scholarly journals New antituberculosis drugs: from clinical trial to programmatic use

2016 ◽  
Vol 8 (2) ◽  
Author(s):  
Gina Gualano ◽  
Susanna Capone ◽  
Alberto Matteelli ◽  
Fabrizio Palmieri
Keyword(s):  
Treatment Outcomes ◽  
Selection Process ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Phase Iii ◽  
Current Standard ◽  
Inappropriate Use ◽  
Clinical Phase ◽  
Mdr Tb ◽  
Culture Conversion

Treatment of multidrug-resistant tuberculosis (MDR-TB) cases is challenging because it relies on second-line drugs that are less potent and more toxic than those used in the clinical management of drug-susceptible TB. Moreover, treatment outcomes for MDR-TB are generally poor compared to drug sensitive disease, highlighting the need for of new drugs. For the first time in more than 50 years, two new anti-TB drugs were approved and released. Bedaquiline is a first-in-class diarylquinoline compound that showed durable culture conversion at 24 weeks in phase IIb trials. Delamanid is the first drug of the nitroimidazole class to enter clinical practice. Similarly to bedaquiline results of phase IIb studies showed increased sputum-culture conversion at 2 months and better final treatment outcomes in patients with MDR-TB. Among repurposed drugs linezolid and carbapenems may represent a valuable drug to treat cases of MDR and extensively drugresistant TB. The recommended regimen for MDR-TB is the combination of at least four drugs to which <em>M. tuberculosis</em> is likely to be susceptible for the duration of 20 months. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Clinical phase III trials on new regimen are ongoing that could prove transformative against MDR-TB, by being shorter (six months), simpler (an alloral regimen) and safer than current standard therapy. It is fundamental that the adoption of the new drugs is done responsibly to avoid inappropriate use. Concentration of inpatient MDR-TB treatment in specialized centers could be considered in countries with low numbers of cases in order to provide appropriate clinical case management and to prevent emergence of drug resistance.

scholarly journals Effectiveness and cardiovascular safety of delamanid-containing regimens in adults with multidrug-resistant or extensively drug-resistant tuberculosis: A nationwide cohort study from Belarus, 2016-18

2021 ◽  
Vol 91 (1) ◽  
Author(s):  
Vera Auchynka ◽  
Ajay M.V. Kumar ◽  
Hennadz Hurevich ◽  
Yuliia Sereda ◽  
Varvara Solodovnikova ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Multivariable Analysis ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Resistant Tuberculosis ◽  
Unsuccessful Treatment ◽  
Mdr Tb ◽  
Ecg Abnormalities ◽  
Culture Conversion

To address the sub-optimal treatment outcomes among patients with multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the National TB Programme in Belarus started using new drugs such as bedaquiline and delamanid in 2015-16. In this study, we assessed cardiovascular safety and effectiveness (culture conversion, treatment outcomes and post-treatment recurrence) of delamanid-containing regimens among adults (>18 years) with MDR-TB or XDR-TB from June 2016 to February 2018. This was a nationwide cohort study involving analysis of routinely collected programme data from the national and six regional TB hospitals. Cardiovascular adverse events (AEs) were classified as serious or not, based on international guidelines. We conducted Cox proportional hazards regression and calculated adjusted hazards ratio(aHR) and 95% confidence intervals(CI) to evaluate factors associated with AEs and unsuccessful treatment outcomes (death, failure and lost-to-follow-up). Of 125 patients enrolled (35, 28% females; mean age 43 years), 85(68%) had XDR-TB. All the patients received delamanid and 20 patients received both delamanid and bedaquiline. Cardiovascular AEs (177 episodes in total), were observed in the majority (73%) of patients but were mild and managed easily. The most common cardiovascular AEs were QTcF prolongation (64/177, 36%) and other electrocardiography (ECG) abnormalities (40/177, 23%). There were two instances of serious AEs leading to death, both of which were not related to delamanid. In multivariable analysis, male sex (aHR 0.72; 95% CI 0.51-0.99), and baseline ECG abnormalities (aHR 1.68; 95% CI 1.19-2.36) were associated with cardiovascular AEs. Median time to culture conversion was 1.1 months (interquartile range: 1.0-2.1). Culture conversion was observed in 115 (92%) patients at six months of treatment and 110 (88%) completed the treatment successfully. Loss to follow-up, failure and death were observed in 6%, 4% and 2% patients respectively. Among those assessed at 12 months post-treatment (n=33), recurrence was seen in one patient. The only factor associated with unsuccessful treatment outcomes in multivariable analysis was baseline Hepatitis C co-infection (aHR 3.61; 95% CI 1.09-11.95). In conclusion, treatment using delamanid-containing regimens was effective and had a favourable safety profile. We hope our findings inform the development of national clinical guidelines and scale-up of new drugs in other countries.

