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Effective treatment reduces a tuberculosis patient's ability to infect others even before they test negative in sputum or culture. Currently, the basis of reduced infectiousness of the Mycobacterium tuberculosis (Mtb) with effective treatment is unclear. We evaluated changes in aerosolized bacteria expelled by patients through a transcriptomic approach before and after treatment initiation (up to 14 days) by RNA sequencing. A distinct change in the overall transcriptional profile was seen post-treatment initiation compared to pretreatment, only when patients received effective treatment. This also led to the downregulation of genes associated with cellular activities, cell wall assembly, virulence factors indicating loss of pathogenicity, and a diminished ability to infect and survive in new host cells. Based on this, we identified genes whose expression levels changed with effective treatment. The observations of the study open up avenues for further evaluating the changes in bacterial gene expression during the early phase of treatment as biomarkers for monitoring response to tuberculosis treatment regimens and provide means of identifying better correlates of Mtb transmission., (© 2021. The Author(s).)

We aimed to investigate the effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti- tuberculosis (TB) drugs in Chinese population. Newly diagnosed TB patients administered the anti-TB drugs under fasting conditions orally, and then had prepared breakfast at 30 minutes and 120 min after dosing, respectively. Blood sampling was also performed 120  minutes after dosing for the detection of Cmax purpose. Overall, twenty-five participants were included in our analysis. The Cmaxs of 30  minutes interval and 120  minutes interval were 21.8 ± 2.0 and 19.2 ± 2.0 μg/mL for rifampin, 1.6 ± 0.2 and 2.1 ± 0.2 μg/mL for isoniazid (INH), 1.5 ± 0.1and 1.5 ± 0.2 μg/mL for ethambutol (EMB), and 49.2 ± 3.7 and 41.5 ± 3.9 μg/mL for pyrazinamide, respectively. Statistical analysis revealed that there was no statistical difference between 2 groups. Additionally, 88.0% and 72.0% of the 25 participants at 2-hour interval group had peak concentrations less than the lower limit of the reference range for INH and EMB, respectively. The Cmaxs of INH were 0.9 ± 0.4 μg/ml for rapid acetylator, which was significantly lower than those of intermediate (1.4 ± 1.0 μg/mL), and slow acetylator (2.5 ± 1.0 μg/mL), respectively (P < .01). In conclusion, our data demonstrate that early food intake at 30 minutes after drug administration had no significant influence on the plasma concentrations. In addition, a high proportion of patients receiving first-line anti-TB regimen fail to achieve the expected plasma drug ranges of INH and EMB (P > .05).

Background: To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives., Methods: This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers., Discussion: This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB., Trial Registration: ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Background: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure., Objectives: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment., Methods: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies., Results: We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation., Conclusions: Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In high-income countries, the presentation of tuberculosis is changing, primarily because of migration, and understanding the specific health needs of susceptible populations is becoming increasingly important. Although disseminated tuberculosis is well documented in HIV-positive patients, the disease is poorly described and less expected in HIV-negative individuals. In this Grand Round, we report eight HIV-negative refugees, who presented with extensively disseminated tuberculosis. We discuss the multifactorial causes, such as deprivations during long journeys, precarious living conditions, and the experience of violence, which might add to nutritional factors and chronic disorders, eventually resulting in a state of predisposition to immune deficiency. We also show that disseminated tuberculosis is often difficult to diagnose when pulmonary symptoms are absent. Communication difficulties between refugees and health-care workers are another major hurdle, and every effort should be made to get a valid patient history. This medical history is crucial to guide imaging and other diagnostic procedures to establish a definite diagnosis, which should be confirmed by a positive tuberculosis culture. Because many of these patients are at risk for multidrug-resistant tuberculosis, drug susceptibility testing is imperative to guide therapy. In the absence of treatment guidelines for this entity, clinicians can determine treatment duration according to recommendations provided for extrapulmonary tuberculosis and affected organs. Paradoxical expansion of tuberculous lesions during therapy should be treated with corticosteroids. In many cases, treatment duration must be individualised and might even exceed 12 months., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB., Methods and Analysis: We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug-drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants., Ethics and Dissemination: The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system., Trial Registration Number: CTRI/2018/01/011176; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Ulcerative skin tuberculosis (TB) is a rare form of extrapulmonary TB., Case Report: We present a case of a 65-year-old patient with perianal ulcer, which had been present for 1 year. Anamnesis revealed he had been persistently coughing for the same period of time. Histological examination of perianal skin showed necrotizing granulomatous lesions, acid-fast staining in sputum samples was ++++, TB antibody in the blood was positive, TB DNA test was positive, and chest scan that showed secondary pulmonary TB accompanied by possible pulmonary cavity formation in the 2 upper lungs., Interventions: Anti-TB therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide for 6 months. The skin ulcer completely healed after 6 months., Conclusion: TB should be suspected for nonhealing ulcers. Pertinent studies should be done early during the lesion; finally, TB treatment should be initiated immediately after diagnosis is made.

