MDR-TB Treatment Research Articles

Clinical Features and Outcome of Multidrug-Resistant Osteoarticular Tuberculosis: A 12-Year Case Series from France.

The optimal treatment for osteoarticular infection due to multidrug-resistant tuberculosis strains (MDR-OATB) remains unclear. This study aims to evaluate the diagnosis, management and outcome of MDR-OATB in France. We present a case series of MDR-OATB patients reviewed at the French National Reference Center for Mycobacteria between 2007 and 2018. Medical history and clinical, microbiological, treatment and outcome data were collected. Twenty-three MDR-OATB cases were reported, representing 3% of all concurrent MDR-TB cases in France. Overall, 17 were male, and the median age was 32 years. Six patients were previously treated for TB, including four with first-line drugs. The most frequently affected site was the spine (n = 16). Bone and joint surgery were required in 12 patients. Twenty-one patients (91%) successfully completed the treatment with a regimen containing a mean of four drugs (range, 2–6) for a mean duration of 20 months (range, 13–27). Overall, high rates of treatment success were achieved following WHO MDR-TB treatment guidelines and individualized patient management recommendations by the French National TB Consilium. However, the optimal combination of drugs, duration of treatment and role of surgery in the management of MDR-OATB remains to be determined.

Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.

The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.

The chamber of secretome in Mycobacterium tuberculosis as a potential therapeutic target

ABSTRACT Mycobacterium tuberculosis (MTB) causes one of the ancient diseases, Tuberculosis, affects people around the globe and its severity can be understood by its classification as a second infectious disease after COVID-19 and the 13th leading cause of death according to a WHO report. Despite having advanced diagnostic approaches and therapeutic strategies, unfortunately, TB is still spreading across the population due to the emergence of drug-resistance MTB and Latent TB infection (LTBI). We are seeking for effective approaches to overcome these hindrances and efficient treatment for this perilous disease. Therefore, there is an urgent need to develop drugs based on operative targeting of the bacterial system that could result in both efficient treatment and lesser emergence of MDR-TB. One such promising target could be the secretory systems and especially the Type 7 secretory system (T7SS-ESX) of Mycobacterium tuberculosis, which is crucial for the secretion of effector proteins as well as in establishing host–pathogen interactions of the tubercle bacilli. The five paralogous ESX systems (ESX-1 to EXS-5) have been observed by in silico genome analysis of MTB, among which ESX-1 and ESX-5 are substantial for virulence and mediating host cellular inflammasome. The bacterium growth and virulence can be modulated by targeting the T7SS. In the present review, we demonstrate the current status of therapeutics against MTB and focus on the function and cruciality of T7SS along with other secretory systems as a promising therapeutic target against Tuberculosis.

Cost of TB prevention and treatment in the Philippines in 2017.

SUMMARYBACKGROUND :The Philippines aims to accelerate TB reduction through the provision of universally accessible and affordable services. The objectives of this paper are to estimate the costs of TB services and interventions using a health systems’ perspective, and to explore cost differences in service delivery via primary care facilities or hospitals.METHODS :Data were collected from a multi-stage stratified random sampling of 28 facilities in accordance with Global Health Cost Consortium costing standards and analysis tools. Unit costs (in US$) estimated using top-down (TD) and bottom-up (BU) approaches, are summarised following Value TB reporting standards and by broad facility type.RESULTS :Cost of delivering 32 TB services and eight interventions varied by costing method and delivery platform. Average BU costs ranged from US$0.38 for treatment support visits, US$2.5 for BCG vaccination, US$19.48 for the Xpert® MTB/RIF test to US$3,677 for MDR-TB treatment using the long regimen. Delivering TB care in hospitals was generally more costly than in primary care facilities, except for TB prevention in children and MDR-TB treatment using the long regimen.CONCLUSION :Comprehensive costing data for TB care in the Philippines are now available to aid in the design, planning, and prioritisation of delivery models to End TB.

