Group 5 drugs for multidrug-resistant tuberculosis: individual patient data meta-analysis.

The role of so-called "group 5" second-line drugs as a part of antibiotic therapy for multidrug-resistant tuberculosis (MDR-TB) is widely debated. We performed an individual patient data meta-analysis to evaluate the effectiveness of several group 5 drugs including amoxicillin/clavulanic acid, thioacetazone, the macrolide antibiotics, linezolid, clofazimine and terizidone for treatment of patients with MDR-TB.Detailed individual patient data were obtained from 31 published cohort studies of MDR-TB therapy. Pooled treatment outcomes for each group 5 drug were calculated using a random effects meta-analysis. Primary analyses compared treatment success to a combined outcome of failure, relapse or death.Among 9282 included patients, 2191 received at least one group 5 drug. We found no improvement in treatment success among patients taking clofazimine, amoxicillin/clavulanic acid or macrolide antibiotics, despite applying a number of statistical approaches to control confounding. Thioacetazone was associated with increased treatment success (OR 2.6, 95% CI 1.1-6.1) when matched controls were selected from studies in which the group 5 drugs were not used at all, although this result was heavily influenced by a single study.The development of more effective antibiotics to treat drug-resistant TB remains an urgent priority.

The relationship between chitotriosidase activity and tuberculosis.

Chitotriosidase, secreted by activated macrophages, is a biomarker of activated macrophages. In this study, we explored whether chitotriosidase could be adopted as a biomarker to evaluate the curative effect on tuberculosis (TB). Five counties were randomly selected out of 122 counties/cities/districts in Hunan Province, China. Our cases were all TB patients who were newly diagnosed or had been receiving treatment at the Centers for Disease Control (CDCs) of these five counties between April and August in 2009. Healthy controls were selected from a community health facility in the Kaifu district of Changsha City after frequency-matching of gender and age with the cases. Chitotriosidase activity was evaluated by a fluorometric assay. Categorical variables were analysed with the χ 2 test. Measurement data in multiple groups were tested with analysis of variance and least significant difference (LSD). Correlation between chitotriosidase activity and the degree of radiological extent (DRE) was examined by Spearman's rank correlation test. The average chitotriosidase activity levels of new TB cases, TB cases with different periods of treatment (6 months) and the control group were 54·47, 34·77, 21·54, 12·73 and 10·53 nmol/h.ml, respectively. Chitotriosidase activity in TB patients declined along with the continuity of treatment. The chitotriosidase activity of both smear-positive and the smear-negative pulmonary TB patients decreased after 6 months' treatment to normal levels (P < 0·05). Moreover, chitotriosidase activity was positively correlated with DRE (r = 0·607, P < 0·001). Our results indicate that chitotriosidase might be a marker of TB treatment effects. However, further follow-up study of TB patients is needed in the future.

Haemorheological variables in Nigeria pulmonary tuberculosis patients undergoing therapy.

Haemorheological changes in response to therapy have not been fully determined in pulmonary tuberculosis patients living in developing countries. This study was aimed at monitoring haemorheological parameters in newly diagnosed pulmonary tuberculosis patients undergoing therapy. Haemorheological parameters were studied in 40 tuberculosis patients (17 males and 23 females, mean age 33.4+/-1.4 years, range 23-45 years) undergoing treatment and 10 newly diagnosed patients (5 males and 5 females mean age 33.0+/-2.1 years) along with 50 apparently healthy controls age and sex matched. There were significantly lower packed cell volume (PCV), platelet count (PC), and total white blood cell count (p<0.0001). Whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte sedimentation rate (ESR), and plasma fibrinogen (PF) were significantly higher in pulmonary tuberculosis patients than controls (p<0.0001). The packed cell volume was significantly increased by the 8th week of therapy (p<0.01), there was a significant reduction in the erythrocyte sedimentation rate from the 4th week of therapy (p<0.0001). There was no significant change in blood viscosity by the 4th week of therapy (p>0.05), while the plasma fibrinogen showed significant reduction from the 4th week of therapy till 8th week of therapy (p<0.01 and p<0.0001 respectively). We conclude that thrombocytopaenia, stasis and hyperfibrinogenemia may predispose African PTB patients to bleeding and thrombotic disorders. Haemorheological parameters may be useful indices in assessing response to therapy and drug compliance in pulmonary tuberculosis patients living in developing countries.

