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Prevention and treatment of drug-resistant tuberculosis.

Therapy recommended for preventing and treating drug-resistant tuberculosis is discussed. Drug-resistant strains of Mycobacterium tuberculosis can be transmitted by an infected individual, or resistance can be acquired during therapy for drug-susceptible disease. At least until susceptibility test data are available, the recommended initial treatment for tuberculosis consists of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Resistance has led to variations on this regimen that sometimes include more toxic alternative drugs, including ethionamide, aminosalicylic acid, cycloserine, and capreomycin, as well as ciprofloxacin and ofloxacin. Drug regimens used for retreatment usually include the alternative drugs. Success in treating drug-resistant tuberculosis varies. Therapy to prevent resistant tuberculosis is recommended for any individual with a positive skin-test result and any of the following: infection with the human immunodeficiency virus (HIV), close contact with a newly diagnosed patient, recent conversion to a positive skin-test result, or a predisposing medical condition. Although isoniazid is the only drug with FDA-approved labeling for use as prophylaxis in patients with latent tuberculosis, the Centers for Disease Control and Prevention suggests several two-drug combinations. Fluoroquinolones are recommended for both treatment and prevention. Patient compliance and HIV infection are special issues in managing resistant tuberculosis. Drug-resistant tuberculosis is a growing problem that must be addressed through appropriate prophylactic and treatment measures.

AIDS-Related Opportunistic Infections↗

Pulmonary disease due to Mycobacterium xenopi in a renal allograft recipient: report of a case and review.

A 39-year-old man with pulmonary disease due to Mycobacterium xenopi is described. He had received prednisone and azathioprine for 5 years and prednisone in combination with cyclosporin A for 1 year in an effort to prevent rejection of his renal transplant. Shortly after the renal allograft was removed because of chronic rejection, the patient developed dyspnea and a decrease in vitality. He had no history of preexisting lung disease. A chest roentgenogram showed multiple nodular infiltrates in both lungs. M. xenopi was cultured from three sputum samples. The organism was susceptible to isoniazid, streptomycin, ethambutol, rifampin, pyrazinamide, and ethionamide. The patient was treated successfully with isoniazid, ethambutol, and rifampin for 3 months and with isoniazid in combination with rifampin for an additional 9 months, while he was maintained on continuous ambulatory peritoneal dialysis (CAPD). The literature on mycobacterial disease, especially in renal transplant recipients and patients on CAPD, is reviewed.

Adult↗

Overview and epidemiologic assessment of the current global tuberculosis situation with an emphasis on control in developing countries.

The global epidemiologic situation of tuberculosis is reviewed, with emphasis on the disappointing achievements in its control in developing countries over the last three decades. In developed countries where prevalence of tuberculosis is low, it will take at least 30-50 years to eliminate the disease because of exacerbation by individuals who acquire infection abroad. In developing countries, 2-3 million deaths will occur among the estimated 4 million new smear-positive and 4 million new smear-negative and extrapulmonary cases of tuberculosis. The low cure rate with standard chemotherapy is the chief reason for failure of tuberculosis control in developing countries. The basic chemotherapeutic regimen (streptomycin for 2 months then a combination of isoniazid and thiacetazone for 12 months) does not achieve a high cure rate in developing countries. Under routine conditions the cure rate is high (90%) with an inexpensive 8-month regimen consisting of 2 months of strictly supervised daily administration of isoniazid, rifampin, pyrazinamide, and streptomycin and then 6 months of self-administration of a tablet containing both isoniazid and thiacetazone. A substantial decrease in the risk of tuberculous infection in developing countries is essential because of the increase in number of AIDS patients with tuberculosis. Vaccination alone, at least with the present vaccine, cannot substantially influence the epidemiologic situation but should be continued for children when its use is justified for prevention.

Acquired Immunodeficiency Syndrome↗

Tuberculosis in the elderly.

