Multidrug-resistant Tuberculosis Disease Research Articles

Cost-Effectiveness Analysis of the Optimal Control Strategies for Multidrug-Resistant Tuberculosis Transmission in Ethiopia

Despite the recent progress of global control efforts, tuberculosis (TB) remains a significant public health threat worldwide, especially in developing countries, including Ethiopia. Furthermore, the emergence of multidrug-resistant tuberculosis (MDR-TB) has further complicated the situation. This study aims at identifying the most effective strategies for combating MDR-TB in Ethiopia. We first present a compartmental model of MDR-TB transmission dynamics in Ethiopia. The model is shown to have positive solutions, and the stability of the equilibrium points is analyzed. Then, we extend the model by incorporating time-dependent control variables. These control variables are vaccination, distancing, and treatment for DS-TB and MDR-TB. Finally, the optimality system is numerically simulated by considering different combinations of the strategies, and their cost effectiveness is analysed. Our finding shows that, among single control strategies, the successful treatment of drug-susceptible tuberculosis (DS-TB) is the most effective control factor for eliminating MDR-TB transmission in Ethiopia. Furthermore, within the six dual control strategies, the combination of distancing and successful treatment of DS-TB is less costly and more effective than other strategies. Finally, out of the triple control strategies, the combination of distancing, successful treatment for DS-TB, and treatment for MDR-TB is the most efficient strategy for curbing the MDR-TB disease in Ethiopia. Thus, to reduce MDR-TB efficiently, it is recommended that authorities focus on treating MDR-TB, effective treatment of DS-TB, and promoting social distancing through public health education and awareness programs.

MOSR and NDHA Genes Comprising G-Quadruplex as Promising Therapeutic Targets against Mycobacterium tuberculosis: Molecular Recognition by Mitoxantrone Suppresses Replication and Gene Regulation.

Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The mosR and ndhA genes involved in pathways of oxidation sensing regulation and ATP generation, respectively, make Mycobacterium tuberculosis (Mtb) bacteria responsible for oxidative stress inside host macrophage cells. Circular Dichroism spectra demonstrate stable hybrid G4 DNA conformations of mosR/ndhA DNA sequences. Real-time binding of mitoxantrone to G4 DNA with an affinity constant ~105-107 M-1, leads to hypochromism with a red shift of ~18 nm, followed by hyperchromism in the absorption spectra. The corresponding fluorescence is quenched with a red shift ~15 nm followed by an increase in intensity. A change in conformation of the G4 DNA accompanies the formation of multiple stoichiometric complexes with a dual binding mode. The external binding of mitoxantrone with a partial stacking with G-quartets and/or groove binding induces significant thermal stabilization, ~20-29 °C in ndhA/mosR G4 DNA. The interaction leads to a two/four-fold downregulation of transcriptomes of mosR/ndhA genes apart from the suppression of DNA replication by Taq polymerase enzyme, establishing the role of mitoxantrone in targeting G4 DNA, as an alternate strategy for effective anti-tuberculosis action in view of deadly multi-drug resistant tuberculosis disease causing bacterial strains t that arise from existing therapeutic treatments.

Treatment and outcomes of multidrug-resistant tuberculosis in Auckland, 1995-2018.