[A case of multidrug-resistant pulmonary tuberculosis cured by the regimen including thiacetazone].

A 30 years-old-male was referred to our hospital for surgical treatment of multidrug-resistant tuberculosis in April 1998, three years after diagnosis of tuberculosis. All first-line anti-tuberculosis drugs and second-line anti-tuberculosis drugs were resistant on drug susceptibility tests by Ogawa medium. The right upper lobectomy was done because of massive hemoptysis and enlargement of cavitary lesion in June 1998, but this surgical operation was complicated with, bronchial fistula and chronic empyema. Open drainage surgical treatment for chronic empyema was done one month after lobectomy. Sputum culture for M. tuberculosis converted 4 months after the lobectomy, but bacteriological relapse occurred 17 months after initial operation. The new cavitary lesion on middle left lung field developed and sputum smear and culture were continuously positive. Immunotherapy with interferon-gamma via aerosol didn't show any clinical effect. Thiacetazone, sparfloxcin, pyrazinamide, cycloserine was prescribed after 21 months of the initial operation. Four months after changing the regimen sputum smear and culture converted to negative. Chemotherapy was terminated in June 2003, two years after negative conversion. Three years after the termination of treatment no relapse occurred. We considered thiacetazone was effective in this case, because all of the drugs was companied with thiacetazone were resistant by the drug susceptibility tests and were previously used.

Extension of the intensive phase reduces unfavourable outcomes with the 8-month thioacetazone regimen.

SETTING: Damien Foundation tuberculosis (TB) control projects in Bangladesh. OBJECTIVE: To assess the effectiveness of a 1-month extension of the intensive phase for smear-positives at 2 months of an 8-month regimen with a continuation phase consisting of isoniazid (INH) and thioacetazone (Th). DESIGN: A prospective study of two cohorts of newly registered smear-positive cases, with extension of the intensive phase for the control cohort, but not for the study cohort. Culture and drug susceptibility testing (DST) of smear-defined failures and relapses and of random samples of new cases. RESULTS: Among 8230 study patients (86.7% 2-month conversion) and 7206 controls (83.4% conversion), smear-defined failure or relapse outcome was 3.0% for 2-month smear-negatives vs. 3.1% for 2-month smear-positives with extension (non-significant, NS), and 8.2% for 2-month smear-positives with no extension (P < 0.00001). Culture-confirmed failure and relapse reached 1.9% in 2-month smear-negatives and 1.6% (NS) in 2-month smear-positives with vs. 3.7% (P < 0.001) in 2-month smear-positives with no extension. The relative risk (RR) of non-extension in 2-month smear-positives was 2.4 (cultures) to 2.7 (smears). The same RR and borderline significance was found for non-extension of patients with pan-susceptible strains. CONCLUSIONS: Extension of the intensive phase considerably reduces failures and relapses with a weaker regimen in patients smear-positive at 2 months. Its effectiveness may vary with extent of initial drug resistance vs. power of the regimen.

Use of nonlinear mixed-effects analysis for improved precision of early pharmacodynamic measures in tuberculosis treatment.

Nonlinear mixed-effects analysis of serial sputum colony-counting data supports the existence of two bacillary subpopulations in sputum, eliminated at different rates. It distinguishes between combination regimens, removes bias, and greatly improves precision, with significant implications for the analysis of surrogate endpoints of "sterilization" in the development of new antituberculosis regimens.

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.

Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice.

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.

Drug resistance in tuberculosis in Delhi: a 2 year profile (2001--2002).