Rationale: Unilateral hypoplasia of the lung is a rare congenital condition, the mechanism of which is poorly understood. Primary pulmonary hypoplasia occurring in an adult is extremely rare and we present what is probably the first case of a link to a tuberculous pleural effusion in a young woman after childbirth., Patient Concerns: Herein, we describe a 31-year-old woman with left lung hypoplasia, and she not only survived to adulthood without problems, but was able to deliver a baby in natural labor., Diagnoses: Left lung hypoplasia, right tuberculous pleural effusion., Interventions: We initiated an anti-tuberculosis treatment for this patient with dose adjustments to her weight of isoniazid (0.3 g/day), rifampicin (0.45 g/day), pyrazinamide (1.5 g/day), and ethambutol (0.75 g/day) for 2 months then isoniazid and rifampicin for another 4 months., Outcomes: Ten days later after beginning therapy, she became afebrile and the pleural effusion resolved. No recurrence was observed during a 6-month follow-up period., Lessons: In clinical practice, if one sees a chest x-ray revealing complete or incomplete opacification of a hemithorax with volume loss and history of repeated respiratory infections, one should consider the possibility of unilateral pulmonary hypoplasia. In such cases, regular close follow-up is important to minimize infections and to prevent development of cor pulmonale or respiratory failure.

Importance: The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven., Objective: To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB., Design, Setting, and Participants: This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016., Interventions: Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using standard criteria., Main Outcomes and Measures: The primary outcome was favorable response, defined as treatment completion with all available sputum cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment. Unfavorable responses included treatment failures, dropouts, deaths, and toxic effects among regimens., Results: Of 331 patients (251 [76%] male; mean [SD] age, 39 [9] years; mean [SD] HIV viral load, 4.9 [1.2] log10 copies/mL; and median [interquartile range] CD4 lymphocyte count, 138 [69-248] cells/μL), favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O'Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. A total of 18 patients died and 18 patients dropped out during the treatment period in the 3 regimens. Six, 4, and 6 patients in the daily, part-daily, and intermittent regimens, respectively, had TB recurrence., Conclusions and Relevance: Among HIV-positive patients with pulmonary TB receiving antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice-weekly regimen in terms of efficacy and emergence of rifampicin resistance., Trial Registration: clinicaltrials.gov Identifier: NCT00933790.

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients., Methods: CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis., Results: A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903)., Conclusions: This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Linezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We started a trial to test whether the use of linezolid instead of ethambutol could increase the rate of sputum culture conversion as of 8 weeks of treatment in patients with drug-susceptible tuberculosis., Methods/design: This is a phase II, multicenter, randomized study with three arms. We are enrolling patients with pulmonary tuberculosis without rifampicin resistance screened by the Xpert MTB/RIF® assay. The standard treatment arm uses isoniazid (6 months), rifampicin (6 months), pyrazinamide (2 months), and ethambutol (2 months). Experimental arm 1 uses linezolid (600 mg/day) for 4 weeks instead of ethambutol. Experimental arm 2 uses linezolid (600 mg/day) for 2 weeks instead of ethambutol. The primary outcome is the sputum culture conversion rate on liquid media after 2 months of treatment. Secondary outcomes include the sputum culture conversion rate on solid media after 2 months of treatment, time to sputum culture conversion on liquid and solid media, cure rate, and treatment success rate. The frequencies of total adverse events (AEs) and serious AEs will be described and documented. Based on an α = 0.05 level of significance, a power of 85%, a 15% difference in the culture conversion rate after 2 months between the control arm and experimental arm 1 (75% vs. 90%), a 10% default (loss to follow-up) rate, and a 10% culture failure, the required number per arm was calculated to be 143 (429 in total)., Discussion: This trial will reveal the effectiveness and safety of 2 or 4 weeks of use of linezolid instead of ethambutol for patients with drug-susceptible pulmonary tuberculosis. If a new regimen including linezolid shows a higher culture conversion rate by week 8, and is safe, it could be tested as a 4-month antituberculosis treatment regimen in the future., Trial Registration: ClincalTrials.gov, NCT01994460 . Registered on 13 November 2013.

Objective: To study the efficacy and tolerability of Risorine Capsule (A fixed dose combination of Rifampicin 200 mg + INH 300 mg + Piperine 10 mg) therapy in the treatment of drug-susceptible pulmonary tuberculosis patients who developed GI intolerance with standard WHO anti TB regimen., Methods: 33 patients with pulmonary tuberculosis were treated with one Risorine kit, daily consisting of one capsule of Risorine, one tablet of ethambutol (800 mg) and two tablets of Pyrazinamide 750 mg each, for first two months of therapy. All the patients received one capsule of Risorine daily for next four months. Symptomatic improvement, Sputum conversion and radiological improvement were monitored at regular intervals., Results: Out of 27 patients who were sputum positive at baseline, 24 patients became sputum negative during the first two months of treatment. Out remaining three patients, one became sputum negative at the end of third month of treatment and the other two became sputum negative at the end of sixth month of treatment. Out of 33 patients, only two patients developed mild nausea, which subsided spontaneously. One patient who was HIV positive, developed hepatitis., Conclusions: Risorine, a novel formulation of rifampicin 200 mg with bioenhancer piperine 10mg, is found to be highly effective and well tolerated in the treatment of drug - susceptible pulmonary tuberculosis.

