Clinical Pharmacist, Department of Pharmacy; and BARRY O. KASSEN, M.D., FRCP(C), is a Clinical Associate Professor, Department of Medicine, University Hospital (Shaughnessy Site), Vancouver, BC. Reprints: Marc Levine, Ph.D., Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
time. The woman had quit smoking 25 years previously. A spusample revealed acid-fastbacilli and the patient was initially prescribedisoniazidand rifampin.Subsequentcultures grew Mycobacterium fortuitum andM. avium-intracellulare susceptible to ethambutol and rifampin and the therapy was changed to a daily regimen of these two agents. The patient stated that she took the medications on and off during the next four months, interrupting therapy when she noticed an itchy rash and welts which she attributed to the medications. She also complainedof a "flu-like" feeling when taking her medications.The intervalsduring which she took no medication were a week or longer. One week prior to admission she again interruptedtherapy. On the morningof her hospitaladmissionthe patient took two rifampin 300-mg capsules.Within one-half hour she noticed the onset of flushing, nausea, vomiting, diaphoresis, feverishness, chills, and severe back pain. She came immediately to the emergency department and was noted to be hypotensive and diaphoretic. Catheterization yielded "black" urine. Laboratory tests revealedthe following (normal values in parentheses): 1. Elevated prothrombin time 14.5 s (10-12), activated partial thromboplastintime 38.6 s (22.5-32.6), lactate dehydrogenase 1671 U/L (297-537), plasma hemoglobin 1.95 gIL (0.Ql-0.06), reticulocyte count 128 x l(f/L (50-120), fibrin degradation products>160 but < 320 mgIL « 10), unconjugatedbilirubin 35.9 j.UIlollL (0-19). 2. At the time of admission, the patient's blood urea nitrogen (BUN) and creatinine were within nonnallimits but rose to 10.7 mmol/L (1.8-7.1) and I581lmollL (44-88), respectively, during the next eight hours. Urine samples on days I and II showed large amounts of hemoglobin. 3. Serum haptoglobinwas decreased and methemalbuminwas detected in the serum. The direct antiglobulintest was positive with complement (C3d) only. The patient's serum contained a hemolytic rifampin-dependent antibody demonstrable in an indirectantiglobulintest using the patient's serum, rifampin-treated red cells, and fresh (ABO compatible) serum as a source of complement. These serologic features are typical of immune complex-mediated hemolysis. Tests for hepatitis B surface antigen,myoglobinprecipitation, and glucose-6-phosphate dehydrogenasewere negative. Examination of the patient and other laboratory tests revealed no further abnormalities. The patient was admitted to the hospital and maintained on a low input of sodium, potassium,and protein.Her urine output began to fall and renal failure progressed.The patient's fluid intake was balancedwith her output and dialysiswas consideredbut not performed, as she was asymptomatic and her serum electrolytes remained within normal limits, During the hospital stay, the patient's serum creatinine rose to a maximum of 1024 umol/l, (44-88) on day 10 and her BUN rose to a maximum of 55.8 mmol/L (1.8-7.1) on day 14. Her urine output fell to a low of 786 mL/24 h on day 6 but was maintained for the most part between 1500 and 2000 mL/24 h. The patient was discharged on day 16, at which time her serum creatinine and BUN were 525 umol/l, and 49 mmol/L, respectively. From the time of admission, her antibiotictherapy was discontinuedand upon discharge tum
DICP,TheAnnalsofPharmacotherapy • 1991 July/August, Volume 25 •
743
she was advised not to take rifampin again. She had an uneventful recovery and at a follow-up visit approximately six months later, she remained well on no antibiotic therapy and had normal values for serum creatinine, BUN, unconjugated and conjugated bilirubin, and liver enzymes.
