• View in gallery
    Figure 1.

    Time plots for trends in laboratory parameters over four episodes of immunoallergic reactions to rifampin in a 66-year-old woman for A, hemogloblin concentration; B, platelet count. C, creatinine; D, prothrombin time; E, international normalized ratio; and F, fibrinogen levels. Black arrows indicate times of ingestion of rifampin.

  • 1.

    Johnson ST, Fueger JT, Gottschall JG, 2007. One center's experience; the serology and drugs associated with drug-induced hemolytic anemia – a new paradigm. Transfusion 47: 697702.

    • Search Google Scholar
    • Export Citation
  • 2.

    Forget EJ, Menzies D, 2006. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 5: 231249.

  • 3.

    World Health Organization, 1994. Chemotherapy of Leprosy: Report of a WHO Study Group - WHO Technical Report Series No. 847. Available at:

    • Search Google Scholar
    • Export Citation
  • 4.

    Martinez E, Muniz E, Domingo P, 1994. Evidence implicating rifampin-independent antiplatelet antibodies in the pathogenesis of rifampin-induced immune thrombocytopenia. Clin Infect Dis 19: 351353.

    • Search Google Scholar
    • Export Citation
  • 5.

    Worlledge S, 1973. Rifampicin-induced antibodies. Chemotherapy 4: 273278.

  • 6.

    Grosset J, Leventis S, 1983. Adverse effects of rifampin. Rev Infect Dis 5: S440S446.

  • 7.

    De Vriese AS, Robbrecht DL, Vanholder RC, Vogelaers DP, Lameire NH, 1998. Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features. Am J Kidney Dis 31: 108115.

    • Search Google Scholar
    • Export Citation
  • 8.

    A Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council Investigation, 1974. A controlled clinical trial of small weekly doses of rifampicin in the prevention of adverse reactions to the drug in a once-weekly regimen of chemotherapy in Hong Kong: a second report: the results at 12 months. Tubercle 55: 193210.

    • Search Google Scholar
    • Export Citation
  • 9.

    Riska N, Mattson K, 1972. Adverse reactions during rifampicin treatment. Scand J Respir Dis 53: 8796.

  • 10.

    Brasil MT, Opromolla DV, Marzliak ML, Nogueira W, 1996. Results of a surveillance system for adverse effects in leprosy's World Health Organization/Multidrug Therapy. Int J Lepr 64: 97104.

    • Search Google Scholar
    • Export Citation
  • 11.

    Denis J, Robert A, Johanet C, Homberg JC, Opolon P, Levy VG, 1983. Immunoallergic reaction to rifampicin with disseminated intravascular coagulation. Presse Med 12: 14791481.

    • Search Google Scholar
    • Export Citation
  • 12.

    Fujita M, Kunitake R, Nagano Y, Maeda F, 1997. Disseminated intravascular coagulation associated with pulmonary tuberculosis. Intern Med 36: 218220.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ip M, Cheng KP, Cheung WC, 1991. Disseminated intravascular coagulopathy associated with rifampicin. Tubercle 72: 2913.

  • 14.

    Luzzati R, Giacomazzi D, Franchi F, Barcobello M, Vento S, 2007. Life-threatening, multiple hypersensitivity reactions induced by rifampicin in one patient with pulmonary tuberculosis. South Med J 100: 854855.

    • Search Google Scholar
    • Export Citation
  • 15.

    Nowicka J, Kotschy M, Chwistecki K, Jelen M, 1977. Disseminated intravascular coagulation (DIC) during superacute haemolysis in a patient with ovarian dermatoid cyst treated with rifampicin. Haematologia (Budap) 11: 359364.

    • Search Google Scholar
    • Export Citation
  • 16.

    Namisato M, Ogawa H, 2000. Serious side effects of rifampin on the course of World Health Organization/Multidrug Treatment: a case report. Int J Lepr Other Mycobact Dis 68: 277282.

    • Search Google Scholar
    • Export Citation
  • 17.

    Souza CS, Alberto PL, Foss NT, 1997. Disseminated intravascular coagulopathy as an adverse reaction to intermittent rifampin schedule in the treatment of leprosy. Int J Lepr Other Mycobact Dis 65: 366370.

    • Search Google Scholar
    • Export Citation
  • 18.

    Dacso M, Jacobson RR, Stryjewska BM, Prestigiacomo J, Scollard DM, 2011. Evaluation of multi-drug therapy for leprosy in the USA using daily rifampin. South Med J 104: 16.

