Drugs For Multidrug-resistant Tuberculosis Research Articles

Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis

Tuberculosis (TB) is a leading cause of mortality worldwide, and resistance to anti-tuberculosis drugs is a challenge to effective treatment. Multi-drug resistant TB (MDR-TB) can be difficult to treat, requiring long durations of therapy and the use of second line drugs, increasing a patient’s risk for toxicities and treatment failure. Given the challenges treating MDR-TB, clinicians can improve the likelihood of successful outcomes by utilizing therapeutic drug monitoring (TDM). TDM is a clinical technique that utilizes measured drug concentrations from the patient to adjust therapy, increasing likelihood of therapeutic drug concentrations while minimizing the risk of toxic drug concentrations. This review paper provides an overview of the TDM process, pharmacokinetic parameters for MDR-TB drugs, and recommendations for dose adjustments following TDM.

Clinical research progress of novel antituberculosis drugs on multidrug-resistant tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) has become a critical challenge to public health, and the prevention and treatment of MDR-TB are of great significance in reducing the global burden of tuberculosis. How to improve the effectiveness and safety of chemotherapy for MDR-TB is a pressing issue that needs to be addressed in tuberculosis control efforts. This article provides a comprehensive review of the clinical application of new antituberculosis drugs in MDR-TB, aiming to provide a scientific basis for the prevention and treatment strategy of MDR-TB.

Toxicological Profiling of Potential Shikimate Kinase Inhibitors Against Mycobacterium tuberculosis.

Over the last decade, Mycobacterium tuberculosis has mutated into a putative 'superbug', as treatments against it have failed due to increasing antimicrobial resistance. As a result, the rising incidence of multidrug-resistant tuberculosis (MDR-TB) is posing a significant public health threat, thus, the need to develop effective drugs for MDR-TB has become an urgent priority. To identify new drug candidates for the treatment of MDR-TB, the present study was based on mycobacterial shikimate kinase (MtSK) as the pharmacological target. One hundred potential MtSK inhibitors were identified from literature and database searches to identify compounds that were designed to specifically function as MtSK antagonists. The ADME properties of these compounds were evaluated by using the SwissADME web tool. ProTox-II software was also used to investigate any potential endocrine disrupting effects, mediated through their interaction with oestrogenic and/or androgenic receptors. This study also aimed to predict LD50 values of potential drug candidates that would be active against the standard H37Rv strain of M. tuberculosis, by using the ProTox-II in silico tool. The molecules for which no structural hazard alerts were identified with these software tools were further subjected to molecular docking analyses and molecular dynamic simulations to estimate their ability to interact with the MtSK enzyme. Preliminary results from SwissADME indicated that 30 molecules were drug-like, due to their physicochemical and pharmacokinetic properties. However, subsequent analysis with ToxTree and ProTox-II indicated that only three of these 30 drug-like molecules were suitable for taking forward into further in vitro experiments. This study, which is based on the use of commonly used open-source in silico tools, identified new MtSK ligands for potential use in the development of new drugs for the therapeutic management of tuberculosis. An initial prediction of their safety profile was also generated.

Factors Associated with the Level of Non-Adherence to Take Antituberculosis drugs

Non-adherence to take antituberculosis drugs is one of the causes of tuberculosis (TB) resistance. However, in Indonesia no study identified the factors associated with the level of non-adherence to take antituberculosis drugs in Multi-Drug Resistant Tuberculosis (MDR-TB) patients when they were still pulmonary drug-sensitive TB survivors. The aim of this study was to identify factors associated with the level of non-adherence to take antituberculosis drugs. This was a cross-sectional study which was conducted from October 2021 to December 2021 at Dr. Soetomo Hospital Surabaya. The dependent variable was the level of non-adherence to take antituberculosis drugs, while the independent variables were age, gender, education level, income, distance from home to health care service, role of health workers, role of superintendent of swallowing drugs (PMO), and side effects. Forty out of the 195 secondary-resistant MDR-TB patients were selected as subjects for this study based on their willingness. The instrument was questionnaire which had been tested for its validity and reliability. The results of bivariate analysis showed that gender, the role of PMO, and side effects had a significance of p0.05. The results of the bivariate analysis indicated that gender, role of PMO, and side effects have significance value p0.05. The conclusion of this study is gender, role of PMO, and side effects are associated with the level of non-adherence to take antituberculosis drugs.