New Zealand has a low burden of tuberculosis; however, multidrug-resistant tuberculosis (MDR-TB) still represents a challenge for clinicians. This is the first description of clinical aspects of MDR-TB in New Zealand. To evaluate the treatment and outcomes of patients with MDR-TB disease in Auckland. Secondary aims were to review the incidence and clinical characteristics of MDR-TB disease. Clinical data were obtained for patients treated for MDR-TB at Auckland District Health Board (ADHB). There were 60 patients nationally with MDR-TB between 1989 and 2018; 41 (69%) of 60 patients received care at ADHB. Pulmonary infection was present in 36 (88%) of 41 patients, with 19 (46%) of 41 patients with smear-positive sputum (smear 1-2+ in 6/41, 15%; smear 3-4+ in 13/41, 32%). The median duration of treatment was 22 months (range 7.5-26) for 18 (44%) of 41 patients who completed MDR-TB treatment by August 2018. The median duration of amikacin treatment was 6 months (range 2-12) for the 23 (61%) of 38 patients in whom these data were available. All 38 patients who received treatment for MDR-TB experienced adverse effects, most commonly gastrointestinal (66%), neurological (50%), ototoxicity (47%) and psychiatric (37%). Complications of intravenous access were experienced by 10 (27%) of 37 patients. Of the 19 (46%) of 41 patients who completed treatment, 18 (95%) achieved cure. There was one case who had recurrence because of inadequate treatment, and one case who had spontaneous resolution without treatment. Seventeen (41%) patients left Auckland prior to completion of treatment, mostly to return to their country of origin (15/17, 88%). MDR-TB is uncommon in New Zealand. Treatment is frequently associated with adverse events; however, rates of cure for people completing treatment in New Zealand are high.

Identifying Factors that Affect the Probability of Being Cured from MDR-TB Disease, KwaZulu-Natal, South Africa: A Competing Risks Analysis

Setting: Four decentralised sites are located in rural areas and one centralised hospital in KwaZulu-Natal province, South Africa. Objective: To analyse risk factors associated with multidrug-resistant tuberculosis (MDR-TB) using competing risks analysis. Understanding factors associated with MDR-TB and obtaining valid parameter estimates could help in designing control and intervention strategies to lower TB mortality. Method: A prospective study was performed using a competing risk analysis in patients receiving treatment for MDR-TB. The study focused on 1542 patients (aged 18 years and older) who were diagnosed of MDR-TB between July 2008 and June 2010. Time to cure MDR-TB was used as the dependent variable and time to death was the competing risk event. Results: The Fine-Gray regression model indicated that baseline weight was highly significant with sub-distribution hazard ration (SHR) = 1.02, 95% CI: 1.01 - 1.02. This means that weight gain in a month increased chances of curing MDR-TB by 2%. Results show that lower chances to cure MDR-TB were among patients between 41 to 50 years compared to those patients who were between 18 to 30 years old (SHR = 0.80, 95% CI: 0.61 - 1.06). The chances of curing MDR-TB in female patients were low compared to male patients (SHR = 0.84, 95% CI = 0.68 - 1.03), however this was not significant. Furthermore, HIV negative patients had higher chances to cure MDR-TB (SHR = 1.07, 95% CI: 0.85 - 1.35) compared to HIV positive patients. Patients who were treated in the decentralised sites had lower chances to be cured of MDR-TB (SHR = 0.19, 95% CI: 0.07 - 0.54) as compared to patients who were treated in the centralised hospital. Conclusion: Identifying key factors associated with TB and specifying strategies to prevent them can reduce mortality of patients due to TB disease, hence positive treatment outcomes leading to the goal of reducing or end TB deaths. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people with drug-resistant TB.

Protocol for a case–control study of vitamin D status, adult multidrug-resistant tuberculosis disease and tuberculosis infection in Mumbai, India

IntroductionVitamin D status may be an important determinant of multidrug-resistant tuberculosis (MDR-TB) infection, progression to disease and treatment outcomes. Novel and potentially cost-effective therapies such as vitamin D supplementation are...

Reducing delays to multidrug-resistant tuberculosis case detection through a revised routine surveillance system

