In a recent study published in the journal Clinical Infectious Diseases, researchers reported on the treatment of rifampin-resistant tuberculosis in the United States (U.S.) using the Food and Drug Administration (FDA) approved bedaquiline, pretomanid, and linezolid (BPaL) therapy.
The 2021 tuberculosis mortality rate was 1.6 million worldwide, and many patients had rifampin-resistant tuberculosis. Only a third of the patients with rifampin-resistant tuberculosis initiate treatment, and only 60% of these treatments are successful. Between 2014 and 2018, there were 618 cases of rifampin-resistant tuberculosis in the U.S.; of these, 8% died before their treatment regimen was completed, while 62% of the patients could complete the treatment across 24 months.
The standard treatment of both rifampin-resistant and rifampin-sensitive tuberculosis in the U.S. involved a 15 to 24 months long regimen comprising intensive and continuation phases, and about five and four drugs, respectively.
Furthermore, apart from the long treatment regimen, high pill burden, the toxicity of some of the drugs, prolonged respiratory isolation, and complex protocols for monitoring, rifampin-resistant tuberculosis has severe economic and psychosocial impacts on the lives of the patients and their loved ones.
About the study
In the present study, the researchers reported on the outcomes and management of rifampin-resistant tuberculosis in the U.S. using BPaL. BPaL was approved by the U.S. FDA in 2019 after clinical trials conducted in South Africa reported that a six-month regimen of BPaL with a 1200 mg dose of linezolid was effective in treating tuberculosis that was resistant to isoniazid and rifampin and the extensively drug-resistant tuberculosis which was also resistant to fluoroquinolones and other injectable agents approved by the World Health Organization.
However, that high dose of linezolid was found to cause neurologic and hematologic toxicity, which led to the prescription of BPaL with a lower (600 mg) dose of linezolid combined with therapeutic drug monitoring. The treatment comprised a daily dose of 400 mg bedaquiline for two weeks, which was changed to 200 mg administered thrice every week, and a daily dose of 200 mg pretomanid, along with provider-determined doses of linezolid.
While the existing protocols and guidelines for monitoring and treating patients with drug-resistant tuberculosis were followed, the management protocol was not standardized. Pre-treatment testing included physical examinations, various laboratory tests, visual acuity tests, and blood biochemistry, including metabolic, liver, and thyroid panels.
Monthly assessments for response to treatment and adverse reactions were conducted. The QT interval was monitored, in some cases by the patients themselves using a personal electrocardiogram, and chest radiographs were taken every two months till the end of treatment.
The Centers for Disease Control and Prevention (CDC) tested for drug resistance by conducting deoxyribonucleic acid (DNA) sequencing to identify mutations linked to resistance to isoniazid, rifampin, pyrazinamide, ethambutol, fluoroquinolones, and other injectable drugs. Liquid chromatography-tandem mass spectrometry was used to monitor the blood samples from the patients for linezolid absorption.
The results indicated that treatment with BPaL was successful for rifampin-resistant tuberculosis, with the treatment duration being less than half of those required by previous treatments for drug-resistant tuberculosis. Furthermore, the personalized dosing of linezolid implemented through therapeutic drug monitoring ensured the completion of the treatment regimen with minimum adverse reactions.
Out of the 70 patients who were administered the BPaL treatment regimen, two patients successfully converted to rifampin-based therapy, while the remaining 68 were able to complete the BPaL treatment regimen. However, two of these 68 patients had a relapse after the completion of the BPaL regimen.
The therapeutic drug monitoring of linezolid dosage through laboratory and clinical testing for side effects indicated that three patients experienced hematologic toxicity while four patients had neurologic toxicity to the linezolid doses, which resulted in a change in the dosage and frequency of linezolid during their treatment regimen.
Linezolid inhibits tuberculosis growth by targeting the bacterial mitochondria and can have similar effects on human mitochondria, leading to myelosuppression in the bone marrow by inhibiting adenosine triphosphate (ATP) synthesis in the bone marrow precursor cells.
The neurologic and hematologic toxicity of linezolid can also be influenced by individual variations in the genetic factors governing mitochondrial function, as well as by pre-existing medical conditions. However, the toxicity and efficacy of linezolid are duration and dose-dependent, and the treatment and toxicity can be reduced by therapeutic drug monitoring.
Overall, the findings indicated that treatment of rifampin-resistant tuberculosis using BPaL was effective and significantly reduced the treatment duration. Furthermore, a therapeutic drug monitoring approach successfully ensured the safety and efficacy of the treatment regimen by detecting adverse reactions and ensuring a timely change of linezolid dose and frequency.
The results from this BPaL Implementation Group (BIG) study suggested that an early implementation of the new BPaL treatment regimen against rifampin-resistant tuberculosis is feasible in the U.S.
- Haley, C. A., Schechter, M. C., Ashkin, D., Peloquin, C. A., Peter, C. J., Andrino, B. B., Burgos, M., Caloia, L. A., Chen, L., ColonSemidey, A., DeSilva, M. B., Dhanireddy, S., Dorman, S. E., Dworkin, F. F., HammondEpstein, H., Easton, A. V., Gaensbauer, J. T., Ghassemieh, B., Gomez, M. E., & Horne, D. (2023). Implementation of BPaL in the United States: Experience using a novel all-oral treatment regimen for treatment of rifampin-resistant or rifampin-intolerant TB disease. Clinical Infectious Diseases, ciad312. doi: https://doi.org/10.1093/cid/ciad312 https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad312/7186062?login=false