An 89-year-old man presented with an inflammatory erythematous plaque on the left thigh that closely mimicked cellulitis. Empiric therapies with ordinary antibiotics were not effective. A skin biopsy showed epithelioid cell granulomas throughout the dermis and subcutis. Ziehl-Neelsen stain revealed numerous acid-fast bacilli. Additionally, Mycobacterium tuberculosis was isolated from a skin biopsy specimen as well as gastric fluid and sputum cultures. He was diagnosed with tuberculous cellulitis with pulmonary tuberculosis. Cellulitis is a common disease seen by dermatologists; however, sometimes other diseases may masquerade as this banal illness. Among them, cutaneous tuberculosis should be excluded because of its clinical significance. Most cases of cutaneous tuberculosis are symptom free, but tuberculous cellulitis is sometimes painful. Therefore, cutaneous tuberculosis should always be considered in the differential diagnosis of a cellulitislike rash if the lesions do not respond to ordinary antibiotic therapy, especially in countries with a high incidence of tuberculosis.

Background: There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries., Methods: A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase- 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase- 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months' treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result., Results: In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%- 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%- 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment., Interpretation: The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries., Trial Registration: ISRCTN Registry 95204603.

The proportion of the elderly in patients with pulmonary tuberculosis is increasing, and failure to complete the standard treatment regimen is not uncommon in these patients. We examined the compliance rate and prob- lems of the standard regimen in the late elderly pulmonary tuberculosis patients. [Methods] We reviewed the medical records of late elderly patients with pulmonary tuberculosis aged 75 or above who were smear-positive and treated in Kanagawa Cardiovascular and Respiratory Center between January 2011 and December 2014. Our retrospective study examined patient characteris- tics, imaging findings, laboratory results, and outcomes. The compliance rate of standard regimen during the hospitaliza- tion period was calculated. We compared the discontinua- tion rate and the incidence of adverse drug reactions by body weight equivalent doses of anti-tuberculosis drugs. [Results] A total of 298 patients were included in this study, and 76% of those patients were aged 80 or above. Anti-tuberculosis therapy was not able to be initiated for 3 patients (1%), and treatment other than standard regimen was inevitably introduced at initiation in 21 patients. The remaining 274 patients (92%) were administered the stan- dard regimen. Among them, at least one medication was subsequently discontinued for 85 patients (29%), and the medication was changed due to drug resistance in 6 patients . (2%). The remaining 183 patients (61%) complied with the standard regimen during hospitalization. In the comparison by body weight equivalent dose, significantly more patients discontinued their medication in the group using ethambutol with a higher standard dose per weight (37% vs. 21%, p=0.02). [Conclusion] Nearly 40% of the late elderly patients could not comply with the standard regimen. We may need to be more careful when calculating ethambutol equivalent dose.

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Objective: To observe the clinical effect on type 2 diabetes mellitus (T2DM) complicated with pulmonary tuberculosis (TB) of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol (conventional medication) administered together with Qi-boosting and Yin-nourishing decoction derived from Traditional Chinese Medicine (TCM)., Methods: A total of 60 patients with T2DM complicated with pulmonary TB were randomly and equally divided into positive control group and treatment group. The control group was treated with Western conventional regiment (WCR): insulin, isoniazid, rifampicin, pyrazinamide, and ethambutol, whereas the treatment group was given both WCR and Qi-boosting and Yin-nourishing decoction prepared from TCM., Results: After the treatment, 20 (66.7%) and 11 (36.7%) cases showed sputum bacteria negative conversion in the WCR plus TCM group and WCM group respectively (P < 0.05). A total of 25 (83.3%) and 18 (60%) cases showed improvement in lung lesion in the WCR plus TCM group and WCM group respectively (P < 0.05). Compared with WCR group, fasting plasma glucose and 2-hour postprandial blood glucose levels in the WCR plus TCM group significantly decreased (P < 0.05 and P < 0.01, respectively)., Conclusion: Qi-boosting and Yin-nourishing decoction combined with the Western medication showed better curative effect in treating T2DM complicated with pulmonary TB compared with the group using the conventional Western Medicine alone.

Rationale: Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity, and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment., Objectives: To evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin., Methods: Patients with drug-susceptible tuberculosis were enrolled into a control group of eight patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20, 25, 30, and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide, and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed., Measurements and Main Results: Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were five grade 3 events of which one was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively., Conclusions: Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a nonlinear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registered with www.clinicaltrials.gov (NCT 01392911).