    • Search Google Scholar
    • Export Citation
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Recurrent Disseminated Intravascular Coagulation Caused by Intermittent Dosing of Rifampin

Thomas C. HaveyDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Hematology and Oncology, and Division of Infectious Diseases, University Health Network, Toronto, Canada

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Christine Cserti-GazdewichDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Hematology and Oncology, and Division of Infectious Diseases, University Health Network, Toronto, Canada

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Michelle SholzbergDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Hematology and Oncology, and Division of Infectious Diseases, University Health Network, Toronto, Canada

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Jay S. KeystoneDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Hematology and Oncology, and Division of Infectious Diseases, University Health Network, Toronto, Canada

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Wayne L. GoldDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Hematology and Oncology, and Division of Infectious Diseases, University Health Network, Toronto, Canada

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Daily rifampin therapy is associated with minimal adverse effects, but administration on an intermittent or interrupted basis has been associated with severe immunoallergic reactions such as hemolytic anemia, acute renal failure, and disseminated intravascular coagulation. We describe a patient with Mycobacterium leprae infection who experienced recurrent episodes of disseminated intravascular coagulation after intermittent exposures to rifampin, and review eight previously reported cases of rifampin-associated disseminated intravascular coagulation. In six (75%) cases, previous exposure to rifampin was reported and seven (87.5%) patients were receiving the medication on an intermittent or interrupted basis. Clinical features of rifampin-associated disseminated intravascular coagulation included fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Average time to reaction was 3–6 doses if rifampin was being administered on a monthly schedule. Three (37.5%) of eight reported cases were fatal. A complete history of previous exposure to rifampin is recommended before intermittent therapy with this medication.

Case Report

A 66-year-old woman was hospitalized in July 2009 after acute onset of fever, nausea, and vomiting. Her medical history was significant for lepromatous leprosy diagnosed at age 19, for which she had received multiple courses of therapy that included dapsone, rifampin, clofazimine, and thalidomide. Her leprosy remained quiescent on monotherapy with dapsone from 1986 until November 2008. At that time, she was started on the World Health Organization multidrug treatment regimen for leprosy that included ofloxacin, 300 mg orally/day; dapsone, 100 mg orally/day; and rifampin, 600 mg orally/month to alleviate the need for lifetime monotherapy with dapsone. Minocycline, 50 mg orally/day was substituted for ofloxacin after development of diarrhea. Other medical history included pulmonary tuberculosis diagnosed at age 37 that was treated with multidrug therapy including rifampin, cirrhosis secondary to hepatitis B virus infection for which she was receiving lamivudine, papillary thyroid cancer, bipolar affective disorder, and type II diabetes mellitus.

On July 21, 2009, she ingested her ninth monthly dose of rifampin as part of her intermittent dosing regimen. Within three hours, she experienced sudden onset of fever, nausea, and hematemesis and came to the Emergency Department. On examination, her blood pressure was 81/38 mm of Hg, her heart rate was 130/minute, and her temperature was 39.0°C. She was icteric. There was bleeding from the nares, oral cavity, urinary tract, and venipuncture sites. There was mild tenderness to palpation of the abdomen.

Laboratory investigations obtained within 12 hours of admission were compatible with disseminated intravascular coagulation (DIC): international normalized ratio = 3.33 (reference = 0.8–1.2); prothrombin time = 80 seconds (reference = 26–28 seconds); fibrinogen < 1.5 g/L (reference = 1.5–3.50 g/L), and D-dimers > 4,000 μg/L (reference = < 250 μg/L) and with intravascular hemolysis: hemoglobin = 89 g/L (reference = 120–160 g/L); bilirubin = 6·8 mg/dL (reference = < 1.3 mg/dL), and lactate dehydrogenase = 1,317 U/L (reference = 125–243 U/L). The serum creatinine level was 2.9 mg/dL (reference = 0.6–1.1 μmol/L). Abdominal ultrasound showed trace free fluid adjacent to the gallbladder.

Her hypotension responded to two liters of intravenous normal saline. Pantoprazole was infused, and empiric antimicrobial therapy with piperacillin/tazobactam was initiated for a suspected intra-abdominal focus of infection. She required transfusion of two units of fresh-frozen plasma, 10 units of cryoprecipitate, and 2 units of packed erythrocytes to correct her hematologic abnormalities. Within 24 hours of presentation, she was afebrile, hemodynamically stable, and had laboratory evidence of resolving DIC. Blood cultures obtained on admission were negative. Gastroscopy showed antral gastritis and mild duodenitis without evidence of varices.

