Comprehensive findings on clinical, bacteriological, histopathological and therapeutic aspects of cutaneous tuberculosis

OBJECTIVE: To define the bacteriological and histological correlates of the three predominant clinical forms of cutaneous tuberculosis and to evaluate the efficacy of a 9-month daily regimen containing rifampicin and isoniazid. METHODS: In the dermatological clinics of two major teaching hospitals in Chennai, 213 patients with suspected clinical manifestations of cutaneous tuberculosis underwent examination and a skin biopsy for bacteriological and histological tests. They were treated with a daily regimen of rifampicin and isoniazid for 9 months and follow-up for 3 years. RESULTS: Bacteriological and/or histological confirmation of tuberculosis was obtained in 88% of the cases. Lupus vulgaris lesions were seen mainly in the extremities and verrucosa cutis occurred predominantly on the sole and foot, while the cervical and axillary regions were the commonest sites for scrofuloderma. Ninety-two per cent of the patients showed resolution of the lesions within the first 6 months of chemotherapy; 1% failed to respond to this regimen. There was no relapse in any of the cases during the follow-up period of 3 years. CONCLUSIONS: Clinical findings were adequate to identify major forms of cutaneous tuberculosis as evidenced by bacteriological and histopathological examination. A daily regimen of rifampicin and isoniazid for 9 months was effective in treating cutaneous tuberculosis.     

Short-course chemotherapy of pulmonary tuberculosis in pneumoconiotic patients

This is the first prospective clinical trial recorded to date of short-course chemotherapy in pulmonary tuberculosis complicated by pneumoconiosis. Forty-eight anthrasillicotic and 11 silicotic patients with previously untreated pulmonary tuberculosis completed 9-month, short-course chemotherapy regimens: 2 months of daily streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid and rifampicin for 7 months (2SHRZ/7HR). There were 3 treatment failures (5%). The remaining 56 patients (95%) all had their sputum converted within 4 months (mean, 1.5 months). Bacteriologic relapses were noted in 3 patients (5%) after 18 to 40 months of follow-up (mean, 28.4 months). The relapses occurred within 7 months after chemotherapy was stopped. There were 2 deaths from nontuberculosis causes during the follow-up period. Fifty-one patients (90%) remained bacteriologically sterile for 28.4 +/- 6.1 months. These results suggest that the 2SHRZ/7HR regimen is satisfactory in treating anthrasilicotic or silicotic patients with pulmonary tuberculosis, though antituberculosis chemotherapy seemed less effective in patients with pneumoconiosis than in those without pneumoconiosis.     

New technologies in the prevention,detection, diagnosis and treatment of tuberculosis in children

If the epidemiological situation is tense, new technologies should be developed and put into practice to enhance the efficiency of specific prevention, early detection, diagnosis and treatment of tuberculosis in children. There is evidence for the high efficacy and low reactogenicity of lower antigenicity-loading BCG-M vaccine that causes a 15-fold decrease in infant morbidity, as compared with that among non-vaccinated children, and this vaccine shows a 5-fold reduction in postvaccination complications as compared with BGC vaccine. The 26-year use of tuberculin diagnosis via Mantoux test with 2TE PPD-L during mass vaccination of children and adolescents has proved itself in early identification of tuberculosis and risk groups. A new risk group has been identified. This includes children with increasing tuberculin reactions; three-month intermittent chemoprevention with isoniazid reduces tuberculin sensitivity in the children and prevents tuberculosis in them. The developed short-term (6-9 months) courses of chemotherapy in preschool and school children by using drugs (isoniazid + rifampicin + pyrazinamide) yield the best healing without residual changes of uncomplicated forms of tuberculosis in 83 and 60% of the children with complicated events, respectively. The chemotherapy regimens have been divided into 4 groups of different dosage schedules.     

