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Clinical Pharmacology "Adverse Drug
Event of the month"
Adverse event reported by the department of medicine Possible Rifampicin/Streptomycin induced Thrombocytopenia Case report: A 45 year old female normotensive, nondiabetic, resident of Mumbai was evaluated in a private healthcare setting for fever, cough and breathlessness of 1 month duration.There was no significant past, personal or family history. She had no past history of any drug reactions/allergic diathesis. She was investigated extensively (see table 1). Chest x-ray showed military mottling and 2-D Echocardiography showed mild pulmonary artery hypertension. She was diagnosed to have Ischemic heart disease along with lower respiratory tract infection and was treated with Inj.Cefpirome 1g I.V Q12 hrly, Inj. Amikacin 500 mg I.V Q12 hourly(both for 14 days), Tab. aspirin 325 mg OD, Tab. Clopidogrel 75 mg OD, Tab. Digoxin 0.25 OD, Tab. Spironolactone 50 mg + Tab. Frusemide 20 mg half OD, Inj. Deriphylline 1 ampoule(containing 160 mg etophylline+50 mg of deriphylline) Q8hrly, Inj. Ranitidine 50 mg I.V Q12hrly till the time of her hospitalization (day 20) in the private setting. She was marginally better with the above medications but on the 16th day of hospitalization she developed another spike of fever with exacerbation of cough. She was re- evaluated and it is was decided to start her on Anti-Tuberculosis therapy. She was started on Cap.Rifampicin 450 mg OD, Tab INH 300 mg OD, Tab. Ethambutol 800 mg OD and Tab. Ofloxacin 400 mg OD from day 17 . Her treating physician also started her on Inj. Streptomycin 0.75 g on day 19. Twelve hours after the first dose of streptomycin the patient developed multiple, discrete, erythematous maculo-papular rashes and patches with scaling (on few areas) all over the body(see picture). The macules were non-blanching in both lower limbs. Patient had bilateral pitting pedal edema. On day 20 and 21 the rashes coalesced over the lower limbs and majority of body areas. She was investigated and thrombocytopenia was documented. Streptomycin, Rifampicin and Isoniazid were discontinued immediately. She was referred to our institute for further management on day 20. In the Medicine ward she was treated with Platelet transfusions (4 units), Tab. Prednisolone 60 mg OD(which was discontinued on 23rd day of admission),Tab. Ethambutol 800mg OD, Tab. Pyrazinamide 750 mg BD, Tab. Pyridoxine 40 mg OD and other symptomatic measures. She was better by day 28 of hospitalization and the platelet counts showed a steady return to normal (Platelet count at time of discharge was 1.23 lakh/cu mm on the 33rd day of hospitalization).She was continued on Antituberculosis drug therapy and is symptomatically better at the time of discharge with slow disappearance of the dermatological-hematological lesions. Sputum AFB was negative on three consecutive days from 28/2/04 to 1/3/04(day 1 to 3). It was again negative for 3 consecutive times on 29/3/04 to 31/3/04 (day 31 to 33). ECG showed normal sinus rhythm .She was seronegative for HIV. HBsAg and blood Widal was negative on 1/3/04. ANA done was negative .Platelet associated antigen tests were advised but the patient declined the same. The adverse event was classified as possible (score of 4) by the Naranjo scoring system for Adverse drug events. Diagnosis: Ischemic Heart Disease, Sputum negative Pulmonary Tuberculosis, possible? Rifampicin /Streptomycin induced thrombocytopenia. Confirmation and classification of Drug induced Thrombocytopenia : The discovery of isolated thrombocytopenia in a patient who is taking several medications presents a challenging clinical problem1. The important diagnostic issue is to distinguish between drug-induced thrombocytopenia and idiopathic thrombocytopenic purpura because the latter diagnosis requires the exclusion of other causes of thrombocytopenia. Laboratory confirmation of drug-induced thrombocytopenia at the time of initial presentation is not possible because tests for drug-dependent antiplatelet antibodies are not available in most clinical laboratories. Furthermore, the safety of continuing treatment with a suspected drug if results of drug-dependent antibody tests are negative has not been established. The diagnosis of drug-induced thrombocytopenia can be supported only by the resolution of thrombocytopenia after discontinuation of therapy with the suspected drug. To avoid unnecessarily interrupting required therapy, the clinician must often decide whether to discontinue therapy with one or more of the