Browsing by Subject "Antitubercular Agents"
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Item Open Access A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis.(Nature communications, 2022-08) Kim, Manse; Johnson, Claire E; Schmalstig, Alan A; Annis, Ayano; Wessel, Sarah E; Van Horn, Brian; Schauer, Amanda; Exner, Agata A; Stout, Jason E; Wahl, Angela; Braunstein, Miriam; Victor Garcia, J; Kovarova, MartinaTuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.Item Open Access A randomized controlled trial of standard versus intensified tuberculosis diagnostics on treatment decisions by physicians in Northern Tanzania.(BMC Infect Dis, 2014-02-20) Reddy, Elizabeth A; Njau, Boniface N; Morpeth, Susan C; Lancaster, Kathryn E; Tribble, Alison C; Maro, Venance P; Msuya, Levina J; Morrissey, Anne B; Kibiki, Gibson S; Thielman, Nathan M; Cunningham, Coleen K; Schimana, Werner; Shao, John F; Chow, Shein-Chung; Stout, Jason E; Crump, John A; Bartlett, John A; Hamilton, Carol DBACKGROUND: Routine tuberculosis culture remains unavailable in many high-burden areas, including Tanzania. This study sought to determine the impact of providing mycobacterial culture results over standard of care [unconcentrated acid-fast (AFB) smears] on management of persons with suspected tuberculosis. METHODS: Adults and children with suspected tuberculosis were randomized to standard (direct AFB smear only) or intensified (concentrated AFB smear and tuberculosis culture) diagnostics and followed for 8 weeks. The primary endpoint was appropriate treatment (i.e. antituberculosis therapy for those with tuberculosis, no antituberculous therapy for those without tuberculosis). RESULTS: Seventy participants were randomized to standard (n = 37, 53%) or intensive (n = 33, 47%) diagnostics. At 8 weeks, 100% (n = 22) of participants in follow up randomized to intensive diagnostics were receiving appropriate care, vs. 22 (88%) of 25 participants randomized to standard diagnostics (p = 0.14). Overall, 18 (26%) participants died; antituberculosis therapy was associated with lower mortality (9% who received antiuberculosis treatment died vs. 26% who did not, p = 0.04). CONCLUSIONS: Under field conditions in a high burden setting, the impact of intensified diagnostics was blunted by high early mortality. Enhanced availability of rapid diagnostics must be linked to earlier access to care for outcomes to improve.Item Open Access Are tuberculosis patients adherent to prescribed treatments in China? Results of a prospective cohort study.(Infect Dis Poverty, 2016-05-05) Lei, Xun; Huang, Ke; Liu, Qin; Jie, Yong-Feng; Tang, Sheng-LanBACKGROUND: Tuberculosis (TB) patients face numerous difficulties adhering to the long-term, rigorous TB treatment regimen. Findings on TB patients' treatment adherence vary across existing literature and official reports. The present study attempted to determine the actual treatment adherence of new TB patients and to identify factors leading to non-adherence. METHODS: A prospective cohort of 481 newly confirmed TB patients from three counties in western China were enrolled during June to December 2012 and was followed until June 2013. Patients who missed at least one dose of drugs or one follow-up re-examination during the treatment course were deemed as non-adherent. Influencing factors were identified using a logistic regression model. RESULTS: A total of 173 (36.0 %) patients experienced non-adherence and the loss to follow-up cases reached 136 (28.2 %). Only 13.9 % of patients took drugs under direct observation, and 60.5 % of patients were supervised by phone calls. Factor analyses suggested that patients who were observed by family members (OR:5.54, 95 % CI:2.87-10.69) and paying monthly service expenses above 450 RMB (OR:2.08, 95 % CI:1.35-3.19) were more likely to be non-adherent, while supervision by home visit (OR:0.06, 95 % CI:0.01-0.28) and phone calls (OR:0.27, 95 % CI:0.17-0.44) were protective factors. CONCLUSIONS: Despite recent efforts, a large proportion of newly confirmed TB patients could not adhere to standard TB treatment, and patients' lost to follow-up was still a serious problem. Poor treatment supervision and heavy financial burden might be the main causes for non-adherence. More needs to be done to enhance treatment supervision policies and financial supports to both health providers and TB patients.Item Open Access Bacteremic disseminated tuberculosis in sub-saharan Africa: a prospective cohort study.