Multidrug-resistant Tuberculosis Treatment Regimen Research Articles

Formation of treatment regimens in newly diagnosed patients before the diagnosis of pulmonary tuberculosis verification

Abstract. One of the basic principles of treatment of tuberculosis patients is the appointment of treatment taking into account the drug resistance of Mycobacterium tuberculosis (MBT). However, during treatment, it may be necessary to change the intake regimen when new data on drug resistance become available. The search for ways to choose the optimal treatment method seems relevant.Aim: To analyze the prescribed regimens and the reason for their correction in newly identified patients before verifying the diagnosis of tuberculosis.Material and Methods. The following methods were used to detect MBT: luminescent microscopy, molecular genetic methods and seeding on liquid and solid media. Tests for drug sensitivity were conducted in parallel. The study group consisted of patients with established bacterial excretion (n = 79), whose diagnosis was confirmed by cultural methods. A retrospective method was used in the analysis.Results. At the beginning of treatment with bacterioscopy and polymerase chain reaction methods MBT was detected in 65/79 (82.2%) cases, the remaining 14 cases were detected only by culture methods. Forced change of the therapy regimen during treatment after receiving the results was in 25/79 (31.6%) cases, of which 1/25 (4%) with isoniazid resistance, 7/25 (28%) with multidrug-resistant tuberculosis, 17/25 (68%) with the pre-extensive drug resistance regimen. The latter was prescribed only after receiving results of tests for drug sensitivity on liquid and solid media after 1–3 months. The multidrug-resistant tuberculosis treatment regimen decreased after receiving data on resistance to fluoroquinolones in accordance with the seeding data, but the largest number of patients still remained on this regimen – 41/79 (51.9%). Among these patients a change in chemotherapy regimen from multidrug-resistant tuberculosis to pre-extensive drug resistance during the intensive phase of treatment occurred in 17/25 (68%).Conclusion. When prescribing a regimen, it is recommended to assess the risk of changing the regimen and, if there are predictors, apply a chemotherapy regimen before treatment.

Assessing the Effectiveness of a Short Injectable Treatment Regimen for Multidrug-Resistant Tuberculosis: Clinical Outcomes in Khyber Pakhtunkhwa

Assessing the Effectiveness of a Short Injectable Treatment Regimen for Multidrug-Resistant Tuberculosis: Clinical Outcomes in Khyber Pakhtunkhwa

Clinical application of whole-genome sequencing in the management of extensively drug-resistant tuberculosis: a case report

BackgroundWhole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens.MethodsWe utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong’oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes.ResultsDrug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs.ConclusionWe propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.

ТЕРАПЕВТИЧЕСКИЙ ЛЕКАРСТВЕННЫЙ МОНИТОРИНГ БЕДАКВИЛИНА ПРИ ЛЕЧЕНИИ ДЕТЕЙ С ТУБЕРКУЛЕЗОМ ОРГАНОВ ДЫХАНИЯ С МНОЖЕСТВЕННОЙ ЛЕКАРСТВЕННОЙ УСТОЙЧИВОСТЬЮ

Use of Bedaquiline in children is studied relatively rarely therefore, according to the WHO experts, it is necessary to further conduct the research on the effectiveness and safety of including of the Bedaquiline drug in chemotherapy regimens in children as well as to obtain the new data on the characteristics of its metabolism in routine clinical practice. The purpose of this research was to evaluate the therapeutic monitoring performance of the Bedaquiline drug use in treatment of pediatric patients with multidrug-resistant tuberculosis (TB). Materials and methods used: pharmacokinetic (PK) parameters were determined in 10 patients of both genders aged 6 to 17 y/o who had received Bedaquiline drug as part of complex therapy in the treatment regimen for multidrug-resistant TB (MDR-TB). All patients had not received anti-tuberculosis drugs previously. Results: during the period of initial daily administration (saturation) of the Bedaquiline drug, Cmax was 3901 ng/ml, Cmin 165 ng/ml, Me 1672 (781.7-2562.3; 95% CI) ng/ml. During the period of maintenance dose intake (3 times per week) prior to taking the drug, Cmax was 987 ng/ml, Cmin 251 ng/ml, Me 504 (340.2-667.7; 95% CI) ng/ml, two hours after Bedaquiline intake Cmax was 2387 ng/ml, Cmin 576 ng/ml, Me 1429 (1005.9-1852.1; 95% CI) ng/ml. Conclusion: the data obtained coincide with the bibliographical data on the Bedaquiline PK in children aged 5 to 8 y/o issues.