Because of the temporal relationship between the ingestion of rifampin and her acute illness, further history was obtained. Three months earlier on April 19, 2009 after her sixth monthly dose of rifampin, she had abrupt onset of nausea and oliguria. Outpatient laboratory investigations showed evidence of acute kidney injury and a decrease in hemoglobin concentration from baseline. Urinalysis showed heme-granular casts. Although a cause was not identified, the laboratory abnormalities resolved without need for therapeutic intervention. One month later on May 17, 2009, after her seventh monthly dose of rifampin, she was hospitalized with fever, abdominal pain, and anuria. Laboratory investigations showed acute and chronic kidney injury and laboratory abnormalities compatible with DIC with intravascular hemolysis. An infectious etiology was not identified. A renal biopsy showed acute tubular necrosis. She recovered after receiving blood product support and temporary hemodialysis. One month later on June 19, 2009, immediately after her eighth monthly dose of rifampin, she was hospitalized with a repeat diagnosis of DIC and anuric renal failure requiring re-initiation of hemodialysis. A precipitant was not identified, and she again recovered. Laboratory abnormalities associated with her four presentations are shown in Figure 1.

Figure 1.
Figure 1.

Time plots for trends in laboratory parameters over four episodes of immunoallergic reactions to rifampin in a 66-year-old woman for A, hemogloblin concentration; B, platelet count. C, creatinine; D, prothrombin time; E, international normalized ratio; and F, fibrinogen levels. Black arrows indicate times of ingestion of rifampin.

Citation: The American Society of Tropical Medicine and Hygiene 86, 2; 10.4269/ajtmh.2012.11-0598

Serologic investigations performed within 48 hours of the ninth monthly intermittent dose of rifampin in July 2009 showed that she was blood group B+, erythrocyte antibody screen negative, and direct antiglobulin test negative. However, testing of her serum against rifampin-treated erythrocytes showed a rifampin-dependent antibody that was not reactive with rifampin metabolites or dapsone.1

Discussion

Rifampin is most commonly used in the treatment of mycobacterial infections in which it is given as part of multidrug therapy. It may be administered on a daily basis or on an intermittent dosing schedule. Adverse effects of rifampin, when administered on a daily basis, include IgE-mediated allergic reactions, rash, minor gastrointestinal upset, hepatotoxicity, and clinically important drug-drug interactions.2

Rifampin is currently recommended as part of the World Health Organization multidrug treatment for Mycobacterium leprae infection, in which it is given on a once per month schedule in combination with dapsone and clofazimine.3 Rifampin administered on an intermittent or interrupted schedule can produce distinct and severe adverse effects known as immunoallergic reactions, which are mediated by IgG and IgM directed against erythrocytes, platelets, and other target cells that express the I blood antigen, including renal tubular epithelial cells.4 These antibodies can be detected in the serum of up to 30% of patients after 3–4 doses of monthly intermittent therapy with rifampin,5 and may also fix complement to rifampin-treated target cells.4,6 Infrequent dosing of rifampin on either intermittent or interrupted schedules can result in sensitization with a rapid increase in antibody titer after repeat drug exposure.7 Treatment with even a single dose of rifampin may induce sensitization and result in immunoallergic reactions upon repeat exposure.7 In contrast, daily administration of rifampin is believed to confer immunologic tolerance against these reactions.8

Immunoallergic reactions to rifampin occur in a dose- and schedule-dependent manner: 4–8% when 600 mg is given twice a week, 22–31% when 900 mg is given once a week, and > 35% when 1,200 mg is given once a week.6,8,9 A surveillance program of more than 20,000 patients receiving intermittent monthly dosing of rifampin for treatment of leprosy demonstrated that these reactions are rare when rifampin is administered on a monthly basis, and include fever and chills (0.26%), hemolytic anemia (0.03%), immune-mediated thrombocytopenia (0.01%), acute renal failure (0.1%) and DIC with hemodynamic compromise (0.005%).10 In that program, 78% of patients who showed development of immunoallergic reactions had known prior exposure to rifampin, and 75% of reactions were observed after five or fewer doses.10 Clinical manifestations may occur abruptly after re-exposure, and some reactions occur within 30 minutes of ingestion.4,6

A review of the English language literature identified eight previously reported cases of DIC associated with rifampin therapy, which are shown in Table 1. Five patients had received rifampin for treatment of pulmonary tuberculosis,1115 and three patients received rifampin on an intermittent monthly schedule for treatment of leprosy.10,16,17 In six (75%) cases, prior exposure to rifampin was documented.10,1317 In the remaining two cases, there was no comment about prior exposure.11,12 Seven (87.5%) patients received rifampin on an intermittent or interrupted schedule,10,11,1317 and when administered on a monthly basis, the development of DIC occurred after 3–6 doses.10,16,17 Clinical features of rifampin-associated DIC included fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Laboratory evidence of concomitant intravascular hemolysis was present in six (75%) cases.11,1317