Although the cause of the steady increase in tuberculosis (TB) notifications in England and Wales since 1987 is multifactorial, the elderly have made an appreciable contribution. From 1987-1989 the increase was 6% for all ages combined, but 13% in females and 16% in males over the age of 75. Tuberculosis in the elderly therefore remains an appreciable problem. Although the characteristic presentation of chronic cough, malaise and weight loss, with cavitatory changes in the upper lobes still predominates in the elderly, there has been an increased incidence of cryptic miliary disease in which the onset is insidious and chest X-ray often normal. The diagnosis must often be made on suspicion and treatment started before a positive diagnosis is obtained. The elderly are more likely to suffer adverse effects from the anti-tuberculous chemotherapy than the younger population and greater care must be taken. Drug resistance is uncommon in the elderly in the UK. Isoniazid, rifampicin and pyrazinamide are appropriate for the initial two months of treatment. Rifampicin and isoniazid should be continued for a further four months for disease at virtually any site, with the exception of TB meningitis, when a further 10 months therapy should be given. In the UK, preventative therapy in the form of isoniazid or rifampicin and isoniazid probably has no place in disease control in an elderly population; tuberculin tests are frequently negative, even in the presence of active disease, as elderly patients are often anergic.

Aged↗

Inhibition of the respiration of multi-drug resistant clinical isolates of Mycobacterium tuberculosis by thioridazine: potential use for initial therapy of freshly diagnosed tuberculosis.

Chlorpromazine and thioridazine are phenothiazines employed in the treatment of psychosis. These agents inhibited the respiration of clinical isolates of Mycobacterium tuberculosis resistant to streptomycin, rifampin, isoniazid, ethambutol and/or pyrazinamid, all first line drugs. Since any adverse reaction to thioridazine is generally less severe than to chlorpromazine, the possibility is attractive that thioridazine may have a potential in the initial management of patients with newly diagnosed tuberculosis with an as yet undetermined antibiotic susceptibility profile.

Antipsychotic Agents↗

Activity of a new class of isonicotinoylhydrazones used alone and in combination with isoniazid, rifampicin, ethambutol, para-aminosalicylic acid and clofazimine against Mycobacterium tuberculosis.

The activities of six derivatives of a new class of isonicotinoylhydrazones were investigated in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294, isoniazid-resistant M. tuberculosis ATCC 35822, rifampicin-resistant ATCC 35838, pyrazinamide-resistant ATCC 35828, streptomycin-resistant ATCC 35820 and 16 clinical isolates of M. tuberculosis. Several compounds showed interesting antimycobacterial activity against both ATCC strains and clinical isolates, but were less active against isoniazid-resistant M. tuberculosis. Combinations of five isonicotinoylhydrazone derivatives and rifampicin, ethambutol, para-aminosalicylic acid, isoniazid and clofazimine were also investigated against M. tuberculosis H37Rv ATCC 27294 and against ATCC drug-resistant strains. Addition of sub-MICs of some isonicotinoylhydrazone derivatives resulted in a four- to 16-fold reduction in MICs of ethambutol, para-aminosalicylic acid and rifampicin with fractional inhibitory concentrations (FICs) ranging between 0.17 and 0.37, suggesting a synergic interaction against M. tuberculosis H37Rv. Increased activity was also observed with other combinations (FICs 0.53-0.75), including isoniazid, and a synergic interaction between one of the isonicotinoylhydrazone derivatives and isoniazid (FIC 0.26) was shown against isoniazid-resistant M. tuberculosis ATCC 35822, whereas no effects were observed on combining the isonicotinoylhydrazones with clofazimine. The ability of isonicotinoylhydrazones to inhibit specifically the growth of M. tuberculosis, the high selectivity index and their ability to enhance the activity of standard antituberculous drugs in vitro indicate that they may serve as promising lead compounds for future drug development for the treatment of M. tuberculosis infections.

Aminosalicylic Acid↗

Chemotherapeutic potential of alginate-chitosan microspheres as anti-tubercular drug carriers.

