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Treatment of Mycobacterium avium disease remains challenging when macrolide resistance develops. We infected C57 beige mice and treated them with mefloquine, SRI-286, and moxifloxacin. SRI-286 (80 mg/kg) was bactericidal in the liver. Mefloquine plus moxifloxacin or mefloquine plus SRI-286 were better than mefloquine alone.

Introduction: Toxic epidermal necrolysis is a severe disease often leading to death or to mucosal, particularly ocular, after effects. The principle drugs responsible are antibacterial sulfonamides, anti-epileptics, non-steroid anti-inflammatories, allopurinol and chlormezanone. We report a series of 38 cases of toxic epidermal necrolysis, observed in Dakar, imputable to thiacetazone and lethal in 60 percent of cases., Patients and Methods: Our study was retrospective. Diagnosis of toxic epidermal necrolysis was made in patients presenting more than 30 p. 100 of the epidermis of their total body surface stripped off, multi-orificial mucosal damage and epidermal necrosis revealed on histological examination. Drug imputability was established on classical criteria. Treatment was composed of reanimation and antibiotics., Results: Among the 38 cases of toxic epidermal necrolysis counted, 24 were imputable to thiacetazone. All the patients presented typical clinical features, confirmed histologically. Evolution was lethal in 60 p. 100 of cases. The causes of death were frequently hypovolemic shock during the first week and septic shock during the second. The deceased were generally aged over 50, had more than 50 p. 100 of total epidermis stripped off, presented evolving tuberculosis at the time of the accident and HIV infection at the AIDS stage. After effects were vaginal synechia and 2 cases of blindness., Comments: Our series is exceptional in that a) the drug responsible: thiacetazone, an economic tuberculostatic of minor efficacy, was systematically introduced after 2 months of intensive treatment with 4 major anti-tuberculosis agents; b) the 60 percent mortality rate, two-fold greater that that usually observed. Other than the known elements of poor prognosis in our patients, the treatment conditions of this dermatological emergency explain this high rate of mortality.

From 1980 to 1997 we had observed 50 cases of cutaneous side effects of thiacetazone. There were 25 cases of Steven-Jonhson syndrome, 23 cases of Lyell syndrome, a case of erythrodermia and a case of lichenoid toxidermia. The mortality was 40% with 16 cases of Lyell syndrome and 4 cases of Steven Johnson syndrome. Thiacetazone is a minor tuberculostatic drug used widely in the national program against tuberculosis. Our results confirm the seriousness of cutaneous side effects due to this drug. So like in other neighboring countries, we suggest to avoid use of this drug in Senegal.

Because the number of cases of multiforme skin lesions encountered in the medical department of Yekatit 12 Hospital has increased in recent years, we conducted a retrospective study to identify the likely precipitating factors and the possible relationship of these with HIV infection. Forty-seven patients with Multiforme Skin Lesions (29 males, 18 females) were admitted between 1976 and January 1994, of whom 43 (92%) were admitted in the past 5 years. Most patients were aged 15-49 years. Thirty patients (64%) were discharged improved and 14 (30%) expired in hospital. The outcome of 3 patients are not known. The charts of only 16 patients could be retrieved for review. Fifteen of these (94%) gave a history of intake of streptomycin, isoniazed and thiacetazone prior to developing the skin manifestation. The anti-TB medications were discontinued initially; 14 patients were restarted on STM, INH and ethambutol without recurrence of the rash. All but 1 were discharged improved. HIV screening tests were done on 24 patients with multiforme skin lesion of whom 21 (88%) were seropositive. Our study suggested that the adverse effects of thiacetazone are increased in HIV associated tuberculous patients. We recommend that further studies be conducted in HIV seropositive and seronegative patients.