Background: The available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used. Also, there is lack of consensus regarding the effect of malnutrition on pharmacokinetics of anti-tubercular drugs in children. We conducted this study with the aims of determining the plasma concentrations of isoniazid, rifampicin, pyrazinamide and ethambutol achieved with different dosage of the anti-tubercular drugs so as to provide supportive evidence to the revised dosages and to evaluate the effects of malnutrition on the pharmacokinetics of these drugs in children. We also attempted to correlate the plasma concentrations of these drugs with clinical outcome of therapy., Method: Prospective drug estimation study was conducted in two groups of children, age 6 months to 15 years, with tuberculosis, with or without severe malnutrition, receiving different dosage of daily anti- tubercular therapy. The dosage (range) of isoniazid was 5 (4-6) and 10 (7-15) mg/kg in the two groups, respectively, that of rifampicin-10 (8-12) and 15 (10-12) mg/kg, respectively, both the groups received same dose of pyrazinamide (30-35 mg/kg) and ethambutol (20-25 mg/kg). All four drugs were simultaneously estimated by liquid chromatography-mass spectrometry (LC-MS/MS)., Results and Conclusion: The median (IQR) Cmax of isoniazid increased significantly from 0.6 (0.3,1.2) μg/mL to 3.4 (1.8, 5.0) μg/mL with increase in the dose. Plasma rifampicin concentrations increased only marginally on increasing the dose [median (IQR) Cmax: 10.4 (7.2, 13.9) μg/mL vs. 12.0 (6.1, 24.3) μg/mL, p=0.08]. For ethambutol, 55.9% of the children had inadequate 2-hour concentrations. Two-hour plasma concentrations of at least one drug were low in 59 (92.2%) and 54 (85.7%) children in the two dosing regimen, respectively. We did not observe any effect of malnutrition on pharmacokinetic parameters of the drugs studied. We did not observe an association between low plasma drug concentrations and poor outcome. We may have to be cautious while increasing the doses and strive to asses other factors influencing the drug concentrations and treatment outcomes in children.

Setting: One urban tertiary care and one rural secondary care hospital in Nigeria., Objective: To compare the epidemiological characteristics and treatment outcomes of tuberculosis (TB) patients treated with an 8-month or 6-month anti-tuberculosis regimen in a low-resource setting., Design: Retrospective cohort study., Results: A total of 928 newly diagnosed smear-positive TB patients were treated with either daily ethambutol (EMB), isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) for 2 months followed by EMB and INH for 6 months (2RHZE/6EH), or the same intensive phase as the first regimen followed by 4 months of daily RMP and INH (2RHZE/4RH). The proportion of successful outcomes was 381/490 (77.8%) with 2RHZE/6EH and 373/438 (85.2%) with 2RHZE/4RH (P = 0.004). Defaulting was significantly more frequent in patients who received 2RHZE/6EH (14.3% vs. 5.5%; P < 0.001). Treatment failure was not significantly higher in patients who received 2RHZE/6EH (2.9% vs. 1.6%; P = 0.15). After adjusting for confounders, older age (adjusted odds ratio [aOR] 1.7), 2RHZE/6EH treatment (aOR 1.6) and male sex (aOR 1.5) independently predicted unsuccessful outcomes in human immunodeficiency virus negative TB patients., Conclusions: Newly diagnosed TB patients on 2RHZE/4RH have a higher treatment success rate than those treated with 2RHZE/6EH under programme conditions in a low-resource, high-burden setting. Current World Health Organization recommendations should be maintained.

Background: In 2009, Brazil was the sole high-burden country to use three drugs [rifampin (R), isoniazid (H) and pyrazinamide (Z)] as the standard treatment for sensitive tuberculosis, with RH in fixed-dose combination (FDC). In December 2009, the country has adopted the FDC four-drug regimen including ethambutol (E). The rationale was the expectation to reduce default and resistance rates, by increasing adherence to treatment and avoiding monotherapy. However, there is no consensus on the superior effectiveness of the RHZE-FDC regimen over RH-FDC + Z. In particular, few studies evaluated its influence on default and smear negativation rates., Methods: We conducted a historic cohort study to assess the effectiveness of RHZE-FDC for the treatment of tuberculosis in Brazil, measured by the rates of treatment default and smear negativation in the second month of treatment, using secondary data from the national information system known as SINAN-TB., Results: The RHZE-FDC had a protective effect against treatment default compared to RH-FDC + Z, reducing it by 14%. However, it was not possible to show an effect of the RHZE-FDC on the rate of second month smear negativation. In addition to the regimen, other well-studied individual characteristics, such as older age (over 38 years) and higher education occupation were also protective against default. Conversely, alcoholism increased the probability of defaulting. These programmatic findings suggests the benefits of RHZE-FDC over RH-FDC + Z., Conclusion: Our analysis of a cohort database in a high burden country shows that compared to RH-FDC + Z, RHZE-FDC reduces the default rates, independently of other influencing individual or health service factors.

Background: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection., Methods/design: STREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites., Discussion: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB., Trial Registration: This trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010.