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.

scholarly journals An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis

2017 ◽  
Vol 49 (3) ◽  
pp. 1600803 ◽  
Author(s):  
Mayara Lisboa Bastos ◽  
Zhiyi Lan ◽  
Dick Menzies
Keyword(s):  
Systematic Review ◽  
Treatment Outcomes ◽  
Multidrug Resistant ◽  
Current Evidence ◽  
Aminosalicylic Acid ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
End Of Treatment ◽  
Mdr Tb ◽  
Culture Conversion

This systematic review aimed to update the current evidence for multidrug-resistant tuberculosis (MDR-TB) treatment.We searched for studies that reported treatment information and clinical characteristics for at least 25 patients with microbiologically confirmed pulmonary MDR-TB and either end of treatment outcomes, 6-month culture conversion or severe adverse events (SAEs). We assessed the association of these outcomes with patients' characteristics or treatment parameters. We identified 74 studies, including 17 494 participants.The pooled treatment success was 26% in extensively drug-resistant TB (XDR-TB) patients and 60% in MDR-TB patients. Treatment parameters such as number or duration and individual drugs were not associated with improved 6-month sputum culture conversion or end of treatment outcomes. However, MDR-TB patients that received individualised regimens had higher success than patients who received standardised regimens (64% versus 52%; p<0.0.01). When reports from 20 cohorts were pooled, proportions of SAE ranged from 0.5% attributed to ethambutol to 12.2% attributed to para-aminosalicylic acid. The lack of significant associations of treatment outcomes with specific drugs or regimens may reflect the limitations of pooling the data rather than a true lack of differences in efficacy of regimens or individual drugs.This analysis highlights the need for stronger evidence for treatment of MDR-TB from better-designed and reported studies.

scholarly journals Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy

2011 ◽  
Vol 55 (12) ◽  
pp. 5421-5429 ◽  
Author(s):  
Howard Takiff ◽  
Elba Guerrero
Keyword(s):  
Multidrug Resistant ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
First Line ◽  
Current Standard ◽  
Standard Drug ◽  
First Line Therapy ◽  
Development Of Resistance ◽  
Mdr Tb ◽  
Phase Iii Trials

ABSTRACTWhile fluoroquinolones (FQs) have been successful in helping cure multidrug-resistant tuberculosis (MDR TB), studies in mice have suggested that if used as first-line agents they might reduce the duration of therapy required to cure drug-sensitive TB. The results of phase II trials with FQs as first-line agents have been mixed, but in at least three studies where moxifloxacin substituted for ethambutol, there was an increase in the early percentage of sputa that converted to negative for bacilli. Phase III trials are in progress to test the effectiveness of 4-month FQ-containing regimens, but there is concern that the widespread use of FQs for other infections could engender a high prevalence of FQ-resistant TB. However, several studies suggest that despite wide FQ use, the prevalence of FQ-resistant TB is low, and the majority of the resistance is low-level. The principal risk for resistance may be when FQs are used to treat nonspecific respiratory symptoms that are in fact TB, so curtailing this use of FQs could reduce the development of resistance and also the delays in TB diagnosis and treatment that have been documented when an FQ is given in this setting. While the future of FQs as first-line therapy will likely depend upon the results of the ongoing phase III trials, if they are to be effectively employed in high-TB-burden regions their use for community-acquired pneumonias should be restricted, the prevalence of FQ-resistant TB should be monitored, and the cost of the treatment should be comparable to that of current standard drug regimens.

scholarly journals Effectiveness and safety of delamanid- or bedaquiline-containing regimens among children and adolescents with multidrug resistant or extensively drug resistant tuberculosis: A nationwide study from Belarus, 2015-19

2021 ◽  
Vol 91 (1) ◽  
Author(s):  
Varvara Solodovnikova ◽  
Ajay M.V. Kumar ◽  
Hennadz Hurevich ◽  
Yuliia Sereda ◽  
Vera Auchynka ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Multidrug Resistant ◽  
Post Treatment ◽  
New Drugs ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Culture Conversion