Antituberculosis treatment containing thiacetazone is associated with a high incidence of life-threatening cutaneous drug reactions in patients infected with the human immunodeficiency virus (HIV). In order to develop a local policy concerning the use of this drug, a study was undertaken to determine the incidence of such reactions in a total of 1063 Ghanaian adult patients treated for pulmonary tuberculosis (PTB) with thiacetazone-containing regimens. The incidence was retrospectively determined in 3 different treatment groups, comparing: (A) unselected use of thiacetazone; (B) exclusion of thiacetazone from all patients with positive HIV serology; (C) selective exclusion of thiacetazone from patients with clinical criteria suggesting HIV infection plus education of health workers and patients. Of the 408 patients in group A receiving thiacetazone, 9 (2.2%) developed life-threatening cutaneous reactions and 7 of these were HIV-positive. Overall, 6.8% of HIV-positive patients compared to 0.65% of HIV-negative patients developed severe reactions (P < 0.01; relative risk = 10.5). Six of the 9 patients with reactions died. All 379 patients in group B were screened for HIV antibodies and positive cases (23%) received a regimen in which thiacetazone was substituted by ethambutol. In contrast to Group A, only one HIV-negative patient (0.26%) developed a severe cutaneous reaction (P = 0.02). Among 276 patients in group C, thiacetazone was substituted with ethambutol only in those with clinical evidence of HIV infection (8%) and staff and patients were educated about early recognition of the side-effect. With this policy, these were no admissions with severe cutaneous reactions compared to 2.2% of those in group A (P = 0.01). In conclusion, a policy of selective use of thiacetazone in the treatment of PTB based on clinical criteria combined with patient and staff education was found to be a practical and cost-effective strategy combating severe cutaneous reactions to thiacetazone.

Setting: Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda., Objective: To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB., Design: Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR)., Results: Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02)., Conclusion: Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.

Study Objective: To investigate the steady-state pharmacokinetics of thiacetazone (TB-1), which is active in vitro against Mycobacterium avium complex (MAC)., Design: Open-label phase I study., Setting: Specialized referral hospital., Patients: Twelve healthy men and women., Interventions: Oral TB-1 150 mg/day was administered for 7 days, followed by blood and urine collection over 48 hours., Measurements and Main Results: The serum concentration versus time curves of TB-1 showed sustained concentrations, with maximum values of 1.59 +/- 0.47 micrograms/ml, time to maximum 3.30 +/- 1.18 hours, and serum half-life of 15-16 hours. Less than 25% of TB-1 was recovered unchanged in the urine over 48 hours. Rashes occurred in two subjects at the end of the 7-day dosing period and resolved without progression or sequelae., Conclusions: Based on these data, we initiated a phase II study of TB-I in patients with pulmonary MAC infection who do not have the acquired immunodeficiency syndrome.

We have studied the relationship between the plasma concentration-time profile of thiacetazone over the 24 h between doses [AUC(0.24h)] and the incidence of cutaneous reactions among HIV-infected patients with tuberculosis in Kenya. Cutaneous reactions due to thiacetazone occurred in 4/14 [28.6%] HIV+ve patients compared with 3/47 [6.4%] HIV-ve patients [RR = 4.48, 95% CI-1.1 to 17.7], and all resolved on alternative therapy. Among the HIV+ve patients, those with cutaneous reactions had higher AUC(0.24h) values, although the difference was not significant. These results do not exclude pharmacokinetic change as being at least partly responsible for cutaneous reactions to TCZ in HIV+ve patients, and do not refute an immunological basis for the reaction. With regard to the operational use of TCZ in Africa, there is no indication that a modification of the dose will reduce the frequency of drug reactions.

Setting: Severe skin reactions due to thiacetazone (T) in Human Immunodeficiency Virus (HIV) positive tuberculosis patients have been reported in several publications, one of them from Kenya. However, the abandoning of T may not be feasible in Kenya as this may increase the cost of drugs by about three-fold per regimen., Objective: To compare the cost-effectiveness and total cost of three strategies in which T is replaced with ethambutol (E)., Design: Three strategies are compared with a baseline strategy in which T is not replaced. The indicator for cost-effectiveness is the cost-per-averted-death attributable to T., Results: Education of patients on the possibility of side-effects and replacement of T with E is the most cost-effective strategy at HIV prevalence rates of 1-90%. Abandonment of T and replacement with E is the most cost-effective at over 90% HIV prevalence., Conclusion: In Kenya, education of patients on the possibility of skin reactions should be preferred at low range HIV prevalence rates. Routine HIV testing would be the most attractive strategy in the middle range, and total replacement of T with E is to be preferred in the higher range of HIV prevalence.

