Browsing by Author "Mitnick, Carole D."

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    Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes : an individual patient data meta-analysis of 9,153 patients
    (Public Library of Science, 2012-08-28) Ahuja, Shama D.; Ashkin, David; Avendano, Monika; Banerjee, Rita; Bauer, Melissa; Bayona, Jamie N.; Becerra, Mercedes C.; Benedetti, Andrea; Burgos, Marcos; Centis, Rosella; Chan, Eward D.; Chiang, Chen-Yuan; Cox, Helen; D'Ambrosio, Lia; DeRiemer, Kathy; Dung, Nguyen Huy; Enarson, Donald; Falzon, Dennis; Flanagan, Katherine; Flood, Jennifer; Garcia-Garcia, Maria L.; Ghandi, Neel; Granich, Reuben M.; Hollm-Delgado, Maria G.; Holtz, Timothy H.; Iseman, Michael D.; Jarlsberg, Leah G.; Keshavjee, Salmaan; Kim, Hye-Ryoun; Koh, Won-Jung; Lancaster, Joey; Lange,Christophe; Lange, Wiel C. M. de; Leimane, Vaira; Leung, Chi Chiu; Li, Jiehui; Menzies, Dick; Migliori, Giovanni B.; Mishustin, Sergey P.; Mitnick, Carole D.; Narita, Masa; O'Riordan, Philly; Pai, Madhukar; Palmero, Domingo; Park, Seung-kyu; Pasvol, Geoffrey; Pena, Jose; Perez-Guzman, Carlos; Quelapio, Maria I. D.; Ponce-De-Leon, Alfredo; Riekstina, Vija; Robert, Jerome; Royce, Sarah; Schaaf, H. Simon; Seung, Kwonjune J.; Shah, Lena; Shim, Tae Sun; Shin, Sonya S.; Shiraishi, Yuji; Sifuentes-Osornio, Jose; Sotgiu, Giovanni; Strand, Matthew J.; Tabarsi, Payam; Tupasi, Thelma E.; Altena, Robert van; Van der Walt, Martie; Werf, Tjip S. van der; Vargas, Mario H.; Viiklepp, Pirett; Westenhouse, Janice; Yew, Wing Wai; Yim, Jae-Joon
    Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and Findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]). Conclusions: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
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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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    Propensity score-based approaches to confounding by indication in individual patient data meta-analysis: non-standardized treatment for multidrug resistant tuberculosis
    (Public Library of Science, 2016) Fox, Gregory J.; Benedetti, Andrea; Mitnick, Carole D.; Pai, Madhukar; Menzies, Dick; The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB
    Background: In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB). Methods: Two antibiotic classes were evaluated, fluoroquinolones—considered the cornerstone of effective MDR-TB treatment—and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches. Results: Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success. Conclusions: In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias.