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Takanori Asakura - One of the best experts on this subject based on the ideXlab platform.
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sitafloxacin containing regimen for the treatment of refractory mycobacterium avium complex lung disease
Open Forum Infectious Diseases, 2019Co-Authors: Takanori Asakura, Shoji Suzuki, Hanako Fukano, Satoshi Okamori, Tatsuya Kusumoto, Yoshifumi UwaminoAbstract:Background Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFX-containing regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive Sputum Cultures for >6 months of macrolide-based standard therapy. Results Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative Sputum Culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative Sputum Culture conversion. Conclusions Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.
Mercedes C. Becerra - One of the best experts on this subject based on the ideXlab platform.
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pyrazinamide resistance assays and two month Sputum Culture status in patients with multidrug resistant tuberculosis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Mercedes C. Becerra, Carole D Mitnick, Gustavo E Velasquez, Roger Calderon, Chuanchin HuangAbstract:Phenotypic drug susceptibility testing is the current "gold standard" for detecting Mycobacterium tuberculosis susceptibility to antituberculous drugs. Pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. Here we performed latent class analysis (LCA) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. We then compared this consensus measure to the 2-month Culture results for patients with multidrug-resistant tuberculosis (MDR-TB) who were treated for 2 months with first-line antituberculous drugs before their resistance results were known. Among 121 patients with MDR-TB, 60 (49.6%) were resistant to pyrazinamide by the Wayne method (L. G. Wayne, Am Rev Respir Dis 109:147-151, 1974), 71 (58.7%) were resistant by the Bactec MGIT 960 method, and 68 (56.2%) were resistant by pncA sequencing. LCA grouped isolates with positive results by at least two assays into a category which we considered the "consensus gold standard" for pyrazinamide resistance. The sensitivity and specificity for this consensus gold standard were 82.4% and 92.5%, respectively, for the Wayne method; 95.6% and 88.7%, respectively, for the Bactec MGIT 960 method; and 92.6% and 90.6%, respectively, for pncA sequencing. After we adjusted for other factors associated with poor outcomes, including age, sex, alcohol use, and baseline ethambutol resistance, patients whose isolates were resistant by the LCA-derived consensus gold standard were more likely to be Culture positive at 2 months with an odds ratio of 1.95 (95% confidence interval, 0.74 to 5.11), but this result was not statistically significant. These findings underscore the need for improved diagnostics for routine use in programmatic settings.
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Sputum Culture conversion as a prognostic marker for end of treatment outcome in patients with multidrug resistant tuberculosis a secondary analysis of data from two observational cohort studies
The Lancet Respiratory Medicine, 2015Co-Authors: Ekaterina V Kurbatova, Mercedes C. Becerra, Jaime Bayona, Peter J Cegielski, Christian Lienhardt, Rattanawadee Akksilp, Janice Campos Caoili, Carmen Contreras, Tracy Dalton, Manfred DanilovitsAbstract:Summary Background Sputum Culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of Sputum Culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. Methods We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined Sputum Culture conversion as two or more consecutive negative Cultures from Sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. Findings We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to Sputum Culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1–3] vs 7 months [3 to ≥24]; log-rank p Interpretation Time to Sputum Culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of Sputum Culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. Funding US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
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time to Culture conversion and regimen composition in multidrug resistant tuberculosis treatment
PLOS ONE, 2014Co-Authors: Dylan B Tierney, Cesar Bonilla, Felix Alcantara A Viru, Molly F. Franke, Mercedes C. Becerra, Epifanio SanchezAbstract:Sputum Cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on Culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid Sputum Culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and Sputum Culture conversion. Sputum Culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had Sputum Culture conversion, the median time to conversion was 59 days (IQR: 31–92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with Sputum Culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to Culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs.