Because thiacetazone has been linked with serious adverse cutaneous reactions, we undertook 1 year of systematic surveillance for cutaneous thiacetazone-associated adverse reactions within the national tuberculosis programme of Tanzania. For individual cases, we collected information on age, sex, interval between commencing thiacetazone-containing treatment and occurrence of adverse reaction, most severe clinical presentation (toxic epidermal necrolysis, rash without necrolysis, itching without rash), and outcome (dead or alive) within 2 weeks of onset. Univariate and multivariate analyses were done of variables relevant to outcome. 1273 patients with adverse reactions were reported. The frequency of fatal outcome from any cutaneous reaction was 3.1 per 1000 among all tuberculosis patients, and 19.1% among patients with toxic epidermal necrolysis. About 60% of all adverse reactions and deaths occurred within 20 days of starting thiacetazone. Case fatality from adverse cutaneous reactions was considerably less frequent than reported previously, suggesting that improved management might allow retention of thiacetazone in the armamentarium of national tuberculosis programmes even where infection with HIV is prevalent.

Among HIV-positive patients who received treatment for active tuberculosis, thiacetazone has been associated with cutaneous hypersensitivity and recurrent tuberculosis. No controlled trials have investigated the safety and efficacy of thiacetazone-containing regimens compared with alternative regimens among patients with HIV. In a randomised clinical trial of 191 HIV-positive patients with active pulmonary tuberculosis, we examined the safety and short-term efficacy of isoniazid, rifampicin, and pyrazinamide for two months followed by isoniazid and rifampicin for seven months (RHZ) compared with streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for ten months (STH). Between May, 1990, and September, 1991, 191 HIV-positive adult Ugandan patients with acid-fast bacilli sputum smear-positive pulmonary tuberculosis (93% confirmed by culture) received either STH or RHZ. Subjects had a standard evaluation that included Mantoux skin test, complete blood count with differential white blood cell count, and chest radiography. After starting therapy, subjects were followed-up over one year for three outcomes: complications of anti-tuberculosis therapy, early sterilisation of cultures, and survival. Of 191 eligible subjects, 90 received STH and 101 received RHZ. The overall one-year survival was similar for STH and RHZ (65% vs 72%), but when controlled for baseline differences in Mantoux reaction size and absolute lymphocyte count, the relative risk of death for STH compared with RHZ was 1.57 (95% CI 1.0-2.48). Overall, 12 adverse drug reactions occurred in the STH arm (18.2 reactions per 100 person years [PYO]) compared with one in the RHZ arm (1.6 reactions per 100 PYO) for a relative risk of 11.7 (95% CI 1.52-90.0). 10 cutaneous reactions occurred in the STH arm (15.2 events per 100 PYO) compared with one event in the RHZ arm (1.6 events per 100 PYO) for a relative risk of 9.7 (95% CI: 1.24, 75.8). A greater proportion of RHZ patients compared with STH patients had sterilised their sputum within two months (74% vs 37%, p < 0.001). In developing countries, rifampicin-containing regimens should be given, when possible, to HIV-positive patients to reduce drug toxicity and to prolong survival.