Outcomes and adherence of shorter MDR TB regimen in patients with multidrug resistant tuberculosis

BackgroundIn 2016 WHO guidelines conditionally recommended standardized shorter 9–12 months regimen for MDR-TB treatment. The objective is to study outcome analysis of cured, lost to follow-up, treatment completed, treatment failure and mortality of MDR Patients on shorter standardized MDR TB regimen. MethodsIn this prospective study, 360 adults with confirmed Rifampicin Resistant pulmonary TB were studied between March 2018 to February 2020 at Department of Pulmonary Medicine, Guntur Medical College, Govt. Fever Hospital, Guntur. ResultsAmong 360 confirmed MDR Patients, 42.50% patients were cured, 41.60% completed treatment, 6.11% of them were lost to follow-up, 0.50% were considered as treatment failure and 9.10% of them were died. ConclusionOverall success with a standardized shorter MDR regimen was high with low treatment failure. When introducing shorter regimens base line drug susceptibility testing and minimizing missed doses are critical.

Social and health factors associated with adverse treatment outcomes among people with multidrug-resistant tuberculosis in Sierra Leone: a national, retrospective cohort study

SummaryBackgroundMultidrug-resistant tuberculosis (MDR-TB) is a global health emergency. We aimed to evaluate treatment outcomes among people with MDR-TB in Sierra Leone and investigate social and health factors associated with adverse treatment outcomes.MethodsThis national, retrospective cohort study recruited all people notified with MDR-TB to the Sierra Leone National TB Programme, admitted to Lakka hospital (Lakka, Western Area Rural District, Freetown, Sierra Leone) between April, 2017, and September, 2019. Participants were followed up to May, 2021. People who were eligible but had no social or health data available, or were subsequently found to have been misdiagnosed, were excluded from participation. MDR-TB treatment was with the 2017 WHO-recommended short (9–11 month) or long (18–24 month) aminoglycoside-containing regimens. Multivariable logistic regression models examined associations of programmatic social and health data with WHO-defined adverse treatment outcomes (death, treatment failure, loss to follow-up).FindingsOf 370 notified MDR-TB cases, 365 (99%) were eligible for study participation (five participants were excluded due to lack of social or health data or misdiagnosis). Treatment was started by 341 (93%) of 365 participants (317 received the short regimen, 24 received the long regimen, and 24 received no treatment). Median age was 35 years (IQR 26–45), 263 (72%) of 365 were male and 102 (28%) were female, 71 (19%) were HIV-positive, and 127 (35%) were severely underweight (body-mass index <16·5 kg/m2). Overall, 267 (73%) of 365 participants had treatment success, 95 (26%) had an adverse outcome, and three (1%) were still on treatment in May, 2021. Age 45–64 years (adjusted odds ratio [aOR] 2·4, 95% CI 1·2–5·0), severe underweight (aOR 4·2, 1·9–9·3), untreated HIV (aOR 10, 2·6–40·0), chronic lung disease (aOR 2·0, 1·0–4·2), previously unsuccessful drug-sensitive tuberculosis retreatment (aOR 4·3, 1·0–19), and a long regimen (aOR 6·5, 2·3–18·0) were associated with adverse outcomes. A sensitivity analysis showed that prothionamide resistance (aOR 3·1, 95% CI 1·5–10·0) and aminoglycoside-related complete deafness (aOR 6·6, 1·3–35) were independently associated with adverse outcomes.InterpretationMDR-TB treatment success in Sierra Leone approached WHO targets and the short regimen was associated with higher success. The social and health factors associated with adverse outcomes in this study suggest a role for integrated tuberculosis, HIV, and non-communicable disease services alongside nutritional and socioeconomic support for people with MDR-TB and emphasise the urgent need to scale up coverage of all-oral aminoglycoside-sparing regimens.FundingWellcome Trust, Joint Global Health Trials.

The effects of MDR-TB Treatment Regimens through Socioeconomic and Spatial characteristics on Environmental-Health Outcomes: Evidence from Chinese Hospitals

This study examines socioeconomic and spatial factors and its influences on the outcomes of environmental-health through “multi-drug resistance tuberculosis” (MDR-TB) treatment regimes in China. For this purpose, a survival analysis is conducted by applying “multivariable Cox Proportional Hazard model” on secondary data starts from 2010 to 2019. The data set is consisting of six hundred and fifty five (655) TB patients from different hospitals of China. The findings of this study indicate us that there is no alteration in patient survival rates between the two treatment departments, hospital and ambulatory care. The spatial characteristics of time expenditure and medical expenditure are significantly correlated with “supporting distance bias methods” and “environmental health results”. On the other side, travel expenditures and male gender results show negatively associated with the “environmental-health outcome”. This study reveals with these remarks that Ministry of Health, China should take serious actions to control MDR-TB and launch a comprehensive policy with the help of WHO recommendation.