Microwave-assisted organic synthesis, antimycobacterial activity, structure–activity relationship and molecular docking studies of some novel indole-oxadiazole hybrids

ABSTRACT Multidrug-resistant tuberculosis (MDR-TB) is a severe threat to mankind because most drugs are ineffective in inhibiting tubercular strains. Due to the increase of MDR-TB, many first and second-line drugs are ineffective against tubercular strains. To combat the resistance of currently accessible drugs, structural changes must be made on a regular basis. Thus, in the search for new antimycobacterial drugs, a series of 1-(2-(1H-indol-3-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-3-phenylprop-2-en-1-ones (5a-o) have been developed, synthesized, characterized, and screened for antimycobacterial activity. The synthetic approach includes imine generation and cyclization using both conventional and microwave methods to create hybrid molecules with indole and oxadiazole motifs. The set of synthesized compounds have demonstrated some promising activity against tubercular strains of Mycobacterium tuberculosis (ATCC 25177) and M. bovis (ATCC 35734). Compound 5l inhibited M. bovis strain 100% in 10 µg/mL concentration, while compound 5m inhibited M. tuberculosis strain 90.4% in 30 µg/mL concentration. Molecular docking study against mycobacterial enoyl reductase (InhA) could provide well-clustered solutions to the binding modes and affinity for these molecules as compound 5l showed glide score of −12.275 and glide energy of −54.937 kcal/mol.

Explorative Analysis of Treatment Outcomes of Levofloxacin- and Moxifloxacin-Based Regimens and Outcome Predictors in Ethiopian MDR-TB Patients: A Prospective Observational Cohort Study

Purpose/BackgroundAlthough Ethiopia is among the thirty high multi-drug resistant tuberculosis (MDR-TB) burden countries in the world, comparative therapeutic efficacy of moxifloxacin and levofloxacin has not been explored, particularly in MDR-TB patients. We therefore aimed to prospectively compare clinical outcomes and determine potential predictors of the outcomes among patients on moxifloxacin or levofloxacin-based MDR-TB drug regimens.MethodsWe analyzed clinical parameters and laboratory data of eighty MDR-TB patients on moxifloxacin- or levofloxacin-based regimens. The clinical outcomes were compared using the Kaplan–Meier survival functions and the outcome definitions of the 2013 World Health Organization. Monthly sputum culture conversions and a molecular line probe assay results were also assessed. Observed outcomes and patient-related variables between the two groups were compared using chi-square, Wilcoxon Rank and Fisher exact tests. We also determined the potential predictors influencing treatment outcomes of moxifloxacin and levofloxacin using Cox proportional hazard model.ResultsThe levofloxacin-based treatment group had a lower failure rate and adverse drug events as well as better treatment success than the moxifloxacin-based group. Overall treatment success was 65%. Disaggregating the data revealed that 53.8% were cured, 11.2% completed treatment, 10.0% died, 11.2% failed, and 13.8% were lost-to-follow-up. The line probe assay result showed that 11.3% of the clinical isolates were resistant to fluoroquinolones and 3.8% were resistant to both fluoroquinolones and injectable anti-TB agents. Treatment regimen type, culture conversion rate, alcohol use, cavity lesion, serum levels of creatinine and alanine aminotransferase were independent predictors of treatment outcome.ConclusionThe levofloxacin-based regimen group has a better overall treatment success than the moxifloxacin-based group among MDR-TB patients. Clinical parameters and substance use history of the patients influenced treatment outcomes. We recommend further broader clinical studies to substantiate our findings as an input to review MDR-TB treatment guidelines.

Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach.