BackgroundImplementation of an effective Tuberculosis Routine Surveillance System in low-income countries like Tanzania is problematic, despite being an essential tool for the detection and effective monitoring of drug resistant tuberculosis. Long delays in specimen transportation from the facilities to reference laboratory and results dissemination back to the health facilities, result in poor patient management, particularly where multidrug-resistant tuberculosis disease is present.MethodsFollowing a detailed qualitative study, a pilot intervention of a revised Tuberculosis Routine Surveillance System was implemented in Mwanza region, Tanzania. This included the use of rapid molecular methods for the detection of both tuberculosis and drug resistance using Xpert MTB/RIF in some Mwanza sites, the use of Xpert MTB/RIF and Line Probe Assay at the Central Tuberculosis Reference Laboratory, a revised communication strategy and interventions to address the issue of poor form completion. A before and after comparison of the intervention on the number of drug resistant tuberculosis cases identified and the time taken for results feedback to the requesting site was reported.ResultsThe revised system for previously treated cases tested at the Central Reference Laboratory was able to obtain the following findings; the number of cases tested increased from 75 in 2016 to 185 in 2017. The times for specimen transportation from health facilities to the reference laboratory were reduced by 22% (from 9 to 7 days). The median time for the district to receive results was reduced by 36% (from 11 to 7 days). Overall the number of drug resistant tuberculosis cases starting treatment increased by 67% (from 12 to 20).ConclusionDetection of drug resistance could significantly be enhanced, and delays reduced by introduction of new technologies and improved routine surveillance system, including better communication using mobile applications such as ‘WhatsApp’ and close follow-ups. A larger scale study is now merited to ascertain if these benefits are robust across different contexts.

THE TREATMENT CASCADE: THE USE OF PREVENTATIVE PHARMACOTHERAPY FOR LATENT TB INFECTION FOLLOWING HIGH RISK NOSOCOMIAL EXPOSURE TO MULTIDRUG-RESISTANT TB

SESSION TITLE: Tuesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: This observational cohort study assessed the uptake and tolerability of preventative therapy for high-risk contacts of an index case with smear positive pulmonary MDR-TB across two tertiary hospitals in Sydney, Australia. With almost half a million new cases of multidrug resistant tuberculosis (MDR-TB) in 2018, active case finding and consideration of preventative therapy among specific high-risk contacts is a top priority. Patient acceptance and tolerability of preventative for latent MDR-TB was examined through a telephone delivered questionnaire. METHODS: Contacts were investigated if they had a high risk of exposure, defined as greater than 8 hours of close contact with the index case during the period of infectiousness. After the exclusion of active tuberculosis, contacts with evidence of latent tuberculosis were offered a 9-month course of a fluoroquinolone (moxifloxacin) and all were followed with chest X-ray and clinical review for two years from exposure. Following informed consent, contacts were further invited to complete a questionnaire relating to their experience. RESULTS: In total, 122 people were identified as having high risk exposure to the index case (household contacts, patients and health care workers). Of these, 94 (77%) attended an initial assessment in the chest clinic and 32 (34%) had evidence of latent tuberculosis (positive IGRA or TST). Of the 32 high-risk MDR-TB contacts with latent tuberculosis, 22 choose ongoing CXR surveillance, 9 commenced preventative treatment and 1 did not attend follow up. Reasons cited for not choosing preventative therapy were risks of adverse side effects and concerns about negative job consequences. Of those that took preventative pharmacotherapy, 7 of 9 (78%) attended final 2-year follow up. 6 of 7 (86%) patients treated for latent tuberculosis completed the prescribed course. No cases of incident tuberculosis were detected after 2 years of follow up. CONCLUSIONS: Preventative therapy with moxifloxacin was tolerated well by high risk MDR-TB contacts with evidence of latent tuberculosis infection; however uptake of preventive therapy was limited. CLINICAL IMPLICATIONS: Each case of MDR-TB disease may expose multiple people to their disease and it is known that these people are at an increased risk of developing tuberculosis disease in the future, there is a lack of high quality evidence on the effectiveness of preventative therapy. Research that explores patient acceptance and tolerability of preventative for latent MDR-TB is lacking. Our study adds to the body of knowledge in ascertaining how to treat and manage high risk contacts of MDR-TB disease. DISCLOSURES: no disclosure on file for Byrne Anthony; No relevant relationships by Liam Beiglari, source=Web Response Recipient of study drug (rifapentine) relationship with Sanofi Please note: $20001 - $100000 Added 06/20/2019 by Greg Fox, source=Web Response, value=in kind supply of study drug No relevant relationships by PAUL LILBURN, source=Web Response