Tuberculosis in patients infected with human immunodeficiency virus (HIV) is a growing threat to public health in Africa. Thiacetazone, one of the continent's most widely used antituberculous agents, may lead to severe cutaneous reactions in the HIV infected individual. We describe the impact of this reaction on the tuberculosis (TB) control programme of a district hospital in Zambia in 1990, and examine the cost implications of changing the standard treatment regime. We carried out a retrospective survey of records of all patients beginning TB treatment in 1990, together with HIV test results and the cost of all treatments given. From this we derived estimates of costs of different regimes which are and could be used in TB control in Zambia. Severe reactions occurred in 18.7% of all HIV seropositive patients receiving thiacetazone, fatally so in 1.2% (odds ratio 16.6). The greatest part of the cost of the current regime is that attributable to the inpatient stay; we estimated that 29.4% of patients would be unable to receive drugs as out-patients but, even allowing for this, rifampicin-based regimes given to outpatients where possible would not cost more than the current strategy. We conclude that ethical and economic considerations support a change to rifampicin-based regimes in areas of Africa where HIV seroprevalence is high.

There is evidence that in human immunodeficiency virus 1 (HIV-1) infected patients with tuberculosis the rate of recurrence of tuberculosis is increased in those patients treated with a standard thiacetazone-containing regimen. To assess the impact of HIV-1 on tuberculosis in Kenya, patients with tuberculosis were studied prospectively. After treatment with either a standard thiacetazone plus isoniazid regimen or a short-course thiacetazone-containing regimen, overall recurrence rate of tuberculosis was 34 times greater in 58 HIV-1-positive patients than in 138 HIV-1-negative patients (adjusted rate ratio 33.8, 95% CI 4.3-264). Recurrence in the HIV-1-positive group was strongly associated with a cutaneous hypersensitivity reaction due to thiacetazone during initial treatment (rate ratio 13.2, 95% CI 3.1-56.2). In all patients with a cutaneous hypersensitivity reaction ethambutol was substituted for thiacetazone. No significant association was found between recurrence among HIV-1-positive patients and initial resistance, initial treatment regimen, a diagnosis of AIDS (WHO definition), or poor compliance. DNA fingerprinting suggested that both relapse and new infection may have produced recurrence of tuberculosis. In patients who had a cutaneous hypersensitivity reaction, increased recurrence rate may have been related to interruption of treatment, subsequent poor compliance, or more advanced immunosuppression. Alternatively, a change to the combination of ethambutol and isoniazid in the continuation phase for 11 months only may not be adequate.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening illnesses that have often been linked to drug exposure., Methods: We looked retrospectively for all cases of SJS and TEN that were admitted to Siriraj Hospital between 1981 and 1990 to determine the drug etiology., Results: Fifty-eight cases of SJS and 20 cases of TEN were identified. Eight patients initially had an SJS-like aspect, which subsequently evolved into TEN. A culpable drug was determined in 60 patients (77%). The mean time from first drug administration to onset of SJS or TEN was 6.8 +/- 6.5 days (range, 1 to 28 days). A longer incubation period was observed with thiacetazone (10.5 +/- 5.6 days), phenytoin (12 +/- 8.5 days), and carbamazepine (11.3 +/- 3.4 days)., Conclusions: The culprit drugs included the following: antibiotics, 32 cases (penicillin, sulfonamides, tetracycline, erythromycin); anticonvulsants, nine (phenytoin, carbamazepine, barbiturates); antitubercular drugs, eight (thiacetazone); analgesics, four (acetylsalicylic acid, fenbufen); sulfonylurea, two; allopurinol, one; and others, four. The most frequent underlying diseases justifying the ingestion of one or more drugs in our patients were infections (52.7%), followed by pulmonary tuberculosis (10.8%), and by seizures (8.1%). The total mortality rate was 14%; 5% for SJS, and 40% for TEN. Mortality was not affected by the type of drug responsible.