OBJECTIVES: This study was designed to develop alginate-chitosan microspheres as drug carriers to reduce dose/dosing frequency in the management of tuberculosis (TB), which otherwise demands prolonged chemotherapy. METHODS: Alginate-chitosan microspheres encapsulating three frontline anti-tuberculous drugs (ATDs), rifampicin, isoniazid and pyrazinamide, were formulated. A therapeutic dose and a half-therapeutic dose of the microsphere-encapsulated ATDs were orally administered to guinea pigs for pharmacokinetic/chemotherapeutic evaluations, respectively. RESULTS: The drug encapsulation efficiency ranged from 65% to 85% with a loading of 220-280 mg of drug per gram microspheres. Administration of a single oral dose of the microspheres to guinea pigs resulted in sustained drug levels in the plasma for 7 days and in the organs for 9 days. The half-life and mean residence time of the drugs were increased 13- to 15-fold by microsphere encapsulation, along with an enhanced relative/absolute bioavailability. The sustained release and increase in bioavailability were also observed with a sub-therapeutic dose of the microspheres. In Mycobacterium tuberculosis H37Rv-infected guinea pigs, administration of a therapeutic dose of microspheres spaced 10 days apart produced a clearance of bacilli equivalent to conventional treatment for 6 weeks. The most important observation, however, was the documentation of therapeutic benefit with a half-therapeutic dose of the microspheres administered weekly. CONCLUSION: Alginate-chitosan microspheres hold promise as a potential natural polymer-based oral ATD carrier for better management of TB.

Alginates↗

Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?

The inappropriate treatment of drug-susceptible tuberculosis can lead to the selection and transmission of multidrug-resistant tuberculosis (MDR-TB), indicating resistance to at least isoniazid and rifampicin. In the treatment of MDR-TB, residual first-line drugs, such as ethambutol, pyrazinamide and streptomycin must be appropriately combined with additional second-line drugs, guided by individual susceptibility patterns. The clinical pharmacology of these second-line antituberculous drugs is reviewed. Fluoroquinolones represent the only substantial therapeutic advance in the last 20 years. Many factors potentially affect the outcome of MDR-TB. Treatment adherence, prior exposure to antituberculous drugs, the number of drugs to which the infection is still susceptible and the time since the first diagnosis of tuberculosis are the most relevant. The management of MDR-TB requires considerable expertise. When initiating or revising therapy for MDR-TB, the process of selecting drugs should rely on prior treatment history, results of susceptibility testing and an evaluation of the patient's adherence. In making drug selection, we propose to follow a hierarchy based on the intrinsic activity against Mycobacterium tuberculosis and the clinical evidence of efficacy of the available active compounds.

Antitubercular Agents↗

Oral nanoparticle-based antituberculosis drug delivery to the brain in an experimental model.

OBJECTIVES: To evaluate the potential of orally administered poly-lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated antituberculosis drugs (ATDs) (rifampicin + isoniazid + pyrazinamide + ethambutol) for cerebral drug delivery in a murine model. METHODS: The formulation was prepared using the multiple emulsion technique and administered orally to mice for biodistribution, pharmacokinetic and chemotherapeutic studies. RESULTS: A single oral dose of the formulation to mice could maintain sustained drug levels for 5-8 days in the plasma and for 9 days in the brain. There was a significant improvement in the pharmacokinetic parameters such as mean residence time and relative bioavailability as compared with free drugs. The pharmacodynamic parameters such as the ratio of area under the curve to minimum inhibitory concentration (AUC/MIC) and the time up to which MIC levels were maintained in plasma (T(MIC)) were also improved. In Mycobacterium tuberculosis H(37)Rv infected mice, five oral doses of the nanoparticle formulation administered every 10th day resulted in undetectable bacilli in the meninges, as assessed on the basis of cfu and histopathology. CONCLUSIONS: Polymeric nanoparticles bear significant potential for ATD delivery to the brain.

Administration, Oral↗

Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro.

OBJECTIVES: The purpose of this study was to determine interactions of SQ109, a new asymmetric diamine tuberculosis (TB) drug candidate, with existing antitubercular drugs in vitro and assess its potential to improve combination drug activities against Mycobacterium tuberculosis. METHODS: Two-drug combinations at various concentrations below their MICs were tested for growth inhibition of M. tuberculosis using the BACTEC 460 system in vitro. Drug interactions were evaluated based on the quotient values that were derived numerically from the growth indices of cultures treated with a single antibiotic or combination treatment with two antibiotics. RESULTS: SQ109 at 0.5 of its MIC demonstrated strong Synergistic activity with 0.5 MIC isoniazid and as low as 0.1 MIC rifampicin in inhibition of M. tuberculosis growth. Additive effects were observed between SQ109 and streptomycin, but neither synergy nor additive effects were observed with the combination of SQ109 with ethambutol or pyrazinamide. The synergy between SQ109 and rifampicin was also demonstrated using rifampicin-resistant (RIFR) M. tuberculosis strains; SQ109 lowered the MIC of rifampicin for these drug-resistant strains. CONCLUSIONS: SQ109 interacts Synergistically with isoniazid and rifampicin, two of the most important front-line TB drugs. This finding supports efforts to further evaluate new combination therapies containing SQ109 in experimental animal models of TB that emulate future clinical trial studies in humans.