Thrombocytopenia induced by rifampicin in the absence of prior sensitization is exceptional, especially when it occurs in a patient without risk factors. We report the case of a patient aged 25 years with no past history of medical, surgical or knowledge of having taken rifampicin previously, who was hospitalized for treatment of thrombocytopenic purpura occurring after the initiation of fixed combination quadruple therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) for pulmonary tuberculosis. The biological pretreatment and therapeutic education had not been made. The patient presented with thrombocytopenic purpura 30000/mm(3) on day 9 after the initiation of treatment. The platelet count returned to normal 10 days after discontinuation of treatment. We elected not to reintroduce rifampicin given the strong likelihood that it was responsible for this complication. We conducted a phased reintroduction of isoniazid, ethambutol and pyrazinamide. No recurrence of the thrombocytopenia occurred. Thus, the diagnosis of rifampicin-induced thrombocytopenia appears to have been confirmed and the patient tolerated the remainder of their treatment well., (Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Fixed-dose combination (FDC) formulations are currently recommended for the treatment of active tuberculosis (TB). We have conducted a systematic review to evaluate the risk of treatment failure or disease relapse, acquired drug resistance, bacterial conversion after 2 months of treatment, adverse events, adherence and treatment satisfaction associated with treatment of active TB using FDC or separate drug formulations. We searched four electronic databases for randomised controlled trials and cohort studies. Results from trials that directly compared FDC to separate drug formulations were pooled. Results from other studies were reported separately. We identified 2450 citations from which 15 controlled trials and four additional relevant studies were included. In the 15 trials there were no differences in acquired drug resistance, bacterial conversion after 2 months of treatment or adverse drug reactions with FDC or separate drug formulations. There was a trend toward higher risk of failure or relapse with FDC (pooled relative risk 1.28 (95% CI 0.99-1.7)). Based on individual study results, only one of two trials that assessed treatment satisfaction, and none of five that assessed patient adherence, favoured FDCs. Although FDC formulations simplify TB therapy, the current evidence does not indicate that these formulations improve treatment outcomes among patients with active TB.

Background: To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients., Methods: This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART)., Results: A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported., Conclusions: Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.

Unlabelled: Medicaton used to treat tuberculosis is responsible for numerous side effects that have a major impact on patient's health, with a negative influence on the quality of life. Patients of all ages must be trained in order to recognize all the adverse effects and the undesirable reactions produced by antituberculosis medication. We report the case of a 24-year-old woman with generalized psoriasis and psoriatic arthropathy who was treated against tuberculosis. After 7 days of treatment with isoniazid, rifampicin, ethambutol and pyrazinamid she had severe allergic reaction with generalized pruritus and rash which were difficult to control with antiallergic treatment., Conclusions: Particular to this case is the absence in patient's history of the allergic reactions to medication. The re-establishment of treatment of tuberculosis was done by clinical trials and the patient had responded to only three drugs: isoniazid, rifampicin and ofloxacin, so the patient received an individual treatment due to adverse reactions to tuberculosis medications.

The outcomes of directly observed therapy of tuberculosis (DOT) between 1/1/1979 and 12/31/2009 were analyzed. Results obtained in the 1979-1999 period were compared with those achieved in the 2000-2009 period. In a Buenos Aires City hospital, 582 HIV negative TB patients received rifampin, isoniazid, pyrazinamide and ethambutol or streptomycin in the initial stage, followed by a second stage where patients were included in two groups: G1 composed by 424 patients (period 1/1/1979-12/31/1999) who received either rifampin and isoniazid or rifampin and streptomicin twice a week, and G2, with 158 patients (period 1/1/2000-12/31/2009) who received either rifampin and isoniazid twice or three times a week. National and Buenos Aires City TB Control Programs recommendations were followed. Patients who underwent DOT had higher completeness rates than those included in self-administered therapy (82.8% vs. 48.7%), (p <0.0001). Mean age: 36.3 ± 15.3 years, males: 63.1% and 69.4% were Argentine citizens. A 8.9% had been previously treated, 6.1% had co-morbidities. A 70.6% of pulmonary cases was bacteriologically confirmed, 82.8% of them completed the treatment, while 11.5% defaulted. Adverse effects to antituberculosis drugs were observed in 9.5% of cases; male patients showed higher rates of non adherence. G2 had a lower proportion of native people (48.7% vs. 77.1%), (p = 0.0001), higher frequency of co-morbidities (10.7% vs. 4.4%), (p = 0.005), of bacteriologically confirmed pulmonary cases (95% vs. 87%), (p = 0.02) and more adverse effects than G1 (17% vs. 6.6%), (p = 0.0001). In coincidence with other experiences, this work shows high treatment success rates in patients treated under DOT strategy.

A case of isoniazid induced gynecomastia is being reported in an 18-year old male, who received a re-treatment regimen for the relapse of pulmonary tuberculosis (TB). At the end of two months of the treatment, the patient developed a painless unilateral gynecomastia, which completely disappeared after a month of the cessation of isoniazid. A review of literature on isoniazid induced gynecomastia is discussed.

