Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China

ABSTRACTOur study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined forM. tuberculosisisolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.

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National treatment outcome and predictors of death and treatment failure in multidrug-resistant tuberculosis in Ethiopia: a 10-year retrospective cohort study

BMJ Open ◽

10.1136/bmjopen-2020-040862 ◽

2021 ◽

Vol 11 (8) ◽

pp. e040862

Author(s):

Habteyes Tola ◽

K Holakouie-Naieni ◽

Mohammad Ali Mansournia ◽

Mehdi Yaseri ◽

Dinka Fikadu Gamtesa ◽

...

Keyword(s):

Treatment Outcome ◽

Treatment Failure ◽

Treatment Success ◽

Multidrug Resistant ◽

The Past ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

ObjectivesTreatment success rate in patients treated for multidrug-resistant tuberculosis (MDR-TB) is low, but predictors of treatment failure and death have been under-reported. Thus, we aimed to determine the national proportion of treatment success rate in the past 10 years and factors that predict treatment failure and death in patients with MDR-TB in Ethiopia.SettingA retrospective cohort study with a 10-years follow-up period was conducted in 42 MDR-TB treatment-initiating centres in Ethiopia.ParticipantsA total of 3395 adult patients with MDR-TB who had final treatment outcome and who were treated under national TB programme were included. Data were collected from clinical charts, registration books and laboratory reports. Competing risk survival analysis model with robust standard errors (SE) was used to determine the predictors of treatment failure and death.Primary and secondary outcomesTreatment outcome was a primary outcome whereas predictors of treatment failure and death were a secondary outcome.ResultsThe proportion of treatment success was 75.7%, death rate was 12.8%, treatment failure was 1.7% and lost to follow-up was 9.7%. The significant predictors of death were older age (adjusted hazard ratio (AHR)=1.03; 95% CI 1.03 to 1.05; p<0.001), HIV infection (AHR=2.0; 95% CI 1.6 to 2.4; p<0.001) and presence of any grade of anaemia (AHR=1.7; 95% CI 1.4 to 2.0; p<0.001). Unlike the predictors of death, all variables included into multivariable model were not significantly associated with treatment failure.ConclusionIn the past 10 years, although MDR-TB treatment success in Ethiopia has been consistently favourable, the proportion of patients who died is still considerable. Death could be attributed to advanced age, HIV infection and anaemia. Prospective cohort studies are necessary to further explore the potentially modifiable predictors of treatment failure.

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Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

BioMed Research International ◽

10.1155/2017/4563826 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Y. Hu ◽

L. Xu ◽

Y. L. He ◽

Y. Pang ◽

N. Lu ◽

...

Keyword(s):

Gene Mutations ◽

Multidrug Resistant ◽

Rapid Screening ◽

Second Line ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Improper Use ◽

Mdr Tb

This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations inMycobacterium tuberculosis(M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P<0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates containedgyrAmutation and 88.5% KAN-resistant isolates hadrrsmutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.

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Increasing multidrug-resistant tuberculosis in Ho Chi Minh City: a retrospective study of 2,266 cases from 2011 to 2015

10.21203/rs.2.12034/v2 ◽

2019 ◽

Author(s):

Le Hong Van ◽

Phan Trieu Phu ◽

Dao Nguyen Vinh ◽

Vo Thanh Son ◽

Nguyen Thi Hanh ◽

...

Keyword(s):

Risk Factors ◽

Treatment Outcome ◽

Multidrug Resistant ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Poor Treatment ◽