Adamantane↗

Selective intracellular accumulation of the major metabolite issued from the activation of the prodrug ethionamide in mycobacteria.

BACKGROUND: Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB). Like isoniazid, and pyrazinamide, ethionamide is a prodrug that needs to be activated by a mycobacterial enzyme. Activation pathways of prodrugs are generally problematic to uncover as they produce intermediates potentially difficult to characterize, to purify and that might prove unstable outside of their cellular context. OBJECTIVES AND METHODS: We have used high resolution magic angle spinning-NMR (HRMAS-NMR) to follow ethionamide activation directly within living mycobacterial cells. RESULTS: Data indicated that the intracellular metabolization of ethionamide strictly depends on the presence of the monooxygenase EthA and that EthA-dependent activation of ethionamide is coupled to a precise molecular sorting mechanism of the ethionamide metabolites. We found that the previously identified ethionamide metabolite 2-ethyl-4-hydroxymethylpyridine is produced in substantial amounts by the ethionamide-treated mycobacteria and that it is present exclusively outside of the bacteria. In contrast, the still unidentified ethionamide metabolite ETH* is the only ethionamide derivative detected within the bacterial cell. Moreover, ETH* appears to be unable to cross the bacterial envelope and consequently accumulates within the cytoplasm of the ethionamide-treated mycobacteria. CONCLUSIONS: These results strongly suggest that ETH* is the active antimycobacterial ethionamide derivative and open new perspectives for the understanding of the mode of action of prodrugs.

Bacterial Proteins↗

Case report: disseminated Mycobacterium gordonae infection in a nonimmunocompromised host.

Mycobacterium gordonae is considered the least pathogenic of the Runyon Group II mycobacteria, although there are now well-documented reports of infection varying from localized soft tissue infection to disseminated life threatening diseases. We report a 40-year-old Pakistani housewife, treated in childhood for tuberculosis, who presented with severe systemic illness, fever, ascites, hepatomegaly, persistent dysuria with sterile pyuria, pulmonary disease, and anorexia with weight loss. Liver biopsy histology showed multiple granulomata and multiple isolation of M. gordonae from sputum and urine, in keeping with disseminated mycobacterial infection. She had dramatic response to antituberculosis therapy with streptomycin, isoniazid, rifampicin, and pyrazinamide. No evidence existed for disturbed humoral or cellular immunity and HIV infection. This represents the fifth reported case of disseminated M. gordonae infection, the first from the Arabian Gulf. It was treated successfully with standard antituberculosis regimen.

Adult↗

Characteristics of tuberculosis in HIV-infected patients: a case-control study.

To test the hypothesis that HIV infection can modify the clinical characteristics of tuberculosis, 65 consecutive cases of tuberculosis in HIV-seropositive patients diagnosed in Barcelona (Spain) were compared with 65 HIV-seronegative controls matched for age and sex. Thirty of the 65 cases were accepted as AIDS cases (August 1987 Centers for Disease Control criteria) only because of the tuberculosis. Among the cases 54 (83%) were parenteral drug addicts and 88% were males. The tuberculosis was pulmonary or pleural in 62 controls (96%) but in only 25 cases (39%; P less than 0.0001). Lymph nodes were involved in 25 cases (39%) and in none of the controls (P less than 0.0001). Disseminated forms of tuberculosis were present in seven cases (11%) and in no controls (P less than 0.007). Bone, joints and central nervous system involvement were also significantly (P less than 0.05) more frequent in cases. The treatment (isoniazid and rifampin for 6 months plus ethambutol and pyrazinamide during the first 2 months) was always effective. One relapse was detected after a median follow-up of 55 months in cases and none in controls after a median follow-up of 43 months. Twenty-five cases (39%) and 14 controls (22%) developed mild or severe side effects related to the treatment (P less than 0.004). In conclusion, most of the HIV-infected patients with tuberculosis were drug addicts with extrapulmonary or disseminated forms. A short course of treatment (6 or 9 months) may be enough but side effects were frequent.