Objective: To describe the outcomes of retreatment in tuberculosis patients receiving the regimen known, in Brazil, as regimen 3 (streptomycin, ethambutol, ethionamide, and pyrazinamide for 3 months + ethambutol and ethionamide for 9 months) after treatment failure with the basic regimen (rifampin, isoniazid, and pyrazinamide for 2 months + rifampin and isoniazid for 4 months)., Methods: A descriptive, uncontrolled, historical cohort study involving adult tuberculosis patients treated with regimen 3. We evaluated adverse drug effects, recurrence, treatment outcomes, and associated factors., Results: The study included 229 patients. The overall cure rate was 62%. For the patients who used the medications regularly and those who did not, the cure rate was 88% and 31%, respectively. Adverse events occurred in 95 patients (41.5%), and most of those events were related to the gastrointestinal tract. In the five-year follow-up period, relapse occurred in 17 cases (12.0%)., Conclusions: Overall, the outcomes of treatment with regimen 3 were unsatisfactory, in part because this regimen was administered to a selected population of patients at high risk for noncompliance with treatment, as well as because it presents high rates of adverse effects, especially those related to the gastrointestinal tract, which might be caused by ethionamide. However, for those who took the medications regularly, the cure rate was satisfactory. The recurrence rate was higher than that recommended in international consensus guidelines, which might be attributable to the short (12-month) treatment period. We believe that regimen 3, extended to 18 months, represents an option for patients with proven treatment compliance.

Background & Objectives: In the Revised National Tuberculosis Control Programme (RNTCP) in India prior to 2005, TB patients were offered standard DOTS regimens without knowledge of HIV status. Consequently such patients did not receive anti-retroviral therapy (ART) and the influence of concomitant HIV infection on the outcome of anti-tuberculosis treatment remained undetermined. This study was conducted to determine the results of treatment of HIV seropositive pulmonary tuberculosis patients with the RNTCP (DOTS) regimens under the programme in comparison with HIV negative patients prior to the availability of free ART in India., Methods: Between September 2000 and July 2006, 283 newly diagnosed pulmonary TB patients were enrolled in the study at the TB Outpatient Department at the Talera Hospital in the Pimpri Chinchwad Municipal Corporation area at Pune (Maharashtra): they included 121 HIV seropositive and 162 HIV seronegative patients. They were treated for tuberculosis as per the RNTCP in India. This study was predominantly conducted in the period before the free ART become available in Pune., Results: At the end of 6 months of anti-TB treatment, 62 per cent of the HIV seropositive and 92 per cent of the HIV negative smear negative patients completed treatment and were asymptomatic; among smear positive patients, 70 per cent of the HIV-seropositive and 81 per cent of HIV seronegative pulmonary TB patients were cured. Considering the results in the smear positive and smear negative cases together, treatment success rates were substantially lower in HIV positive patients than in HIV negative patients, (66% vs 85%). Further, 29 per cent of HIV seropositive and 1 per cent of the HIV seronegative patients expired during treatment. During the entire period of 30 months, including 6 months of treatment and 24 months of follow up, 61 (51%) of 121 HIV positive patients died; correspondingly there were 6 (4%) deaths among HIV negative patients., Interpretation & Conclusions: The HIV seropositive TB patients responded poorly to the RNTCP regimens as evidenced by lower success rates with chemotherapy and high mortality rates during treatment and follow up. There is a need to streamline the identification and management of HIV associated TB patients in the programme with provision of ART to achieve high cure rates for TB, reducing mortality rates and ensuring a better quality of life.

Context: Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance., Objective: To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis., Design, Setting, and Patients: The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis., Interventions: Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n = 798 patients) or separately (n = 787) in the 8-week intensive phase of treatment., Main Outcome Measure: Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%., Results: In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups., Conclusions: Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations., Trial Registration: clinicaltrials.gov Identifier: NCT00216333.

Method: We prospectively studied patients with pulmonary TB, with or without HIV-1 co-infection, from December 1, 2007 to December 1, 2008. Two groups of patients naive for TB and antiretroviral treatment (group A: 96 co-infected TB/HIV and group B: 171 TB infected but HIV negative) were selected randomly. The CD4 count was assessed according to HIV status, and all patients received RHEZ TB treatment for 2 months. Pulmonary smear was assessed at two weeks, four weeks, six weeks, and eight weeks., Result: Two hundred and sixty seven patients were treated (26.6% of admissions). The mean age was 34.62 ± 11 years and the sex ratio was 1.3. A proportion of 35.75% patients were HIV co-infected with a median CD4 count at 157 cells per millimeter cube. The sputum smear conversion was obtained for more than 87.5% of patients in group A and 24.56% in group B at two weeks; 94% of patients in group A and 61.83% in group B at four weeks; 100% of patients in group A and 87.33% in group B at six weeks, and 100% of patients in group A and 96.77% in group B at eight weeks. P<0.05 at six weeks., Conclusion: HIV infected TB patients were more susceptible to treatment than TB/HIV infected patients in the first six weeks., (Copyright © 2011. Published by Elsevier SAS.)