Mdr Tb ◽

Poor Outcomes ◽

Poor Treatment Outcome

Abstract Background: Multidrug resistant tuberculosis (MDR-TB) remains a serious public health problem with poor treatment outcome. Predictors of poor outcomes vary in different regions. Vietnam is among the 30 countries with high burden of MDR-TB. We aim to describe demographic characteristics and identify risk factors for poor outcome of MDR-TB in Ho Chi Minh City (HCMC), the most populous city in Vietnam. Methods: This retrospective study included 2,266 patients who initiated MDR-TB treatment from 2011 to 2015 in HCMC. Treatment outcomes were available in 2,240 patients. Data was collected from standardized paper-based treatment cards and electronic records. Kruskal Wallis test was used to diagnose the change of median of age and body mass index (BMI) over 5 years, and Wilcoxon test to compare median BMI of patients with and without diabetes mellitus. Chi squared test was used to compare categorical variables. Multivariate logistic regression on multiple imputation was used to identify risk factors for poor outcomes. Statistical analysis was performed using R program. Results: Among 2,266 eligible cases, 60.2% were failure of category I or II regimen, 57.7% were underweight, 30.2% had diabetes mellitus and 9.6% were HIV positive. Notification rate increased 24.7% from 2011 to 2015.Treatment success rate was 73.3%. Risk factors for poor treatment outcome included HIV co-infection (adjusted odds ratio (aOR): 2.94), advanced age (aOR: 1.45 for every increase of 5 years for patients 60 years or older), having history of MDR-TB treatment (aOR: 5.53), sputum smear grade scanty and 1+ (aOR: 1.47), smear grade 2+ or 3+ (aOR: 2.06), low BMI (aOR: 0.83 for every increase of 1kg/m2 of BMI for patients with BMI<21). Conclusion: Our study describes the increasing cases of MDR-TB in HCMC during 2011 to 2015. Patients with HIV, high smear grade, malnutrition and history of previous MDR-TB treatment should receive additional care. Keywords: multidrug resistant tuberculosis; retrospective; treatment outcome; risk factors; Vietnam

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Different profiles of body mass index evolutions among patients with multidrug-resistant tuberculosis: a retrospective cohort study.

10.21203/rs.2.16913/v1 ◽

2019 ◽

Author(s):

Alhassane Diallo ◽

Boubacar Djelo Diallo ◽

Lansana Mady Camara ◽

Lucrèce Ahouéfa Nadège Kounoudji ◽

Boubacar Bah ◽

...

Keyword(s):

Body Mass Index ◽

Treatment Outcome ◽

Body Mass ◽

Mixed Model ◽

Multidrug Resistant ◽

The Body ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Abstract Background Despite the predictor role of the body weight variation on multidrug-resistant tuberculosis (MDR-TB) treatment outcome, little data are available to corroborate this finding. We aimed to study the course of weight in patients with MDR-TB, to identify subgroups of weight evolutions, and to determine factors that influence these evolutions.Methods Patients treated with a shorter MDR-TB treatment regimen between June 07, 2016 and June 22, 2018 from three major drug-resistance TB centres in Guinea, who had rifampicin resistance, and who were cured or died were analysed. Patients were seen monthly until the end of treatment. Clinical outcome was the Body Mass Index (BMI). We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup of BMI evolutions.Results Of 232 patients treated for MDR-TB during the study period, 165 (71%) were analysed. These patients had a total of 1387 visits, with a median of 5 visits (interquartile range, 3 – 8 visits). Monthly BMI increase was 0.24 (SE 0.02) per kg/m 2 . Factors that associated with faster BMI progression were cured to MDR-TB treatment (0.24 [SE 0.09] per kg/m 2 ; p = 0.0205), and the absence of lung cavities on X-ray (0.18 [0.06] per kg/m 2 ; p = 0.0068). Two subgroups of BMI evolution were identified: “Rapid BMI (n = 121; 85%) and “Slow BMI evolution (n = 22; 15%). Patients in the slow increasing BMI group were mostly female (68%) without history of TB treatment (41%) with most severe clinical condition at baseline, characterized by a higher frequency of symptoms including HIV infection (59%), depression (18%), dyspnea (68%), poor adherence to MDR-TB treatment (64%), lower platelets count, and higher liver SGOT count. These patients had also a longer time to-initial culture conversion delay (log-rank test: p = 0.0087).Conclusion The available data provide quantitative information on BMI progression of patients with MDR-TB treated with a shorter regimen, and allowed the identification of the subgroup of patients with different BMI evolutions. Furthermore, they emphasize the usefulness of BMI as biomarker to monitor MDR-TB treatment outcome.

