Technical Report on critical concentrations for drug susceptibility testing of medicines used in the treatment of drug-resistant tuberculosis
Overview
The End TB Strategy calls for early diagnosis and prompt treatment of all persons of all ages with any form of drug-susceptible or drug-resistant TB. The effective management of multi-drug and extensively-drug resistant TB (M/XDR-TB) relies upon the rapid diagnosis and treatment of resistant infections. Culture-based phenotypic drug susceptibility testing (DST) methods are currently the gold standard for drug resistance detection although these methods are time-consuming; require sophisticated laboratory infrastructure, qualified staff and strict quality assurance mechanisms.
DST uses critical concentrations of anti-TB agents to determine the susceptibility or resistance of a culture of Mycobacterium tuberculosis complex. The critical concentration of an anti-TB agent has been adopted and modified from an international standard.1 The critical concentration is defined as the lowest concentration of an anti-TB agent in vitro that will inhibit the growth of 99% of phenotypically wild type strains of M. tuberculosis complex.
Laboratory tests of the sensitivity of tubercle bacilli to anti-tuberculosis agents serve three main purposes. Firstly, they can be used as guidance in the choice of chemotherapy to be given to a patient. Secondly, they are of value in confirming that drug resistance has emerged when a patient failed to show a satisfactory response to treatment and thirdly can be used for the surveillance of emerging drug resistance.
WHO Global TB Programme commissioned FIND to perform a systematic review of available minimum inhibitory concentration (MIC) data for phenotypically wild type as well as phenotypically non-wild type strains, including associated sequencing data for relevant resistance genes. The medicines included in the review were the second-line injectable agents (kanamycin, amikacin and capreomycin), clofazimine and bedaquiline, cycloserine and terizidone, linezolid, delamanid, and the fluoroquinolones (ofloxacin, levofloxacin, gatifloxacin and moxifloxacin). The following media were considered: Löwenstein Jensen, Middlebrook 7H10/7H11 and BACTEC™ Mycobacterial Growth Indicator Tube™ 960.
In April 2017, WHO Global TB programme convened a Technical Expert Group to review the evidence for different critical concentrations and clinical breakpoints used for DST for the abovementioned drug-media combinations. The revised or newly established breakpoints can be found in Table 1. A clinical breakpoint for the higher dose of moxifloxacin (800 mg/day) was established for the first time. Rifampicin and isoniazid critical concentrations were not evaluated as part of this review but should be re-evaluated as a priority. Finally, the Technical Expert Group highlighted the need for greater standardisation of DST protocols to minimise inter-laboratory differences.
