Short course chemotherapy in children suffering from respiratory tuberculosis and exposed to multiple and extensive drug resistant tuberculosis

The objective: to study the effect of short course chemotherapy regimens on treatment outcomes in children with drug resistant tuberculosis.Subjects and methods. In 2017-2019, 31 children at the age from 3 to 17 years old, received short course chemotherapy which lasted for 12-15 months. Children of both genders were enrolled in the study, they all were new pulmonary tuberculosis cases with multiple drug resistance or at risk of MDR, with no history of previous treatment with reserve anti-tuberculosis drugs, and without severe concomitant diseases. Before the treatment was prescribed, all children underwent lung computed tomography additionally to general clinical and laboratory tests.Results. The chemotherapy regimen for each child consisted of 4-6 drugs selected individually with the consideration of resistance pattern of the child or suspected index case. In all cases, the combination of drugs included fluoroquinolones (levofloxacin or moxifloxacin). Amikacin (67.7%), aminosalicylic acid (80.6%) and prothionamide (74.2%) were frequently prescribed. 54.8% of children received pyrazinamide and 48.4% – cycloserine. Given the limited lesions, only 16.1% of children received linezolid and 9.7% of children received bedaquiline. The main chemotherapy course made 13.2 ± 0.5 months (from 12 to 15 months depending on the form of tuberculosis and changes during treatment). The duration of the intensive phase made 4.8 ± 0.3 on the average. 2 (6.5 ± 4.4%) of 31 children developed adverse events requiring the cancellation of the drugs causing them.Conclusion. This study has demonstrated satisfactory tolerability and good efficacy of these short course regimens for treatment of multiple drug resistant tuberculosis. No relapses of tuberculosis were reported.

Download Full-text

THE SHORT-COURSE CHEMOTHERAPY IN THE TREATMENT OF MULTIPLE DRUG RESISTANT TUBERCULOSIS IN CHILDREN WITH DIFFERENT HIV STATUS

Tuberculosis and lung diseases ◽

10.21292/2075-1230-2019-97-8-27-31 ◽

2019 ◽

Vol 97 (8) ◽

pp. 27-31

Author(s):

E. YU. ZORKАLTSEVА ◽

◽

S. V. PUGАCHEVА ◽

L. V. ZАRITSKАYA ◽

D. А. KUDLАY ◽

...

Keyword(s):

Multiple Drug ◽

Drug Resistant ◽

Hiv Status ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Short Course ◽

Multiple Drug Resistant ◽

Short Course Chemotherapy ◽

Tuberculosis In Children

Download Full-text

Is short-course therapy enough at drug-resistant tuberculosis?

Tuberkuloz ve Toraks ◽

10.5578/tt.67339 ◽

2018 ◽

Vol 66 (4) ◽

pp. 280-287

Author(s):

Hamza OGUN ◽

İpek ÖZMEN ◽

Elif ÖZARI YILDIRIM ◽

Tülay TÖRÜN ◽

Haluk Celalettin ÇALIŞIR

Keyword(s):

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Short Course

Download Full-text

The study of adverse drug reactions in indoor patients of tuberculosis taking standardized antitubercular therapy (directly observed treatment short-course and programmatic management of drug resistant tuberculosis) in a tertiary care hospital at Surat

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20211644 ◽

2021 ◽

Vol 10 (5) ◽

pp. 507

Author(s):

Payal P. Naik ◽

Arvindsingh Panwar ◽

Swati Patel

Keyword(s):

Tertiary Care Hospital ◽

Tertiary Care ◽

P Value ◽

Care Hospital ◽

Drug Resistant ◽

Drug Reactions ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Short Course ◽

Directly Observed Treatment

Background: Tuberculosis is a serious public health issue in India. The treatment regimen followed is Directly observed treatment short-course (DOTS) and Programmatic Management of Drug resistant Tuberculosis (PMDT) approach. In a long period of treatment adverse drug reactions (ADRs) can be an important programmatic issue. Thus, study was undertaken to assess the ADRs caused by antitubercular therapy in indoor patients in a tertiary care hospital at Surat.Methods: The Observational, prospective study was carried out for one year period. The causality was determined by WHO UMC scale and severity was determined by Modified Hartwig and Siegel scale. Chi square test was applied for statistical analysis.Results: Among 255 tuberculosis patients, 85 (33.3%) patients developed ADRs. Occurrence of ADRs was more among females (46.6%). The commonly involved systems are gastrointestinal (40.6%) followed by haematological (17.9%). The most common ADRs observed were nausea and vomiting (21.7%). High percentage of ADRs causing drugs were isoniazid (30.6%) followed by rifampicin (26.1%). Causality assessment showed 60.4% ADRs were possible, 37.7% ADRs were probable and 1.9% ADRs was certain. Severity assessment scale showed 81.1% of moderate, 12.3% of mild and 6.6% of severe grading. Occurrence of ADRs was more among PMDT (60%) in comparison to DOTS therapy (31.06%) [p value = 0.0084 (significant p value < 0.05)].Conclusions: Antitubercular treatment is safer but early detection, management and reporting of ADRs is required to prevent it at initial stage and helps to decrease default rate.

