The adverse reactions of anti-tuberculosis drugs and its management

This paper reviews adverse reactions to anti-tuberculous drugs. Hepatotoxicity occur with isoniazid, rifampicin, pyrazinamide and ethionamide. Risk factors include high age, malnutrition and high alcohol consumption. Liver function should be followed every two weeks to prevent serious hepatotoxicity. If this occurs drugs should be stopped until improvement of liver functions. Fulminant hepatitis has poorer prognosis in regimen with pyrazinamide than without. The Combination of pyrazinamide and ethionamide is frequently hepatotoxic and should be avoided. Gastric reactions occur frequently. Elderly persons are highly intolerant to rifampicin. Peripheral neuritis is reported with isoniazid, ethambutol and ethionamide, but effectively prevented with pyridoxine. Allergic reaction including fever or rash occur with many anti-tuberculosis drugs. If necessary desensitization to re-introduce the drugs. Ocular toxicity due to ethambutol occur infrequently with a dose of 15 mg/kg. Drug interactions are frequent in tuberculosis treatment. Rifampicin reduce serum the concentration of such drugs as Methadone, Corticosteroid, and Theophylline.     

Removal of a torn Racz catheter from lumbar epidural space

A 45-year-old man with the acquired immune deficiency syndrome (AIDS) developed disseminated Mycobacterium tuberculosis infection and was started on isoniazid, rifampin, pyrazinamide and ethambutol. The treatment was interrupted because of side effects. On resumption of treatment be developed a rapidly progressive neurological illness characterized by left hemiparesis, right gaze preference, convulsions, coma, evidence of cerebral edema on computed tomography scan and death 9 days later. Autopsy showed the presence of miliary tuberculosis affecting the lungs, liver, spleen, lymph nodes and bone marrow. The brain showed evidence of acute hemorrhagic leukoencephalitis (AHL)-the first such case in a patient with AIDS. We speculate that treatment-induced lysis of mycobacteria with concomitant release of mycobacterial lipoproteins may have activated T-lymphocytes to cause AHL in this patient.     

Should we change our point of view on pregnancy in adolescence?]

A 55-year-old man presented with the suspicion of pulmonary tuberculosis. He was treated with isoniazid, ethambutol, rifampicin and pyrazinamide. However, he developed high fever, skin rash and pulmonary infiltrates following 10 days of treatment. The above-mentioned conditions subsided promptly after stopping ethambutol therapy and reappeared after rechallenge, marking ethambutol as the offender. To present knowledge, this is the second case of an ethambutol-induced hypersensitivity lung reaction reported in English literature.     

Magnetic resonance imaging of a case of central nervous system tuberculosis with tuberculous arachnoiditis and multiple tuberculomas

A 62-year-old woman developed headache, vomiting and fever. On admission to hospital, she showed an imparied level of consciousness, diplopia on left lateral gaze, bilateral hearing loss and left hemiparesis. Cranial contrast computed tomography (CT) revealed basal meningeal enhancement. Lumbar cerebrospinal fluid (CSF) showed an increase in cell count (80/mm3) and total protein (3000 mg/dl), and a decrease in glucose (65 mg/dl) in comparison with blood sugar (173 mg/dl). Polymerase chain reaction was positive for Mycobacterium tuberculosis in the CSF. She was diagnosed as having tuberculous meningitis and was treated with anti-tuberculous chemotherapy. Her level of consciousness recovered and other clinical signs improved gradually the first month after admission. However, in spite of the combination of anti-tuberculous chemotherapy and steroid therapy, her combination of anti-tuberculous chemotherapy and steroid therapy, her consciousness level worsened again in association with paraplegia at the sixth week after admission and magnetic resonance imaging (MRI) revealed multiple tuberculomas, spinal arachnoiditis and spinal cord infarction. On T2-weighted imaging some of the tuberculomas showed a central hyperintense area (a central bright core) with an isointense periphery, which was surrounded by a hyperintense area. The lesion appeared hypointense with an isointense rim on T1-weighted imaging, showing a ring enhancement on post-contrast T1W imaging. The spinal cord infarction was situated at the third thoracic cord, which corresponded to the borderline of spinal artery perfusion. This is a rare case of progression of spinal arachnoiditis and spinal cord infarction during anti-tuberculous chemotherapy, and who had tuberculoma with a central bright core on MRI.     

Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis

The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.     