This study aimed to predict the impacts of shorter duration treatment regimens for multidrug-resistant tuberculosis (MDR-TB) on both MDR-TB percentage among new cases and overall MDR-TB cases in the WHO Southeast Asia Region. A deterministic compartmental model was constructed to describe both the transmission of TB and the MDR-TB situation in the Southeast Asia region. The population-level impacts of short-course treatment regimens were compared with the impacts of conventional regimens. Multi-way analysis was used to evaluate the impact by varying programmatic factors (eligibility for short-course MDR-TB treatment, treatment initiation, and drug susceptibility test (DST) coverage). The model predicted that overall TB incidence will be reduced from 246 (95% credible intervals (CrI), 221–275) per 100,000 population in 2020 to 239 (95% CrI, 215–267) per 100,000 population in 2035, with a modest reduction of 2.8% (95% CrI, 2.7%–2.9%). Despite the slight reduction in overall TB infections, the model predicted that the MDR-TB percentage among newly notified TB infections will remain steady, with 2.4% (95% CrI, 2.1–2.9) in 2020 and 2.5% (95% CrI, 2.3–3.1) in 2035, using conventional MDR-TB treatment. With the introduction of short-course regimens to treat MDR-TB, the development of resistance can be slowed by 38.6% (95% confidence intervals (CI), 35.9–41.3) reduction in MDR-TB case number, and 37.6% (95% CI, 34.9–40.3) reduction in MDR-TB percentage among new TB infections over the 30-year period compared with the baseline using the standard treatment regimen. The multi-way analysis showed eligibility for short-course treatment and treatment initiation greatly influenced the impacts of short-course treatment regimens on reductions in MDR-TB cases and percentage resistance among new infections. Policies which promote the expansion of short-course regimens and early MDR-TB treatment initiation should be considered along with other interventions to tackle antimicrobial resistance in the region.

Prevalence and factors associated with non-adherence to multi-drug resistant tuberculosis (MDR-TB) treatment at Mulago National Referral Hospital, Kampala, Uganda.

In Uganda, 12% of previously treated TB cases and 1.6% of new cases have MDR-TB and require specialized treatment and care. Adherence is crucial for improving MDR-TB treatment outcomes. There is paucity of information on the extent to which these patients adhere to treatment and what the drivers of non-adherence are. We conducted a cohort study using retrospectively collected routine program data for patients treated for MDR-TB between January 2012 - May 2016 at Mulago Hospital. We extracted anonymized data on non-adherence (missing 10% or more of DOT), socio-economic, demographic, and treatment characteristics of the patients. All participants were sensitive to MDR-TB drugs after second line Drug Susceptible Testing (DST) at entry into the study. Factors associated with non-adherence to MDR-TB treatment were determined using generalized linear models for the binomial family with log link and robust standard errors. We considered a p- value less than 0.05 as statistically significant. The records of 227 MDR- TB patients met the inclusion criteria, 39.4% of whom were female, 32.6% aged between 25 - 34 years, and 54.6% living with HIV/AIDS. About 11.9% of the patients were non-adherent. The main driver for non-adherence was history of previous DR-TB treatment; previously treated DR-TB patients were 3.46 (Adjusted prevalence ratio: 3.46, 95 % CI: 1.68 - 7.14) times more likely to be non-adherent. One in 10 MDR-TB patients treated at Mulago hospital is non-adherent to treatment. History of previous DRTB treatment was significantly associated with non-adherence in this study. MDR-TB program should strengthen adherence counselling, strengthen DST surveillance, and close monitoring for previously treated DR-TB patients.

PP581 Catastrophic Costs Of Multidrug-Resistant Tuberculosis: Estimation Based On The Cost Of Treatment In China