Therapeutic drug monitoring may be useful in tuberculosis management, but programmatic implementation is understudied. We performed a retrospective cohort study to determine prevalence of lower than expected levels of isoniazid, rifampin, ethambutol, and pyrazinamide measured at time of estimated peak serum concentration. Patients were tested for serum concentration at 2 hours after medication administration. When patients were tested, 22 had concentrations lower than expected range for rifampin, 23 of 39 patients had low levels of isoniazid, and 8 of 26 patients had low levels of ethambutol; all 20 patients tested for pyrazinamide were within expected range. Over 26 months, 42 patients met criteria for slow response. Diabetes was associated with slow response (p<0.001), and persons with diabetes were more likely than persons without diabetes to have low rifampin levels (p = 0.03). Dosage adjustment of rifampin was more likely to elevate serum concentration to the target range than adjustment of isoniazid given in daily doses (p = 0.01).

A retrospective study was carried out from January 2000 to December 2003 to assess the resistance of Mycobacterium tuberculosis to antituberculosis drugs and the impact of this on the treatment result. Two hundred and two patients' files were studied (average age: 36 years; sex-ratio: 1.7). Pulmonary localisation (85.7%) or extrapulmonary localisation (14.3%). HIV status is negative (71.3%), positive (10.8%) or unknown (17.9%). The overall recovery rate is 60.7% (61.4% in HIV-; 46.1% in HIV+), the rate of treatment failure is 2.7% (1.1% in HIV-; 15.4% in HIV+), the death rate due to tuberculosis is 6.3% (2.3% in HIV-; 23.1% in HIV+), and the rate of patients who disappeared from the system is 30.3% (35.2% in HIV-; 14.2% in HIV+). Hepatotoxicity that occurred during treatment is observed in 14.3% of cases (recovery: 56.2%; failure: 6.2%; lost from the system: 18.8%). Eighty-four percent of patients never received antituberculosis treatment (group A) versus 15.8% of patients who had already received one or more antituberculosis drugs (group B). The rates of resistance to isoniazid are 6.4% (A) and 12.5% (B), to rifampicin 1.7% (A) and 12.5% (B), to ethambutol 0.5% (A) and 0% (B), to streptomycin 24.1% (A) and 46.8% (B). The percentage of multiresistant strains is 1% in patients not treated previously and 11% in those who had already received antituberculosis treatment. When the patients are carriers of a strain that is responsive to the treatment administered, the recovery rate is 64.2% versus 46.7% in patients whose strain is resistant to at least one of the treatments administered., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Three chemotherapy regimens (Group 1: 2HRZ/4HR, n = 31; Group 2: 2HRZ/4HZ, n = 33; Group 3: 6HR, n = 33) were comparatively assessed in children with minor forms of intrathoracic tuberculosis diagnosed by the computed tomography (CT). The leading criteria for therapeutic effectiveness were regression of intoxication symptoms and changes in the CT pattern. The results of treatment were equal in all the groups. With the 6HR regimen, varying unavoidable adverse reactions were 4.3-fold less frequently (3.0 ± 3.0% and 12.5 ± 4.1%, respectively; p = 0.25). CT pattern changes by months 2-3 and 6 of therapy were compared. Single control CT investigation by 6 months of therapy was optimal. Additional CT study at 2-3 months of therapy reflected positive changes in most cases, but failed to affect treatment policy.

Children who undergo treatment for malignancies are at high for infection with both typical and opportunistic pathogens. Fever in these children prompts extensive evaluation and empiric treatment with broad-spectrum antimicrobials. In the United States (US), tuberculosis is an infrequently reported cause of fever in the pediatric cancer patient and has not been well described. In this report we describe a case of primary pulmonary tuberculosis (TB) in a boy with precursor B-cell acute lymphoblastic leukemia (ALL) and review the pertinent literature., ((c) 2009 Wiley-Liss, Inc.)

Rationale: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients., Objectives: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months., Methods: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment., Measurements and Main Results: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10)., Conclusion: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Background: Rifampicin (RMP) is an essential drug in paediatric anti-tuberculosis treatment. The current World Health Organization (WHO) guidelines recommend an oral dosage of 10 (8-12) mg per kg body weight., Objective: To present a study investigating RMP serum levels in children after oral medication of RMP alone and after combination treatment with ethambutol (EMB)., Design: RMP serum levels in children of different age groups were determined after a single oral administration of 10 mg/kg RMP alone as well as after combination with 35 mg/kg EMB., Results: RMP serum levels were lower than those expected in adults receiving a similar oral dose. RMP serum levels in combination treatment were even lower than in monotherapy., Conclusion: Currently recommended RMP dosages in childhood tuberculosis lead to serum levels lower than those recommended for adults, probably due to different pharmacokinetics and pharmacodynamics in children. In children, it appears to be more valid to calculate RMP dosage on the basis of body surface area rather than body weight, leading to higher dosages especially in younger children.

Objective: To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB)., Design: This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations., Results: Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups., Conclusion: The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

The use of endoscopic ultrasound in staging non-small cell lung cancer is well known. Its role in diagnosing non-malignant conditions that cause mediastinal adenopathy is still not well established. We diagnosed Coccidioides immitis and Mycobacterium tuberculosis in two patients using endoscopic ultrasound. To our knowledge this is the first case of Coccidioidomycosis to be diagnosed by endoscopic ultrasound.