Adaptive evaluation of mHealth and conventional adherence support interventions to optimize outcomes with new treatment regimens for drug-resistant tuberculosis and HIV in South Africa (ADAP-TIV): study protocol for an adaptive randomized controlled trial

BackgroundHighly effective, short-course, bedaquiline-containing treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and integrase strand transfer inhibitor (INSTI)-containing fixed dose combination antiretroviral therapy (ART) have radically transformed treatment for MDR-TB and HIV. However, without advances in adherence support, we may not realize the full potential of these therapeutics. The primary objective of this study is to compare the effect of adherence support interventions on clinical and biological endpoints using an adaptive randomized platform.MethodsThis is a prospective, adaptive, randomized controlled trial comparing the effectiveness of four adherence support strategies on a composite clinical outcome in adults with MDR-TB and HIV initiating bedaquiline-containing MDR-TB treatment regimens and receiving ART in KwaZulu-Natal, South Africa. Trial arms include (1) enhanced standard of care, (2) psychosocial support, (3) mHealth using cellular-enabled electronic dose monitoring, and (4) combined mHealth and psychosocial support. The level of support will be titrated using a differentiated service delivery (DSD)-informed assessment of treatment support needs. The composite primary outcome will include survival, negative TB culture, retention in care, and undetectable HIV viral load at month 12. Secondary outcomes will include individual components of the primary outcome and quantitative evaluation of adherence on TB and HIV treatment outcomes.DiscussionThis trial will evaluate the contribution of different modes of adherence support on MDR-TB and HIV outcomes with WHO-recommended all-oral MDR-TB regimens and ART in a high-burden operational setting. We will also assess the utility of a DSD framework to pragmatically adjust levels of MDR-TB and HIV treatment support.Trial registrationClinicalTrials.gov NCT05633056. Registered on 1 December 2022

Hearing assessment and treatment outcome in ENT tuberculosis at a tertiary hospital in India

AimAn attempt has been made to observe the response of anti-Koch’s treatment and the effect of anti-Koch’s treatment on hearing in ENT tuberculosis patients by pure tone audiometry.Material and methodsA prospective observational study was carried out at the Government Medical College Hospital. A total of 200 cases diagnosed with tuberculosis in the head and neck regions were included in the study. Sputum/pus of patients were sent for cartridge-based nucleic acid amplification test (CBNAAT). Hearing assessment was done with PTA1 at the start of the treatment, PTA2 after the intensive phase (IP) at 2 months for newly diagnosed patients and at 3 months for previously treated patients, and PTA3 at the end of the AKT treatment given as per guidelines.ResultsAmong 200 ENT tuberculosis patients, 176 patients were cured with a new case regimen, and one patient was a defaulter. Among 19 patients who were previously treated cases (CAT II regimen), two patients had treatment failure, and the other 17 patients were cured. Four patients diagnosed to have multidrug-resistant tuberculosis (MDR-TB) on the initial drug susceptibility testing (DST) were given 24 months’ treatment according to the recent guidelines of MDR-TB treatment regimen, and the patients were cured. In the present study of 200 patients, in the first PTA, 192 patients had normal hearing; in the second PTA, 106 patients had normal hearing; and in the third PTA, 35 patients had normal hearing. 21.7% of cases who were on aminoglycoside therapy developed significant sensorineural hearing loss in high frequency.ConclusionAnti-Koch’s treatment (AKT) has proven effective in ENT tuberculosis. All patients taking anti-Koch’s treatment should be regularly monitored for hearing loss, adherence to treatment, drug-resistant variants, and local recurrences.

Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen

Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB). The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens. Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log10 cfu/mL/day) of 0.31 (95% CI 0.17-0.58) and 0.34 (95% CI 0.21-0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12-0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism. Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.

