A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials

McKenna, Lindsay; Frick, Mike; Lee, Cynthia; Namutamba, Dorothy; Smit, Liezl; Theunissen, Marie; Vandevelde, Wim; Madoori, Suraj; Snow, Kathryn; Seaworth, Barbara

doi:10.1093/cid/cix533

Cited by 19 publications

(20 citation statements)

References 11 publications

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“…Since 2013, concurrent ART and TB treatment without considering CD4 count for all HIV infected pregnant women was implemented [ 10 ]. Possible adverse effects on the foetus are unknown during DR-TB treatment as pregnant women are commonly excluded from clinical trials [ 11 , 12 ]. DR-TB treatment in pregnant women present management dilemmas, with care providers suggesting initiation of treatment after the first trimester to protect the foetus from the teratogenic impact [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa

et al. 2020

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Background Tuberculosis (TB) is amongst the top five causes of death in women of childbearing age (15-�44 years). Little is known about treatment of pregnant women with drug-resistant TB (DR-TB). Treatment for pregnant women remains challenging and more complex in DR-TB/HIV co-infection, where an evidence-based guide to clinical practice is limited. The study reviewed treatment and pregnancy outcomes and birth outcomes of their newborn in a cohort of pregnant women with DR-TB from three MDR-TB hospitals during 2010 and 2018. Design/Methods Data were extracted from: TB register and patient clinic notes using a standardized case record form. Information on DR-TB treatment, pregnancy and Adverse Drug Events (ADEs) of twenty-six pregnant women treated with individualized second-line TB medications were captured. The frequency of favourable and adverse outcomes regarding disease and pregnancy were evaluated. Results The mean age was 29 years (SD ±5.1), with the minimum and maximum age of 21 and 40 years, respectively. Eleven (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 women, 15 (57.7%) had at least one ADE, but most had more than one ADE. Seventeen women were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively.

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Section: Introductionmentioning

confidence: 99%

Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa

et al. 2020

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“…There has been recent community advocacy calling for stakeholders to design treatments for pregnant women with TB, given the dire need ( 59 ). TB in pregnant women is associated with a 2-fold increase in premature birth and low birth weight and a 6-fold-higher perinatal death rate ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis

Deshpande

Srivastava

Bendet

et al. 2018

Antimicrob Agents Chemother

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The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis. In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the β-lactamase inhibitor avibactam, benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M. tuberculosis was 6.80 ± 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 ± 2.31 mg/liter, while for intracellular M. tuberculosis it was 2.42 ± 0.14 log10 CFU/ml at an EC50 of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical M. tuberculosis strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth M. tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M. tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M. tuberculosis, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log10 CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

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“…Concerns of potential harm from TB therapeutics to mother and fetus have led to exclusion of pregnant women from most trials of TB therapies [53]. As a result, evidence for TB treatment during pregnancy or breastfeeding has come mainly from case reports and small series [54].…”

Section: How Can We Include Vulnerable Populations Such As Childrenmentioning

confidence: 99%

Advances in clinical trial design: Weaving tomorrow’s TB treatments

et al. 2020

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A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials

Cited by 19 publications

References 11 publications

Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa

Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa

Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis

Advances in clinical trial design: Weaving tomorrow’s TB treatments

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