Cerebral tuberculosis presenting as complex febrile convulsions

Complex febrile convulsions were the initial clinical manifestation of miliary tuberculosis in a 4-year-old immigrant girl. The cerebral lesions were visible only after contrast-enhanced cranial computed tomography (CT) while native CT scan as well as cell count and glucose concentration in the cerebrospinal fluid were normal. Mycobacterium tuberculosis was cultured from gastric aspirate and liver biopsy tissue. Treatment with isoniazid and rifampin for 12 months, pyrazinamide for 9 months, and ethambutol for the initial 6 weeks resulted in resolution of the cerebral lesions but a retinal scar after granuloma formation in the right eye caused reduced visus. This case demonstrates the importance of thorough search for tuberculosis even in the absence of overt clinical pulmonary signs especially in high-risk individuals such as immigrants.     

Correlation between steady-state plasma concentration of antituberculous drugs and age, inclusion of rifampicin in the treatment regimen, adverse drug reactions and other clinical parameters

A regional hospital in Hong Kong examined the correlation between plasma concentrations of rifampicin, pyrazinamide, isoniazid and its metabolite hydrazine and age, inclusion of rifampicin in the treatment regimen, adverse drug reactions and other clinical parameters. One hundred eighty subjects with tuberculosis were admitted consecutively to the medical wards of the Prince of Wales Hospital over a one and a half year period. Elderly patients > 65 years were randomized into one of two treatments with and without rifampicin in addition to isoniazid, pyrazinamide and ethambutol; younger patients received all four drugs. Plasma antituberculous drug concentrations were determined using high performance liquid chromatography. Elderly patients taking rifampicin had a higher mean steady-state concentration of isoniazid, together with a higher incidence of adverse effects compared with those not taking rifampicin. No age related differences were observed for the other drugs. For the whole group, higher mean concentrations of hydrazine, rifampicin and pyrazinamide were associated with a higher incidence of adverse effects and the presence of coexisting diseases. It is concluded that in sick elderly patients with coexisting diseases, use of rifampicin in the antituberculous regimen should be accompanied by close monitoring for side effects, and that there may be an indication for use of lower dosages of antituberculous drugs in such patients.     

Determination of iron by the Ferrochem II: interference by tuberculostatics

Iron levels in samples from certain treated tuberculous patients are underestimated by the Ferrochem II analyser. Of the tuberculostatic drugs examined for a possible interference, isoniazid, ethambutol, rifampicin, pyrazinamide and Rifater (a mixture of rifampicin, isoniazid and pyrazinamide), only pyrazinamide and Rifater (due to its pyrazinamide content) were associated with iron levels differing significantly (p < 0.001) from those of controls, with means of -317.2 and -185.6 mumol l-1 for pyrazinamide and Rifater respectively as against 9.91 mumol l-1 for the controls. The negative interference (I) due to pyrazinamide was independent of iron level in the samples but dependent on pyrazinamide concentration in the same (P) (r = 0.9993), I = -0.4380P-0.4276.     

Bone density changes in postmenopausal women with the administration of ipriflavone alone or in association with low-dose ERT

BACKGROUND: Reports suggest that antituberculosis drugs are malabsorbed in patients with advanced HIV disease. OBJECTIVE: To evaluate the pharmacokinetics of antituberculosis agents in HIV-seropositive patients at different stages of disease. DESIGN: Parallel study. SETTING: Two hospital outpatient clinics. PARTICIPANTS: 12 healthy volunteers, 12 patients with asymptomatic HIV disease, 12 patients with symptomatic HIV disease, and 12 patients with symptomatic HIV disease and diarrhea. MEASUREMENTS: Drug plasma concentrations were measured over 24 hours on day 4 of concurrent therapy. INTERVENTION: Oral isoniazid (300 mg/d), rifampin (600 mg/d), pyrazinamide (1000 mg/d), and ethambutol (1000 mg/d). RESULTS: Reduced total drug exposure to rifampin and pyrazinamide was associated with D-xylose malabsorption in persons with HIV infection or AIDS. Peak drug exposure to isoniazid was lower in patients with diarrhea. CONCLUSIONS: Reduced total drug exposure may be related to malabsorption in persons with HIV infection or AIDS.     