Tuberculosis is one of the most common infections in Zambian adults and children infected with HIV. In Africa, cutaneous hypersensitivity reactions attributed to thiacetazone during treatment of tuberculosis in adults infected with HIV-I have been well documented. This study monitored adverse drug reactions during treatment for tuberculosis over an 18 month period (1 April 1990 to 31 October 1991) in 237 children with a clinical diagnosis of tuberculosis (125 boys and 112 girls; 88/237 (37%) infected with HIV-I) and 242 control children (149 boys and 93 girls; 26/242 (11%) infected with HIV-I). Twenty two (9%) of the 237 children with tuberculosis developed hypersensitivity skin reactions during the course of treatment. Adverse skin reactions were seen more often in children infected with HIV than in those who were not (odds ratio 11.65, 95% confidence interval 3.07 to 34.88). These represented 19 (21%) of 88 children infected with HIV and three (2%) of 149 children not infected with HIV. These skin reactions occurred after a period of treatment ranging between two and four weeks among 14 children receiving the HST (isoniazid, streptomycin, thiacetazone) regimen and eight children receiving the HSTR (isoniazid, streptomycin, thiacetazone, rifampicin) regimen. Twelve (55%) of the 22 children who reacted adversely to treatment developed the Stevens-Johnson syndrome. All 12 of these children with the Stevens-Johnson syndrome were infected with HIV. The mortality among these children who developed the Stevens-Johnson syndrome was 91% (11 of 12 died within three days of the onset of the reaction). No further reactions were observed in the 11 children who recovered from the cutaneous hypersensitivity reactions after thiacetazone was discontinued over a period of six months of further treatment of tuberculosis. The results of this study were in part responsible for the recommendations put forward by the World Health Organization to avoid the use of thiacetazone in the treatment of tuberculosis in children infected with HIV.

Concurrent infection with HIV-1 and Mycobacterium tuberculosis is increasingly common in East Africa. In the past, a drug regimen consisting of 2 months of intramuscular streptomycin plus 12 months of isoniazid and thiacetazone has been used in tuberculosis control programs with acceptable efficacy and low incidence of adverse reactions. Anecdotal reports of increasing cases of Stevens-Johnson syndrome prompted a 2 month prospective search for cases of severe cutaneous hypersensitivity reactions at Muhimbili Medical Centre in Dar es Salaam, Tanzania. Five such patients were admitted to a single ward during this time, 4 of whom were HIV-seropositive and all of whom were being treated with isoniazid and thiacetazone. These findings have implications for the management of tuberculosis in East Africa and perhaps other countries with high prevalence of both HIV-1 and tuberculosis.

Objective: To document the influence of HIV status on drug reactions occurring in patients on antituberculous therapy in Harare, Zimbabwe., Design: Retrospective cohort study., Setting: City of Harare Tuberculosis Unit., Patients: Records of 906 patients with tuberculosis, of whom 162 reacted to antituberculous therapy, were analysed., Results: Reactions to antituberculous drugs were more frequent in HIV-positive (98 out of 363) than in HIV-negative (64 out of 543; P less than 0.0001) patients. The most common drug reaction was cutaneous hypersensitivity, occurring in 139 patients, 89 (64%) of whom were HIV-positive. Thiacetazone was implicated in 115 (82.7%) of the 139 cutaneous reactions and streptomycin in 10 (7.2%). Almost all cutaneous reactions occurred within 8 weeks of beginning treatment. Severe cutaneous reactions occurred more often in HIV-positive patients (P less than 0.001) and the only two deaths occurred in this group. Reactions to multiple drugs occurred in 18 HIV-positive and three HIV-negative patients (P = 0.017)., Conclusions: The use of thiacetazone and streptomycin in antituberculous drug regimens should be reassessed in those countries where coinfection with HIV and tuberculosis is common.