There is limited evidence describing the safety and effectiveness of bedaquiline and delamanid containing regimens in children and adolescents with Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) globally. In this nationwide descriptive cohort study from Belarus, we examined adverse drug events, time to culture conversion, treatment outcomes including post-treatment recurrence among children and adolescents (<18 years of age) treated with bedaquiline and/or delamanid containing regimens from 2015 to 2019. Of the 40 participants included (55% females; age range 10-17 years), 20 (50%) had XDR-TB and 15 (38%) had resistance to either fluoroquinolone or second-line injectable. Half of the patients received delamanid and another half received bedaquiline with one patient receiving both drugs. AEs were reported in all the patients. A total of 224 AEs were reported, most of which (76%) were mild in nature. Only 10 (5%) AEs were graded severe and one AE was graded life-threatening. A total of 7 AEs (3%) were classified as ‘serious’ and only one patient required permanent discontinuation of the suspected drug (linezolid). Most of the AEs (94%) were resolved before the end of treatment. All patients culture-positive at baseline (n=34) became culture-negative within three months of treatment. Median time to culture conversion was 1.1 months (interquartile range: 0.9-1.6). Two patients were still receiving treatment at the time of analysis. The remaining 38 patients successfully completed treatment. Among those eligible and assessed at 6 (n=32) and 12 months (n=27) post-treatment, no recurrences were detected. In conclusion, treatment of children and adolescents with MDR-TB and XDR-TB using bedaquiline and/or delamanid containing regimens was effective and had favourable safety profile. Achieving such excellent outcomes under programmatic settings is encouraging for other national tuberculosis programmes, which are in the process of introducing or scaling-up the use of these new drugs in their countries.

scholarly journals Effectiveness and Safety of Bedaquiline-containing Regimens for Treatment on Patients With Refractory Rifampicin/multidrug-resistant Tuberculosis: A Retrospective Cohort Study in East China

2021 ◽  
Author(s):  
Shao-Jun Zhang ◽  
Yan Yang ◽  
Wen-Wen Sun ◽  
Zhong-Shun Zhang ◽  
He-ping Xiao ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Treatment Success ◽  
Multidrug Resistant ◽  
East China ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Conversion Rates ◽  
Mdr Tb ◽  
Culture Conversion ◽  
Closing Rate

Abstract Objective: To compare the effectiveness and safety of bedaquiline-containing and bedaquiline-free regimens for treatment of patients with refractory rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB).Methods: Patients with refractory RR/MDR-TB receiving bedaquiline-containing regimens (bedaquiline group, n=102) and bedaquiline-free regimens (non-bedaquiline group, n=100) were included in this retrospective historical control study across East China. The culture conversion, end-of-treatment outcomes, cavity closing rate, and adverse events (AEs) were compared between the two groups. Univariate and multivariate analyses were performed to identify independent predictors of treatment success and culture reversion.Results: The baseline characteristics of the patients were well balanced between the two groups. The culture conversion rates in the bedaquiline group at month 3 (89.2% vs. 66.0%), month 6 (90.2% vs. 72.0%), month 9 (91.2% vs. 66.0%), and month 12 (94.1% vs. 65.0%) were all significantly higher than those in the non-bedaquiline group (all p<0.001). Similar results were observed in the cavity closing rate at month 9 (19.6% vs. 8.0%, p=0.017) and month 12 (39.2% vs. 15.0%, p<0.001). Patients receiving bedaquiline-containing regimens had more treatment success than those receiving bedaquiline-free regimens (p<0.001; cure rate, 69.6% vs. 45.0%; complete the treatment, 22.5% vs. 18.0%; treatment success, 92.2% vs. 63.0%). The use of bedaquiline was identified as an independent predictor of both treatment success (OR=7.356, 95% CI: 2.920–18.530, p<0.001) and culture reversion (OR=0.124, 95% CI: 0.035–0.452, p<0.001). AEs were similarly reported in 26.5% of patients in the bedaquiline group and 19.0% in the non-bedaquiline group (p=0.206).Conclusions: Bedaquiline-containing regimens resulted in better treatment outcomes and similar safety relative to bedaquiline-free regimens for patients with refractory pulmonary RR/MDR-TB.

scholarly journals Xpert MTB/RIF use is associated with earlier treatment initiation and culture conversion among patients with sputum smear-negative multidrug-resistant tuberculosis

2021 ◽  
Author(s):  
Maia Kipiani ◽  
Daniel S Graciaa ◽  
Mariana Buziashvili ◽  
Lasha Darchia ◽  
Zaza Avaliani ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Treatment Initiation ◽  
Multidrug Resistant ◽  
Sputum Smear ◽  
Line Treatment ◽  
Second Line ◽  
Sputum Culture Conversion ◽  
Mdr Tb ◽  
Smear Negative ◽  
Culture Conversion

Abstract Background While rapid molecular diagnostic tests for tuberculosis (TB) have decreased detection time of M. 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. Methods A retrospective cohort of adult patients initiating treatment for sputum smear-negative MDR-TB at the National Center for Tuberculosis and Lung Diseases in Tbilisi, Georgia from 2011-2016. 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 from. Time to event was compared using a Cox proportional hazards model. Results Among 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&lt;0.0001) and culture conversion (61 vs. 93 days, aHR 1.93, p&lt;0.001). There was no difference in treatment outcomes. Conclusions Use 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.

