scholarly journals Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug resistant tuberculosis: a multi-centre prospective cohort study in China

2021 ◽  
pp. 2101925
Author(s):  
Xubin Zheng ◽  
Lina Davies Forsman ◽  
Ziwei Bao ◽  
Yan Xie ◽  
Zhu Ning ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Multidrug Resistant ◽  
Target Attainment ◽  
Cart Analysis ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
The Impact ◽  
Culture Conversion

BackgroundUnderstanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimize treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.MethodsDrug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and classification and regression tree (CART) analysis was used to identify key predictors and their clinical targets among patients on WHO-recommended regimens.ResultsDrug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. Target attainment was highly variable ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had higher probability of two-month culture conversion (56.3% versus 28.6%, OR 2.91, 95% CI 1.42–5.94) and favourable outcome (88.8% versus 68.8%, OR 2.89, 95% CI 1.16–7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin AUC/MIC of 231 and linezolid AUC/MIC of 287 as best predictors for six-month culture conversion in patients receiving identical Group A-based regimen. These association were confirmed in multivariate analysis.ConclusionsOur findings indicated that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomized controlled study to improve the MDR-TB treatment outcome.

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

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248846
Author(s):  
Win Min Han ◽  
Wiriya Mahikul ◽  
Thomas Pouplin ◽  
Saranath Lawpoolsri ◽  
Lisa J. White ◽  
...  
Keyword(s):  
Southeast Asia ◽  
Treatment Initiation ◽  
Multidrug Resistant ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Short Course ◽  
Mdr Tb ◽  
The Impact

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.

scholarly journals Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis

2019 ◽  
Vol 23 (10) ◽  
pp. 1068-1074 ◽  
Author(s):  
R. Court ◽  
M. T. Chirehwa ◽  
L. Wiesner ◽  
N. de Vries ◽  
J. Harding ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Geometric Mean ◽  
Area Under The Curve ◽  
Compartmental Analysis ◽  
Multidrug Resistant ◽  
Geometric Mean Ratio ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

SETTING: Treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) are poor. Due to drug toxicity and a long treatment duration, approximately half of patients are treated successfully. Medication is often crushed for patients who have difficulty swallowing whole tablets. Whether crushing tablets affects drug exposure in MDR-TB treatment is not known.OBJECTIVE AND DESIGN: We performed a sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment at two hospitals in Cape Town, South Africa. We compared the bioavailability of pyrazinamide, moxifloxacin, isoniazid (INH), ethambutol and terizidone when the tablets were crushed and mixed with water before administration vs. swallowed whole. We sampled blood at six time points over 10 h under each condition separated by 2 weeks. Non-compartmental analysis was used to derive the key pharmacokinetic measurements.RESULTS: Twenty participants completed the study: 15 were men, and the median age was 31.5 years. There was a 42% reduction in the area under the curve AUC0–10 of INH when the tablets were crushed compared with whole tablets (geometric mean ratio 58%; 90%CI 47–73). Crushing tablets of pyrazinamide, moxifloxacin, ethambutol and terizidone did not affect the bioavailability significantly.CONCLUSION: We recommend that crushing of INH tablets in the MDR-TB treatment regimen be avoided. Paediatric INH formulations may be a viable alternative if the crushing of INH tablets is indicated.

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

2016 ◽  
Vol 60 (8) ◽  
pp. 4786-4792 ◽  
Author(s):  
Xubin Zheng ◽  
Rongrong Zheng ◽  
Yi Hu ◽  
Jim Werngren ◽  
Lina Davies Forsman ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Treatment Success ◽  
Multidrug Resistant ◽  
Classification And Regression Tree ◽  
Second Line ◽  
Cart Analysis ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

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.

scholarly journals Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia

2021 ◽  
Author(s):  
Rika Yuliwulandari ◽  
Kinasih Prayuni ◽  
Intan Razari ◽  
Retno W Susilowati ◽  
Yenni Zulhamidah ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Resistance Rate ◽  
Published Data ◽  
Drug Induced ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Appropriate Treatment ◽  
Acetylator Status ◽  
Mdr Tb

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
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.