CHALLENGES IN INITIATION OF TREATMENT OF MULTI DRUG RESISTANT-TB PATIENTS: A HOSPITAL BASED CROSS SECTIONAL STUDY IN JHARKHAND.

BACKGROUND: Multi-drug resistant tuberculosis has become major public health problem and obstacle to effective control of tuberculosis. Over a period of time, there are several landmark achievements including policy and system preparedness for universal access to TB care including mandatory notication of TB cases, development of standard for TB care in India, comprehensive real time TB information management system-NIKSHAY, use of rapid molecular diagnostics, successful innovations in private sector engagement for TB care-Universal access to TB care. Objective was to nd out the challenges in initiation of treatment of Multi Drug Resistant-TB patients get admitted in ITKI Sanatorium Ranchi Jharkhand. METHODS: It was a hospital based cross sectional study carried out from August 2016 to Nov.2018 on Multi drug resistant tuberculosis patients admitted in MDR-TB centre Itki Sanatorium Ranchi after approved from institutional ethics committee. Total study subjects included in study was 64. RESULTS: Most of the study subjects 58 (90.6%) did not know about the MDR-TB. Most of the study subjects 40 (62.5%) had been given reports of CB-NAAT test on same day followed by study subjects 24 (37.5%) on alternate day. No one study subjects 64 (100%) had been given any type of incentive for travelling to pretreatment evaluation centre. In above table, most of the patients 51 (79.7%) had made payment for investigations at district hospital/ SDH level followed by 13 (20.3%) who were free of any expenditure for investigations. Most of the study subjects 60 (93.7%) were not visited by any health staff between nal diagnosis of MDR-TB and initiation of treatment for MDR-TB followed by subjects 4 (6.3%) who were being visited by health staff. Most of the study subjects 48 (75%) were unaware about the NIKSHAY POSHAN SCHEME for MDR-TB patients followed by subjects 16 (25%) who knew about the NIKSHAY POSHAN SCHEME for MDR-TB patients by means of various medium.

MULTI DRUG RESISTANT TUBERCULOSIS IN PREGNANCY

Tuberculosis can develop to multi drug resistant tuberculosis, this will be a serious health problem, not only in Indonesia, also in the world. This disease complexity, length of treatment, adverse effect of drug, make it management become challenging. Pregnancy with physiological changes in it made pregnant woman susceptible to infection, include tuberculosis infection. Data about MDR TB in pregnancy were not much, because TB screening in pregnancy were not often done, also pregnancy it self almost exclude from any trial. Because of MDR TB regiment adverse effect, much of clinician suggest woman in MDR TB treatment to not get pregnant while on it. Management MDR TB on pregnancy use individual regiment, by keep secure and safety aspect of patient, also her fetus.

Safety and Efficacy of Multiple Drug Resistant Tuberculosis Treatment in Patients with Different HIV Statuses

The objective: to analyze and compare frequency and variety of adverse events (AEs) and their impact on outcomes of tuberculosis therapy when treating patients with multiple drug resistant tuberculosis (MDR TB) and different HIV statuses.Subjects and Methods: retrospective observational case-control study of patients registered for treatment with the 4th regimen of chemotherapy for tuberculosis in the city of Vladimir and Vladimir Region in 2014-2016.Results. The proportion of patients who reported any AE during the MDR TB treatment was similar among HIV positive and HIV negative patients and made 85.5%. In patients with concurrent HIV infection and MDR TB, hematopoietic AEs such as anemia, thrombocytopenia were more frequent, while neutropenia was significantly more frequent when comparing groups by the cumulative event probability method. Elevated eosinophil level during treatment was more typical of MDR TB patients. Treatment outcomes in the group of patients with HIV and MDR TB were statistically significantly worse due to the higher frequency of fatal outcomes. At the same time, there was no correlation of AE with unfavorable treatment outcomes. The early initiation of combination therapy with thorough monitoring of hematologic parameters in patients with HIV and MDR TB was safe and effective.