Lomefloxacin in complex treatment of acute progressive form of pulmonary tuberculosis

The effect of lomefloxacin in combination with isoniazid, pyrazinamide, streptomycin or ethambutol on the process of tuberculosis and concomitant nonspecific pathological processes in the lungs was investigated in the treatment of 69 patients with newly diagnosticated acute progressive destructive tuberculosis of the lungs and isolation of Mycobacterium tuberculosis. It was shown that lomefloxacin provided rapid disappearance of the disease clinical signs and bacillus isolation in the patients with tuberculosis due to the tubercle bacilli susceptible or resistant to the main antituberculosis drugs, acceleration of the resolution of the infiltrates and caseous lesions in the lungs and elimination of the pathological processes in the bronchi. The tolerance of lomefloxacin was satisfactory and it did not affect the tolerance of the other antituberculosis drugs.     

Flow cytometric testing of susceptibilities of Mycobacterium tuberculosis isolates to ethambutol, isoniazid, and rifampin in 24 hours

Susceptibility testing of Mycobacterium tuberculosis is seriously limited by the time required to obtain results. We show that susceptibility testing of clinical isolates of M. tuberculosis can be accomplished rapidly with acceptable accuracy by using flow cytometry. The susceptibilities of 35 clinical isolates of M. tuberculosis to various concentrations of isoniazid, rifampin, and ethambutol were tested by the agar proportion method and by flow cytometry. Agreement between the results from the two methods was 95, 92, and 83% for isoniazid, ethambutol, and rifampin, respectively. Only 11 discrepancies were detected among 155 total tests. The results of flow cytometric susceptibility tests were available within 24 h of inoculation of drug-containing medium, while the proportion method required 3 weeks to complete. The flow cytometric method is also simple to perform.     

Differential diagnosis of pulmonary tuberculosis

Differential diagnosis of pulmonary tuberculosis is discussed. Chest X-ray findings of pulmonary tuberculosis may be greatly varied, because tuberculosis may cause three different lesions: an exudative lesion, a proliferative lesion, and a fibrotic lesion, and because it may invade all the structure. Thus, the differential diagnosis of pulmonary tuberculosis includes very many diseases. The most important differential diagnosis of nodule is tuberculoma and lung cancer. The clue of the diagnosis is the feature of the nodule and surrounding structure, such as pleural indentation, or knotching. There is, however, the limitation of the diagnosis by imaging: some tuberculoma may show the identical feature with the pulmonary adenocarcinoma. It is important to gather the pathological or bacteriological evidences by means of suitable procedures.     

Case report of miliary TB, with mediastinal TB involving the aorta, trachea and esophagus with death due to hemorrhage from perforation of aorta into the esophagus during treatment

A 32-year-old male was diagnosed as having miliary tuberculosis in May 1990. In spite of antituberculosis chemotherapy, he developed tuberculous meningitis and intracranial tuberculoma in September 1990. Miliary shadows on chest X-ray disappeared in December 1990. However, he developed left atelectasis, and bronchofiberscopy revealed soft tumor in the left main bronchus in January 1991. He suddenly vomited large amounts of blood and expired in February 1991. At autopsy, tuberculous lymphadenitis and cavitation were noted in the mediastinum, through which the left main bronchus, esophagus and descending aorta communicated. The patient died of massive bleeding which resulted from the rupture of tuberculous aortitis into the esophagus. This is a very rare case of tuberculous aortic aneurysm rupturing into both the bronchus and esophagus.     

Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children

BACKGROUND: This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children. METHODS: A total of 114 children ages 6 months to 15 years (4.5 +/- 3.4 years) with diagnosed pulmonary tuberculosis from 1985 to 1995 entered the trial. A 2-month regimen of isoniazid, rifampin and pyrazinamide, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to all children. Clinical adverse effects specifically investigated were gastrointestinal disturbances, rash, signs of hepatotoxicity and arthralgias. Laboratory toxicity data (number of leukocytes, erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and serum uric acid) were collected before treatment and 1, 3 and 5 months after the beginning of chemotherapy. RESULTS: Clinical adverse effects were mild in all cases. Three children (2.6%) had fever and 5 (4.4%) had gastrointestinal disturbances. Aspartate aminotransferase and alanine aminotransferase mean values showed no differences along time and no patients had clinical signs of hepatotoxicity. Only 11 children (19.6%) showed a slight increase in alanine aminotransferase (< 194 units/l). Serum uric acid increased in 92.2% of the children compared with pretreatment values. This increase remained within the normal range in all but 9.8% of patients. There was a significant increase in uric acid mean concentrations after 1 month of therapy (from 3.7 +/- 0.7 mg/dl to 5.7 +/- 1.6 mg/dl, P < 0.05), which fell again (4.0 +/- 1.1) 1 month after pyrazinamide was stopped. There were no signs of gout or arthralgias. In no case was the treatment interrupted. CONCLUSION: The addition of pyrazinamide in chemotherapy for pulmonary tuberculosis in children was found to be safe. The slight increase in uric acid concentration during its administration had no recognized adverse consequences.     