Genotypic Resistance of Pyrazinamide but Not Minimum Inhibitory Concentration Is Associated With Longer Time to Sputum Culture Conversion in Patients With Multidrug-resistant Tuberculosis

2020 ◽  
Author(s):  
Johanna Kuhlin ◽  
Lina Davies Forsman ◽  
Mikael Mansjö ◽  
Michaela Jonsson Nordvall ◽  
Maria Wijkander ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Sputum Culture ◽  
Sputum Culture Conversion ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Culture Conversion

Abstract Background Pyrazinamide (PZA) resistance in multidrug-resistant tuberculosis (MDR-TB) is common; yet, it is not clear how it affects interim and treatment outcomes. Although rarely performed, phenotypic drug susceptibility testing (pDST) is used to define PZA resistance, but genotypic DST (gDST) and minimum inhibitory concentration (MIC) could be beneficial. We aimed to assess the impact of PZA gDST and MIC on time to sputum culture conversion (SCC) and treatment outcome in patients with MDR-TB. Methods Clinical, microbiological, and treatment data were collected in this cohort study for all patients diagnosed with MDR-TB in Sweden from 1992–2014. MIC, pDST, and whole-genome sequencing of the pncA, rpsA, and panD genes were used to define PZA resistance. A Cox regression model was used for statistical analyses. Results Of 157 patients with MDR-TB, 56.1% (n = 88) had PZA-resistant strains and 49.7% (n = 78) were treated with PZA. In crude and adjusted analysis (hazard ratio [HR], 0.49; 95% conficence interval [CI], .29-.82; P = .007), PZA gDST resistance was associated with a 29-day longer time to SCC. A 2-fold decrease in dilutions of PZA MIC for PZA-susceptible strains showed no association with SCC in crude or adjusted analyses (HR, 0.98; 95% CI, .73–1.31; P = .89). MIC and gDST for PZA were not associated with treatment outcome. Conclusions In patients with MDR-TB, gDST PZA resistance was associated with a longer time to SCC. Rapid PZA gDST is important to identify patients who may benefit from PZA treatment.

scholarly journals Multidrug-resistant tuberculosis (MDR-TB) and multidrug-resistant HIV (MDR-HIV) syndemic: challenges in resource limited setting

2019 ◽  
Vol 12 (8) ◽  
pp. e230628 ◽  
Author(s):  
Christian Francisco ◽  
Mary Ann Lansang ◽  
Edsel Maurice Salvana ◽  
Katerina Leyritana
Keyword(s):  
Psoas Abscess ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Resource Limited ◽  
Persons Living With Hiv ◽  
Mdr Tb ◽  
Living With Hiv

Tuberculosis (TB) is common among persons living with HIV. This public health concern is aggravated by infection with multidrug-resistant organisms and adverse effects of polypharmacy. There are few published cases of multidrug-resistant tuberculosis (MDR-TB) in multidrug-resistant HIV (MDR-HIV) infected patients. We report a case of a 29-year-old Filipino man with HIV on zidovudine (AZT)-containing antiretroviral therapy (ART) but was eventually shifted to tenofovir due to anaemia. He presented with left flank tenderness, which was found to be due to an MDR-TB psoas abscess, and for which second-line anti-TB treatment was started. HIV genotyping showed MDR-HIV infection susceptible only to AZT, protease inhibitors and integrase inhibitors. Subsequently, he developed neck abscess that grew Mycobacterium avium complex and was treated with ethambutol and azithromycin. ART regimen was revised to AZT plus lamivudine and lopinavir/ritonavir. Erythropoietin was administered for recurrent AZT-induced anaemia. Both abscesses resolved and no recurrence of anaemia was noted.

Multidisciplinary advisory teams to manage multidrug-resistant tuberculosis: the example of the French Consilium

2019 ◽  
Vol 23 (10) ◽  
pp. 1050-1054
Author(s):  
L. Guglielmetti ◽  
J. Jaffré ◽  
C. Bernard ◽  
F. Brossier ◽  
N. El Helali ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
World Health ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Health Organization

SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.

scholarly journals Task-shifting directly observed treatment and multidrug-resistant tuberculosis injection administration to lay health workers: stakeholder perceptions in rural Eswatini

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Ernest Peresu ◽  
J. Christo Heunis ◽  
N. Gladys Kigozi ◽  
Diana De Graeve
Keyword(s):  
Healthcare Workers ◽  
Health Workers ◽  
Multidrug Resistant ◽  
Task Shifting ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Key Stakeholders ◽  
Mdr Tb ◽  
Directly Observed Treatment

