SRI-286, a thiosemicarbazole, in combination with mefloquine and moxifloxacin for treatment of murine Mycobacterium avium complex disease.

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.

[Skin toxicity of thiacetazone (TB1) at a hospital service in Dakar]. / Toxidermies au Thiacétazone (TB1) dans un service hospitalier à Dakar.

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.

[Lyell syndrome in Senegal: responsibility of thiacetazone]. / Syndrome de Lyell au Sénégal: responsabilité de la thiacétazone.

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.

Multiforme skin lesions in Yekatit 12 Hospital, 1976-1994.

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.

Life-threatening cutaneous reactions to thiacetazone-containing antituberculosis treatment in Kumasi, Ghana.

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.

Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults.

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.

Pharmacokinetic evaluation of thiacetazone.

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.

Cost-effectiveness and total costs of three alternative strategies for the prevention and management of severe skin reactions attributable to thiacetazone in the treatment of Human Immunodeficiency Virus positive patients with tuberculosis in Kenya.

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.

PIP: In Kenya, the National Leprosy Tuberculosis Programme (NLTP) used previously reported data from Nairobi to compare the cost-effectiveness and total costs of a hypothetical strategy with three intervention strategies for the prevention and management of severe skin reactions caused by thiacetazone in treating HIV-positive patients with tuberculosis (TB). The hypothetical strategy was continued use of thiacetazone despite adverse skin reactions. The intervention strategies included patient education about possible side effects of anti-TB drugs (discontinue use if skin rash develops, report situation to clinic, replace thiacetazone with ethambutol when other skin diseases have been excluded), abandonment of thiacetazone and replacement with ethambutol, and HIV testing and pre- and post-test counseling. NLTP currently used the education strategy. It assumed a mortality rate of 5%. When the HIV prevalence rate is 1-90%, the education strategy is the most cost-effective strategy. In terms of total costs, the education strategy was also the most inexpensive strategy regardless of the HIV prevalence. At an HIV prevalence rate greater than 65%, the abandonment of thiacetazone strategy was the cheapest strategy. When the assumed mortality rate was 3%, the cost per averted death for the education strategy was reduced from about US$120 to about US$80 and the education strategy became the most cost-effective strategy over the entire range of HIV prevalence. In addition, the cost of HIV testing significantly increased the cost per averted death. Thus, the findings of this study are truly sensitive to different program conditions. Based on these findings, the authors recommended that the education strategy be applied with a range of HIV prevalence of 1-45%, that HIV testing be applied with a range of 46-72%, and that total abandonment be applied with an HIV prevalence greater than 72%.

Cutaneous hypersensitivity reactions to thiacetazone, HIV infection and thiacetazone concentrations in plasma.

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.

Adverse cutaneous reactions to thiacetazone for tuberculosis treatment in Tanzania.

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.

PIP: Thiacetazone is a useful and inexpensive companion drug in the treatment of tuberculosis (TB). Its main contribution is its ability to prevent failure and relapse in patients with initially isoniazid-resistant strains. Early toxicity studies showed that the drug was generally better tolerated in East Africa than in many other countries. Thiacetazone is an essential drug in the Tanzania National Tuberculosis/Leprosy Program. Under trial conditions in Tanzania, before the HIV epidemic, adverse reactions associated with thiacetazone were uncommon. Serious, and occasionally fatal, toxic cutaneous reactions to sulphur-containing drugs in HIV-infected patients have been recognized for several years. Recently, the use of thiacetazone in HIV-infected patients has been linked with serious adverse cutaneous reactions, including toxic epidermal necrolysis. Most reports, however, concerned only patients admitted to referral hospitals, so the Tanzania National Tuberculosis Program began a nationwide one-year systematic surveillance study to determine the frequency and severity of adverse cutaneous reactions. Individual-level data were collected on each case's age, sex, interval between commencing thiacetazone-containing treatment and occurrence of adverse reaction, most severe clinical presentation, and outcome within two weeks of onset. The study identified 1273 patients with adverse reactions. 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. Approximately 60% of all adverse reactions and deaths occurred within twenty days of starting thiacetazone. Case fatality from adverse cutaneous reactions was considerably less frequent than previously reported, suggesting that improved management may allow the retention of thiacetazone as a weapon against TB even where infection with HIV is prevalent.

Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere University-Case Western University Research Collaboration.

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.