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predictors of Sputum Culture conversion among patients treated for multidrug resistant tuberculosis
International Journal of Tuberculosis and Lung Disease, 2012Co-Authors: Ekaterina V Kurbatova, Vaira Leimane, Mercedes C. Becerra, Victoria M Gammino, Jaime Bayona, Manfred Danilovitz, Dennis Falzon, Irina Gelmanova, Salmaan Keshavjee, Carole D MitnickAbstract:Objective To identify predictors of initial Sputum Culture conversion, estimate the usefulness of persistent positive Cultures at different time points in predicting treatment failure, and evaluate different definitions of Culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. Methods Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'Culture conversion' on the balance between sensitivity and specificity. Results Overall, 1209/1416 (85%) of patients with baseline positive Cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of Culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative Cultures. Conclusion Patients with identified risk factors were less likely to achieve Sputum Culture conversion during MDR-TB treatment.
David E Griffith - One of the best experts on this subject based on the ideXlab platform.
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amikacin liposome inhalation suspension for refractory mycobacterium avium complex lung disease sustainability and durability of Culture conversion and safety of long term exposure
Chest, 2021Co-Authors: David E Griffith, Rachel Thomson, Patrick A Flume, Timothy R Aksamit, Stephen K Field, Doreen Addrizzoharris, Kozo Morimoto, Wouter Hoefsloot, Kevin C Mange, Dayton W YuenAbstract:Background In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased Culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P Research Question In patients who achieved Culture conversion by month 6 in the CONVERT study, was conversion sustained (negative Sputum Culture results for 12 months with treatment) and durable (negative Sputum Culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Study Design and Methods Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving Culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. Results More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P Interpretation In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. Trial Registry ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov
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semiquantitative Culture analysis during therapy for mycobacterium avium complex lung disease
American Journal of Respiratory and Critical Care Medicine, 2015Co-Authors: David E Griffith, Kenneth N Olivier, Jennifer Adjemian, Barbara A Brownelliott, Julie V Philley, Rebecca D Prevots, Christopher Gaston, Richard J WallaceAbstract:Rationale: Microbiologically based criteria such as Sputum Culture conversion to negative have traditionally been used to define treatment success for mycobacterial diseases. There are, however, limited data regarding whether nontuberculous mycobacterial Sputum Culture conversion or semiquantitative Culture analysis correlates with subjective or nonmicrobiologic objective indices of treatment response.Objectives: To determine whether a semiquantitative mycobacterial Culture scale correlated with clinical disease status and was predictive of long-term Sputum mycobacterial Culture conversion to negative in a cohort of patients with nodular/bronchiectatic Mycobacterium avium complex lung disease undergoing therapy.Methods: One hundred and eighty patients undergoing standard macrolide-based therapy for M. avium complex lung disease were monitored at standard frequent intervals with symptomatic, radiographic, and microbiologic data collected, including semiquantitative mycobacterial Culture analysis. Analyses ...
Richard J Wallace - One of the best experts on this subject based on the ideXlab platform.
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semiquantitative Culture analysis during therapy for mycobacterium avium complex lung disease
American Journal of Respiratory and Critical Care Medicine, 2015Co-Authors: David E Griffith, Kenneth N Olivier, Jennifer Adjemian, Barbara A Brownelliott, Julie V Philley, Rebecca D Prevots, Christopher Gaston, Richard J WallaceAbstract:Rationale: Microbiologically based criteria such as Sputum Culture conversion to negative have traditionally been used to define treatment success for mycobacterial diseases. There are, however, limited data regarding whether nontuberculous mycobacterial Sputum Culture conversion or semiquantitative Culture analysis correlates with subjective or nonmicrobiologic objective indices of treatment response.Objectives: To determine whether a semiquantitative mycobacterial Culture scale correlated with clinical disease status and was predictive of long-term Sputum mycobacterial Culture conversion to negative in a cohort of patients with nodular/bronchiectatic Mycobacterium avium complex lung disease undergoing therapy.Methods: One hundred and eighty patients undergoing standard macrolide-based therapy for M. avium complex lung disease were monitored at standard frequent intervals with symptomatic, radiographic, and microbiologic data collected, including semiquantitative mycobacterial Culture analysis. Analyses ...