Effectiveness of chemotherapy of intrathoracic tuberculosis in children: late follow-up data

Clinical and X-ray studies were made in 148 children 2-10 years after hospital treatment to evaluate the stability of clinical recovery by the frequency of relapses in relation to the use of different drug treatment regimens. Children from an experimental group (n = 75) received shorter chemotherapy with 3-4 drugs (isoniazid, rifampicin, pyrazinamide in uncomplicated tuberculosis plus streptomycin in complicated one) in the intensive phase of chemotherapy. Pyrazinamide was not used in the intensive phase in the control group (n = 73). Long-term follow-ups showed a high efficiency of shorter chemotherapy regimens in treating intrathoracic tuberculosis in children since they do not lead to the higher incidence of recurrences--2.7% in both groups. The latter occurred in adolescents who had severe residual changes, who had been irregularly followed up at the tuberculosis control dispensary after hospital discharge, who had not received seasonal preventive chemotherapy courses, and who had experienced complicated, generalized or acute tuberculosis.     

Treatment failure in tuberculosis.

Treatment of latent tuberculosis (TB) infection with 3 months of rifampicin/isoniazid is a major part of preventive TB programmes. The effectiveness of treatment of latent TB infection can only be assessed by rates of subsequent breakdown and there are few outcome data for this combination of rifampicin/isoniazid. Therefore, the aim of the present study was to estimate the failure rate following treatment for the latent TB infection. A questionnaire survey was carried out in all parents of children aged <16 yrs who completed treatment for latent TB infection at Leicester Royal Infirmary (Leicester, UK) over the period 1997-2003. Cases of treatment failure were identified by reviewing all re-referrals to the clinic, identifying children developing TB while on treatment and by postal questionnaire to all patients discharged. Of the 400 eligible children, 344 (86%) replied. Three children who had latent TB infection subsequently developed TB disease over the time period. Of those three patients, one developed chest radiograph signs at the end of treatment and two presented with symptoms within 2 yrs of completing treatment. Overall, the mean treatment failure rate was 0.87% (95% confidence interval 0.3-2.5) or 2.2 cases per 1,000 patient-yrs. In conclusion, rates of tuberculosis breakdown after treatment for latent tuberculosis infection with 3 months rifampicin/isoniazid are acceptably low.     

Prospective comparative study of ofloxacin or ethambutol for the treatment of pulmonary tuberculosis.

The efficacy of ofloxacin, rifampicin and isoniazid was prospectively compared with the regimen of ethambutol, rifampicin and isoniazid for the primary treatment of pulmonary tuberculosis in 124 patients. All drugs were given orally daily for nine months. Culture conversion rates three months after starting treatment were 98 percent in the ofloxacin group and 94 percent in the ethambutol group; by six months all patients in both groups were culture-negative. Significant radiological improvement of pulmonary infiltrates was observed in 83 percent of the ofloxacin group and 85 percent of the ethambutol group one year after starting treatment. No relapse in either group was observed during a two-year follow-up period after the cessation of chemotherapy. Ofloxacin appears to be as useful as ethambutol in the treatment of pulmonary tuberculosis when either drug is combined with isoniazid and rifampicin.     

Efficiency of shorter chemotherapy courses for intrathoracic tuberculosis in children

To develop differential chemotherapy regimes for intrathoracic tuberculosis in children aged 3-12 years, 255 children with active tuberculosis underwent clinical and X-ray examination. Of them, 120 children received shorter chemotherapy in an early intensive phase by using three drugs (isoniazid, rifampicin, and pyrazinamide supplemented by streptomycin) in complicated tuberculosis. A control group (n = 135) had therapy without pyrazinamide. Shorter courses of therapy were shown not only to reduce total treatment duration on an average to 6.4 and 9.2 months in uncomplicated and complicated tuberculosis, respectively, but to contribute to more perfect healing processes and resolution of abnormal changes in 85.3 and 60.0% of children with uncomplicated and complicated forms, respectively. At the same time shorter treatment is well tolerated. It shows much fewer side effects than does longer treatment (20 and 36%). There are no increases in the incidence of recurrent tuberculosis late at follow-up (2.7 and 2.7%, respectively).     

The prevalence of Mycobacterium tuberculosis drug resistance in New Caledonia, 1995-1996.

SETTING: Study of the susceptibility to anti-tuberculosis drugs of Mycobacterium tuberculosis strains isolated in New Caledonia, a French South Pacific Territory, where tuberculosis continues to be a public health problem. OBJECTIVE: To assess the stability of this susceptibility in order to justify both non-systematic susceptibility testing and the implementation of simplified chemotherapy regimens. METHODS: Over a period of nearly 2 years (1995-1996), every new case of tuberculosis confirmed by the laboratory was included in the study. A total of 105 strains were tested against five anti-tuberculosis drugs: isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin. RESULTS: No primary drug resistance was detected for the main drugs. One strain with acquired resistance to isoniazid and streptomycin was isolated from one of the 12 patients suffering a relapse of the disease. CONCLUSIONS: The results of this exhaustive study justify the non-systematic approach to susceptibility testing for new patients. However, for strains isolated from patients suffering from relapse or therapeutic failure, or who belong to a high risk population, drug susceptibility testing should be performed. This kind of management will aid in the detection of possible isoniazid and streptomycin resistance, thus avoiding the selection and possible emergence of strains resistant to rifampicin. The results of the study argue for the use of a fixed dose regimen using triple combination tablets of isoniazid, rifampicin and pyrazinamide (HRZ) for 2 months, followed by dual drug therapy (HR) for 4 months.     

Intermittent chemotherapy in pulmonary tuberculosis — Current aspects

A critical review of the application of various methods of intermittent chemotherapy in the initial treatment of tuberculosis and retreatment of far advanced pulmonary tuberculosis has been presented. Not all drugs are suitable for intermittent chemotherapy in clinical practice, but the introduction in the last years of new drugs in the treatment of tuberculosis, especially rifampicin and ethambutol made possible the application of intermittent chemotherapy also for the groups of patients with far advanced chronic pulmonary tuberculosis with resistant bacilli. For intermittent chemotherapy isoniazid, rifampicin, ethambutol and streptomycin are particularly suitable in clinical practice. The intermittent chemotherapy should be applied only under strict supervision, as it requires a very good monitoring organization system. Still some problems of intermittent chemotherapy in tuberculosis are unsolved and require further studies, but the perspectives of this type of treatment seems to be very promising.     

Tuberculosis treatment today

In West and East Germany the incidence of tuberculosis is declining. However, with an incidence of 22 per 100,000 inhabitants in West Germany and 17 new diseases per 100,000 inhabitants in East Germany it is not a rare disease. In the chemotherapy of pulmonary tuberculosis, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), streptomycin (SM), pyrazinamide (PZA) and prothionamide (PTH) are the most relevant drugs. The chemotherapy of tuberculosis is always carried out as a combination therapy of at least three drugs. A rapid cultural conversion of the sputum as well as low rates of failures and relapses are regarded as parameters of quality. Therefore six-month-regimens with initially four drugs (INH + RMP + PZA + SM or EMB) or nine-(twelve-) month-regimens with initially three medicaments (INH + RMP + PZA, or INH + RMP + EMB or INH + RMP + SM) may be recommended. Peculiarities of the therapy in patients with AIDS, with drug resistance, with relapses.     

Split-drug regimens for the treatment of patients with sputum smear-positive pulmonary tuberculosis--a unique approach