Surveillance of multidrug-resistant tuberculosis in sub-Saharan Africa through wastewater-based epidemiology

The spread of multidrug-resistant tuberculosis (MDR-TB) is a serious public health issue, particularly in developing nations. The current methods of monitoring drug-resistant TB (DR-TB) using clinical diagnoses and hospital records are insufficient due to limited healthcare access and underreporting. This study proposes using Wastewater-Based Epidemiology (WBE) to monitor DR-TB in six African countries (Ghana, Nigeria, Kenya, Uganda, Cameroon, and South Africa) and examines the impact of treated wastewater on the spread of TB drug-resistant genes in the environment. Using droplet-digital polymerase chain reaction (ddPCR), the study evaluated untreated and treated wastewater samples in selected African countries for TB surveillance. There was a statistically significant difference in concentrations of genes conferring resistance to TB drugs in wastewater samples from the selected countries (p-value<0.05); South African samples exhibited the highest concentrations of 4.3(±2,77), 4.8(±2.96), 4.4(±3,10) and 4.7(±3,39) log copies/ml for genes conferring resistance to first-line TB drugs (katG, rpoB, embB and pncA respectively) in untreated wastewater. This may be attributed to the higher prevalence of TB/MDR-TB in SA compared to other African countries. Interestingly, genes conferring resistance to second-line TB drugs such as delamanid (ddn gene) and bedaquiline (atpE gene) were detected in relatively high concentrations (4.8(±3,67 and 3.2(±2,31 log copies/ml for ddn and atpE respectively) in countries, such as Cameroon, where these drugs are not part of the MDR-TB treatment regimens, perhaps due to migration or the unapproved use of these drugs in the country. The gene encoding resistance to streptomycin (rrs gene) was abundant in all countries, perhaps due to the common use of this antibiotic for infections other than TB. These results highlight the need for additional surveillance and monitoring, such as WBE, to gather data at a community level. Combining WBE with the One Health strategy and current TB surveillance systems can help prevent the spread of DR-TB in populations.

Comparing adherence to MDR-TB treatment among patients on self-administered therapy and those on directly observed therapy: non-inferiority randomized controlled trial

BackgroundAdherence is key to the treatment success of multi-drug resistant tuberculosis (MDR-TB) and prevention of community transmission. Directly observed therapy (DOT) is the recommended approach for the management of patients with MDR-TB. Uganda implements a health facility-based DOT approach where all patients diagnosed with MDR-TB report to the nearest private or public health facility for daily observation of ingesting their medicines by a health care provider. Directly observed therapy is very costly for both the patient and health care system. It follows the assumption that MDR TB patients have a history of poor adherence to TB treatment. But only 21% of MDR-TB patients notified globally and 1.4–12% notified in Uganda had been previously treated for TB. The shift to all oral treatment regimen for MDR-TB provides an opportunity for the exploration of self-administered therapy for this group of patients even with use of remotely operated adherence technology. We are conducting a non-inferiority open-label randomized controlled trial to compare adherence to MDR-TB treatment among patients on self-administered therapy (measured by Medication Events Monitoring System (MEMS) technology) with a control group on DOT.MethodsWe plan to enrol 164 newly diagnosed MDR-TB patients aged ≥ 8 years from three regional hospitals based in rural and urban Uganda. Patients with conditions that affect their dexterity and ability to operate the MEMS-operated medicine equipment will not be eligible to participate in the trial. Patients are randomized to either of the two study arms: self-administered therapy with adherence being monitored using MEMS technology (intervention arm) or health facility-based DOT (control arm) and will be followed up monthly. Adherence is measured by the number of days the medicine bottle is open to access medication as recorded by the MEMS software in the intervention arm and treatment complaint days as recorded in the TB treatment card in the control arm. The primary outcome is the comparison of adherence rates between the two study arms.DiscussionThe evaluation of self-administered therapy for patients with MDR-TB is important to inform cost-effective management strategies for these patients. The approval of all oral regimens for the treatment of MDR-TB provides an opportunity for innovations such as MEMS technology to support sustainable options for MDR-TB treatment adherence support in low-resource settings.Trial registrationPan African Clinical Trials Registry, Cochrane #PACTR202205876377808. Retrospectively registered on 13 May 2022

Clinical profile and outcome in patients with rifampicin-resistant tuberculosis taking shorter multidrug-resistant tuberculosis treatment regimen at a tertiary care hospital in South Gujarat