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Effectiveness of Shorter Treatment Regimen in Multidrug-Resistant Tuberculosis Patients in Pakistan: A Multicenter Retrospective Record Review

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1134 ◽

2021 ◽

Author(s):

Abudl Wahid ◽

Nafees Ahmad ◽

Abdul Ghafoor ◽

Abdullah Latif ◽

Fahad Saleem ◽

...

Keyword(s):

Treatment Failure ◽

Success Rate ◽

Treatment Success ◽

Multidrug Resistant ◽

Retrospective Record Review ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Record Review

In Pakistan, the treatment of multidrug-resistant tuberculosis (MDR-TB) with a shorter treatment regimen (STR), that is, 4–6 months of amikacin, moxifloxacin (Mfx), ethionamide, clofazimine (Cfz), pyrazinamide (Z), ethambutol (E), and high-dose isoniazid, followed by 5 months of Mfx, Cfz, Z, and E, was initiated in 2018. However, there is a lack of information about its effectiveness in Pakistani healthcare settings. Therefore, this retrospective record review of MDR-TB patients treated with STR at eight treatment sites in Pakistan aimed to fill this gap. Data were analyzed using SPSS 23. Multivariate binary logistic regression (MVBLR) analysis was conducted to find factors associated with death and treatment failure, and lost to follow-up (LTFU). A P-value < 0.05 was considered statistically significant. Of 912 MDR-TB patients enrolled at the study sites, only 313 (34.3%) eligible patients were treated with STR and included in the current study. Of them, a total of 250 (79.9%) were cured, 12 (3.8%) completed treated, 31 (9.9%) died, 16 (5.1%) were LTFU, and four (1.3%) were declared as treatment failures. The overall treatment success rate was 83.7%. In MVBLR analysis, patients’ age of 41–60 (odds ratio [OR] = 4.9, P-value = 0.020) and > 60 years (OR = 3.6, P-value = 0.035), being underweight (OR = 2.7, P-value = 0.042), and previous TB treatment (OR = 0.4, P-value = 0.042) had statistically significant association with death and treatment failure, whereas patients’ age of > 60 years (OR = 5.4, P-value = 0.040) and previous TB treatment (OR = 0.2, P-value = 0.008) had statistically significant association with LTFU. The treatment success rate of STR was encouraging. However, to further improve the treatment outcomes, special attention should be paid to the patients with identified risk factors.

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Different profiles of body mass index variation among patients with multidrug-resistant tuberculosis: a retrospective cohort study.

10.21203/rs.2.16913/v4 ◽

2020 ◽

Author(s):

Alhassane Diallo ◽

Boubacar Djelo Diallo ◽

Lansana Mady Camara ◽

Lucrèce Ahouéfa Nadège Kounoudji ◽

Boubacar Bah ◽

...

Keyword(s):

Body Mass Index ◽

Treatment Outcome ◽

Body Mass ◽

Mixed Model ◽

Multidrug Resistant ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Weight Variation ◽

Mdr Tb

Abstract Background: Despite the predictive role of body weight variation in treatment outcome in multidrug-resistant tuberculosis (MDR-TB), few corroborating data are available. We studied weight variation in patients with MDR-TB to identify groups of weight change and to determine factors that influence these changes. Methods: We analyzed patients with rifampicin resistance who were treated with an MDR-TB treatment regimen between June 07, 2016 and June 22, 2018 at three major drug-resistant TB centers in Guinea. Patients were seen monthly until the end of treatment. Clinical outcome was the body mass index (BMI). We used a linear mixed model to analyze trajectories of BMI and a latent class mixed model to identify groups of BMI trajectories. Results: Of 232 patients treated for MDR-TB during the study period, 165 were analyzed. These patients had a total of 1387 visits, with a median of 5 visits (interquartile range, 3 – 8 visits). Monthly BMI increase was 0.24 (SE 0.02) per kg/m 2 . Factors associated with faster BMI progression were success of MDR-TB treatment (0.24 [SE 0.09] per kg/m 2 ; p = 0.0205) and absence of lung cavities on X-ray (0.18 [0.06] per kg/m 2 ; p = 0.0068). Two groups of BMI change were identified: rapid BMI increase (n = 121; 85%) and slow BMI increase (n = 22; 15%). Patients in the slow BMI increase group were mostly female (68%) had no history of TB treatment (41%), had a positive HIV infection (59%), and had a more severe clinical condition at baseline, characterized by a higher frequency of symptoms including depression (18%), dyspnea (68%), poor adherence to MDR-TB treatment (64%), lower platelet count, and higher SGOT. These patients also had a longer time to initial culture conversion (log-rank test: p = 0.0087). Conclusion: Quantitative BMI data on patients with MDR-TB treated with a short regimen allowed the identification of subgroups of patients with different trajectories of BMI and emphasized the usefulness of BMI as a biomarker for the monitoring of MDR-TB treatment outcome.