patient's medications by assessing the probability that an agent is causing the thrombocytopenia. Reviews of drug-induced thrombocytopenia have resulted in extensive lists of drugs that have been reported to cause thrombocytopenia(2). However, these lists include so many commonly used drugs that it becomes difficult to decide which therapy to interrupt first. When a causal role for the drug is supported by level I or level II evidence(3) (see table 2), the clinical importance of the drug-induced thrombocytopenia is assessed by using standard criteria to define three levels of severity of bleeding: 1) major bleeding (defined as intracranial or retroperitoneal bleeding) or overt bleeding (defined as visible or symptomatic bleeding) with a decrease of hemoglobin concentration by more than 2 g/dL (20 g/L) or the requirement for transfusion of two or more units of erythrocytes; 2) minor bleeding, defined as overt bleeding that did not meet the criteria for major bleeding (malena, gross hematuria, epistaxis or gingival bleeding that is prolonged for more than 30 minutes or requires medical intervention; excessive menstrual bleeding or vaginal bleeding other than menses); and 3) trivial bleeding, which included petechiae, purpura, brief epistaxis or gingival bleeding, guaiac-positive stool, or microscopic hematuria. Discussion: The diagnosis of drug induced thrombocytopenic remains one of exclusion. Immune thrombocytopenia and secondary forms of the thrombocytopenias occur in association with systemic lupus erythematosus, the antiphospholipid syndrome, immunodeficiency states (IgA deficiency and common variable hypogammaglobulinemia), lymphoproliferative disorders (chronic lymphocytic leukemia, large granular lymphocytic leukemia, and lymphoma), infection with human immunodeficiency virus and hepatitis C virus. The direct assay for the measurement of platelet-bound antibodies has an estimated sensitivity of 49 to 66 percent, an estimated specificity of 78 to 92 percent, and an estimated positive predictive value of 80 to 83 percent. A negative test cannot be used to rule out the diagnosis(1). Rifampicin can occasionally cause thrombocytopenia and purpura with or without other symptoms of abnormal bleeding when used as intermittent therapy. The platelet count falls to a low level within 3 hours of the dose and if treatment is stopped it immediately returns to normal within 36 hours. If the treatment is not stopped, incidents of cerebral hemorrhage have been reported. No permanent effect on platelet production or function has been reported. Patients should be warned to stop treatment if purpura or abnormal bleeding is experienced. If purpura occurs during treatment ,the drug must be stopped at once and never be given again(4). This effect can also occur with continuous therapy with the drug, though this is less common. Thrombocytopenia can also occur as haematological reactions of isoniazid(4).There are also case report of a patient with thrombocytopenia due to ethambutol, perhaps by an immunological mechanism(5). Extremely rarely,streptomycin has been implicated in the causation of thrombocytopenia(4). When possible, it is necessary to administer three dugs not given previously, including one parenteral agent (an aminoglycoside or polypeptide) and two oral agents that are safe when life-threatening ADE has occurred(6). No cross-reactivity is expected between structurally dissimilar agents of the same class or among stereo isomers due to the high specificity of the reaction. So a drug of the same class may be substituted. Daily monitoring of the platelet count is often all that is necessary. Corticosteroids are of no benefit in drug-induced thrombocytopenia(6). However, in patients with severe symptomatic thrombo-cytopenia of unknown origin, they may be administered as the diagnosis may be difficult to distinguish from idiopathic thrombocytopenia purpura (ITP) due to similar clinical features. Platelet Transfusions are recommended in patients with symptomatic thrombocytopenia secondary to bone marrow suppression(7). Platelets normally are transfused in this patient population when the count is less than 20x103/mm3. Newer agents like Interleukin (IL)-11 (oprelvekin) were recently approved for preventing severe thrombocytopenia after chemotherapy in patients with nonmyeloid malignancies who are at high risk of thrombocytopenia. Table
1: Biochemistry and hematology parameters of the patient
Table 4. Mechanisms of Drug-Induced, Antibody-Mediated Thrombocytopenia(2)
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