Background: India remains one of the six countries with an enormous multidrug-resistant tuberculosis (MDR TB) burden. Shorter MDR regimen is more economical/cheaper, shorter and having an improved adherence for Rifampicin resistant (RR)-TB. There were not many studies on this shorter MDR regimen (containing high-dose moxifloxacin) in India, we had carried out this study to find out outcomes and adverse drug reactions (ADRs) of this Shorter MDR regimen. Aims and Objectives: To study the clinical profile, interim and final outcome, and ADRs in RR-TB patients taking shorter MDR regimens. Materials and Methods: Prospective observational longitudinal study which was carried out in the Department of Respiratory Medicine Department, New Civil Hospital, Surat from January 2019 to June 2020. All patients who were diagnosed as RR-TB by cartridge-based nucleic acid amplification were enrolled in the study. Eligible Patients (n = 60) were started on shorter MDR regimen and were followed up. Results: Out of these 60 patients 35 (58.3%) were male and 25 (41.6%) were female. The age group mainly included was between 20 and 40 years. Out of 60 patients, 55 (91.6%) had pulmonary and 5 (8.3%) had extrapulmonary TB. Interim Outcome in the form of culture conversion at the end of 4th, 5th, and 6th month was seen in 21 (45.65%), 37 (80.43%), and 45 (97.83%), respectively. The final outcome among 60 patients were 33 (55%) cured, 12 (20%) treatment completed, 6 (10%) lost to follow-up, 5 (8.33%) regimen changed, 3 (5%) died, and failure in 1 (1.66%). These results were matching with most of the other studies. Conclusion: This study showed successful outcome (cured and treatment completed) in 45 patients (75%) and adverse outcome (died, lost to follow-up, and failure) in 10 patients (16.67%). A shorter MDR regimen is shorter, cheaper, effective in most of the RR-TB patients and is well tolerated with mild side effects.

Prospects of contezolid (MRX-I) against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis.

Tuberculosis has become a great global public health threat. Compared with drug-susceptible tuberculosis (TB), the treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) involve more severe adverse events and poorer treatment outcomes. Linezolid (LZD) is the first oxazolidinones used for TB. Thanks to its potent activity against Mycobacterium tuberculosis, LZD has become one of the key agents in the regimens against MDR/XDR-TB. However, this drug may cause intolerability and other adverse events. Contezolid, another novel oxazolidinone, can also inhibit M. tuberculosis, still with fewer adverse effects compared with LZD. This paper is to prospect the potentials of contezolid in the treatment of MDR/XDR-TB, with focus on its efficacy and possible adverse effects.

Effectiveness and Safety of 9-Month Treatment Regimen for Multidrug-Resistant Tuberculosis in the Philippines

Background: The Philippines has a burden of drug-resistant tuberculosis (DR-TB). One of the key challenges in the programmatic management of DR-TB (PMDT) is the high rate of loss to follow-up (38% in the 2010 cohort). An urgent need for a shorter, more tolerable, less expensive treatment regimen exists. The aim of the operational study is to determine the efficacy and safety of the short treatment regimen among drug resistant TB. Methods: This is a prospective single-arm cohort study evaluating the effectiveness and safety of a shorter 9 - 11-month treatment regimen (9MTR) for rifampicin-resistant/multi-drug resistant TB (RR/MDR-TB) in 10 PMDT facilities. All eligible consenting adult patients with rifampicin-resistant TB were enrolled and received the standardized 9-month treatment regimen (9MTR), including injectables, with a follow-up after 12 months of treatment completion. Results: A total of 329 patients were enrolled from July 2015 to December 2016. At the 6th month post-enrollment, 256 (77.8%) of them had culture-negative test results. The end-of-treatment success rate was 74.1% (224 [68.0%] were cured and 20 [6.1%] completed the treatment). On the other hand, 10 (3.0%) died, 41 (12.5%) lost to follow-up, 33 (10.0%) withdrawn, 1 (0.3%) treatment failure. In the 12th month after 9MTR completion, among the 244 patients with successful treatment, 198 (81.1%) had culture-negative results, while there were 46 patients whose culture tests were not done. One patient developed TB relapse with fluoroquinolone resistance. The majority of the adverse events were mild that occurred mostly during the first 6 months of treatment. Conclusion: The 9-month treatment regimen had a high treatment success rate with a favorable safety profile. The loss to follow-up was reduced; however, it was still a challenge. The introduction of the 9MTR via operational research had a major impact on building national capacity and infrastructure for the programmatic adoption of a new regimen. Ten PMDT centers received training and experience, created diagnostic pathways, and active drug safety monitoring and management were built.

Genomic Profiling of Mycobacterium tuberculosis Strains, Myanmar.