Clinical risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in Mali

BackgroundMDR-TB is a major threat to global TB control. In 2015, 580,000 were treated for MDR-TB worldwide. The worldwide roll-out of GeneXpert MTB/RIF® has improved diagnosis of MDR-TB; however, in many countries laboratories are unable to assess drug resistance and clinical predictors of MDR-TB could help target suspected patients. In this study, we aimed to determine the clinical factors associated with MDR-TB in Bamako, Mali. MethodsWe performed a cross-sectional study of 214 patients with presumed MDR-TB admitted to University of Bamako Teaching Hospital, Point-G between 2007 and 2016. We calculated crude and adjusted odds ratios for MDR-TB disease diagnosis using SPSS. ResultsWe found that age ≤40years (OR=2.56. 95% CI: 1.44–4.55), two courses of prior TB treatment (OR=3.25, 95% CI: 1.44–7.30), TB treatment failure (OR=3.82, 95% CI 1.82–7.79), sputum microscopy with 3+ bacilli load (OR=1.98, 95% CI: 1.13–3.48) and a history of contact with a TB patient (OR=2.48, 95% CI: 1.11–5.50) were significantly associated with confirmation of MDR-TB disease. HIV was not a risk factor for MDR-TB (aOR=0.88, 95% CI: 0.34–1.94). ConclusionWe identified several risk factors that could be used to identify MDR-TB suspects and prioritize them for laboratory confirmation. Prospective studies are needed to understand factors associated with TB incidence and clinical outcomes of TB treatment and disease.

Using Changes in Weight-for-Age z Score to Predict Effectiveness of Childhood Tuberculosis Therapy

International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain. We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment failure or death. Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain. Weight change early in therapy can predict the outcome of childhood TB treatment.

Risk factors of multidrug-resistant tuberculosis in China: A meta-analysis.

Multidrug-resistant tuberculosis (MDR-TB) brings major challenges to the health care workers (HCWs). This study is to determine the risk factors for MDR-TB, latent tuberculosis infection (LTBI), and tuberculosis (TB) disease among HCWs in China. A meta-analysis was conducted to evaluate the risk factors for MDR-TB, LTBI, and TB disease among HCWs using a random-effects model, and the pooled odds ratios (ORs) with 95% confidence interval (CI) were used as effect indicators. We identified 46 eligible studies and found eight factors were associated with MDR. The ORs with 95% CI are migrant population 1.96 (95% CI, 1.50-2.57), low family income 2.23 (95% CI, 1.74-2.85), retreatment 7.22 (95% CI, 5.63-9.26), anti-TB treatment history 5.65 (95% CI, 4.80-6.65), multiple episodes of treatment 3.28 (95% CI, 2.60-4.13), adverse reactions 3.48 (95% CI, 2.54-4.76), interrupted treatment 3.18 (95% CI, 2.60-3.89), and lung cavities 1.42 (95% CI, 1.14-1.77). Work duration as a HCW for 5years and above increased the risk of LTBI and TB. HCWs aged 30years and above were more susceptible to TB (OR=1.70, 95% CI: 1.37-2.09). The risk factors for MDR-TB in China are possibly migrant population, low family income, retreatment, anti-TB treatment history, adverse reactions, interrupted treatment, and lung cavities. Longer work duration and greater age are risk factors for LTBI and TB among HCWs.

Multidrug-Resistant Tuberculosis Disease in North-Kivu Province, Democratic Republic of Congo

Introduction: The emergency of Mycobacterium tuberculosis resistant to the first line drug reduced access possibility to second line drugs for appropriate treatment and required for urgent action especially in le Democratic Republic of Congo (DRC), which counts among the highest tuberculosis (TB) burden countries in Africa. Objective: To present prevalence and describe multidrug-resistant tuberculosis cases in North-Kivu Province identified by using Genexpert technology. Methods: We conducted an observational prospective study on multidrug-resistant tuberculosis (MDR-TB) cases in North-Kivu Province, DRC from 2017 to 2018. All cases of MDR-TB identified by Genexpert MTB/ RIB were included in this series. Result: Of 15,544 tuberculosis cases registered during the study period, 19 cases of MDR-TB were identified. 57.9% was male, 89.5% was retreatment cases and 5.3% was coinfection HIV/TB cases. Conclusion: This new molecular technology diagnostic facilitates multidrug-resistance tuberculosis detection and improves the reporting of data lack.

