Redefining susceptibility and resistance to anti-tuberculosis drugs
Co-hosted between the AMR and TB Centre
Traditionally, the World Health Organization (WHO) had relied on expert opinion to set breakpoints for phenotypic drug-susceptibility testing (DST) for the Mycobacterium tuberculosis complex, the causative agent of tuberculosis (TB). However, the evidence had been mounting that some of these breakpoints were flawed. To remedy these issues, I convinced WHO to adopt modern microbiological principles and became the lead analyst of a systematic review to revise or set the breakpoints for 11 second-line and two new anti-TB drugs (i.e. bedaquiline and delamanid).
Based on our recommendations, WHO established or revised 20 breakpoints (http://apps.who.int/iris/bitstream/10665/260470/1/WHO-CDS-TB-2018.5-eng.pdf). Importantly, five breakpoints for fluoroquinolones or second-line injectables, which represent the backbone of the regimens for drug-resistant TB, were lowered. In other words, some strains that were resistant to these drugs were systematically misclassified as susceptible using the old breakpoints, which likely resulted in inappropriate treatment of thousands of patients and avoidable deaths. The new breakpoints are now being implemented globally by diagnostic laboratories for phenotypic DST and also have implications for ongoing clinical trials (e.g. the STAND trials by the TB Alliance).
I will also discuss the ongoing systematic review by WHO to revise the breakpoints for isoniazid and the rifamycins (rifampicin, rifabutin and rifapentine) and a set of “expert rules” to define under which circumstances genotypic DST results should overrule phenotypic DST results.