Multidrug resistance is a major threat to global elimination of tuberculosis (TB). We performed phenotypic drug-susceptibility testing and whole-genome sequencing for 309 isolates from 342 consecutive patients who were given a diagnosis of TB in Yangon, Myanmar, during July 2016‒June 2018. We identified isolates by using the GeneXpert platform to evaluate drug-resistance profiles. A total of 191 (62%) of 309 isolates had rifampin resistance; 168 (88%) of these rifampin-resistant isolates were not genomically related, indicating the repeated emergence of resistance in the population, rather than extensive local transmission. We did not detect resistance mutations to new oral drugs, including bedaquiline and pretomanid. The current GeneXpert MTB/RIF system needs to be modified by using the newly launched Xpert MTB/XDR cartridge or line-probe assay. Introducing new oral drugs to replace those currently used in treatment regimens for multidrug-resistant TB will also be useful for treating TB in Myanmar.

Diagnostic Accuracy of Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: A Systematic Review with Meta-Analysis.

Introduction: Pyrazinamide (PZA) susceptibility testing plays a critical role in determining the appropriate treatment regimens for multidrug-resistant tuberculosis. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of sequencing PZA susceptibility tests against culture-based susceptibility testing methods as the reference standard. Methods: We searched the MEDLINE/PubMed, Embase, and Web of Science databases for the relevant records. The QUADAS-2 tool was used to assess the quality of the studies. Diagnostic accuracy measures (i.e., sensitivity and specificity) were pooled with a random-effects model. All statistical analyses were performed with Meta-DiSc (version 1.4, Cochrane Colloquium, Barcelona, Spain), STATA (version 14, Stata Corporation, College Station, TX), and RevMan (version 5.3, The Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark) software. Results: A total of 72 articles, published between 2000 and 2019, comprising data for 8,701 isolates of Mycobacterium tuberculosis were included in the final analysis. The pooled sensitivity and specificity of the PZA sequencing test against all reference tests (the combination of BACTEC mycobacteria growth indicator tube 960 (MGIT 960), BACTEC 460, and proportion method) were 87% (95% CI: 85-88) and 94.7% (95% CI: 94-95). The positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve estimates were found to be 12.0 (95% CI: 9.0-16.0), 0.17 (95% CI: 0.13-0.21), 106 (95% CI: 71-158), and 96%, respectively. Deek's test result indicated a low likelihood for publication bias (p = 0.01). Conclusions: Our analysis indicated that PZA sequencing may be used in combination with conventional tests due to the advantage of the time to result and in scenarios where culture tests are not feasible. Further work to improve molecular tests would benefit from the availability of standardized reference standards and improvements to the methodology.

Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam.

ObjectiveManagement of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data.MethodWe conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence.ResultsOut of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91–37.42]), renal dysfunction (HR = 8.46 [1.91–37.42]), alcoholism (HR = 13.28 [5.04–34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14–1.43]).ConclusionWhile a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

Design of Multidrug-Resistant Tuberculosis Treatment Regimens Based on DNA Sequencing.

Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens. NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates. In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST. NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.

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.

Factors affecting outcome of longer regimen multidrug-resistant tuberculosis treatment in West Java Indonesia: A retrospective cohort study.

BackgroundMultidrug-resistant tuberculosis had high treatment failure and mortality. Success rate of treatment currently 56% at global level, 48% in Indonesia and 36% in West Java province, the most populated province and surround Jakarta, the capitol of Indonesia.ObjectiveThis study aimed to evaluate factors affecting success of multidrug-resistant tuberculosis treatment in patients using longer treatment regimen in West Java Indonesia.MethodsThis was a retrospective cohort study of multidrug-resistant tuberculosis patients treated with longer regimen at Hasan Sadikin General Hospital from January 2015 to December 2017. Potential risk factors associated with the treatment outcome were analyzed using multiple logistic regression.ResultsA total of 492 patients were enrolled during the study period. Fifty percents multidrug-resistant tuberculosis patients had successful treatment outcome. Age ≤45 years, male, normal body mass index, no previous tuberculosis treatment, culture conversion ≤2 months, acid fast bacilli sputum smear ≤+1 were independent factors associated with increased treatment success. Sputum culture conversion ≤2 months was the major factor affecting successful outcome (RR 2.79; 95% CI: 1.61–4.84; p-value<0.001). Human Immunodeficiency Virus infection, chronic kidney disease, and cavitary lesion were independent risk factors for unfavourable outcome.ConclusionAge, gender, body mass index, tuberculosis treatment history, time of sputum conversion, acid fast bacilli sputum smear, HIV infection, chronic kidney disease, and cavitary lesion can be used as predictors for longer multidrug-resistant tuberculosis treatment regimen outcome.