234 isolates of Mycobacterium tuberculosis obtained from 1000 suspected cases of tuberculosis reporting at National Institute of Communicable Disease, Delhi for laboratory investigation between Jan 2001 to August 2002 were subjected to invitro drug sensitivity test against the first line drugs (Isoniazid, Streptomycin, Rifampicin, Ethambutol and Thiacetazone) by proportion method using Lowenstein Jensen (LJ) media. Out of 234 isolates of Mycobacterium tuberculosis, 142 were from cases of untreated tuberculosis, whereas only 92 isolates were from treated cases of tuberculosis. An initial drug resistance of 21.83% was seen against INH, 9.85% against Streptomycin, 15.49% against Rifampicin, 4.22% against ethambutol and 2.11% to thiacetazone. Multidrug resistance (MDR-i.e. Resistance to both INH and Rifampicin) was seen in 11.97% of isolates. 4(2.8%) isolates were found to be resistant to all drugs tested. A much higher level of acquired resistance was seen the figures being 61.95% for INH, 53.36% for rifampicin, 35.86% for streptomycin, 20.65% for ethambutol and 10.86% for thiacetazone. Avery high acquired MDR to the tune of 42.39% was seen. 24(26%) isolates were found to be resistant to all drugs tested. No significant difference were observed in the drug resistance pattern between pulmonary and extrapulmonary cases of tuberculosis in both initial and acquired drug resistance category.

Pattern of some haematological indices in newly diagnosed pulmonary tuberculosis cases in Iwo, Nigeria: diagnostic and therapeutic implications.

Five hundred (500) newly diagnosed (ND) cases of pulmonary tuberculosis (PTB) were seen between January 1996 and December 1997 at Iwo, Osun State of Nigeria. They were treated with the regimen of 2 months of ethambutol (E), isoniazid (H), rifampicin (R) and pyrazinamide (Z) (2EHRZ) as directly observed treatment (DOT) followed by six months of daily thiacetazone(T) and isoniazid (6HT). The haematological indices PCV, WBC, ESR, platelet count and blood film were done (using standard methods) at diagnosis, and at 1, 2, 3, 5 and 8 months of follow up. The average values were computed and noted. The average PCV rose from 28 to 38% at diagnosis and by the completion of the eight month of chemotherapy. The mean WBC also rose from 3.5 x 10(9)/L to 5.5 x 10(9)/L during the same period. The average ESR for 200 male patients fell progressively from 20 mm/hr to 10 mm/hr while that for 300 female patients fell progressively from 42 mm/hr to 20 mm/hr during the same period. The mean platelet counts did not change significantly from the initial value of 245 x 10(3)/cm throughout the treatment period. The blood film showed that 475 (95%) had normochromic picture while 25 (5%) cases showed anisocytosis, poikilocytosis and polychromasia. The pattern of changes of these parameters during medications have also been observed. Anaemia is not striking at diagnosis of newly diagnosed pulmonary tuberculosis cases in Nigerians and the low grade anaemia of chronic disorder improves without the need for iron or folic acid supplementation. Possible reasons were given.

Modified short-course chemotherapy of pulmonary tuberculosis in Ibadan, Nigeria--a preliminary report.

Over a 3 year period 3rd of April 1995 and 6th of April 1998 a controlled clinical trial of the modified short-course chemotherapy (SSC) in newly diagnosed cases of pulmonary tuberculosis in Nigeria was carried out. Between The SCC used was the one adopted from World Health Organisation/International Union Against Tuberculosis and Lung Diseases for developing countries by the Nigerian National Tuberculosis and Leprosy Control Programme (NTLCP). The regimen used consisted of streptomycin (S), isoniazid (H), Rifampicin (R) and pyrazinamide (Z) in the initial or intensive phase of 2 months. Ethambutol (E) was sometimes substituted for streptomycin. The continuation phase was 6 months of thiacetazone, (T) and isoniazid (H), i.e., 2SHRZ/6TH or 2EHRZ/6TH. Sputum conversion was 90% at the second month of treatment and there was no bacteriological relapse after 18 months of follow-up. Side effects were few and consisted mainly of acne vulgaris which occurred in twenty (20.6%) of 97 patients during the continuation phase. It is concluded that the 8-month chemotherapy regimen adopted by NTLCP is efficacious in treatment of smearpositive pulmonary tuberculosis (PTB).