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Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan

ERJ Open Research ◽

10.1183/23120541.00537-2020 ◽

2020 ◽

pp. 00537-2020

Author(s):

Philipp du Cros ◽

Khamraev Atadjan ◽

Tigay Zinaida ◽

Tleubergen Abdrasuliev ◽

Jane Greig ◽

...

Keyword(s):

Treatment Failure ◽

Treatment Success ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Fluoroquinolone Resistance ◽

Second Line ◽

Serious Adverse Events ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

BackgroundIn 2016, WHO guidelines conditionally recommended standardised shorter 9–12 month regimens for multidrug-resistant tuberculosis (MDR-TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan.MethodsConsecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between 1st September 2013 and 31st March 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion.ResultsOf 146 enrolled, 128 patients were included: 67 female (52.3%), median age 30.1 (IQR 23.8–44.4) years. At the end of treatment, 71.9% (92/128) patients achieved treatment success, with 68% (87/128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failure with fluoroquinolone resistance amplification in 8 patients (8/22, 36.4%); 12 (9.4%) loss to follow-up; 2 (1.5%) deaths. Recurrence occurred in one patient. 14 patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (aOR 6.13, 95% CI 2.01;18.63) and adherence<95% (aOR 5.33, 95% CI 1.73;16.36) were associated with unsuccessful outcome in multivariable logistic regression.ConclusionsOverall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of DST-confirmed susceptibility.

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Different profiles of body mass index evolutions among patients with multidrug-resistant tuberculosis: a retrospective cohort study.

10.21203/rs.2.16913/v2 ◽

2020 ◽

Author(s):

Alhassane Diallo ◽

Boubacar Djelo Diallo ◽

Lansana Mady Camara ◽

Lucrèce Ahouéfa Nadège Kounoudji ◽

Boubacar Bah ◽

...

Keyword(s):

Body Mass Index ◽

Treatment Outcome ◽

Body Mass ◽

Mixed Model ◽

Multidrug Resistant ◽

The Body ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Abstract Background: Despite the predictor role of the body weight variation on multidrug-resistant tuberculosis (MDR-TB) treatment outcome, little data are available to corroborate this finding. We aimed to study the course of weight in patients with MDR-TB, to identify subgroups of weight evolutions, and to determine factors that influence these evolutions. Methods: Patients treated with a shorter MDR-TB treatment regimen between June 07, 2016 and June 22, 2018 from three major drug-resistance TB centers in Guinea, who had rifampicin resistance, and who were cured or died were analyzed. Patients were seen monthly until the end of treatment. Clinical outcome was the Body Mass Index (BMI). We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup of BMI evolutions. Results: Of 232 patients treated for MDR-TB during the study period, 165 were analyzed. These patients had a total of 1387 visits, with a median of 5 visits (interquartile range, 3 – 8 visits). Monthly BMI increase was 0.24 (SE 0.02) per kg/m 2 . Factors that associated with faster BMI progression were cured to MDR-TB treatment (0.24 [SE 0.09] per kg/m 2 ; p = 0.0205), and the absence of lung cavities on X-ray (0.18 [0.06] per kg/m 2 ; p = 0.0068). Two subgroups of BMI evolution were identified: “Rapid BMI (n = 121; 85%) and “Slow BMI evolution (n = 22; 15%). Patients in the slow increasing BMI group were mostly female (68%) without history of TB treatment (41%), with positive HIV infection (59%), with most severe clinical condition at baseline, characterized by a higher frequency of symptoms including depression (18%), dyspnea (68%), poor adherence to MDR-TB treatment (64%), lower platelets count, and higher liver SGOT count. These patients had also a longer time to-initial culture conversion delay (log-rank test: p = 0.0087). Conclusion: The available data provided quantitative information on BMI progression of patients with MDR-TB treated with a shorter regimen, and allowed the identification of the subgroup of patients with different BMI evolutions. Furthermore, they emphasized the usefulness of BMI as biomarker to monitor MDR-TB treatment outcome.