RAC defers gene therapy approval

We determined the primary and secondary resistance of isolates of M. tuberculosis to the standard antituberculous drugs in Karachi (Pakistan). Primary resistance to one or more anti-tuberculous drugs was found in 17% of 123 isolates of M. tuberculosis (obtained from patients with no history of previous treatment for tuberculosis). Secondary resistance was found in 36% of 33 isolates (obtained from individuals who had received anti-tuberculous treatment in the past). The drug to which organisms were most commonly resistant was isoniazid (11% primary resistance, 30% secondary resistance). Fifteen per cent of isolates obtained from previously-studied patients showed secondary resistance to rifampicin. We discuss the importance of these findings for tuberculosis treatment and control.     

Direct detection of Mycobacterium tuberculosis using polymerase chain reaction assay among patients with hepatic granuloma

BACKGROUND: In liver tuberculosis, demonstration of acid bacilli by conventional methods remains futile. Since the definitive diagnosis of liver tuberculosis is based on the histologic evidence of granulomatous process with caseation necrosis, seen in only a third of cases, the diagnosis is made retrospectively by response to empirical anti-tuberculous drug therapy. AIMS: Our objective is to establish a polymerase chain reaction assay for detection of Mycobacterium tuberculosis affecting the liver using the paraffin-embedded liver biopsy specimens obtained from patients with hepatic granulomas. METHODS: As positive control, patients having either "definitive" (n=8) or "presumptive" (n=9) tuberculosis on the basis of clinical, microbiological, histologic data and their positive response to empirical treatment of anti-tuberculous drugs were used. Patients with hepatic granulomas secondary to schistosomiasis (n=6), sarcoidosis (n=2) and other liver diseases (n=10) were used as negative control. RESULTS: Of those patients who were diagnosed as having "definitive" and "presumptive" liver tuberculosis, positivity by one-step polymerase chain reaction was 100% and 44%, respectively. Using the nested polymerase chain reaction, positivity increased to 78% with "presumptive" liver tuberculosis. In contrast, the polymerase chain reaction assays were negative among all patients with hepatic granuloma due to non-tuberculous-in-origin and other liver diseases. CONCLUSIONS: The overall positivity of this polymerase chain reaction assay (88%) compares favorably with that of other conventional methods (12%). Thus, this polymerase chain reaction assay may be a reliable diagnostic tool for liver tuberculosis in a patient population in which the prevalence of diseases associated with hepatic granuloma is common.     

Short-course chemotherapy of tuberculosis with pyrazinamide

A 6-month regimen consisting of isoniazid (INH. 0.3-0.5 g).rifampicin (RFP. 0.3-0.45 g).pyrazinamide (PZA. 1.2-2.0 g) and streptomycin (SM. 0.75 g) or ethambutol (EB. 0.75-1.0 g) given for 2 month followed by isoniazid and rifampicin for 4 month is the preferred treatment for patients with fully susceptible organism, who adhere to treatment. Consideration should be given to treating all patients with directly observed treatment.     

Evaluation of the ESP culture system II for testing susceptibilities of Mycobacterium tuberculosis isolates to four primary antituberculous drugs

