rifampin and Agranulocytosis

We experienced 4 cases of agranulocytosis due to anti-tuberculosis drugs (rifampicin [RFP], isoniazid [INH], ethambutol [EB], streptomycin [SM] or pyrazinamide [PZA]) among some 6,400 tuberculosis patients who underwent chemotherapy over the past 20 years from 1981 to 2002 in our hospital, and the incidence rate of agranulocytosis was estimated at 0.06%. The 4 cases of agranulocytosis were as follows. CASE 1: A 51-year-old woman with right chest pain and fever was admitted to our hospital on Jan 4, 2001. The white blood cell (WBC) count was 5,200/microliter. The tubercle bacilli were cultured in her sputum. The treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, allopurinol and teprenone was started on Jan 13. Pyrazinamide and allopurinol were stopped because of hyper-uric acidemia on Feb 7. Agranulocytosis and eosinophilia (WBC 1,300 [Neut 1%, Ly 57%, Eos 35%]) developed on Feb 13. All drugs were withdrawn and G-CSF drug nartograstim 100 micrograms was injected subcutaneously for 3 days. The WBC recovered to normal level and she was thereafter treated with INH, EB and Levofloxacin (LVFX) without any further trouble. Agranulocytosis in this case was supposed to be due to RFP. CASE 2: A 66-year-old man who had had nephrotic syndrome and hypothyroidism and has been treated with prednisolone 10 mg/day was admitted to our hospital on Aug 9, 2000 because of miliary tuberculosis. The tubercle bacilli were cultured in his sputum and the treatment with INH 0.3, RFP 0.45, and EB 0.75 g/day were started on Aug 10, but it was withdrawn on Aug 17 because of general skin eruption. After re-starting treatment with EB and INH on Aug 24, RFP was added in small dosage (0.05 g) on Oct 12, but agranulomatosis (WBC 2,300/microliter [Neut 2%]) developed on Nov 21, and all drugs were withdrawn again. The G-CSF drug filgrastim was used once subcutaneously, and WBC recovered immediately. He was thereafter treated with INH, EB, LVFX successfully. Agranulocytosis was supposed to be due to RFP. CASE 3: A 60-year-old woman without symptoms had abnormal chest roentgenograph, and consulted with our hospital on Aug 26, 2002. The broncho-alveolar lavage fluid was smear and culture-negative, but PCR-TB positive, and the case was diagnosed as pulmonary tuberculosis. Treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, alloprinol 300 mg and rebamipide 300 mg/day was started on Sept. 5, 2002. Late in September, she complained of appetite loss. The laboratory data on Oct 3 reveale

Topics: Aged; Agranulocytosis; Antitubercular Agents; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

A 52-year-old woman was admitted to our hospital because of intermittent high fever and chronic renal failure. Computed tomography of the thorax showed swelling of the paratracheal lymph nodes that was confirmed by gallium scintigraphy. Biopsy of the supraclavicular lymph node on the right side showed necrotizing lymphadenitis with Langhans giant cells surrounded by epithelioid cells. Anti-tuberculosis treatment, including isoniazid, rifampicin, ethambutol, and pyrazinamide was initiated. One month after treatment, the patient developed agranulocytosis (white blood cell [WBC], 2100 cells/microl; neutrophils, 5%) accompanied by severe diarrhea. Bone marrow histology showed poor development of granulocytes, but no atypical cells were observed. Therefore, rifampicin was discontinued, and treatment with granulocyte colony-stimulating factor (G-CSF) was initiated. Subsequently, the white blood cell count and the proportion of neutrophils increased to 12500 cells/microL and 80%, respectively. Rifampicin in the anti-tuberculosis chemotherapy regimen was replaced with levofloxacin. This is a rare case of agranulocytosis caused by rifampicin administered during anti-tuberculosis treatment in a chronic renal failure patient.

Topics: Agranulocytosis; Antibiotics, Antitubercular; Female; Humans; Kidney Failure, Chronic; Middle Aged; Rifampin; Tuberculosis, Lymph Node

Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; Cephalosporins; Drug Eruptions; Drug Therapy, Combination; Eosinophilia; Female; Humans; Rifampin; Syndrome; Vancomycin

Multidrug therapy (WHO/MDT) in multibacillary leprosy consists of treatment with rifampicin, dapsone and clofazimine. However, adverse effects can cause the patient to abandon treatment. We report on a patient who presented agranulocytosis and hemolytic anemia associated with this treatment regime. We also examined the importance of laboratory exams for diagnosis and follow-up of the patient, and for early detection of adverse effects,with a view to improving adhesion to treatment and contributing to the eradication of Hansen's disease as a public health issue.