IntroductionChina bears a considerably high burden of multidrug-resistant tuberculosis (MDR-TB). Second-line anti-TB drugs are urgently needed yet domestic MDR-TB drugs are expensive and lack policy support. Patients’ living conditions are closely related to the drug affordability. The national TB prevention programs should play a critical role. The purpose of this study is to measure the cost of treating MDR-TB patients under different treatment schemes and price sources. The results of this study are expected to inform the relevant drug protection policies and provide inputs for further cost-effectiveness analyses.MethodsBased on the treatment plan of China's Multidrug-Resistant Pulmonary Tuberculosis Clinical Path (2012 edition) and the World Health Organization (WHO) Drug-Resistant Tuberculosis Treatment Guide (2018 edition), the treatment costs of MDR-TB were measured under different scenarios. Catastrophic health expenditure was then calculated if the treatment cost exceeds 40 percent of the household's non-subsistence income. National, rural and disposable income per capita in 2018, were used to represent Chinese patients’ affordability.ResultsUnder varied treatment schemes and market price sources in China, the total costs for MDR-TB patients range from 19,401 to 126,703 CNY [2,853 to 18,633 USD] per person. Under current prices, all treatment schemes recommended by the WHO will incur catastrophic costs for Chinese MDR-TB patients. Significant differences were found between rural and urban areas as 52.8 percent of the treatment listed in the 2012 China Guideline would lead to catastrophic cost for rural patients but not urban ones.ConclusionsOur study concludes that the domestic drugs are more expensive than the international purchase price and the treatment of MDR-TB imposes substantial economic burden on patients, especially in the rural areas. The results of the study also indicate that it is urgent for the state to emphasize government responsibility and initiate centralized procurement for price negotiations to reduce the market price of MDR-TB drugs. The urban-rural gap should also be addressed in the design of future policies to ensure the drug affordability for all patients in need.

Adverse drug reactions and risk factors for discontinuation of multidrug-resistant tuberculosis regimens in Gujarat, western India.

The predictors for discontinuation of multidrug-resistant tuberculosis (MDR-TB) regimens have not been studied in Gujarat. We aimed to find out the adverse drug reactions (ADRs) and predictors for discontinuation of MDR-TB regimens. We conducted this cross-sectional study in Bhavnagar district of Gujarat from September to November 2016 through home visits and personal interviews of 94 patients with MDR-TB. Sixty-nine patients with MDR-TB (73%) reported ADRs. Tingling (42.6%), headache (37.2%), numbness (36.2%), dizziness (34%) and nausea (33%) were the most common ADRs. Of the 94 patients, 7.4% were compelled to think of discontinuing their treatment due to ADRs; 8.5% had discontinued Cat-I/Cat-II regimen in the past; 11.7% had discontinued their MDR-TB regimen in the past; 13.8% had their drug regimen changed due to ADRs and 94.7% had good adherence to their current regimen (took at least 80% of their doses till date). ADRs were the reason for 75% of the patients who discontinued their Cat-I/Cat-II regimen in the past and 64% of the patients who discontinued their MDR-TB regimen in the past. Tobacco chewing, poor adherence and thought of discontinuing an MDR-TB regimen due to ADRs were significant predictors for discontinuation on bivariate analysis. On multiple logistic regression, none of the predictors were significant. The frequency of ADRs among patients with MDR-TB is high. ADRs were the primary reason for discontinuing MDR-TB drugs.

Is short-course therapy enough at drug-resistant tuberculosis?

Tuberculosis drug resistance can be assessed by physicians with different approaches on issues such as the choice of treatment protocol and duration of treatment. In this study, we aimed to evaluate the treatment regimens and treatment results of patients with non multi-drug resistant tuberculosis (MDR-TB) drug resistance implemented in different chest disease clinics in our hospital. The 167 culture-positive patients with nonMDR-TB drug resistance diagnosed between 2008-2010 were analyzed retrospectively. Patients' age, gender, previous TB treatments, bacteriological cruise, drug resistance patterns and treatment outcomes were analyzed. One hundred sixty-seven patients with eligible data were evaluated; there were 117 (70.1%) men and 50 (29.9%) women, mean age was 42.35 (18-90) years, respectively. Among mono drug resistance; H resistance in 75 (44.9%) patients and R resistance in 11 patients was detected. In 19 (11.4%) patients HS resistance was detected as multiple drug resistance. One hudred and twenty-five (74.9%) were new cases. When treatment the results of in all patients evaluated, 136 (81.4%) of the patients achieved treatment success. Sixty-four (51.2%) of the new TB cases treated with "standard treatment protocols for new cases" (2HRZE/4H) and 51 (40.8%) of them treated with "other treatment protocols". Ten (23.8%)of the recurrent TB cases" standard treatment for recurrent cases (2HRZES/HRZE/5HRE) and 9 (21.4%) 33 (19.8%) of them treated with other protocols. The combination of the rthe treatment protocol and descriptive information about the duration of the treatment could not be created as 33 (19.8%) of the cases left without completing their treatment. As a result of the analysis, patients have completed their treatment, there was no significant difference in treatment outcomes. Patients with Non MDR-TB drug resistance should be monitored well and should be careful in terms of MDR-TB.

Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study

IntroductionIndividualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in...

The Potential of Ganoderma Lucidum as Antimicrobial Agent for Multidrug- Resistant Mycobacterium Tuberculosis

Background: The problem of bacterial resistance of Mycobacterium tuberculosis should be solved by seeking for alternative substances that potentially inhibit the growth or kill the bacteria. Ganoderma lucidum is one type of fungus which is potential to be an antimicrobial agent. This study aimed to determine the potential of G. lucidum on inhibiting the growth of multidrug-resistant bacteria of M. tuberculosis in vitro. Methods: This study used a solid dilution method to test the extract of G. lucidum as an antibacterial agent. Results and Conclusion: Results showed that all strains of multidrug-resistant tuberculosis (MDR-Tb) gave similar responses to G. lucidum extract at various concentrations. The bacteria did not grow on the medium containing G. lucidum extract at the smallest concentration of 12.5%, as well as concentrations of 25% and 50%. Ganoderma lucidum can be used as one of the alternatives for MDR-Tb drugs in the future.

Diagnostic Opportunities for Optimizing Management of Multidrug-Resistant Tuberculosis (MDR-TB) in Tanzania

Tanzania is one of the countries confronting a multidrug-resistant tuberculosis (MDR-TB) epidemic.Research studies on drug susceptibility testing (DST) for second-line TB drugs given to Tanzanian MDR-TB patients has demonstrated mycobacterial resistance to important MDR-TB drugs, such as ethionamide, ofloxacin, amikacin, kanamycin, and pyrazinamide. Likewise, pharmacokinetic studies have shown a high frequency of patients with circulating serum drug levels below the expected ranges, especially for levofloxacin and kanamycin - key drugs in MDR-TB treatment that also affect ex-vivo plasma drug activity.We suggest using molecular diagnostic assays, such as the GenoType MTBDRplus test, and inhA and/or katG genotypic results to optimize MDR-TB treatment. Quantitative drug susceptibility can guide the selection of options for second-line anti-TB drugs. The TB drug assay, an alternative biomarker for therapeutic drug monitoring, can identify patients who have extensively drug-resistant TB or are exposed to suboptimal serum drug levels of, specifically, levofloxacin and kanamycin.