Antiproliferative and cytotoxic effects of geldanamycin, cytochalasin E, suramin and thiacetazone in human prostate xenograft tumor histocultures.

PURPOSE: We have shown that the three human prostate xenograft tumors, i.e. the androgen-dependent CWR22 tumor, and the androgen-resistant CWR22R and CWR91 tumors, are comparable to patient tumors in their expression of prostate specific antigen, multidrug resistance p-glycoprotein, p53 and Bcl-2 and in their sensitivity to doxorubicin and paclitaxel. The present study used histocultures of these xenograft tumors to evaluate the antiproliferative and cytotoxic effects of several drugs (geldanamycin, cytochalasin E and thiacetazone), which have diverse action mechanisms and have shown activity against primary cultures of human prostate cancer cells. Suramin, a clinically active compound was included for comparison. Methods. The antiproliferative effect of 96 h drug treatment was measured by inhibition of DNA precursor incorporation, and the cytotoxic or cell kill effect was measured by in situ DNA end labeling of apoptotic and necrotic cells and by reduction of live cell density. RESULTS: The rank order of molar potency was geldanamycin > cytochalasin E > suramin > or = thiacetazone. Thiacetazone produced antiproliferation only in CWR22 tumor and had no cytotoxicity, whereas the other three drugs produced both antiproliferation and cytotoxicity in all three tumors. Geldanamycin, but not cytochalasin E and suramin, showed greater antiproliferation and cytotoxicity in tumor cells compared to normal stromal cells. The two androgen-resistant tumors were 4 to >40-fold less sensitive than the androgen-dependent tumor to drug-induced antiproliferation but were about equally or 4 to >20-fold more sensitive to drug-induced cytotoxicity. The ratios of drug concentrations that produced 50% antiproliferation to the concentrations that produced 50% cytotoxicity ranged from <0.04 to 0.3 in CWR22 tumor, but ranged from 0.3 to 2.7 in CWR22R and CWR91 tumors, indicating a shift from antiproliferation as the predominant drug effect in the androgen-dependent tumor to cytotoxicity in the androgen-resistant tumors. CONCLUSIONS: Our results indicate (a) differential drug effects in human prostate xenograft tumors with antiproliferation and cytotoxicity as the predominant drug effect in the androgen-dependent and androgen-resistant tumors, respectively, (b) that progression of tumors from androgen-dependent state to androgen-resistant state appears to be associated with a lower sensitivity to drug-induced antiproliferation and an equal or greater sensitivity to drug-induced cytotoxicity, and (c) that geldanamycin but not thiacetazone warrants further development.

Impact of human immunodeficiency virus type-1 infection on the initial bacteriologic and radiographic manifestations of pulmonary tuberculosis in Uganda. Makerere University-Case Western Reserve University Research Collaboration.

SETTING: TB Treatment Centre, Kampala, Uganda. OBJECTIVE: To evaluate the impact of human immunodeficiency virus (HIV) co-infection on the bacteriologic and radiographic presentation of pulmonary tuberculosis (TB) in Uganda, a nation with high rates of Mycobacterium tuberculosis and HIV infection. DESIGN: To compare baseline characteristics among HIV-infected and non-HIV-infected adults with initial newly-diagnosed episodes of culture-confirmed pulmonary TB screened for participation in a randomized prospective TB treatment trial. RESULTS: Negative and paucibacillary (very scanty or scanty) sputum acid fast bacilli (AFB) smears were more frequent in HIV-infected patients presenting with pulmonary TB (P = 0.007). More HIV-infected individuals also had sputum cultures that required 7-8 weeks incubation until positivity than non-HIV-infected patients (P < 0.01). Lower lung field and diffuse pulmonary infiltrates were more frequent among HIV-infected patients. Rates of atypical X-ray presentations and cavitary disease were comparable between HIV-seropositive and -seronegative patients; however, atypical disease was more frequent in HIV-infected patients with small tuberculin reactions or tuberculin anergy (PPD = 0 mm). CONCLUSION: HIV co-infection was associated with a higher frequency of negative and paucibacillary sputum AFB smears. The differences in the diagnostic yields of microscopy and culture between HIV-infected and non-HIV-infected individuals were small and do not, in our opinion, significantly affect the utility of these important diagnostic tests in developing countries. Examining more than one sputum specimen and monitoring cultured specimens for a full 8 weeks may assist in optimizing the diagnostic yield. Upper lobe infiltrates and cavitary disease are still the most frequent radiographic presentations of pulmonary TB in HIV-infected and non-HIV-infected adults in countries with a high prevalence of TB.