OBJECTIVE: To evaluate the efficacy of split-drug regimens for treatment of patients with sputum smear-positive pulmonary tuberculosis in south India. DESIGN: Randomized controlled clinical trial where eligible patients were randomly allocated to: (i) 2RE(3)HZ(3)(alt)/4RH(2) (split I): rifampicin plus ethambutol given on one day and isoniazid plus pyrazinamide the next day for first 2 months followed by rifampicin plus isoniazid twice weekly for 4 months, or (ii) 3RE(3)HZ(3)(alt)/3RH(2) (split II): similar to regimen 1, except duration was 3 months in each phase, or (iii) 2REHZ(3)/4RH(2) (control): rifampicin, isoniazid, ethambutol and pyrazinamide, given thrice weekly for 2 months followed by isoniazid and rifampicin twice weekly for 4 months. All patients were followed up clinically and bacteriologically every month up to 2 years and every 6 months for up to 5 years. RESULTS: A favourable response (cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment) was observed in 91% of 407 patients in split I, 94% of 415 in split II and 89% of 418 in the control regimen. Ninety-one per cent of 370 patients in split I, 93% of 389 in split II and 90% of 370 in control regimens had quiescent disease at the end of 60 months. Gastrointestinal symptoms were more frequent under the control regimen (P = 0.01). CONCLUSION: Split-drug regimens were as effective as the control regimen in terms of favourable response at the end of treatment and quiescent disease at 5 years, and caused fewer gastrointestinal side-effects.     

Tisamide in the complex treatment of tuberculosis

The outcomes of tisamid treatment of newly diagnosed patients with bacillary pulmonary tuberculosis were analysed. To estimate the efficacy of tisamid and its administration indications, chemotherapy of the patients was performed with the use of two therapeutic regimens. Isoniazid, rifampicin and streptomycin (or ethambutol) were given to 73 patients, while other 72 ones were treated with the same drugs plus tisamid. The patients in each group were subdivided into slow, rapid and homozygotic (the most rapid) acetylators. Tisamid, when prescribed to newly-discovered patients with destructive tuberculosis, accelerates recovery, by excluding the risk of a hepatotoxic action. Tisamid in a combined treatment with isoniazid, rifampicin and streptomycin is mostly recommended for patients with a rapid acetylation phenotype, i.e. the cases for whom a short-term chemotherapy is possible.     

Effect of antitubercular preparations on the function of the ciliary epithelium of the respiratory tract mucosa

The effect of various concentrations of streptomycin, isoniazid, rifampicin and ethambutol on the function of the siliated epithelium of the frog oral mucosa was studied (110 experiments with 50 frogs). The level of inhibition of the siliated epithelium function depended on the properties of the drugs and their concentration in solution. More pronounced inhibition was induced by 15 per cent ethambutol solution and 10 per cent isoniazid solution. The least inhibition of the siliated epithelium function was observed with the use of 6.25 per cent streptomycin solution, 5 per cent isoniazid solution, 7.5 per cent ethambutol solution and 3.75 per cent rifampicin solution.     

Controlled clinical trial of a regimen of two durations for the treatment of isoniazid resistant pulmonary tuberculosis

Patients with pulmonary tuberculosis who were failures of primary chemotherapy with strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 (4RE) or 9 months (7RE), supplemented in both treatment series by streptomycin plus pyrazinamide for the first 2 months. The patients were treated in hospital for the first 2 months and thereafter treatment was supervised on a daily basis in the nearest health institution by an appointed member of staff or at home by responsible members of the community. A total of 306 patients was admitted and 226 patients remained for analysis at the end of chemotherapy, 179 with a strain resistant to isoniazid alone and 47 with a strain resistant to isoniazid and streptomycin. There were only two failures at the end of chemotherapy, one in the 6-month series who had resistance to both isoniazid and streptomycin pretreatment, and one in the 9-month series who had resistance to isoniazid alone. For the 144 patients with initial resistance to isoniazid alone assessed up to 30 months, the relapse rates were low in both series: 4% for the 72 patients in the 6-month series and 3% for the 72 patients in the 9-month series. However, for the 34 patients with resistance to both drugs, three of the 14 in the 6-month but none of 20 in the 9-month series relapsed.     

Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.     