Ekaterina V Kurbatova - One of the best experts on this subject based on the ideXlab platform.
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isoniazid and rifampin resistance mutations associated with resistance to second line drugs and with Sputum Culture conversion
The Journal of Infectious Diseases, 2020Co-Authors: Eleanor S Click, Ekaterina V Kurbatova, Tracy Dalton, Heather Alexander, Michael P Chen, James E Posey, Julia Ershova, Peter J CegielskiAbstract:BACKGROUND Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics. METHODS In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in Sputum isolates using the Hain MTBDRplus line probe assay. For specific mutations, we performed bivariate analysis to determine relative risk of baseline or acquired resistance to other TB drugs. We compared time to Sputum Culture conversion (TSCC) using Kaplan-Meier curves and stratified Cox regression. RESULTS In total, 447 participants enrolled from January 2005 to December 2008 from 7 countries were included. Relative to rpoB S531L, isolates with rpoB D516V had less cross-resistance to rifabutin, increased baseline resistance to other drugs, and increased acquired fluoroquinolone resistance. Relative to mutation of katG only, mutation of inhA promoter and katG was associated with baseline extensively drug resistant (XDR) TB, increased acquired fluoroquinolone resistance, and slower TSCC (125.5 vs 89.0 days). CONCLUSIONS Specific mutations in inhA and katG are associated with differences in resistance to other drugs and TSCC. Molecular testing may make it possible to tailor treatment and assess additional drug resistance risk according to specific mutation profile.
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association between regimen composition and treatment response in patients with multidrug resistant tuberculosis a prospective cohort study
PLOS Medicine, 2015Co-Authors: Courtney M Yuen, Ekaterina V Kurbatova, Jaime Bayona, Janice Campos Caoili, Thelma E Tupasi, Martie Van Der Walt, Charlotte Kvasnovsky, Martin Yagui, Carmen ContrerasAbstract:Background For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to Sputum Culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen. Methods and Findings We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly Sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial Sputum Culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, Sputum smear result, and extent of disease on chest radiograph. In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of Sputum Culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of Sputum Culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen). The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial Sputum Culture conversion, not reversion or long-term relapse. Conclusions MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens.
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Sputum Culture conversion as a prognostic marker for end of treatment outcome in patients with multidrug resistant tuberculosis a secondary analysis of data from two observational cohort studies
The Lancet Respiratory Medicine, 2015Co-Authors: Ekaterina V Kurbatova, Mercedes C. Becerra, Jaime Bayona, Peter J Cegielski, Christian Lienhardt, Rattanawadee Akksilp, Janice Campos Caoili, Carmen Contreras, Tracy Dalton, Manfred DanilovitsAbstract:Summary Background Sputum Culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of Sputum Culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. Methods We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined Sputum Culture conversion as two or more consecutive negative Cultures from Sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. Findings We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to Sputum Culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1–3] vs 7 months [3 to ≥24]; log-rank p Interpretation Time to Sputum Culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of Sputum Culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. Funding US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
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predictors of Sputum Culture conversion among patients treated for multidrug resistant tuberculosis
International Journal of Tuberculosis and Lung Disease, 2012Co-Authors: Ekaterina V Kurbatova, Vaira Leimane, Mercedes C. Becerra, Victoria M Gammino, Jaime Bayona, Manfred Danilovitz, Dennis Falzon, Irina Gelmanova, Salmaan Keshavjee, Carole D MitnickAbstract:Objective To identify predictors of initial Sputum Culture conversion, estimate the usefulness of persistent positive Cultures at different time points in predicting treatment failure, and evaluate different definitions of Culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. Methods Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'Culture conversion' on the balance between sensitivity and specificity. Results Overall, 1209/1416 (85%) of patients with baseline positive Cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of Culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative Cultures. Conclusion Patients with identified risk factors were less likely to achieve Sputum Culture conversion during MDR-TB treatment.