Psychiatric Co-Morbidity and its Associated Risk Factors among Tuberculosis Patients

Aim: To assess psychiatric co-morbidity (i.e., depression and anxiety) and its associated risk factors among Multidrug/Rifampicin Resistant Tuberculosis (MDR/RR-TB) patients. Methods: It was an analytical cross-sectional study carried out in Department of Chest Medicine, Jinnah Post Graduate Medical Centre from February to August, 2015. Eighty diagnosed and registered patients of MDR/RR-TB, able to comprehend Urdu language, between the age range of 18 to 60 years were approached by using convenient sampling technique. Psychiatric co-morbidity i.e., depression and anxiety were assessed by using the Urdu adapted version of Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Questionnaire (GAD – 7). Results: By applying the standard cut off score of 10 or more on PHQ-9 and GAD-7, the frequency of depression was 58 (72.5%) and for anxiety it was 53 (66.25%) out of 80 MDR/RR-TB patients. The multivariant analysis, intensive phase of TB treatment (OR = 3.02; 95% CI = 0.97-9.41) was found to be significantly associated with depression by using PHQ-9 and age group of 18 to 30 years (OR=0.156; 95% CI= 0.02-0.86), pulmonary TB (OR=6.33e+7; 95% CI=0.00-inf) and intensive phase of treatment (OR= 3.892; 95% CI=1.14-13.20) were significantly associated with anxiety by using GAD-7. Conclusion: Frequency of psychiatric co-morbidity was higher among MDR/RR-TB patients. Age group of 18 to 30 years, pulmonary TB and intensive phase of treatment were found to be the risk factors for depression and anxiety among TB patients. Psycho-social factors are strong factors in the successful treatment of tuberculosis. Early detection and proper management of psychiatric co-morbidity during the treatment of MDR-TB needs special attention. Keywords: Anxiety, Depression, Drug resistance, Multidrug resistance tuberculosis, psychiatric co-morbidity,

Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort.

BackgroundSafety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.MethodsMulticentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.ResultsAmong 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8–23.2), 20.7 (95% CI: 19.1–22.4), and 9.7 (95% CI: 8.6–10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4–2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0–80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9–24.8) times/1000 patient-months of linezolid exposure.ConclusionsAEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations.Clinical Trials RegistrationNCT02754765.

Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.

Background Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.MethodsWe conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.ResultsOf 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6–2.4]) or adjusted (HR, 0.8 [95% CI, .5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]).ConclusionsIn a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

Xpert MTB/RIF Use Is Associated With Earlier Treatment Initiation and Culture Conversion Among Patients With Sputum Smear-Negative Multidrug-Resistant Tuberculosis.

BackgroundAlthough rapid molecular diagnostic tests for tuberculosis (TB) have decreased detection time of Mycobacterium tuberculosis and drug resistance, whether their use improves clinical care and outcomes is uncertain. To address these knowledge gaps, we evaluated whether use of the Xpert MTB/RIF assay impacts treatment and clinical outcome metrics among patients treated for sputum smear-negative multidrug-resistant (MDR)-TB.MethodsWe conducted a retrospective cohort study of adult patients initiating treatment for sputum smear-negative MDR-TB at the National Center for Tuberculosis and Lung Diseases in Tbilisi, Georgia from 2011 to 2016. The Xpert MTB/RIF was introduced in Georgia in 2010 and implemented into programmatic use in 2014. Exposure was availability of an Xpert result at time of diagnosis. Time to second-line treatment initiation, sputum culture conversion, and end-of-treatment outcomes were determined. Time to event was compared using a Cox proportional hazards model.ResultsAmong 151 patients treated for sputum smear-negative MDR-TB (96% culture positive), the Xpert was utilized in the clinical management of 78 (52%) patients and not used in 73 (48%). An adjusted analysis controlling for potential confounders found that patients in the Xpert group had shorter median time to second-line treatment (13 vs 56 days; adjusted hazard ratio [aHR], 10.21; P < .0001) and culture conversion (61 vs 93 days; aHR, 1.93; P < .001). There was no difference in treatment outcomes.ConclusionsUse of the Xpert in the management of sputum smear-negative MDR-TB decreases time to second-line therapy and sputum culture conversion, providing evidence of its clinical impact and supporting its programmatic utility.

A Dual Marker for Monitoring MDR-TB Treatment: Host-Derived miRNAs and M. tuberculosis-Derived RNA Sequences in Serum.