scholarly journals Time to sputum culture conversion and its predictors among patients with multidrug resistant tuberculosis in Hangzhou, China: a retrospective cohort study

2019 ◽  
Author(s):  
Qingchun Li ◽  
Min Lu ◽  
Evelyn Hsieh ◽  
Limin Wu ◽  
Yifei Wu ◽  
...  
Keyword(s):  
Cohort Study ◽  
Treatment Outcomes ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Multidrug Resistant ◽  
Sputum Culture Conversion ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Culture Conversion

Abstract Background To investigate the time to initial sputum culture conversion (SCC) and its predictors among multidrug-resistant tuberculosis (MDR-TB) patients in Hangzhou, China.Methods A retrospective cohort study was conducted among patients initiating treatment for MDR-TB from 2011-2015 in Hangzhou, China. Time to initial SCC was analyzed using the Kaplan-Meier method, and Cox proportional hazards regression was used to identify predictors of SCC.Results Among 384 patients enrolled with MDR-TB, 359 (93.5%) successfully achieved initial SCC after a median of 85 days (inter-quartile range, 40-112 days). A higher rate of SCC was observed in participants with successful treatment outcomes than those with poor treatment outcomes (P<0.01). Multivariate analysis showed that age 25-64 years (adjusted odds ratio [AOR], 0.7; 95% confidence interval [CI], 0.5-0.9; P<0.01), age ≥65 years (AOR, 0.5; 95%CI, 0.3-0.8; P<0.01) and household registration in Hangzhou (AOR, 1.3; 95%CI, 1.0-1.5; P<0.05) were found to be associated with SCC.Conclusions Although high SCC and treatment success rates were observed among MDR-TB patients in Hangzhou, the prolonged duration to initial SCC underscores the importance of emphasizing measures for infection control. A new policy of shifting outpatient treatment to inpatient treatment in China may reduce the risk of transmission from patients in the time window prior to SCC.

scholarly journals SILVER COMPLEXES FOR TUBERCULOSIS TREATMENT: A SHORT REVIEW

Química Nova ◽  
2021 ◽  
Author(s):  
Bruno Biagioni ◽  
Maurício Cavicchioli ◽  
Antonio Massabni
Keyword(s):  
Metal Complexes ◽  
Bacterial Resistance ◽  
Treatment Time ◽  
Short Review ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Silver Complexes ◽  
Inappropriate Use ◽  
Mdr Tb

This paper is a brief review of silver complexes that have been identified as antibacterial drugs with promising use for the treatment of tuberculosis (TB). This treatment aims to cure and discontinue the transmission of the disease. The excessive and inappropriate use of drugs has jeopardized the effectiveness of antibiotics for the TB treatment, bringing bacterial resistance to them. To achieve these objectives, the drugs used must be able to eliminate rapidly the bacterial population, avoiding the selection of drug-resistant strains and preventing its recurrence. The number of new cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) continues to rise. So, it is important to develop more research to introduce new drugs or improve existing ones, which can reduce the treatment time, increasing drug adherence and reducing MDR-TB and XDR-TB. The Ag(I) complexes were described with different types of ligands, and bonds to Ag(I) occur by N, O, P, and S atoms. Metal complexes are presented as options for antiTB treatments. There are no cases of TB treatments using metal complexes but research in this area show that they could be used in the future to eradicate the bacteria that contaminate environments, surgical materials and other objects.

scholarly journals Overcoming barriers to the access and uptake of newer drugs for multidrug-resistant TB

2020 ◽  
Vol 24 (10) ◽  
pp. 1054-1057
Author(s):  
I. Zabsonre ◽  
S. S. Thi ◽  
V. Cox
Keyword(s):  
Treatment Outcomes ◽  
Treatment Regimen ◽  
Technical Assistance ◽  
Clinical Skills ◽  
Multidrug Resistant ◽  
Short Term ◽  
Mdr Tb

To improve the unsatisfactory treatment outcomes of multidrug-resistant TB (MDR-TB), it is essential we use new regimens based on newer drugs. To address challenges in the introduction of BDQ and the shorter treatment regimen (STR), the USAID has committed to support countries receiving BDQ (through the USAID/Janssen Bedaquiline Donation Program), with targeted short-term technical assistance (TA). Six MDR-TB clinical consultants were recruited and provided TA to 17 countries between 2017 and 2019. Building on other in-country support, this short-term TA proved instrumental in overcoming barriers, such as misconceptions about BDQ safety, inadequate clinical skills to manage patients and limited expansion plans to increase access to BDQ and the STR.

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