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Patient- and provider-related factors in the success of multidrug-resistant tuberculosis treatment in Colombia

Revista Panamericana de Salud Pública ◽

10.26633/rpsp.2021.74 ◽

2021 ◽

Vol 45 ◽

pp. 1

Author(s):

Gloria Mercedes Puerto Castro ◽

Fernando Nicolás Montes Zuluaga ◽

Jacqueline Elizabeth Alcalde-Rabanal ◽

Freddy Pérez

Keyword(s):

Treatment Outcome ◽

Treatment Success ◽

Multidrug Resistant ◽

Insurance Scheme ◽

Related Factors ◽

Successful Treatment Outcome ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Nursing Professionals

Objective. To identify patient- and provider-related factors associated with the success of multidrug-resistant tuberculosis (MDR-TB) treatment in the six municipalities of Colombia with the highest number of MDR-TB cases. Methods. Bivariate and multivariate logistic regressions were used to analyze the association between treatment success (cure or treatment completion) and characteristics of the patients and physicians, nursing professionals, and psychologists involved in their treatment. The importance of knowledge in the management of MDR-TB cases was explored through focus groups with these providers. Results. Of 128 cases of TB-MDR, 63 (49.2%) experienced treatment success. Only 52.9% of the physicians and nursing professionals had satisfactory knowledge about MDR-TB. Logistic regression showed that being HIV negative, being affiliated with the contributory health insurance scheme, being cared for by a male physician, and being cared for by nursing professionals with sufficient knowledge were associated with a successful treatment outcome (p ≤ 0.05). Qualitative analysis showed the need for in-depth, systematic training of health personnel who care for patients with MDR-TB. Conclusion. Some characteristics of patients and healthcare providers influence treatment success in MDR-TB cases. Physicians’ and nurses’ knowledge about MDR-TB must be improved, and follow-up of MDR-TB patients who are living with HIV and of those affiliated with the subsidized health insurance scheme in Colombia must be strengthened, as these patients have a lower likelihood of a successful treatment outcome.

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Phase 2b Open-label Randomized Controlled Trial to Evaluate the Efficacy, Safety and Tolerability of N-acetylcysteine in Reducing Adverse Drug Reactions among Adults Treated for Multidrug-resistant Tuberculosis in Tanzania. (Trial Acronym NAC Trial).

10.21203/rs.3.rs-153835/v1 ◽

2021 ◽

Author(s):

Stellah George George Mpagama ◽

Happiness C Mvungi ◽

Peter M Mbelele ◽

Hadija H Semvua ◽

Alphonce A Liyoyo ◽

...

Keyword(s):

Controlled Trial ◽

Multidrug Resistant ◽

Second Line ◽

Drug Reactions ◽

Open Label ◽

Randomized Controlled ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

Abstract Background: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality . N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions. We therefore designed a pilot clinical trial to study the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. Methods: This is a phase 2b randomized open label clinical trial with 3 treatment arms including a control arm , an interventional arm of NAC 900mg daily , and an interventional arm of NAC 900mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong’oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania . The minimum anticipated sample size is 66 ; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis . Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. Discussion: Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress , it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Trial registration: PACTR202007736854169 Registered 03 July 2020 https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12163

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