Browsing by Author "Horsburgh, C. R."

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    Impact of alcohol consumption on tuberculosis treatment outcomes : a prospective longitudinal cohort study protocol
    (BioMed Central, 2018-09-29) Myers, Bronwyn; Bouton, Tara C.; Ragan, Elizabeth J.; White, Laura F.; McIlleron, Helen; Theron, Danie; Parry, Charles D. H.; Horsburgh, C. R.; Warren, Robin M.; Jacobson, Karen R.
    Background: An estimated 10% of tuberculosis (TB) deaths are attributable to problematic alcohol use globally, however the causal pathways through which problem alcohol use has an impact on TB treatment outcome is not clear. This study aims to improve understanding of these mechanisms. Specifically, we aim to 1) assess whether poor TB treatment outcomes, measured as delayed time-to-culture conversion, are associated with problem alcohol use after controlling for non-adherence to TB pharmacotherapy; and 2) to determine whether pharmacokinetic (PK) changes in those with problem alcohol use are associated with delayed culture conversion, higher treatment failure/relapse rates or with increased toxicity. Methods: Our longitudinal, repeated measures, prospective cohort study aims to examine the associations between problem alcohol use and TB treatment outcomes and to evaluate the effect of alcohol on the PK and pharmacodynamics (PD) of TB drugs. We will recruit 438 microbiologically confirmed, pulmonary TB patients with evidence of rifampicin susceptibility in Worcester, South Africa with 200 HIV uninfected patients co-enrolled in the PK aim. Participants are followed for the six months of TB treatment and an additional 12 months thereafter, with sputum collected weekly for the first 12 weeks of treatment, alcohol consumption measures repeated monthly in concert with an alcohol biomarker (phosphatidylethanol) measurement at baseline, and in person directly observed therapy (DOT) using real-time mobile phone-based adherence monitoring. The primary outcome is based on time to culture conversion with the second objective to compare PK of first line TB therapy in those with and without problem alcohol use. Discussion: Globally, an urgent need exists to identify modifiable drivers of poor TB treatment outcomes. There is a critical need for more effective TB treatment strategies for patients with a history of problem alcohol use. However, it is not known whether poor treatment outcomes in alcohol using patients are solely attributable to noncompliance. This study will attempt to answer this question and provide guidance for future TB intervention trials. Trial registration: Clinicaltrials.gov, Registration Number: NCT02840877. Registered on 19 July 2016.
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    The impact of alcohol use on tuberculosis treatment outcomes : a systematic review and meta-analysis
    (International Union Against Tuberculosis and Lung Disease, 2020-01) Ragan, E. J.; Kleinman, M. B.; Sweigart, B.; Gnatienko, N.; Parry, C. D.; Horsburgh, C. R.; LaValley, M. P.; Myers, B.; Jacobson, K. R.
    Alcohol use is associated with increased risk of developing tuberculosis (TB) disease, yet the impact of alcohol use on TB treatment outcomes has not been summarized. We aimed to quantitatively review evidence of the relationship between alcohol use and poor TB treatment outcomes. We conducted a systematic review of PubMed, EMBASE, and Web of Science (January 1980–May 2018). We categorized studies as having a high- or low-quality alcohol use definition and examined poor treatment outcomes individually and as two aggregated definitions (i.e., including or excluding loss to follow-up [LTFU]). We analyzed drug-susceptible (DS-) and multidrug-resistant (MDR-) TB studies separately. Our systematic review yielded 111 studies reporting alcohol use as a predictor of DS- and MDR-TB treatment outcomes. Alcohol use was associated with increased odds of poor treatment outcomes (i.e., death, treatment failure, and LTFU) in DS (OR 1.99, 95% CI 1.57–2.51) and MDR-TB studies (OR 2.00, 95% CI 1.73–2.32). This association persisted for aggregated poor treatment outcomes excluding LTFU, each individual poor outcome, and across sub-group and sensitivity analyses. Only 19% of studies used high-quality alcohol definitions. Alcohol use significantly increased the risk of poor treatment outcomes in both DS- and MDR-TB patients. This study highlights the need for improved assessment of alcohol use in TB outcomes research and potentially modified treatment guidelines for TB patients who consume alcohol.
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    An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens : study protocol for a randomized controlled trial
    (BioMed Central, 2017-11-25) Bouton, Tara C.; Phillips, Patrick P. J.; Mitnick, Carole D.; Peloquin, Charles A.; Eisenach, Kathleen; Patientia, Ramonde F.; Lecca, Leonid; Gotuzzo, Eduardo; Gandhi, Neel R.; Butler, Donna; Diacon, Andreas H.; Martel, Bruno; Santillan, Juan; Hunt, Kathleen R.; Vargas, Dante; Von Groote-Bidlingmaier, Florian; Seas, Carlos; Dianis, Nancy; Moreno-Martinez, Antonio; Horsburgh, C. R.
    Background: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. Methods/design: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient’s Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. Discussion: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens.
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    Pediatric multidrug-resistant tuberculosis clinical trials : challenges and opportunities
    (Elsevier on behalf of International Society for Infectious Diseases, 2017) McAnaw, S. E.; Hesseling, A. C.; Seddon, J. A.; Dooley, K. E.; Garcia-Prats, A. J.; Kim, S.; Jenkins, H. E.; Schaaf, H. Simon; Sterling, T. R.; Horsburgh, C. R.
    On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.