Frequency of Circulating CD4+Ki67+HLA-DR- T Regulatory Cells Prior to Treatment for Multidrug Resistant Tuberculosis Can Differentiate the Severity of Disease and Predict Time to Culture Conversion.

Identifying a blood circulating cellular biomarker that can be used to assess severity of disease and predict the time to culture conversion (TCC) in patients with multidrug resistant tuberculosis (MDR-TB) would facilitate monitoring response to treatment and may be of value in the design of future drug trials. We report on the frequency of blood Ki67+HLA-DR− CD4+ T regulatory (Treg) cells in predicting microbiological outcome before initiating second-line treatment for MDR-TB. Fifty-one patients with MDR-TB were enrolled and followed over 18 months; a subset of patients was sputum culture (SC) negative at baseline (n = 9). SC positive patients were divided into two groups, based on median TCC: rapid responders (≤71 days TCC; n = 21) and slow responders (>71 days TCC; n = 21). Whole blood at baseline, months 2 and 6 was stimulated with M tuberculosis (Mtb) antigens and Treg cells were then identified as CD3+CD4+CD25hiFoxP3+CD127−CD69− and further delineated as Ki67+HLA-DR− Treg. The frequency of these cells was significantly enlarged at baseline in SC positive relative to SC negative and smear positive relative to smear negative patients and in those with lung cavitation. This difference was further supported by unsupervised hierarchical clustering showing a significant grouping at baseline of total and early differentiated memory Treg cells in slow responders. Conversely, there was a clustering of a lower proportion of Treg cells and activated IFNγ-expressing T cells at baseline in the rapid responders. Examining changes over time revealed a more gradual reduction of Treg cells in slow responders relative to rapid responders to treatment. Receiver operating curve analysis showed that baseline Mtb-stimulated Ki67+HLA-DR− Treg cells could predict the TCC of MDR-TB treatment response with 81.2% sensitivity and 85% specificity (AUC of 0.87, p < 0.0001), but this was not the case after 2 months of treatment. In conclusion, our data show that the frequency of a highly defined Mtb-stimulated blood Treg cell population at baseline can discriminate MDR-TB disease severity and predict time to culture clearance.

A Case-Control Study to Identify Community Venues Associated with Genetically-clustered, Multidrug-resistant Tuberculosis Disease in Lima, Peru

The majority of tuberculosis transmission occurs in community settings. Our primary aim in this study was to assess the association between exposure to community venues and multidrug-resistant (MDR) tuberculosis. Our secondary aim was to describe the social networks of MDR tuberculosis cases and controls. We recruited laboratory-confirmed MDR tuberculosis cases and community controls that were matched on age and sex. Whole-genome sequencing was used to identify genetically clustered cases. Venue tracing interviews (nonblinded) were conducted to enumerate community venues frequented by participants. Logistic regression was used to assess the association between MDR tuberculosis and person-time spent in community venues. A location-based social network was constructed, with respondents connected if they reported frequenting the same venue, and an exponential random graph model (ERGM) was fitted to model the network. We enrolled 59 cases and 65 controls. Participants reported 729 unique venues. The mean number of venues reported was similar in both groups (P = .92). Person-time in healthcare venues (adjusted odds ratio [aOR] = 1.67, P = .01), schools (aOR = 1.53, P < .01), and transportation venues (aOR = 1.25, P = .03) was associated with MDR tuberculosis. Healthcare venues, markets, cinemas, and transportation venues were commonly shared among clustered cases. The ERGM indicated significant community segregation between cases and controls. Case networks were more densely connected. Exposure to healthcare venues, schools, and transportation venues was associated with MDR tuberculosis. Intervention across the segregated network of case venues may be necessary to effectively stem transmission.