[The results of retreatment of pulmonary tuberculosis using a short 6-month protocol 1985-1991 in the pneumo-phthisiology department of the Point G hospital in Bamako]. / Résultats du retraitement de la tuberculose pulmonaire par un régime court de 6 mois de 1985-1991 dans le service de pneumo-phtisiologie de l'hôpital du point G à Bamako.

This study concerns 321 files of smear positive tuberculosis patients admitted in the pneumo-phtysiology service of Pt G Hospital for re-treatment from April 1985 to December 1991. The re-treatment pulmonary tuberculosis with positive spits represent 13.3% of pulmonary tuberculosis cases and 10.1% of the whole tuberculosis diseases. High rate with a ratio of 3 men for a woman was found among men. The same conclusion was reached by SAMAKE (7). Patients age raking from 20 to 49 were the most affected in a proportion of 75.7%. Evolutive relapses were the principal reasons for re-treatment (71.2%) and take place above all among patient treated with the 12 months conventional regime. The conclusion reached corroborates those of STYBLO (8). The regime was 3RHZES3/3R3H3E3. The maximum of negating has been reached during the 3rd month with 93.4% rate. It has been during these 3 last months consolidation phase that the highest drop out has been noticed (17.1%). This is certainly due to the better off felt by patients. At the end of treatment 76.3% of the patients have recovered against 1.5% failure rate and 5.3% drop out. Our treatment regime, though different from those advised by WHO and IUATLD, is an efficient one. However in the new programme of fighting against tuberculosis of Mali, it has been decided to replace our treatment with that of WHO and IUATLD.

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.

Risk factors for relapse in human immunodeficiency virus type 1 infected adults with pulmonary tuberculosis.

SETTING: A study conducted by the Uganda-Case Western Reserve University Research Collaboration in Kampala, Uganda, a country with high incidence rates of tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) infection. OBJECTIVE: To assess clinical, microbiologic and radiographic factors associated with risk for relapse in HIV-infected adults treated for initial episodes of pulmonary TB. DESIGN: Nested case-control study within a randomized prospective clinical trial comparing the safety and efficacy of thiacetazone- and rifampicin-containing regimens for TB treatment in HIV-infected adults. RESULTS: The analysis was based on 119 patients who completed therapy. Median follow-up for all subjects was 22.3 months. Ten patients relapsed a median of 12.7 months after the end of therapy; seven of these were initially treated with the thiacetazone (T)-containing regimen. Each relapse case was matched to four controls by length of follow-up after initial TB treatment. In a univariate analysis risk for relapse was associated with treatment with the T-containing regimen (OR = 4.2, P = 0.08), age > or = 30 yrs (OR = 2.9, P = 0.16), and irregular compliance (OR = 3.6, P = 0.1). Baseline anergy on Mantoux tuberculin skin testing, cavitary disease, radiographic extent of disease and sputum bacillary burden, two month culture negativity, and residual cavitary disease at the end of treatment did not differ between relapses and controls. CONCLUSION: Older HIV-1 infected patients, those with poor treatment compliance, and those being treated with T-containing regimens, may be at increased risk for relapse after TB treatment and require closer post-treatment surveillance. Risk for relapse in HIV-infected adults with pulmonary TB after treatment with a nine month rifampicin-containing regimen was low (3.1 per 100 person-years observation) compared with those treated with a thiacetazone-containing regimen (10.1 per 100 person-years observation).