Treatment of pulmonary tuberculosis with short course chemotherapy in south India--5-year follow up

A controlled clinical trial of three short-course chemotherapy regimens was undertaken in patients with newly diagnosed bacteriologically positive pulmonary tuberculosis. The patients were randomly allocated to receive one of three regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), or the same regimen as R/7 but without rifampicin (Z/7). A bacteriological relapse requiring retreatment occurred by 5 years in 7.1% of 126 R/5, 4.0% of 124 R/7 and 6.7% of 253 Z/7 patients with organisms initially sensitive to streptomycin and isoniazid; none of these differences is statistically significant. Of the 31 relapses, 16 occurred within 2 years of the completion of chemotherapy and the remaining 15 between 2 and 5 years. Among 65 patients with initial drug resistance to streptomycin or isoniazid or both, there were six bacteriological relapses requiring retreatment.     

Drug resistant tuberculosis in children and adolescents

The paper presents the results of a follow-up of children and adolescents who isolate drug-resistant Mycobacterium tuberculosis (MBT) strains of those with manifestations of tuberculosis and preserved sensitivity to antibacterial agents. Bacterial isolation in children and adolescents is scanty and multiple. There is a high rate of resistance to isoniazid, streptomycin, and rifampicin. The vast majority of children and adolescents who isolate drug-resistant MBT strains have been found to contact a patient who also isolate drug-resistant MBT. The drug sensitivity of MBT in patients is identical to that of sources of their contamination. Most patients with drug-resistant tuberculosis have been ascertained as having been registered in dispensaries and treated with drugs, which suggests that the use of chemotherapy in prophylactic doses, particularly in patients contacting a bacterial isolator, does not prevent local tuberculosis.     

Treatment of tuberculosis in HIV infection.

Whether tuberculosis patients received short-course chemotherapy with treatment of isoniazid (INH) and rifampicin (RIF), combined or not with pyrazinamide (PZA) and ethambutol (EMB) or streptomycin (SM), or long term chemotherapy with INH, SM and thiacetazone (Tb1), the rate of sputum culture conversion was similar in HIV-positive and HIV-negative patients. To prevent relapses it was recommended to treat patients for a minimum of 9 months and for at least 6 months after culture conversion, or even to administer INH for life after the end of treatment. However, no difference was observed in the percentage of relapses between HIV-positive and HIV-negative patients. Side-effects were observed in approximately 20% of HIV-positive patients treated with INH + RIF + PZA + EMB (or SM) or with INH + SM + Tb1, Tb1 being responsible for epidermal necrolysis, in some cases fatal. The mean survival of HIV-patients with tuberculosis was from 10 to 18 months after the diagnosis of tuberculosis. Other opportunistic infections could have been the main cause of death. Acquired drug resistance is not a common complication of tuberculosis treatment in HIV-positive patients, but several epidemics of nosocomial transmission of multiple drug-resistant tuberculosis have recently been observed in the USA. Sparfloxacin, a new fluoroquinolone with a long half-life and low MIC (0.25-0.50 mg/l) against Mycobacterium tuberculosis, is a promising drug against tuberculosis.     