Evidence from many countries suggests an association of human immunodeficiency virus (HIV) infection and tuberculosis of major public health significance. In order to begin assessing the impact of HIV on tuberculosis in Kenya, we have determined the HIV-1 seroprevalence among tuberculosis patients and compared the clinical characteristics of tuberculosis in HIV-positive and HIV-negative patients in two cross-sectional studies at the Infectious Disease Hospital (IDH) and the Ngaira Avenue Chest Clinic (NACC), Nairobi, Kenya. The diagnosis in 92% of all patients with pulmonary tuberculosis was confirmed by culture. The remainder were diagnosed on histological, clinical or radiological grounds. HIV seroprevalence among tuberculosis patients at IDH was 26.5% (52/196) compared to 9.2% (18/195) at NACC (P less than 0.001). There was no association between numbers of streptomycin injections in the previous 5 years and HIV infection. Positive sputum smear rates in HIV-positive patients were slightly lower than in HIV-negative patients at both study sites (71% vs 83% at IDH and 73% vs 82% at NACC) but the difference was not significant. Only Mycobacterium tuberculosis was isolated. Miliary disease was not associated with HIV infection. Persistent diarrhoea, oral candidiasis, generalized itchy rash, herpes zoster and generalized lymphadenopathy were all associated with HIV infection, but 46% (95% CI:38-54%) of all HIV-positive patients had none of the clinical features listed in the WHO Clinical Criteria for the Diagnosis of AIDS, apart from fever, cough and weight loss. Stevens-Johnson Syndrome was reported in 7/52 (13%) patients with HIV infection, and in 4/144 (3%) patients without (RR 4.85, 95% CI: 1.45-15.88).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the human immunodeficiency virus (HIV) on tuberculosis management was investigated in 227 patients initially treated with a regimen containing streptomycin, isoniazid, and thiacetazone (STH). 93 of these 227 were HIV-seropositive. 60 patients, of whom 18 were HIV-seropositive, received a regimen consisting of streptomycin, isoniazid, rifampicin, and pyrazinamide (SHRZ) in the initial phase, and thiacetazone and isoniazid (TH) in the continuation phase. Cutaneous hypersensitivity reactions occurred in 22 of 111 (20%) HIV-seropositive patients, and in 2 of 176 (1%) HIV-seronegative patients (RR = 18, 95% CI 4.4-76, p less than 10(-7]. During the first 8 weeks of treatment 18 reactions occurred among the 93 HIV-seropositive patients on STH, whereas no reaction occurred in 17 HIV-seropositive patients during the initial phase of SHRZ/TH (p = 0.04). None of the 18 HIV-seropositive patients with cutaneous reactions who were subsequently challenged with isoniazid reacted, nor did any of the 10 tested with streptomycin, but 6 of the 7 challenged with thiacetazone reacted. 3 patients (all HIV-positive and with toxic epidermal necrolysis) died as a result of the cutaneous reaction. These results have major implications for tuberculosis control programmes in Africa.

Thiacetazone is used as a first-line antituberculosis drug in most of the developing countries of the South Pacific. Skine reactions are considered the major side effects of this drug. In Papua New Guinea, 2.5% of Melanesian patients who received thiacetazone for the treatment of tuberculosis developed skin reactions. The reaction appears to be caused by hypersensitivity rather than by toxicity and has distinct clinical features. The therapeutic regimen for tuberculosis in the developing countries of the South Pacific is not likely to change in the near future. Recognition of this potentially fatal complication of thiacetazone is important in the mamnagement of patients with tuberculosis in countries where the drug is used.

In Lyell's syndrome a toxic skin erythema is concerned which leads to the epidermal necrolysis and desquamation. An infantile and an adult form are differed; the latter is usually induced by medicaments. Two patients with apparently medicamentously induced Lyell's syndrome are presented. The evoking medicaments were penicillin and thioacetazone. The two patients showed a severe course with an extensive affection of the body surface. The therapy with glucocorticosteroids, electrolyte substitution and local treatment of the skin lesions was successful in the two cases.

Antitubercular drugs in general are given in various combinations, one being isoniazid and thiacetazone. In the present study, was evaluated the in vivo chromosome-damaging effects of a combination of these two drugs in 72 h lymphocyte cultures. Chromosome aberrations were significantly increased in the patients treated with INH and thiacetazone as compared with two types of controls: (1) tuberculosis patients before starting the drug treatment and (2) individuals from the general population. The most frequently observed aberrations were chromatid breaks and gaps. It has been shown that individually, isoniazid may not be clastogenic on human chromosomes in therapeutic doses. The effects of thiacetazone on human chromosomes are not known. Consequently, the enhancement in chromosomal aberrations in the drug-exposed patients may be due to a synergistic effect of isoniazid and thiacetazone or to the clastogenic effects of thiacetazone alone.