Cost effectiveness of decentralised care model for managing MDR-TB in India

BackgroundIn India, multidrug-resistant tuberculosis (MDR-TB) patients are usually treated in hospitals. Decentralised care model, however, has been suggested as a possible alternative by the World Health Organization (WHO). In the “End TB Strategy”, the WHO highlights, as one of the key targets for 2035, that ‘no TB-affected families should face catastrophic hardship due to the tuberculosis’. Removal of financial barriers to health-care access and mitigation of catastrophic expenditures are therefore considered vital to achieve the universal health coverage (UHC) goal. Since forgoing healthcare due to the financial constraints is a known fact in India, decentralised care as an intervention choice (as against hospital-based care) might enhance equity provided it is an affordable choice. Thus, an economic evaluation was conducted, from the perspective of the national health system in India, to assess the cost-effectiveness of decentralised care compared to centralised care for MDR-TB. MethodsThis study uses a decision-analytic model with a follow-up of two years to assess the expected costs of the decentralised versus the centralised approaches for MDR-TB treatment. A published systematic review of observational studies yielded the MDR-TB treatment outcomes, which included treatment success, treatment default, treatment failure, and mortality parameters. It was observed that these parameters did not vary significantly between the two alternatives. Treatment costs included the following costs: hospital admission costs, clinic costs, visits to laboratory and MDR-TB centre, drug therapy, injections and food. Costs data of drugs, diagnosis, hospital stay and travel to public facilities, based on a simple market survey, were taken from a recently published study on MDR-TB expenditures in the Chhattisgarh state of India. Potential cost savings related to the implementation of decentralised MDR-TB care for all patients who initiated MDR-TB treatment in India were additionally estimated. ResultsEstimated average expected total treatment cost was US$ 3390.56 for the hospital-based model and US$ 1724.1 for the decentralised model for a patient treated for MDR-TB in India, generating potential savings of US$1666.50 per case, with ICER US$ 2382.68 per QALY gained. One of the primary drivers of this difference was the significantly more intensive (thus expensive) stay charges in the hospital. If the costs and treatment probabilities are extrapolated to the whole country, with 48114 MDR-TB patients initiated on treatment in 2017, decentralised care would have additional 1058 patients cured, gain additional 3824 QALYs, and avert 2165 deaths, as compared to centralised care, in India. At various scenarios of coverage rates of decentralised and centralised care the cost difference would range between 23% and 94% for the country. ConclusionOur study provides evidence of cost savings for MDR-TB patients if patients choose decentralised treatment in comparison to suggested hospitalisation of these patients for centralised treatment with similar outcomes. The economic evaluation presented in this study expected significant efficiency gains in choice of two treatment options and the cost savings may improve equity. In India, treatment of MDR-TB using decentralised care is expected to result in similar patient outcomes at markedly reduced public health costs compared with centralised care.

New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations.

It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents.

Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations.

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo® (bedaquiline) and Deltyba® (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug–drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein-binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients.

Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis.

BackgroundNew drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients’ resistance patterns.Methods and FindingsWe created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies. The explored strategies included making bedaquiline available to all patients with MDR TB, restricting bedaquiline usage to patients with MDR plus additional resistance and withholding bedaquiline introduction completely. We compared these strategies according to life expectancy, risks of acquired resistance, and the expected number and health outcomes of secondary cases.For our simulated cohort, the mean (2.5th, 97.5th percentile) life expectancy from time of initiation of MDR TB treatment at age 30 was 36.0 y (33.5, 38.7) assuming all patients with MDR TB received bedaquiline, 35.1 y (34.4, 35.8) assuming patients with pre-extensively drug-resistant (PreXDR) and extensively drug-resistant (XDR) TB received bedaquiline, and 34.9 y (34.6, 35.2) assuming only patients with XDR TB received bedaquiline. Although providing bedaquiline to all MDR patients resulted in the highest life expectancy for our initial cohort averaged across all parameter sets, for parameter sets in which bedaquiline conferred high risks of added mortality and only small reductions in median time to culture conversion, the optimal strategy would be to withhold use even from patients with the most extensive resistance. Across all parameter sets, the most liberal bedaquiline use strategies consistently increased the risk of bedaquiline resistance but decreased the risk of resistance to other MDR drugs. In almost all cases, more liberal bedaquiline use strategies reduced the expected number of secondary cases and resulting life years lost. The generalizability of our results is limited by the lack of available data about drug effects among individuals with HIV co-infection, drug interactions, and other sources of heterogeneity, as well as changing recommendations for MDR TB treatment.ConclusionsIf mortality benefits can be empirically verified, our results provide support for expanding bedaquiline access to all patients with MDR TB. Such expansion could improve patients’ health, protect background MDR TB drugs, and decrease transmission, but would likely result in greater resistance to bedaquiline.