Effectiveness and safety of fully oral modified shorter treatment regimen for multidrug-resistant tuberculosis in Georgia, 2019-2020.

Tuberculosis treatment is challenging, especially among people with drug-resistant forms of tuberculosis. The introduction of fully oral modified short treatment regimen has a great potential to shorten duration of treatment, improve safety and ultimately increase treatment success rate. In 2019 Georgia has piloted the modified fully oral shorter treatment regimen in a routine programmatic condition. Our study aimed to evaluate effectiveness and safety of the modified shorter treatment regimen in Georgia among the first 25 consecutively enrolled patients with rifampicin-resistant tuberculosis with proven sensitivity to fluoroquinolone and without prior exposure to second-line tuberculosis drugs. Regimen consisted of 9-month daily administration of bedaquilline, linezolid, levofloxacin, clofazimine and cycloserine. Study patients were enrolled between March-August 2019. We used a national electronic surveillance system, medical records and active TB drug-safety monitoring and management database to extract study related data. The mean age of the study participants was 48 years, 68% were male, 8% were HIV positive, 16% had diabetes and 12% tested positive for hepatitis C infection. The median time to culture conversion among 16 patients who were culture positive at treatment initiation was 1.0 (95% CI: 1.0–2.0) month. Of those, by the end of treatment 15 patients converted to negative. Out of 25 patients in the study cohort 22 (88%) had successful treatment outcome, one patient (4%) died and two (8%) were lost to follow up. The regimen was largely well tolerated. Three patients (12%) experienced serious adverse events - two cases were possibly related to TB drugs in the regimen. Seven patients developed adverse events of interest in eight instances, including musculoskeletal (twice), psychiatric, gas-trointestinal disorders, hepatotoxicity, peripheral neuropathy, cardiotoxicity and myelosuppression (once each). In four patients (16%) the duration of the treatment was extended beyond nine months due to insufficient radiological improvements. Our findings demonstrate that good treatment outcomes are achievable in people with fluoroquinolone-sensitive tuberculosis within routine programmatic conditions using fully oral modified short treatment regimen. The extensive use of fully oral modified shorter treatment regimen in Georgia and other high priority countries in the World Health Organization European Region is warranted.

Additional Drug Resistance in Patients with Multidrug-resistant Tuberculosis in Korea: a Multicenter Study from 2010 to 2019.

BackgroundDrug-resistance surveillance (DRS) data provide key information for building an effective treatment regimen in patients with multidrug-resistant tuberculosis (MDR-TB). This study was conducted to investigate the patterns and trends of additional drug resistance in MDR-TB patients in South Korea.MethodsPhenotypic drug susceptibility test (DST) results of MDR-TB patients collected from seven hospitals in South Korea from 2010 to 2019 were retrospectively analyzed.ResultsIn total, 633 patients with MDR-TB were included in the analysis. Of all patients, 361 (57.0%) were new patients. All patients had additional resistance to a median of three anti-TB drugs. The resistance rates of any fluoroquinolone (FQ), linezolid, and cycloserine were 26.2%, 0.0%, and 6.3%, respectively. The proportions of new patients and resistance rates of most anti-TB drugs did not decrease during the study period. The number of additional resistant drugs was significantly higher in FQ-resistant MDR-TB than in FQ-susceptible MDR-TB (median of 9.0 vs. 2.0). Among 26 patients with results of minimum inhibitory concentrations for bedaquiline (BDQ) and delamanid (DLM), one (3.8%) and three (11.5%) patients were considered resistant to BDQ and DLM with interim critical concentrations, respectively. Based on the DST results, 72.4% and 24.8% of patients were eligible for the World Health Organization's longer and shorter MDR-TB treatment regimen, respectively.ConclusionThe proportions of new patients and rates of additional drug resistance in patients with MDR-TB were high and remain stable in South Korea. A nationwide analysis of DRS data is required to provide effective treatment for MDR-TB patients in South Korea.