BackgroundIn the absence of a late marker of treatment failure or relapse in MDR-TB patients, biomarkers based on host-miRNAs coupled with M. tuberculosis-RNAs evaluated in extracellular vesicles (EVs) are an alternative follow-up for MDR-TB disease. Characterization of EVs cargo to identify differentially expressed miRNAs before and after treatment, and to identify M. tuberculosis-derived RNA in serum EVs from resistant TB patients.MethodsEVs were isolated from serum of 26 drug-resistant TB (DR-TB) patients and 16 healthy subjects. Differential expression of miRNAs in pooled exosomes from both untreated and treated patients was assessed and individually validated at different time points during treatment. In addition, M. tuberculosis RNA was amplified in the same samples by qPCR.ResultsA multivariate analysis using miR-let-7e-5p, -197-3p and -223-3p were found to be a more sensitive discriminator between healthy individuals and those with TB for both DR-TB (AUC= 0.96, 95%, CI=0.907-1) and MDR-TB groups (AUC= 0.95, 95%, CI= 0.89-1). Upregulation of miR-let-7e-5p were observed at the time of M. tuberculosis negative culture T(3-5) for MDR-TB group or for long-term T(9-15) for MDR-TB group without diabetes (T2DM). A second pathogen-based marker based on 30kDa and 5KST sequences was detected in 33% of the MDR-TB patients after the intensive phase of treatment. The miR-let7e-5p is a candidate biomarker for long-term monitoring of treatment for the group of MDR-TB without T2DM. A dual marker of host-derived miR-let7e-5p and M. tuberculosis-derived RNA for monitoring-TB treatment based in serum EVs.ConclusionA dual marker consisting of host-derived miR-let7e-5p and M. tuberculosis-derived RNA, could be an indicator of treatment failure or relapse time after treatment was completed.

Global scenario and recent advances in molecular diagnosis and management of drug-resistant tuberculosis

Tuberculosis (TB) is one of the oldest communicable bacterial diseases, spreads predominantly by inhalation of infected respiratory droplets. It is a curable and preventable disease yet remains the leading infectious cause of human death worldwide. The TB burden is high among developing nations of Asia and Africa. Major obstacles in controlling TB are patient’s non-compliance to the anti-tubercular therapy, co-infection with Human immunodeficiency virus (HIV), low socioeconomic status, crowded living condition, inadequate rapid diagnostic testing facilities especially in resource-poor developing countries, delay in diagnosis and initiation of therapy, and the emergence of drug-resistant strains of Mycobacterium tuberculosis (MTB). Multidrug-resistant (MDR-TB), extensively drug-resistant (XDR-TB), and total drug-resistant (TDR-TB) MTB strains are difficult to treat and are associated with frequent treatment failures and high mortality. The recent advent of molecular techniques including nucleic acid amplification tests (NAATs) and whole-genome sequencing (WGS) have significantly ameliorated the rapid detection of TB cases and drug-resistant MTB. This, in turn, enabled the early initiation of therapy and development of novel treatment plans which is crucial for the global TB elimination target. The World Health Organization (WHO) 2020 guideline prioritizes the use of newer drugs as part of all-oral regimens for the treatment of MDR-TB. Apart from the use of newer drug delivery methods, host factors including immune functions and cytokine responses as well as mycobacterial enzymatic pathways are targeted in TB drug development. Adjuvant therapy employing host-directed approaches is increasingly studied through the time-tested pathogen-targeted approach remains the mainstay in the current treatment of MDR-TB.

Repurposing Cefazolin-Avibactam for the Treatment of Drug Resistant Mycobacterium tuberculosis.

Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD). Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups. Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children <3 years with disseminated TB, 9.70 and 84.07% for 3–5 years-old children, and 17.20 and 76.13% for 12–15 years-old children. The PK/PD-derived susceptibility breakpoint was dose dependent at 1–2 mg/L. Conclusion: Cefazolin-avibactam combination demonstrates efficacy against both drug susceptible and MDR-TB clinical strains in the HFS-TB and could potentially be used to treat children with tuberculosis. Clinical studies are warranted to validate our findings.