Abstract Background Eswatini is facing a critical shortage of human resources for health (HRH) and limited access to multidrug-resistant tuberculosis (MDR-TB) treatment in rural areas. This study assessed multiple stakeholders’ perceptions of task-shifting directly observed treatment (DOT) supervision and administration of intramuscular MDR-TB injections to lay health workers (LHWs). Methods A mixed methods study comprising a cross-sectional survey using a semi-structured questionnaire with community treatment supporters (CTSs) and a focus group discussion with key stakeholders including representatives from the Eswatini Ministry of Health (MOH), donor organisations, professional regulatory institutions, nursing academia, civil society and healthcare providers was conducted in May 2017. Descriptive statistics, thematic content analysis and data triangulation aided in the interpretation of results. Results A large majority of CTSs (n = 78; 95.1%) were female and 33 (40.2%) were older than 50 years. Most (n = 7; 70.0%) key stakeholders had over 10 years of work experience in policy-making, advocacy in the fields of HRH or day-to-day practice in MDR-TB management. Task-shifting of MDR-TB injection administration was implemented without national policy guidance and regulation. Stakeholders viewed the strategy to be driven by the prevailing shortage of professional frontline HRH and limited access to MDR-TB treatment. Task-shifting was perceived to improve medication adherence, and reduce stigma and transport-related MDR-TB treatment access barriers. Frontline healthcare workers and implementing donor partners fully supported task-shifting. Policy-makers and other stakeholders accepted task-shifting conditionally due to fears of poor standards of care related to perceived incompetence of CTSs. Appropriate compensation, adequate training and supervision, and non-financial incentives were suggested to retain CTSs. A holistic task-shifting policy and collaboration between the MOH, academia and nursing council in regulating the practice were recommended. Conclusions Stakeholders generally accepted the delegation of DOT supervision and administration of intramuscular MDR-TB injections to LHWs as a strategy to increase access to treatment, albeit with some apprehension. Findings from this study stress that task-shifting is not a panacea for HRH shortages, but a short-term solution that must form part of an overall simultaneous strategy to train, attract and retain adequate numbers of professional healthcare workers in Eswatini. To address some of the apprehension and ambivalence about expanding access to MDR-TB services through task-shifting, attention should be paid to important aspects such as competence-based training, certification and accreditation, adequate supportive on-the-job supervision, recognition, compensation, and expediting policy and regulatory support for LHWs.

scholarly journals Treatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South Africa

2020 ◽  
Vol 65 (1) ◽  
pp. e00744-20
Author(s):  
Martha L. van der Walt ◽  
Karen Shean ◽  
Piet Becker ◽  
Karen H. Keddy ◽  
Joey Lancaster
Keyword(s):  
Treatment Outcomes ◽  
Adverse Drug Events ◽  
Drug Effects ◽  
Multidrug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Default Rates ◽  
Conversion Rates ◽  
Mdr Tb ◽  
Culture Conversion

ABSTRACTTreatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine and terizidone were recorded individually. SADEs and factors associated with culture conversion and unfavorable treatment outcomes (default, death, treatment failure) were determined. Of 858 patients, 435 (51%) received ethambutol, 278 (32%) received cycloserine, and 145 (17%) received terizidone. Demographic and baseline clinical data were comparable. Successful treatment occurred in 56%, significantly more in patients receiving cycloserine (60%) and terizidone (62%) than in those receiving ethambutol (52% [P = 0.03]). Defaults rates were 30% in ethambutol patients versus 15% and 11% for cycloserine and terizidone patients, respectively. Terizidone was associated with fewer unfavorable outcomes (adjusted odds ratio [AOR], 0.4; P = 0.008; 95% confidence interval [CI], 0.2 to 0.8). Patients receiving cycloserine were more likely to achieve culture conversion than those receiving ethambutol or terizidone (AOR, 2.2; P = 0.02; 95% CI, 1.12 to 4.38). Failure to convert increased the odds of unfavorable outcomes (AOR, 23.7; P < 0.001; 95% CI, 13 to 44). SADEs were reported in two patients receiving ethambutol, seven patients receiving cycloserine, and three receiving terizidone (P = 0.05). Ethambutol was associated with high culture conversion and default rates. Cycloserine achieved higher culture conversion rates than terizidone. Fewer patients on terizidone experienced SADEs, with lower default rates. The differences that we observed between cycloserine and terizidone require further elucidation.

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