The drug resistance profile of 100 Mycobacterium tuberculosis isolates from pulmonary tuberculosis (PTB) cases in Jos, Nigeria, was investigated between August 2006 and September 2007. Drug susceptibility testing for 50 new, 11 follow-up and 39 unclassified cases of PTB was performed on Löwenstein-Jensen medium by the proportion method, using isoniazid (0.2 microg/ml), rifampicin (40 microg/ml), ethambutol (2 microg/ml) and streptomycin (4 microg/ml). Susceptibility to all four drugs was found in 76, 62 and 55%, and multidrug resistance (combined resistance to isoniazid and rifampicin with or without resistance to any other drug) in 4, 31 and 18% of the new, unclassified and follow-up cases, respectively. Monoresistance was found in 15% of the cases. Nine of the 16 isolates (56%) showing multidrug resistance were resistant to all four drugs. These findings are critical and the risk to public health is high, particularly with an overall multidrug resistance of 16%. We suggest that TB management and control programs in Jos are revised to enhance patient's accessibility to treatment sites, promote patients' adherence to drugs, improve diagnostic practices, regularly assess drug resistance profiles, and undertake contact tracing for patients with multidrug-resistant TB.

The efficiency of treatment was analyzed in 142 children aged 3-14 years who had local forms of primary pulmonary tuberculosis. Therapy was performed according to regimens 3 and 1, by using individual dosage regimens depending on the extent and severity of a specific process, the presence of complications, and age-related features. In minor tuberculosis, solitary calcifications being detected without signs of the activity of tuberculous infection, the basic course of therapy was 6-8 months; it was performed using 2 drugs in individual cases. In disseminated and complicated processes, eliminated intoxication and visible X-ray inflammatory changes were observed in 58.8-61.7% of children by months 3-4 of treatment, which required a longer intensive phase, by administering 3 drugs in the continuation phase till 6-9 months.

A hundred and forty children aged 13 to 17 who had new-onset active pulmonary tuberculosis were examined. There was a predominance of infiltrative tuberculosis (63.6%) in the pattern of its clinical forms. The processes were more frequently disseminated (79.3%) with lung tissue decay in every two patients (55.1%) and bacterial discharge in every three patients (39.3%). Among the new cases of pulmonary tuberculosis, the proportion of its multidrug resistance was 7.9%. The routine regimens were used for treatment. The efficiency of intensive-phase (IF) treatment was evaluated in 85 patients, including 18 patients receiving chemotherapy (CT) (HRZ/E/S) regimen 3 (Group 1), 45 having CT (HRZ/E/S) regimen 1 (Group 2), and 22 having CT (HRZE[A][Fq]/[Pt]) regimen 2B (Group 3). Clinical laboratory, Xray, and microbiological findings were criteria for evaluating the efficiency of IP CT. Abacillation occurred in all cases by month 4 of therapy. By and large, the efficiency of IF CT was 90.6% in new cases of pulmonary tuberculosis among old-age children and adolescents. In patients with disseminated processes, it ranged from 81.8% (Group 3) to 91.1% (Group 2) depending on the extent of lung tissue damage. The efficiency of therapy was as high as 100% in patients with circumscribed processes. Polyresistant resistance of Mycobacterium tuberculosis (MBT) to chemical agents, including multidrug resistance (7.9%), was a main reason of ineffective IF treatment (9.4%) in new cases of pulmonary tuberculosis among old-age children and adolescents. Overall, the actual use rate of routine CT regimens was 65.9% in new cases of pulmonary tuberculosis and adolescents. Uncontrolled adverse reactions to antituberculous drugs and drug resistance in MBT were reasons for deviations of routine regimens (modifications, use of individual regimes).

Objective: We performed a long-term retrospective investigation of pulmonary Mycobacterium avium complex (MAC) disease treated with combined chemotherapy following the ATS guideline or the Japanese Society for Tuberculosis guideline. We also studied when to terminate the combined chemotherapy., Materials and Methods: The subjects of this study consisted of 90 patients who underwent combined chemotherapy according to these guidelines for minimum one-year period and followed up for at least one year since April, 1998., Results: The mean patients' age was 64.8 years old and the gender distribution consisted of 34 males and 56 females. While the sputum negative conversion was observed in 54 of 90 patients (60%), clinical improvement was recognized in 35 patients (39%) following combined chemotherapy administered according to the guidelines. Out of 54 patients with sputum conversion, 30 cases were followed up after the discontinuation of treatment, and sputum relapse later was seen in 18 patients. Out of 24 patients who continued the same treatment, sputum relapse was seen in 10 patients. Out of 35 patients with clinical improvement, 17 cases have been followed up after the discontinuation of treatment, clinical worsening was later recognized in 9 patients. Out of 18 patients who continued the same treatment, clinical worsening was recognized in 6 patients., Conclusions: As the probability of sputum relapse after discontinuation of treatment was high even among patients whose sputum converted to negative by combined treatment according to the guidelines, we think that it is better to continue treatment according to the guidelines as long as possible.