The reliability of the ESP Culture System II (herein referred to as ESP II) for testing susceptibilities of Mycobacterium tuberculosis isolates to isoniazid, rifampin, ethambutol, and streptomycin was evaluated by comparing results to those of the method of proportion (MOP), which was considered the reference method, for 20 clinical isolates and 30 challenge strains provided by the Centers for Disease Control and Prevention (CDC). Clinical isolates also were tested with the BACTEC TB 460 system; these results agreed with those obtained by the MOP for all isolates and all drugs, except the high concentration of isoniazid, for which agreement was 95%. After resolution of discrepancies, levels of agreement between ESP II and MOP for the clinical isolates were 95 and 100%, respectively, for the low and high concentrations of isoniazid, 100% for rifampin and ethambutol, and 95% for streptomycin. For the 30 challenge isolates, ESP II results for both concentrations of isoniazid agreed with the expected results in all cases, whereas agreement was 93% for both rifampin and streptomycin and 90% for ethambutol. All discrepancies with the CDC isolates were due to failure of ESP II to correctly classify resistant strains. By testing isolates yielding discrepant ethambutol and streptomycin results with a lower concentration of both drugs in the ESP II system, agreement increased to 93% for ethambutol and 100% for streptomycin. For the clinical isolates, the times to an ESP II result of susceptible (means +/- standard errors of the means) were 8.47 +/- 0.12 days (range, 7 to 10 days) and 8.73 +/- 0.29 days (range, 5 to 11 days) when the inoculum was prepared from a McFarland equivalent and from a seed bottle, respectively. The time to an ESP II result of resistant varied by drug and method of inoculum preparation, ranging from 5.50 +/- 0.22 days for ethambutol with the inoculum prepared from a McFarland standard to 8. 0 days for ethambutol with the inoculum prepared from a seed bottle. These data suggest that the ESP II system is a rapid and reliable method for testing susceptibilities of M. tuberculosis isolates to isoniazid and rifampin. Performance, however, may be suboptimal for ethambutol and streptomycin. Testing additional ethambutol-resistant and streptomycin-resistant strains with two concentrations of both drugs is necessary.     

Entamoeba histolytica: computer-assisted modeling of phosphofructokinase for the prediction of broad-spectrum antiparasitic agents

Approximately 34 cases of intracranial tuberculomas with paradoxical response to antituberculous chemotherapy have been documented worldwide. In most of the previously reported cases of this entity an associated tuberculous meningitis has been reported. The majority of these patients were children or young adults, who had inoperably located intracranial tuberculomas in high risk regions developing a few weeks or months after the start of appropriate chemotherapy. 53% of them recovered completely, 37% improved with mild neurological deficits and 10% died. It is interesting that these intracranial tuberculomas developed or enlarged at a stage when systemic tuberculosis was being treated successfully. We report our recent experience with these potentially curable tumours of the central nervous system. The literature is reviewed and diagnostic and therapeutic considerations are discussed. The possible immunological mechanisms of this phenomenon are analysed. In conclusion, patients, who are suspected to be suffering from CNS-tuberculosis should receive a prolonged (12-30 months) course of effective antituberculous therapy. Evidence of new intracranial tuberculomas or the expansion of older existing lesions require no change in the antituberculous drug programme. In such cases systemic dexamethasone as adjuvant therapy for 4 to 8 weeks is worthwhile and effective. Surgical intervention may be necessary in situations with acute complications of CNS tuberculosis such as shunting procedures for the treatment of hydrocephalus. When the diagnosis is not firm and there is no response to therapy within 8 weeks, a stereotactic biopsy of a suspected tuberculoma should be performed. If the largest lesion is not located in high risk deep regions of the brain, it should be total removed surgically. With this combined management, a satisfactory outcome can be obtained in the majority of cases.     

Ocular toxicity from ethambutol: a review of four cases and recommended precautions

AIMS: To document the clinical and demographic features of cases of ethambutol ocular toxicity, to review the literature on this subject and to critically review current guidelines for ethambutol administration. METHODS: Cases of ocular toxicity from ethambutol were sought retrospectively at Green Lane and Wellington Hospitals between 1992 and 1995. The records of cases identified were examined. RESULTS: Four subjects with tuberculosis developed ocular toxicity 2 1/2, 7 1/2, 8 and 12 months after starting ethambutol. Normal visual acuity returned in three cases; one patient has severe, permanent visual impairment. Language difficulties were present in three subjects. CONCLUSIONS: Impaired communication was potentially very important in this series. Special care is needed in educating patients about ethambutol. We propose additional recommendations: 1. the usual daily dose of ethambutol should be 15 mg/kg/day, not 25 mg/kg/day; using 25 mg/kg/day (or lesser doses in the presence of renal impairment) should prompt regular formal ophthalmological evaluation (e.g. monthly) in cases with comprehension or communication difficulties; 3. both ethambutol and isoniazid should be stopped immediately if severe optic neuritis occurs. Isoniazid should be stopped if less severe optic neuritis does not improve within six weeks after stopping ethambutol.