Sweet advance for treatment of children with multi-drug resistant TB

Children with multi-drug resistant tuberculosis (MDR-TB) undergo months of life-saving treatment including many doses of foul-tasting medications, which caregivers often struggle to prepare and administer accurately.

New findings from the Global Alliance for TB Drug Development (TB Alliance) and Stellenbosch University, in South Africa now provide detailed blueprints for pharmacists to quickly and safely prepare more palatable, more accurately dosed syrup suspensions for key drugs against MDR-TB. The researchers hope their work will significantly improve treatment outcomes of children with MDR-TB.

In a series of three papers, about delamanid, clofazimine and bedaquiline, in the International Journal of Tuberculosis and Lung Disease, the researchers describe their findings as a leap forward in the treatment of children with MDR-TB. Long delays in developing child-friendly formulations by the pharmaceutical industry make their work particularly welcome. Another paper on the MDR-TB antibiotic, pretomanid, is under review.

Bedaquiline is the only one of the drugs which is also available as a dispersible tablet, but this version is not available in all countries.

As the studies were on available drugs, no further approval is needed from the relevant drug manufacturers for the findings to be put into practice, says lead researcher, Rajneesh Taneja, the TB Alliance vice president for pharmaceutical product development in the United States.

With the detailed, user-friendly instructions provided in the three papers, pharmacists can now quickly and safely prepare age-appropriate medication for children with MDR-TB.

In the case of clofazimine, for instance, a liquid version can be prepared within seven minutes using sugar and water; or a commonly available thickener if a child’s sugar intake must be limited. The result is a smooth, uniform, dark purple to brown syrup with no lumps or clumps. This is much easier for parents and other caregivers to give to young patients with a spoon, dispenser or syringe.

Clofazimine's sugary version can be bottled for 30 days without losing significant efficacy, and those of bedaquiline and delamanid for 15 days. The sugar-free version of Clofazimine can be kept for 15 days, and that of the other two drugs for a month.

The work forms part of continued efforts spanning nearly a decade by partners now involved in the Unitaid funded Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids) project. The five-year research initiative started in 2019 under the guidance of Anneke Hesseling, of the Desmond Tutu TB Centre at Stellenbosch University, and Tony Garcia-Prats, of the Department of Paediatrics at the University of Wisconsin in the US.

Children younger than 5 years old are likely to contract TB, including MDR-TB from adults that they have contact with. Symptoms may include poor weight gain, weight loss, fever, cough, chest pain and lethargy.

An estimated two million children are newly infected with MDR-TB strains globally each year. Of these, nearly 30 000 children under the age of 14 develop MDR-TB disease, but less than 15% receive appropriate treatment. If untreated, many die. "More than 80% of children treated for MDR-TB recover. Despite these good outcomes, relatively few children are diagnosed and treated each year, with only 3,398 and 5,586 children worldwide starting treatment in 2018 and 2019 respectively," says Hesseling.

Drug toxicity and the complexity of regimes makes treatment difficult. Children are given smaller doses of the same drugs that adults are prescribed, if paediatric specific versions are not available. “Currently available formulations of many most important MDR-TB drugs are simply not acceptable for children” says Graeme Hoddinott, socio-behavioral lead at the Desmond Tutu TB Centre at Stellenbosch University.

"Imagine trying to force your 18-month-old child to swallow mouthfuls of foul-tasting drugs every day for months, not knowing if you got the dose right, or if they spat up much of the active ingredient. Imagine doing this while living in a home on the socio-economic margins, where having food each day is no guarantee," he says.

For Taneja better compliance to prescribed therapies and accurate dosing is of utmost importance, given the evolution of super resistant strains of the bacteria Mycobacterium tuberculosis that causes TB and the lack of effective antibiotics.

Taneja sees their work to convert adult formulations into a paediatric friendly form as "a gap filler until appropriate paediatric formulations become available."

doi: https://doi.org/10.1038/d44148-023-00080-9

Original article published by Nature Africa, linked here.