(Clin Infect Dis, 2012-07) Crump, John A; Ramadhani, Habib O; Morrissey, Anne B; Saganda, Wilbrod; Mwako, Mtumwa S; Yang, Lan-Yan; Chow, Shein-Chung; Njau, Boniface N; Mushi, Godfrey S; Maro, Venance P; Reller, L Barth; Bartlett, John ABACKGROUND: Disseminated tuberculosis is a major health problem in countries where generalized human immunodeficiency virus (HIV) infection epidemics coincide with high tuberculosis incidence rates; data are limited on patient outcomes beyond the inpatient period. METHODS: We enrolled consecutive eligible febrile inpatients in Moshi, Tanzania, from 10 March 2006 through 28 August 2010; those with Mycobacterium tuberculosis bacteremia were followed up monthly for 12 months. Survival, predictors of bacteremic disseminated tuberculosis, and predictors of death were assessed. Antiretroviral therapy (ART) and tuberculosis treatment were provided. RESULTS: A total of 508 participants were enrolled; 29 (5.7%) had M. tuberculosis isolated by blood culture. The median age of all study participants was 37.4 years (range, 13.6-104.8 years). Cough lasting >1 month (odds ratio [OR], 13.5; P< .001), fever lasting >1 month (OR, 7.8; P = .001), weight loss of >10% (OR, 10.0; P = .001), lymphadenopathy (OR 6.8; P = .002), HIV infection (OR, undefined; P < .001), and lower CD4 cell count and total lymphocyte count were associated with bacteremic disseminated tuberculosis. Fifty percent of participants with M. tuberculosis bacteremia died within 36 days of enrollment. Lower CD4 cell count (OR, 0.88; P = .049) and lower total lymphocyte count (OR, 0.76; P = .050) were associated with death. Magnitude of mycobacteremia tended to be higher among those with lower CD4 cell counts, but did not predict death. CONCLUSIONS: In the era of free ART and access to tuberculosis treatment, almost one half of patients with M. tuberculosis bacteremia may die within a month of hospitalization. Simple clinical assessments can help to identify those with the condition. Advanced immunosuppression predicts death. Efforts should focus on early diagnosis and treatment of HIV infection, tuberculosis, and disseminated disease.Item Open Access Exogenous reinfection of tuberculosis in a low-burden area.(Infection, 2015-12) Schiroli, Consuelo; Carugati, Manuela; Zanini, Fabio; Bandera, Alessandra; Bandera, Alessandra; Di Nardo Stuppino, Silvia; Monge, Elisa; Morosi, Manuela; Gori, Andrea; Matteelli, Alberto; Codecasa, Luigi; Franzetti, FabioPurpose
Recurrence of tuberculosis (TB) can be the consequence of relapse or exogenous reinfection. The study aimed to assess the factors associated with exogenous TB reinfection.Methods
Prospective cohort study based on the TB database, maintained at the Division of Infectious Diseases, Luigi Sacco Hospital (Milan, Italy). Time period: 1995-2010.Inclusion criteria
(1) ≥2 episodes of culture-confirmed TB; (2) cure of the first episode of TB; (3) availability of one Mycobacterium tuberculosis isolate for each episode. Genotyping of the M. tuberculosis strains to differentiate relapse and exogenous reinfection. Logistic regression analysis was used to assess the influence of risk factors on exogenous reinfections.Result
Of the 4682 patients with TB, 83 were included. Of these, exogenous reinfection was diagnosed in 19 (23 %). It was independently associated with absence of multidrug resistance at the first episode [0, 10 (0.01-0.95), p = 0.045] and with prolonged interval between the first TB episode and its recurrence [7.38 (1.92-28.32) p = 0.004]. However, TB relapses occurred until 4 years after the first episode. The risk associated with being foreign born, extrapulmonary site of TB, and HIV infection was not statistically significant. In the relapse and re-infection cohort, one-third of the patients showed a worsened drug resistance profile during the recurrent TB episode.Conclusions
Exogenous TB reinfections have been documented in low endemic areas, such as Italy. A causal association with HIV infection could not be confirmed. Relapses and exogenous reinfections shared an augmented risk of multidrug resistance development, frequently requiring the use of second-line anti-TB regimens.Item Open Access Impact of Community-Based DOT on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis.(PLoS One, 2016) Zhang, HaiYang; Ehiri, John; Yang, Huan; Tang, Shenglan; Li, YingBACKGROUND: Poor adherence to tuberculosis (TB) treatment can lead to prolonged infectivity and poor treatment outcomes. Directly observed treatment (DOT) seeks to improve adherence to TB treatment by observing patients while they take their anti-TB medication. Although community-based DOT (CB-DOT) programs have been widely studied and promoted, their effectiveness has been inconsistent. The aim of this study was to critical appraise and summarize evidence of the effects of CB-DOT on TB treatment outcomes. METHODS: Studies published up to the end of February 2015 were identified from three major international literature databases: Medline/PubMed, EBSCO, and EMBASE. Unpublished data from the grey literature were identified through Google and Google Scholar searches. RESULTS: Seventeen studies involving 12,839 pulmonary TB patients (PTB) in eight randomized controlled trials (RCTs) and nine cohort studies from 12 countries met the criteria for inclusion in this review and 14 studies were included in meta-analysis. Compared with clinic-based DOT, pooled results of RCTs for all PTB cases (including smear-negative or -positive, new or retreated TB cases) and smear-positive PTB cases indicated that CB-DOT promoted successful treatment [pooled RRs (95%CIs): 1.11 (1.02-1.19) for all PTB cases and 1.11 (1.02-1.19) for smear-positive PTB cases], and completed treatment [pooled RRs (95%CIs): 1.74(1.05, 2.90) for all PTB cases and 2.22(1.16, 4.23) for smear-positive PTB cases], reduced death [pooled RRs (95%CIs): 0.44 (0.26-0.72) for all PTB cases and 0.39 (0.23-0.66) for smear-positive PTB cases], and transfer out [pooled RRs (95%CIs): 0.37 (0.23-0.61) for all PTB cases and 0.42 (0.25-0.70) for smear-positive PTB cases]. Pooled results of all studies (RCTs and cohort studies) with all PTB cases demonstrated that CB-DOT promoted successful treatment [pooled RR (95%CI): 1.13 (1.03-1.24)] and curative treatment [pooled RR (95%CI): 1.24 (1.04-1.48)] compared with self-administered treatment. CONCLUSIONS: CB-DOT did improved TB treatment outcomes according to the pooled results of included studies in this review. Studies on strategies for implementation of patient-centered and community-centered CB-DOT deserve further attention.Item Open Access Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection.(PLoS One, 2011) Holland, David P; Sanders, Gillian D; Hamilton, Carol D; Stout, Jason ERATIONALE: Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability. OBJECTIVES: To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI). METHODS: We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms. RESULTS: Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen. CONCLUSIONS: Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries.Item Open Access Reply to Swindells et al.: Trials of Tuberculosis-Preventive Therapy in People with HIV Infection.(American journal of respiratory and critical care medicine, 2020-07) Stout, Jason E; Turner, Nicholas A; Belknap, Robert W; Horsburgh, C Robert; Sterling, Timothy R; Phillips, Patrick PJItem Open Access Strategies for treating latent multiple-drug resistant tuberculosis: a decision analysis.(PLoS One, 2012) Holland, David P; Sanders, Gillian D; Hamilton, Carol D; Stout, Jason EBACKGROUND: The optimal treatment for latent multiple-drug resistant tuberculosis infection remains unclear. In anticipation of future clinical trials, we modeled the expected performance of six potential regimens for treatment of latent multiple-drug resistant tuberculosis. METHODS: A computerized Markov model to analyze the total cost of treatment for six different regimens: Pyrazinamide/ethambutol, moxifloxacin monotherapy, moxifloxacin/pyrazinamide, moxifloxacin/ethambutol, moxifloxacin/ethionamide, and moxifloxacin/PA-824. Efficacy estimates were extrapolated from mouse models and examined over a wide range of assumptions. RESULTS: In the base-case, moxifloxacin monotherapy was the lowest cost strategy, but moxifloxacin/ethambutol was cost-effective at an incremental cost-effectiveness ratio of $21,252 per quality-adjusted life-year. Both pyrazinamide-containing regimens were dominated due to their toxicity. A hypothetical regimen of low toxicity and even modest efficacy was cost-effective compared to "no treatment." CONCLUSION: In our model, moxifloxacin/ethambutol was the preferred treatment strategy under a wide range of assumptions; pyrazinamide-containing regimens fared poorly because of high rates of toxicity. Although more data are needed on efficacy of treatments for latent MDR-TB infection, data on toxicity and treatment discontinuation, which are easier to obtain, could have a substantial impact on public health practice.