Acquired Immunodeficiency Syndrome↗

HIV infection and primary resistance to antituberculosis drugs in Abidjan, Côte d'Ivoire.

OBJECTIVE: To determine the prevalence of Mycobacterium tuberculosis resistance to antituberculosis drugs, and to relate this resistance to HIV serologic status. DESIGN: Cross-sectional prevalence study. SETTING: The two major outpatient tuberculosis clinics in Abidjan, Côte d'Ivoire, West Africa. PATIENTS: Sixty individuals with newly diagnosed pulmonary tuberculosis and sputum smears positive for acid-fast bacilli. MAIN OUTCOME MEASURES: HIV serologic status and in vitro testing for susceptibility of M. tuberculosis isolates to antituberculosis drugs. RESULTS: M. tuberculosis was isolated from 82% (49 out of 60) of sputum specimens. Thirty-five per cent (17 out of 49) were obtained from HIV-seropositive and 65% (32 out of 49) from HIV-seronegative patients. There was no statistically significant difference in the proportion of resistant isolates from HIV-seropositive versus HIV-seronegative patients, although the relatively small sample size limited power. Of the total number of isolates, 17% were resistant to isoniazid; resistance was less to streptomycin (7%), rifampin (2%), pyrazinamide (0%), and ethambutol (0%). Eighteen and 21% of mycobacterial isolates from HIV-seropositive and HIV-seronegative individuals, respectively, were resistant to one or more of these drugs. CONCLUSIONS: Surveys of this type are useful in planning and evaluating tuberculosis preventive therapy in individuals with dual infection.

AIDS-Related Opportunistic Infections↗

Relapse and mortality among HIV-infected and uninfected patients with tuberculosis successfully treated with twice weekly directly observed therapy in rural South Africa.

OBJECTIVE: To determine post-treatment relapse and mortality rates among HIV-infected and uninfected patients with tuberculosis treated with a twice-weekly drug regimen under direct observation (DOT). SETTING: Hlabisa, South Africa. PATIENTS: A group of 403 patients with tuberculosis (53% HIV infected) cured following treatment with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice weekly to 2 months and HR twice weekly to 6 months in the community under DOT. METHODS: Relapses were identified through hospital readmission and 6-monthly home visits. Relapse (culture for Mycobacterium tuberculosis) and mortality given as rates per 100 person-years observation (PYO) stratified by HIV status and history of previous tuberculosis treatment. RESULTS: Mean (SD) post-treatment follow-up was 1.2 (0.4) years (total PYO = 499); 78 patients (19%) left the area, 58 (14%) died, 248 (62%) remained well and 19 (5%) relapsed. Relapse rates in HIV-infected and uninfected patients were 3.9 [95% confidence interval (CI) 1.5-6.3] and 3.6 (95% CI 1.1-6.1) per 100 PYO (P = 0.7). Probability of relapse at 18 months was estimated as 5% in each group. Mortality was four-fold higher among HIV-infected patients (17.8 and 4.4 deaths per 100 PYO for HIV-infected and uninfected patients, respectively; P<0.0001). Probability of survival at 24 months was estimated as 59% and 81%, respectively. We observed no increase in relapse or mortality among previously treated patients compared with new patients. A positive smear at 2 months did not predict relapse or mortality. CONCLUSION: Relapse rates are acceptably low following successful DOT with a twice weekly rifampicin-containing regimen, irrespective of HIV status and previous treatment history. Mortality is substantially increased among HIV-infected patients even following successful DOT and this requires further attention.

AIDS-Related Opportunistic Infections↗

Tuberculosis preventive therapy for HIV-infected people in sub-Saharan Africa is cost-effective.