Table 1

Nine cases of disseminated intravascular coagulation associated with rifampin therapy

Case no./referenceAge, y/ sexIndication for rifampinRifampin dosagePrior exposure to rifampinConcurrent antimicrobial medicationsTime to development of DICSymptoms/signsOutcome
1/Brasil et al10NA/MLeprosy600 mg/monthYesClofazimine, dapsoneThird doseNADeath
2/Denis and others1148/FPulmonary tuberculosis600 mg/dayNAStreptomycin, ethambutol5 months including many treatment interruptionsFever, jaundice, vomiting, diarrheaRecovery
3/Fujita and others1243/MPulmonary tuberculosis450 mg/dayNAIsoniazid, streptomycin7 daysBleedingRecovery
4/Ip and others1329/FPulmonary tuberculosis600 mg, three times a weekYesIsoniazid6 monthsFever, hypotension, vomiting, oliguria, pruritisRecovery
5/Luzzati and others1435/MPulmonary tuberculosis600 mg/dayYesIsoniazid, pyrazinamide, ethambutolFirst doseFever, rash, hypotension, abdominal pain, vomiting, myalgiasRecovery
6/Namisato and Ogawa1664/MLeprosy600 mg/monthYesClofazimine, dapsoneThird doseFever, hypotension, facial edema, vomiting, abdominal painRecovery
7/Nowicka and others1553/FPulmonary tuberculosis450 mg; dosing schedule unclearYesNAThird doseLumbar and abdominal pain, anuriaDeath
8/Souza and others1746/FLeprosy600 mg/monthYesClofazimine, dapsoneThird doseFever, hematuriaDeath
9/Present report66/FLeprosy600 mg/monthYesDapsone, minocyclineSixth doseFever, hypotension,vomiting, abdominal pain, oliguriaRecovery

DIC = disseminated intravascular coagulation; NA = not available.

It is believed that rifampin-associated DIC results from antibody-mediated complement activation, which is triggered by circulating rifampin-erythrocyte complexes, resulting in erythrocyte destruction. Exposure of the circulation to erythrocyte constituents results in activation of the coagulation cascade. Three patients received empiric antimicrobial therapy for presumed sepsis-associated DIC.11,13,16 This misdiagnosis led to rifampin re-exposure in two instances,11,13 and rapid recurrence of DIC, which is similar to the case presented. Three (37.5%) patients died.10,15,17 In one of the surviving patients, rifampin-dependent antibodies were documented.14

We add to the literature the case of a patient with remote exposure to rifampin for the treatment of pulmonary tuberculosis and M. leprae infection in whom recurrent episodes of DIC and hemolytic anemia developed as a complication of intermittent rifampin therapy for treatment of leprosy. The patient's first immunoallergic reaction, resulting in acute renal failure, occurred immediately after ingestion of her sixth dose of rifampin. In the three subsequent presentations with DIC, broad-spectrum antibiotics were prescribed for suspected sepsis. Confirmation of rifampin as the trigger for DIC was made on the third presentation for DIC by identification of rifampin-dependent antibodies in her serum. This patient and others reported in the literature demonstrate that clinical and laboratory features cannot reliably distinguish between cases of rifampin-associated DIC and cases of DIC secondary to other causes.

In the case presented, temporal association of episodes of DIC with rifampin administration, recurrent reactions with repeat drug exposure, the absence of further episodes of DIC after discontinuation of rifampin, and presence of rifampin-dependent antibodies confirm the causal role of rifampin in this patient's recurrent episodes of DIC. Clinicians must be aware of the presentations of severe immunoallergic reactions to rifampin, which can appear during intermittent therapy, particularly if prior exposure to rifampin has occurred. A detailed drug history is paramount to making this diagnosis. In patients experiencing immunoallergic reactions to rifampin, this medication must be permanently discontinued because these reactions may be fatal.10,15,17 Daily administration of rifampin, as currently recommended in the United States for the multidrug therapy of leprosy, appears to be safer from an immunologic standpoint.8,18

  • 1.

    Johnson ST, Fueger JT, Gottschall JG, 2007. One center's experience; the serology and drugs associated with drug-induced hemolytic anemia – a new paradigm. Transfusion 47: 697702.

    • Search Google Scholar
    • Export Citation
  • 2.

    Forget EJ, Menzies D, 2006. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 5: 231249.

  • 3.

    World Health Organization, 1994. Chemotherapy of Leprosy: Report of a WHO Study Group - WHO Technical Report Series No. 847. Available at:

    • Search Google Scholar
    • Export Citation
  • 4.