A Multilaboratory, Multicountry Study To Determine MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing of Selected First-Line Antituberculosis Drugs, Second-Line Injectables, Fluoroquinolones, Clofazimine, and Linezolid

Our objective was to establish reference MIC quality control (QC) ranges for drug susceptibility testing of antimycobacterials, including first-line agents, second-line injectables, fluoroquinolones, and World Health Organization category 5 drugs for multidrug-resistant tuberculosis using a 7H9 broth microdilution MIC method. A tier-2 reproducibility study was conducted in eight participating laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Three lots of custom-made frozen 96-well polystyrene microtiter plates were used and prepared with 2× prediluted drugs in 7H9 broth-oleic acid albumin dextrose catalase. The QC reference strain was Mycobacterium tuberculosis H37Rv. MIC frequency, mode, and geometric mean were calculated for each drug. QC ranges were derived based on predefined, strict CLSI criteria. Any data lying outside CLSI criteria resulted in exclusion of the entire laboratory data set. Data from one laboratory were excluded due to higher MIC values than other laboratories. QC ranges were established for 11 drugs: isoniazid (0.03 to 0.12 μg/ml), rifampin (0.03 to 0.25 μg/ml), ethambutol (0.25 to 2 μg/ml), levofloxacin (0.12 to 1 μg/ml), moxifloxacin (0.06 to 0.5 μg/ml), ofloxacin (0.25 to 2 μg/ml), amikacin (0.25 to 2 μg/ml), kanamycin (0.25 to 2 μg/ml), capreomycin (0.5 to 4 μg/ml), linezolid (0.25 to 2 μg/ml), and clofazimine (0.03 to 0.25 μg/ml). QC ranges could not be established for nicotinamide (pyrazinamide surrogate), prothionamide, or ethionamide, which were assay nonperformers. Using strict CLSI criteria, QC ranges against the M. tuberculosis H37Rv reference strain were established for the majority of commonly used antituberculosis drugs, with a convenient 7H9 broth microdilution MIC method suitable for use in resource-limited settings.

Community-based management versus traditional hospitalization in treatment of drug-resistant tuberculosis: a systematic review and meta-analysis.

BackgroundMultidrug drug resistant Tuberculosis (MDR-TB) and extensively drug resistant Tuberculosis (XDR-TB) have emerged as significant public health threats worldwide. This systematic review and meta-analysis aimed to investigate the effects of community-based treatment to traditional hospitalization in improving treatment success rates among MDR-TB and XDR-TB patients in the 27 MDR-TB High burden countries (HBC).MethodsWe searched PubMed, Cochrane, Lancet, Web of Science, International Journal of Tuberculosis and Lung Disease, and Centre for Reviews and Dissemination (CRD) for studies on community-based treatment and traditional hospitalization and MDR-TB and XDR-TB from the 27 MDR-TB HBC. Data on treatment success and failure rates were extracted from retrospective and prospective cohort studies, and a case control study. Sensitivity analysis, subgroup analyses, and meta-regression analysis were used to explore bias and potential sources of heterogeneity.ResultsThe final sample included 16 studies involving 3344 patients from nine countries; Bangladesh, China, Ethiopia, Kenya, India, South Africa, Philippines, Russia, and Uzbekistan. Based on a random-effects model, we observed a higher treatment success rate in community-based treatment (Point estimate = 0.68, 95 % CI: 0.59 to 0.76, p < 0.01) compared to traditional hospitalization (Point estimate = 0.57, 95 % CI: 0.44 to 0.69, p < 0.01). A lower treatment failure rate was observed in community-based treatment 7 % (Point estimate = 0.07, 95 % CI: 0.03 to 0.10; p < 0.01) compared to traditional hospitalization (Point estimate = 0.188, 95 % CI: 0.10 to 0.28; p < 0.01). In the subgroup analysis, studies without HIV co-infected patients, directly observed therapy short course-plus (DOTS-Plus) implemented throughout therapy, treatment duration > 18 months, and regimen with drugs >5 reported higher treatment success rate. In the meta-regression model, age of patients, adverse events, treatment duration, and lost to follow up explains some of the heterogeneity of treatment effects between studies.ConclusionCommunity-based management improved treatment outcomes. A mix of interventions with DOTS-Plus throughout therapy and treatment duration > 18 months as well as strategies in place for lost to follow up and adverse events should be considered in MDR-TB and XDR-TB interventions, as they influenced positively, treatment success.