OBJECTIVE: Since antiretroviral therapy is largely unavailable to HIV-infected patients in developing countries and recent clinical trials have shown that tuberculosis (TB) preventive therapy can reduce TB and HIV-associated morbidity and mortality, we studied the effectiveness and cost-effectiveness of TB preventive therapy for HIV-infected persons in sub-Saharan Africa. METHODS: A Markov model that used results of clinical trials of TB preventive therapy in sub-Saharan Africa and literature-derived medical care costs was used to evaluate three preventive therapy regimens in HIV-infected, tuberculin-positive patients in Uganda: (1) daily isoniazid (INH) for 6 months, (2) daily INH and rifampin (RIF) for 3 months, and (3) twice-weekly RIF and pyrazinamide (PZA) for 2 months. RESULTS: All three regimens extend life expectancy and reduce the number of TB cases. When only medical care costs are considered, all three preventive therapy regimens cost more than not providing preventive therapy to extend life and prevent active tuberculosis. When medical care and social costs are considered together, 6-months of daily INH treatment will save money relative to no preventive therapy and when the costs associated with treating secondary infections are included, all three preventive therapy regimens are less expensive than no preventive therapy. With the inclusion of secondary infection costs, 6 months of daily INH results in savings of $24.16 per person. CONCLUSIONS: TB preventive therapy taken by HIV-infected tuberculin reactors in sub-Saharan Africa results in extended life-expectancy, reduction of the incidence of TB and monetary savings in medical care and social costs. TB control policy in sub-Saharan Africa should include preventive therapy.

AIDS-Related Opportunistic Infections↗

Tuberculoma of the conus medullaris: case report.

OBJECTIVE AND IMPORTANCE: Intramedullary spinal tuberculoma is a rare form of central nervous system tuberculosis. This article describes an affected patient who presented with left leg paresis. CLINICAL PRESENTATION: A 46-year-old man presented with a 7-day history of left leg weakness. The patient's medical history included infection with pulmonary tuberculosis 15 years previously, at which time he had been treated with antituberculosis therapy. The neurological examination performed at admission revealed left leg paresis with Grade 2/5 power in all muscle groups. The patient reported no urinary or bowel problems. INTERVENTION: Surgery was performed with the patient in the prone position. The procedure involved laminectomies at T11, T12, and L1, followed by a midline myelotomy. The mass was excised completely. Histopathological examination revealed a granulomatous lesion that contained Langhans' giant cells, inflammatory cells, and evidence of caseating necrosis. The patient was prescribed a 6-month course of antituberculosis therapy with pyrazinamide, isoniazid, and rifampin. CONCLUSION: The outcome was favorable. Recently, a number of authors have reported success with medical management of intraspinal tuberculoma. Intraspinal tuberculoma produces a mass effect that can jeopardize spinal cord function. The optimal treatment is a combination of microsurgical resection and antituberculosis chemotherapy.

Antitubercular Agents↗

Short course chemotherapy for childhood tuberculosis.

A prospective study, with an attempted 24-month-post-treatment follow-up, of children with tuberculosis (TB) treated with short course chemotherapy (SCC) for 6 months was carried out because published experience of SCC in childhood TB was limited. All children in Port Moresby diagnosed as having TB between November, 1984, and November, 1986, entered the trial. Of the 639 children 165 (26%) were younger than 2 years old. Of these, 227 (35%) had extrapulmonary TB (peripheral lymph node, 110; central nervous system, 43; abdominal, 27; miliary, 16; bone and joint, 11; pleural, 11; polyserositis, 9). Clinical response to SCC was rapid. Adverse drug reactions occurred in 15 (2%), mainly to streptomycin. Twelve (2%) died, 38 (6%) transferred out and 145 (28% of the 518 who did not die, transfer or live too far from a treatment centre) defaulted. Three hundred seventy-three (58%) completed a 2-month course of daily rifampin, isoniazid, pyrazinamide and streptomycin followed by a 4-month course of twice weekly rifampin and isoniazid. A further 71 (11%) had their treatment modified because of their distance from a treatment center. Only 70 (19%) of the 373 children available for post-treatment follow-up attended the every-3-month follow-up visits for 24 months, although 223 (60%) attended one or more of the follow-up visits. Seven of the 373 children relapsed, mostly within 3 months. Five of these children had been irregular with their treatment. SCC for childhood TB is safe and effective for pulmonary and extrapulmonary disease.

Antitubercular Agents↗