A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis.
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SUBMITTER: Imperial MZ
PROVIDER: S-EPMC6685538 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTreatment 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 findingsThree 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]).ConclusionsIn 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. Please see later in the article for the Editors' Summary.
| S-EPMC3429397 | biostudies-literature
Project description:Background:Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods:Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results:Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions:Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.
| S-EPMC6005123 | biostudies-literature
Project description:BACKGROUND:Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used. METHODS:iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated. RESULTS:The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6?weeks than in those who received anti-TB drugs not containing pyrazinamide. CONCLUSIONS:The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.
| S-EPMC6988333 | biostudies-literature
Project description:Resistance to isoniazid (INH) is the most common form of drug resistance in pulmonary tuberculosis (TB). Although fluoroquinolones (FQs) are recommended to strengthen treatment regimens for INH-resistant pulmonary TB, few studies have evaluated the clinical efficacy of FQ-containing regimens in patients with INH-resistant pulmonary TB. A retrospective cohort study of 140 patients with INH-resistant pulmonary TB was performed between 2005 and 2012. We evaluated whether FQ-containing regimens yielded improved treatment outcomes for patients with INH-resistant pulmonary TB. Overall, favorable outcomes were achieved in 128 (91.4%) patients. Unfavorable outcomes occurred in 12 patients (8.6%), including 7 with treatment failure (5.0%) and 5 with relapse after initial treatment completion (3.6%). FQs, such as levofloxacin and moxifloxacin, were given to 75 (53.6%) patients. Favorable treatment outcomes were more frequent for patients who received FQs (97.3% [73/75 patients]) than for those who did not receive FQs (84.6% [55/65 patients]) (P = 0.007). Patients who did not receive FQs were more likely to develop treatment failure (9.2% [6/65 patients] versus 1.3% [1/75 patients]) (P = 0.049) than patients who received FQs. The adjusted proportion of unfavorable outcomes was significantly higher among patients who did not receive FQs (8.8%; 95% confidence interval [CI], 3.3 to 21.5%) than among those who did receive FQs (1.5%; 95% CI, 0.3 to 7.7%) (P = 0.037). These results suggest that the addition of FQs can improve treatment outcomes for patients with INH-resistant pulmonary TB.
| S-EPMC4704191 | biostudies-literature
Project description:BackgroundPatients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.MethodsIn an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.ResultsA total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.ConclusionsThe combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
| S-EPMC6955640 | biostudies-literature
Project description:Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.
| S-EPMC5663285 | biostudies-literature
Project description:Background: Adherence to tuberculosis (TB) drugs is one of the key aspects of global TB control, yet there is a lack of epidemiological evidence on the factors influencing adherence to TB drugs. Thus, this study aimed to explore the adherence and factors associated with adherence among TB patients in South Korea. Methods: We conducted a cohort study using a sampled national healthcare database from 2017 to 2018. Our study population included incident TB patients initiating quadruple or triple regimen who were available for follow-up for 180-days. Adherence was evaluated using the proportion of days covered (PDC): 1) adherent group: patients with PDC ≥80%; 2) non-adherent group: patients with PDC <80%. Kaplan-Meier analysis was conducted to calculate the median time-to-discontinuation in the study population. We calculated the adjusted odds ratios (aOR) with 95% confidence intervals (CI) to assess factors associated with adherence to TB drugs using logistic regression. Results: Of 987 patients, 558 (56.5%) were adherent and 429 (43.5%) were non-adherent, with the overall mean PDC of 68.87% (standard deviation, 33.37%). The median time-to-discontinuation was 113 days (interquartile range 96-136) in the study population. Patients initiating quadruple regimen were more likely to adhere in comparison to the triple regimen (aOR 4.14; 95% CI 2.78-6.17), while those aged ≥65 years (aOR 0.53; 95% CI 0.35-0.81), with a history of dementia (aOR 0.53; 95% CI 0.34-0.85), and with history of diabetes mellitus (aOR 0.70; 95% CI 0.52-0.96) were less likely to adhere to the drug. Conclusion: Approximately 45% of TB patients were non-adherent to the drug, which is a major concern for the treatment outcome. We call for intensified attention from the authorities and healthcare providers to reinforce patients' adherence to the prescribed TB drugs.
| S-EPMC8005597 | biostudies-literature
Project description:BackgroundTo ensure patient-centered tuberculosis preventive treatment, it is important to consider factors that make it easier for patients to complete treatment. However, there is little published literature about patient preferences for different preventive treatment regimen options, particularly from countries with high tuberculosis burdens.MethodsWe conducted a qualitative research study using a framework analysis approach to understand tuberculosis preventive treatment preferences among household contacts. We conducted three focus group discussions with 16 members of families affected by tuberculosis in Lima, Peru. Participants were asked to vote for preferred preventive treatment regimens and discuss the reasons behind their choices. Coding followed a deductive approach based on prior research, with data-driven codes added.ResultsIn total, 7 (44%) participants voted for 3?months isoniazid and rifapentine, 4 (25%) chose 3?months isoniazid and rifampicin, 3 (19%) chose 4?months rifampicin, and 2 (13%) chose 6?months isoniazid. Preferences for shorter regimens over 6?months of isoniazid were driven by concerns over "getting tired" or "getting bored" of taking medications, the difficulty of remembering to take medications, side effects, and interference with daily life. For some, weekly dosing was perceived as being easier to remember and less disruptive, leading to a preference for 3?months isoniazid and rifapentine, which is dosed weekly. However, among caregivers, having a child-friendly formulation was more important than regimen duration. Caregivers reported difficulty in administering pills to children, and preferred treatments available as syrup or dispersible formulations.ConclusionsThere is demand for shorter regimens and child-friendly formulations for tuberculosis preventive treatment in high-burden settings. Individual preferences differ, suggesting that patient-centered care would best be supported by having multiple shorter regimens available.
| S-EPMC7802335 | biostudies-literature
Project description:BACKGROUND: Mycobacterium tuberculosis is characterized by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. Here we describe the first documented case of extensively drug-resistant tuberculosis evolved from a susceptible ancestor within a single patient. RESULTS: Genome sequences of nine serial M. tuberculosis isolates from the same patient uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. For most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. Additionally, RNA-sequencing of isolates grown in the absence of drug challenge revealed that the efflux-associated iniBAC operon was up-regulated over time, whereas down-regulated genes include those involved in mycolic acid synthesis. CONCLUSIONS: We observed both rapid acquisitions of resistance to antimicrobial compounds mediated by individual mutations as well as a gradual increase in fitness in the presence of antibiotics, likely driven by stable gene expression reprogramming. The rapid turnover of resistance mutations and hitchhiking neutral mutations has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains.
| S-EPMC4223161 | biostudies-literature
Project description:The emergence of drug-resistant tuberculosis (TB) is a growing problem worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. Therefore, new TB drugs able to bolster the current TB treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multi-drug-resistant (MDR)-TB. This review covers promising novel TB drugs and regimens that are currently under development. Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having a high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains yet to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB. Many regimens consisting of injection free drugs with shorter treatment duration compared to the conventional treatment are now undergoing clinical trials. Therefore a simple and short treatment with higher efficacy, and lesser adverse drug reactions and drug-drug interaction is expected for patients with MDR-TB.
| S-EPMC5457944 | biostudies-literature