The burden of multidrug-resistant tuberculosis in children.

Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB). We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients. Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified. The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.

Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis.

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Targeting bacterial energetics to produce new antimicrobials.

From the war on drug resistance, through cancer biology, even to agricultural and environmental protection: there is a huge demand for rapid and effective solutions to control infections and diseases. The development of small molecule inhibitors was once an accepted "one-size fits all" approach to these varied problems, but persistence and resistance threaten to return society to a pre-antibiotic era. Only five essential cellular targets in bacteria have been developed for the majority of our clinically-relevant antibiotics. These include: cell wall synthesis, cell membrane function, protein and nucleic acid biosynthesis, and antimetabolites. Many of these targets are now compromised through rapidly spreading antimicrobial resistance and the need to target non-replicating cells (persisters). Recently, an unprecedented medical breakthrough was achieved by the FDA approval of the drug bedaquiline (BDQ, trade name Sirturo) for the treatment of multidrug-resistant tuberculosis disease. BDQ targets the membrane-bound F1Fo-ATP synthase, validating cellular energy generating machinery as a new target space for drug discovery. Recently, BDQ and several other FDA-approved drugs have been demonstrated to be respiratory "uncouplers" disrupting transmembrane electrochemical gradients, in addition to binding to enzyme targets. In this review, we summarize the role of bioenergetic systems in mycobacterial persistence and discuss the multi-targeting nature of uncouplers and the place these molecules may have in future drug development.

Modeling the impact of bedaquiline treatment strategies on the multidrug-resistant tuberculosis burden in India.

Bedaquiline (BDQ) has been approved in India for the treatment of multidrug-resistant tuberculosis (MDR-TB), but is currently recommended for MDR-TB patients who have failed initial treatment with standard regimens. While some have argued that such deferred BDQ use allows a second line of defense with a potent drug, this strategy may not be optimal. To compare several distinct scenarios of BDQ access and use, and their potential impact on the MDR-TB disease burden and the associated net economic benefit in India. We used a state-transition model to carry out this evaluation. The scenarios differed in the timing and breadth of BDQ access. The simulations showed that a strategy reliant on reserving the use of BDQ for those who have failed other MDR-TB regimens is likely to result in worse treatment outcomes for patients and in inferior public health outcomes for communities, leading to reduced net monetary benefit. Our study suggests that deferring patient access to new drugs such as BDQ until front-line regimens have failed, in order to 'save' these drugs for later use, could be detrimental to patients and to public health, and could reduce the economic benefit of treating MDR-TB.

Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands.

In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15-20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies. Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL. Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values. Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.

Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis.

Ofloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC0-24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (Cmax), AUC0-8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC0-24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC0-24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47; P = 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.

Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia, 2009-2012.

Few studies have shown the operational feasibility, safety, tolerability, or outcomes of multidrug-resistant latent tuberculous infection (MDR LTBI) treatment. After two simultaneous multidrug-resistant tuberculosis (MDR-TB) outbreaks in Chuuk, Federated States of Micronesia, infected contacts were offered a 12-month fluoroquinolone (FQ) based MDR LTBI treatment regimen. Between January 2009 and February 2012, 119 contacts of MDR-TB patients were followed using a prospective observational study design. After MDR-TB disease was excluded, 12 months of daily FQ-based preventive treatment of MDR LTBI was provided by directly observed therapy. Among the 119 infected contacts, 15 refused, while 104 began treatment for MDR LTBI. Of the 104 who initiated treatment, 93 (89%) completed treatment, while 4 contacts discontinued due to adverse effects. None of the 104 contacts who undertook MDR LTBI treatment of any duration developed MDR-TB disease; however, 3 of 15 contacts who refused and 15 unidentified contacts developed MDR-TB disease. Providing treatment for MDR LTBI can be accomplished in a resource-limited setting, and contributed to preventing MDR-TB disease. The Chuuk TB program implemented treatment of MDR LTBI with an 89% completion rate. The MDR LTBI regimens were safe and well tolerated, and no TB cases occurred among persons treated for MDR LTBI.