异烟肼和利福平联合用药对健康成人原代肝细胞CYP450同工酶1A2和3A4活性的影响

目的明确异烟肼和利福平联合用药对健康成人原代肝细胞CYP450同工酶1A2和3A4活性的影响。方法从健康成人肝脏或肝叶中分离出肝细胞,分为CYP450同工酶1A2和3A4两部分,各分为阴性对照组及药物处理组共15组,放入24孔细胞培养板内,每组6个复孔,原代培养3 d,阴性对照组加入等量的细胞培养液,各药物处理组对应加入临床血药峰浓度范围内的异烟肼(25μmol/L,50μmol/L)、利福平(12.5μmol/L,25μmol/L)或两药联用(CYP1A2:利福平12.5μmol/L加异烟肼50μmol/L,利福平25μmol/L加异烟肼50μmol/L;CYP3A4:利福平12.5μmol/L加异烟肼25μmol/L,利福平25μmol/L加异烟肼25μmol/L,利福平25μmol/L加异烟肼50μmol/L),孵育2 d,再加入CYP450同工酶1A2和3A4的相应底物(非那西丁和睾酮),反应终止后用高效液相仪测量代谢产物(对乙酰氨基酚与6β-羟基睾酮)的峰面积(单位:mAU.m in)代表1A2和3A4的活性。结果(1)单用25μmol/L和50μmol/L浓度异烟肼肝细胞CYP450同工酶1A2的活性分别是(3.33±0.65)、(3.03±0.38)mAU.m in,与阴性对照组的(5.23±0.31)mAU.m in比较差异均有统计学意义(P均<0.01);单用12.5μmol/L浓度利福平肝细胞CYP450同工酶1A2的活性为(6.07±0.55)mAU.m in,与阴性对照组比较差异有统计学意义(P<0.05),单用25μmol/L浓度利福平肝细胞CYP450同工酶1A2的活性为(4.93±0.57)mAU.m in,与阴性对照组比较差异无统计学意义(P>0.05);异烟肼和利福平2种浓度联合配伍,肝细胞CYP450同工酶3A4的活性分别是(3.27±0.96)、(3.97±0.25)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.05)。(2)单用25μmol/L和50μmol/L浓度异烟肼肝细胞CYP450同工酶1A2的活性分别是(5.40±1.35)、(2.63±0.06)mAU.m in,与阴性对照组的(12.53±0.51)mAU.m in比较差异均有统计学意义(P均<0.01);单用12.5和25μmol/L浓度利福平肝细胞CYP450同工酶3A4的活性分别为(165.17±11.47)、(120.20±15.73)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.01);异烟肼和利福平3种浓度联合配伍,肝细胞CYP450同工酶3A4的活性分别是(118.37±8.90)、(77.53±6.91)、(68.73±4.72)mAU.m in,与阴性对照组比较差异均有统计学意义(P均<0.01),但低于相应浓度单用利福平组(P<0.05或0.01)。结论临床血药峰浓度范围的异烟肼与利福平单用或联用对CYP450同工酶1A2活性影响未达到抑制或诱导水平。临床血药峰浓度范围的异烟肼抑制CYP450同工酶3A4的活性,利福平诱导CYP450同工酶3A4的活性,两药联合仍呈诱导作用。     

Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report

BACKGROUND AND AIMS: Hepatotoxicity is a major side-effect of antitubercular drugs (ATD). As these drugs are metabolized in the liver, there is a theoretical risk of increased hepatotoxicity in patients with underlying chronic liver disease (CLD). Ofloxacin has antitubercular activity and has exclusive renal clearance. The aim was to study the efficacy and safety of an ofloxacin-based antitubercular regimen for treating tuberculosis in patients with underlying CLD. METHODS: Thirty-one cases were randomly assigned to two drug regimens using WHO dosage schedules: (i) regimen A (n = 15): isoniazid, rifampicin and ethambutol for 2 months, followed by isoniazid and rifampicin for a further 7 months; and (ii) regimen B (n = 16): isoniazid, pyrazinamide, ethambutol and ofloxacin for 2 months, followed by isoniazid, ethambutol and ofloxacin for a further 10 months. Hepatotoxicity was diagnosed if alanine aminotransferase/aspartate aminotransferase increased > fivefold from the baseline or to > 400 IU/L, or if bilirubin increased by > 2.5 mg/dL from the baseline. RESULTS: The response to ATD was achieved in all the patients who completed the therapy. Four (26.6%) patients on regimen A developed hepatotoxicity as compared to none on regimen B (P = 0.043). None of these patients could be restarted on ATD using the same regimen A because of the persistently deranged liver functions. CONCLUSIONS: In patients with tuberculosis who have underlying CLD: (i) an ofloxacin-based antitubercular regimen without rifampicin is as effective as a rifampicin-based regimen; and (ii) a combination of isoniazid with rifampicin is more hepatotoxic than a combination with ofloxacin and pyrazinamide.