Download Full-text

Eﬃcacy and safety of short course chemotherapy regimens in older children and adolescents with multiple and extensive drug resistant respiratory tuberculosis

Tuberculosis and lung diseases ◽

10.21292/2075-1230-2021-99-10-35-39 ◽

2021 ◽

Vol 99 (10) ◽

pp. 35-39

Author(s):

L. V. Panova ◽

E. S. Ovsyankina ◽

E. A. Krushinskaya ◽

A. Yu. Khiteva ◽

O. A. Piskunova

Keyword(s):

Children And Adolescents ◽

Controlled Study ◽

Drug Resistant ◽

Efficacy And Safety ◽

Older Children ◽

Continuation Phase ◽

Intensive Phase ◽

Resistant Tuberculosis ◽

Short Course ◽

Short Course Chemotherapy

The objective of the study: to evaluate the eﬃcacy and safety of short course chemotherapy regimens for multiple/extensive drug resistant tuberculosis of the respiratory system (MDR/XDR) in older children and adolescents.Subjects and Methods. A cohort prospective controlled study (2017 to 2019) included 23 patients from 13 to 17 years old with various clinical forms of respiratory tuberculosis with multiple/extensive drug resistance.Results. In 22 out of 23 cases, the following chemotherapy regimen was used: 6 months - the intensive phase / 6 months - the continuation phase, in one patient – 3 months of the intensive phase / 9 months of the continuation phase. In 15 out of 23 cases, the chemotherapy regimens in the intensive phase, taking into account the MBT drug sensitivity test, consisted of 5 drugs, in 8 cases – of 4 drugs. During the continuation phase, all patients received 3 drugs. Of the 23 patients, 8 patients used bedaquiline in short course chemotherapy regimens: 2 – 1 course, 6 – 2 courses.Conclusion. The possibility of reducing the main course of chemotherapy for MDR/XDR TB in children and adolescents to 12 months instead of 18-24 months has been proved.

Download Full-text

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis

10.1101/2020.11.17.387977 ◽

2020 ◽

Author(s):

Jian Xu ◽

Paul J. Converse ◽

Anna M. Upton ◽

Khisimuzi Mdluli ◽

Nader Fotouhi ◽

...

Keyword(s):

Mouse Model ◽

Safety Margin ◽

Drug Resistant ◽

The Novel ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Short Course ◽

Potential Safety ◽

Emergence Of Resistance

AbstractSince its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

Download Full-text

Predicting the Outcomes of New Short-Course Regimens for Multi-Drug Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modelling

10.1101/369991 ◽

2018 ◽

Author(s):

Tan N Doan ◽

Pengxing Cao ◽

Theophilus I Emeto ◽

James M McCaw ◽

Emma S McBryde

Keyword(s):

Treatment Duration ◽

Treatment Success ◽

Empirical Evaluation ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multi Drug Resistant Tuberculosis ◽

Short Course ◽

Mdr Tb

ABSTRACTShort-course regimens for multi-drug resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug, bedaquiline (BDQ), may have the potential to shorten MDR-TB treatment to less than six months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modelling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modelling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (four months) while still maintaining a very high treatment success rate (100% for daily BDQ for two weeks, or 95% for daily BDQ for one week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes then we anticipate clear cost-savings and a subsequent improvement in the efficiency of national TB programs.

Download Full-text

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02418-20 ◽

2021 ◽

Author(s):

Jian Xu ◽

Paul J. Converse ◽

Anna M. Upton ◽

Khisimuzi Mdluli ◽

Nader Fotouhi ◽

...

Keyword(s):

Mouse Model ◽

Safety Margin ◽

Drug Resistant ◽

The Novel ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Short Course ◽

Potential Safety ◽

Emergence Of Resistance

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

Download Full-text