    Martinez E, Muniz E, Domingo P, 1994. Evidence implicating rifampin-independent antiplatelet antibodies in the pathogenesis of rifampin-induced immune thrombocytopenia. Clin Infect Dis 19: 351353.

    • Search Google Scholar
    • Export Citation
  • 5.

    Worlledge S, 1973. Rifampicin-induced antibodies. Chemotherapy 4: 273278.

  • 6.

    Grosset J, Leventis S, 1983. Adverse effects of rifampin. Rev Infect Dis 5: S440S446.

  • 7.

    De Vriese AS, Robbrecht DL, Vanholder RC, Vogelaers DP, Lameire NH, 1998. Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features. Am J Kidney Dis 31: 108115.

    • Search Google Scholar
    • Export Citation
  • 8.

    A Hong Kong Tuberculosis Treatment Services/Brompton Hospital/British Medical Research Council Investigation, 1974. A controlled clinical trial of small weekly doses of rifampicin in the prevention of adverse reactions to the drug in a once-weekly regimen of chemotherapy in Hong Kong: a second report: the results at 12 months. Tubercle 55: 193210.

    • Search Google Scholar
    • Export Citation
  • 9.

    Riska N, Mattson K, 1972. Adverse reactions during rifampicin treatment. Scand J Respir Dis 53: 8796.

  • 10.

    Brasil MT, Opromolla DV, Marzliak ML, Nogueira W, 1996. Results of a surveillance system for adverse effects in leprosy's World Health Organization/Multidrug Therapy. Int J Lepr 64: 97104.

    • Search Google Scholar
    • Export Citation
  • 11.

    Denis J, Robert A, Johanet C, Homberg JC, Opolon P, Levy VG, 1983. Immunoallergic reaction to rifampicin with disseminated intravascular coagulation. Presse Med 12: 14791481.

    • Search Google Scholar
    • Export Citation
  • 12.

    Fujita M, Kunitake R, Nagano Y, Maeda F, 1997. Disseminated intravascular coagulation associated with pulmonary tuberculosis. Intern Med 36: 218220.

    • Search Google Scholar
    • Export Citation
  • 13.

    Ip M, Cheng KP, Cheung WC, 1991. Disseminated intravascular coagulopathy associated with rifampicin. Tubercle 72: 2913.

  • 14.

    Luzzati R, Giacomazzi D, Franchi F, Barcobello M, Vento S, 2007. Life-threatening, multiple hypersensitivity reactions induced by rifampicin in one patient with pulmonary tuberculosis. South Med J 100: 854855.

    • Search Google Scholar
    • Export Citation
  • 15.

    Nowicka J, Kotschy M, Chwistecki K, Jelen M, 1977. Disseminated intravascular coagulation (DIC) during superacute haemolysis in a patient with ovarian dermatoid cyst treated with rifampicin. Haematologia (Budap) 11: 359364.

    • Search Google Scholar
    • Export Citation
  • 16.

    Namisato M, Ogawa H, 2000. Serious side effects of rifampin on the course of World Health Organization/Multidrug Treatment: a case report. Int J Lepr Other Mycobact Dis 68: 277282.

    • Search Google Scholar
    • Export Citation
  • 17.

    Souza CS, Alberto PL, Foss NT, 1997. Disseminated intravascular coagulopathy as an adverse reaction to intermittent rifampin schedule in the treatment of leprosy. Int J Lepr Other Mycobact Dis 65: 366370.

    • Search Google Scholar
    • Export Citation
  • 18.

    Dacso M, Jacobson RR, Stryjewska BM, Prestigiacomo J, Scollard DM, 2011. Evaluation of multi-drug therapy for leprosy in the USA using daily rifampin. South Med J 104: 16.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Thomas C. Havey, Toronto General Hospital, 13EN-213, 200 Elizabeth Street, Toronto, Ontario, Canada, M5G 2C4. E-mail: tom.havey@utoronto.ca

Authors' addresses: Thomas C. Havey and Wayne L. Gold, Toronto General Hospital, Toronto, Ontario, Canada, E-mails: tom.havey@utoronto.ca and wayne.gold@uhn.on.ca. Christine Cserti-Gazdewich, Toronto General Hospital, Toronto, Ontario, Canada, E-mail: christine.cserti@uhn.on.ca. Michelle Sholzberg, Princess Margaret Hospital, Toronto, Ontario, Canada, E-mail: michelle.sholzberg@mail.mcgill.ca. Jay S. Keystone, Toronto General Hospital, Toronto, Ontario, Canada, E-mail: jay.keystone@utoronto.ca.

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