High rates of culture conversion and low loss to follow-up in MDR-TB patients managed at Regional Referral Hospitals in Uganda

BackgroundMulti-drug resistant—tuberculosis (MDR-TB) is an emerging public health concern in Uganda. Prior to 2013, MDR-TB treatment in Uganda was only provided at the national referral hospital and two private-not-for profit clinics. From 2013, it was scaled up to seven regional referral hospitals (RRH). The aim of this study was to measure interim (6 months) treatment outcomes among the first cohort of patients started on MDR-TB treatment at the RRH in Uganda.MethodsThis was a cross-sectional study in which a descriptive analysis of data collected retrospectively on a cohort of 69 patients started on MDR-TB treatment at six of the seven RRH between 1st April 2013 and 30th June 2014 and had been on treatment for at least 9 months was conducted.ResultsOf the 69 patients, 21 (30.4%) were female, 39 (56.5%) HIV-negative, 30 (43.5%) resistant to both isoniazid and rifampicin and 57 (82.6%) category 1 or 2 drug susceptible TB treatment failures. Median age at start of treatment was 35 years (Interquartile range (IQR): 27–45), median time-to-treatment initiation was 27.5 (IQR: 6–89) days and of the 30 HIV-positive patients, 27 (90.0%) were on anti-retroviral treatment with a median CD4 count of 206 cells/microliter of blood (IQR: 113–364.5). Within 6 months of treatment, 59 (85.5%) patients culture converted, of which 45 (65.2%) converted by the second month and the other 14 (20.3%) by the sixth month; one (1.5%) did not culture convert; three (4.4%) died; and six (8.8%) were lost-to-follow up. Fifty (76.8%) patients experienced at least one drug adverse event, while 40 (67.8%) gained weight. Mean weight gained was 4.7 (standard deviation: 3.2) kilograms.ConclusionsDespite MDR-TB treatment initiation delays, most patients had favourable interim treatment outcomes with majority culture converting early and very few getting lost to follow-up. These encouraging interim outcomes indicate the potential for success of a scale-up of MDR-TB treatment to RRH.

Pharmacokinetics and Drug-Drug Interactions of Abacavir and Lamuvudine Co-administered With Antituberculosis Drugs in HIV-Positive Children Treated for Multidrug-Resistant Tuberculosis.

Given the high prevalence of multidrug-resistant (MDR)-TB in high HIV burden settings, it is important to identify potential drug-drug interactions between MDR-TB treatment and widely used nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-positive children. Population pharmacokinetic models were developed for lamivudine (n = 54) and abacavir (n = 50) in 54 HIV-positive children established on NRTIs; 27 with MDR-TB (combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, fluoroquinolones, and amikacin), and 27 controls without TB. Two-compartment models with first-order elimination and transit compartment absorption described both lamivudine and abacavir pharmacokinetics, respectively. Allometric scaling with body weight adjusted for the effect of body size. Clearance was predicted to reach half its mature value 2 (lamivudine) and 3 (abacavir) months after birth, with completion of maturation for both drugs at 2 years. No significant difference was found in key pharmacokinetic parameters of lamivudine and abacavir when co-administered with routine drugs used for MDR-TB in HIV-positive children.

Design and prototype of TOMO: an app for improving drug resistant TB treatment adherence.

Background: Drug resistance and multi drugs tuberculosis (DR/MDR-TB) are associated with patients' low adherence to undergoing complex treatment. Driven by the increasing use and penetration of a smartphone and the End of TB Strategy that seeks for digital health solution, Center for Tropical Medicine Universitas Gadjah Mada has developed TOMO, an Android-based app for improving medication adherence in MDR-TB. Objective: This paper aims to present the sequential steps to develop the app, its general architecture, and its functionalities. Methods: It is a design thinking process involving two MDR-TB referral centers, district health offices, primary health centers, and MDR-TB patients in Central Java and Yogyakarta, Indonesia. We adopted the Principles for Digital Development to develop and design the app. MDR-TB treatment guideline from the Indonesian Ministry of Health was used to develop functionalities of the app for improving adherence. Results: TOMO app could be used by patients, primary health centers, clinical teams, and case managers. The app prototype features include adverse event records and reports, medication-taking reminders, and communication between the patient and the TB-MDR case manager. We have successfully tested the functionalities based on four use cases: patients with high adherence, patients with low adherence, patients with adverse events, and patients following treatment in the primary health center without any visit to the MDR-TB center. Conclusion: TOMO app has contributed to the limited body of literature on improving TB-MDR adherence with digital health intervention, especially using a health app. The app has been tested using four scenarios. We will follow up with usability testing before implementing the app in a real setting.