Topics: Adult; Agranulocytosis; Anemia, Hemolytic; Clofazimine; Dapsone; Drug Therapy, Combination; Female; Humans; Leprostatic Agents; Leprosy; Rifampin

The antibacterial efficacies of 4 antibiotics with different modes of action against a penicillin-tolerant and a non-tolerant strain of Staphylococcus aureus were investigated. For the in vitro studies the minimum inhibitory concentration (MIC) and the minimum bacterial concentration (MBC) were determined and short-term growth experiments at different antibiotic concentrations were performed. For the in vivo studies, antibacterial efficacy in an experimental infection in normal and granulocytopenic mice was evaluated. For erythromycin, rifampicin and ciprofloxacin, there was no difference in the MIC and MBC values for the 2 strains. Benzylpenicillin had an MBC value for the tolerant strains which was 256 times higher than the MIC; with the non-tolerant strain there was no difference. EC50 values, calculated from the in vitro short-term growth curves, gave similar results. Only benzylpenicillin exhibited a difference in activity against the tolerant strain, as reflected by the EC50 that was 290 times the EC50 for the non-tolerant strain. Studies in normal and granulocytopenic mice gave similar results: benzylpenicillin was 268 times less active against the tolerant strain than against the non-tolerant strain. Erythromycin, rifampicin and ciprofloxacin were 2-3 times less active against the tolerant strain than against the non-tolerant strain. The presence of granulocytes is important for the antibacterial effect of all antibiotics studied, since in the absence of granulocytes higher doses of the antibiotics are needed in order to obtain the same antibacterial effect as when granulocytes are present.

Topics: Agranulocytosis; Animals; Ciprofloxacin; Drug Resistance, Microbial; Erythromycin; Mice; Penicillin G; Penicillin Resistance; Rifampin; Staphylococcal Infections; Staphylococcus aureus

The effect of rifampicin on Staphylococcus aureus in vitro was assessed as the difference between the logarithms of the numbers of colony forming units (CFU) with and without 3 h of exposure to the drug. The efficacy was expressed as the EC50, i.e. the concentration at which 50% of the maximal effect was obtained, calculated according to the Hill equation. The value found for the EC50 was 3.8 micrograms/l and the mean maximal effect was a log ratio of 5.03 (SEM 0.33). In vivo experiments were performed in normal mice and in mice made granulocytopenic by irradiation. The effect of rifampicin was assessed as the CFU count 5 h after the injection of a suspension of bacteria into the thigh muscle and 4 h after the administration of rifampicin. The efficacy was expressed as the ED50, i.e. the dose at which 50% of the maximal effect is obtained. This value was 0.18 mg/kg for the normal mice and 0.15 mg/kg for the granulocytopenic mice. The corresponding mean plasma concentrations of non-protein-bound drug were 28 and 24 mg/l, respectively. Thus, the EC50 was found to be much higher in vivo than that in vitro. This difference should be taken into account when parameters of in-vitro efficacy are applied to establish dosage schedules.

Topics: Agranulocytosis; Animals; Male; Mice; Rifampin; Specific Pathogen-Free Organisms; Staphylococcal Infections; Staphylococcus aureus

We developed an experimental model of candidiasis in rabbits with prolonged neutropenia. Rabbits were made neutropenic with cytosine arabinoside (Ara-C) administered through an indwelling silastic catheter that had been surgically implanted in the external jugular vein. Neutropenia was sustained with intravenous Ara-C, and bacterial complications were prevented with parenteral ceftazidime plus ampicillin. Candidiasis was established by intravenously administering Candida albicans or Candida tropicalis (1-2 x 10(5) colony-forming units) and resulted in hepatic and splenic lesions that mimicked those associated with hepatosplenic candidiasis in humans. The kidney proved to be the site most refractory to eradication of Candida spp. and offered a target organ for assessing antifungal therapy. We evaluated amphotericin B, 5-flucytosine, ketoconazole, and rifampin, alone and in combination. Although each agent reduced the colony counts of Candida in the liver, spleen, and lung, the combination of amphotericin B and 5-flucytosine was the only regimen effective in eradicating renal candidiasis.

Topics: Agranulocytosis; Amphotericin B; Animals; Antifungal Agents; Candidiasis; Cytarabine; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Flucytosine; Ketoconazole; Neutropenia; Rabbits; Rifampin

Topics: Aged; Agranulocytosis; Antibiotics, Antitubercular; Ethambutol; Humans; Isoniazid; Leukocyte Count; Male; Neutropenia; Neutrophils; Rifampin; Tuberculosis, Pulmonary

Topics: Agranulocytosis; Blood Bactericidal Activity; Candida; Chediak-Higashi Syndrome; Chromosome Aberrations; Chromosome Disorders; Female; Glucosephosphate Dehydrogenase Deficiency; Glutathione Peroxidase; Granulomatous Disease, Chronic; Heterozygote; Humans; Infant, Newborn; Leukocytes; Lupus Erythematosus, Discoid; Male; Neoplasms; Neutropenia; Neutrophils; Peroxidases; Phagocytosis; Pregnancy; Rifampin; Sulfonamides; Vitamin B 6 Deficiency

Topics: Adult; Aged; Agranulocytosis; Anaphylaxis; Antitubercular Agents; Capreomycin; Cycloserine; Drug Hypersensitivity; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Kanamycin; Pyrazinamide; Rifampin; Thrombocytopenia; Viomycin

Topics: Adult; Agranulocytosis; Alkaline Phosphatase; Antitubercular Agents; Aspartate Aminotransferases; Bilirubin; Drug Resistance, Microbial; Eosinophilia; Female; Humans; Isoniazid; Leukopenia; Male; Middle Aged; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary; Uric Acid