Acute hemolysis due to rifampin was first reported in 19713 and since then, fewer than 20 cases have appeared in the literature. In all of the reported cases, the patients had a history of either intermittent or discontinuous use of rifampin.P As in this case, symptoms usually appear within the first few hours after a rifampin dose and complete recovery occurs when the drug is withdrawn. Many patients develop antirifampin antibodies during therapy and acute hemolytic reactions are thought to be immunologically based. One case has been reported in which acute hemolysis was associated with antirifampin antibody of the immunoglobulin G (lgG) class.' It has been suggested that complement-fixing antibody of either the IgG or IgM type is responsible for rifampin-induced hemolysis.w' Acute renal failure caused by rifampin, although rare, appears to occur more frequently than hemolysis. In most cases, renal failure has occurred with intermittent or discontinuous use of rifampin and an immunologic mechanism is also suspected.Pe The typical symptoms at onset are fever, nausea, malaise, chills, and lumbar pain, followed rapidly by oliguria or anuria. In one review it was noted that 22 of 36 patients with rifampin-induced renal failure required dialysis and all but one went on to full recovery.s It is not known whether corticosteroids are of any value in the treatment of rifampin-induced renal failure. There have been only 11 other cases reported in which renal failure followed an acute hemolytic reaction to rifampin. In all of these cases, intermittent or discontinuous use of rifampin was noted. A significant factor in the present case was the patient's prior history of a flu-like reaction and pruritic rash. Cutaneous reactions have been reported in patients on daily or intermittent rifampin therapy. They tend to be mild and in most cases resolve without desensitization, allowing continuation of therapy. 1 The flu syndrome associated with rifampin therapy has been known since the early I970s. It is quite common and nearly always occurs in patients on intermittent or interrupted therapy, usually after three to six months of therapy. The onset of symptoms occurs one to two hours after a dose and they usually resolve within eight hours.' The syndrome may also be accompanied by a cutaneous reaction, as occurred in this case. Patients who have developed hemolysis or renal failure while taking rifampin have often reported prior symptoms characteristic of the flu syndrome. The evidence for an immunologic mechanism appears to be strongest for the flu syndrome as it has been more widely studied and is
well correlated with the presence of antirifampin antibodies. In one prospective study 16 patients with tuberculosis were prescribed intermittent rifampin as part of their regimens. Of these, three developed febrile reactions and other symptoms of the flu syndrome. These three patients continued to take isoniazid and ethambutol daily and were rechallenged in the laboratory with rifampin. Two developed symptoms within four hours and experienced a rise in both plasma hemoglobin and total bilirubin. The third patient had no increase in serum hemoglobin or bilirubin but had a persistent fever that subsequently resolved when isoniazid was withdrawn and did not recur when rifampin therapy was restarted. The authors suggested that the flu syndrome caused by rifampin is due to mild intravascular hemolysis and is only quantitatively different from more serious hemolytic reactions caused by the drug.' Summary
It is clear from the reported cases and prospective studies that intermittent or discontinuous use of rifampin substantially increases patients' risk of developing the flu syndrome, acute hemolysis, or renal failure. When rifampin is indicated, intermittent use should be avoided and patients with a prior history of rifampin therapy who again require the drug should be monitored carefully when therapy is restarted. Patients who are poor compliers should be given an alternative therapy when possible, particularly if they have experienced symptoms of the flu syndrome while taking rifampin. ~ The authors thank S. Krikler, M.B., Ch.B., FRCP(C), Hematopathologist, University Hospital (Shaughnessy site), for his assistance in the interpretation of this patient's hematologic data.
References 1. GIRLING DJ. Adversereactions 10 rifampinin antituberculosis regimens. J
Antimicrob Chemother 1977;3:115-32. 2. TAHAN SR. DIAMOND JR, BLANK JM, HORAN RF.Acute hemolysisand renal failure with rifampicin-dependent antibodiesafter discontinuous administration. Transfusion 1985;25:124-7. 3. HASSE W, POHLE HD, WARNECKE F. WIEK K. Hamolytische krise durch rifampicin. Prax Pneunwl1971;25:466-8. 4. LAKSHMINARAYAN S, SAHN SA, HUDSON LD. Massive hemolysis causedby rifampicin. Br Med J 1973;2:282-3. 5. NESSI R. BONOLDI GL, REDAELLI B. or FILLIPO G. Acuterenalfailure after rifampicin: a case reportand surveyof the literature. Nephron 1976; 16:148-59. 6. ADLER SG, COHEN AH, BORDER WA. Hypersensitivityphenomenaand the kidney: role of drugs and environmentalagents. Am J KidneyDis 1985;5:75-96. 7. MATTSON K. JANNE J. Mild intravasa\ hemolysis associated withflu-syndrome duringintermittent rifampicin treatment. Eur J RespirDis 1982; 63:68-72.
744 • DICP,The Annalsof Pharmacotherapy • 1991 July/August, Volume 25
