Challenging a dogma: antimicrobial susceptibility testing breakpoints for Mycobacterium tuberculosis

Modern principlesAntimicrobial susceptibility testing breakpoints are best determined by breakpoint committees composed of specialists in clinical trial science and in pharmacokinetics and pharmacodynamics, population simulation tools, resistance mechanisms, antimicrobial susceptibility testing methods and bacterial population dynamics.Two such committees are the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute of the United States of America.Modern principles for the determination of clinical antimicrobial susceptibility testing breakpoints call for a definition of wild-type MIC distributions (i.e. the Gaussian MIC distributions for organisms of each target species devoid of resistance mechanisms).Strains included within the wild-type MIC distribution are, by definition, devoid of phenotypically detectable acquired or mutational resistance mechanisms, whereas strains outside the wild-type MIC distribution should be suspected of having such resistance mechanisms, although these may or may not be clinically relevant.The highest MIC within the wildtype MIC distribution has been labelled the epidemiological Abstract The rise in multidrug-resistant tuberculosis makes it increasingly important that antimicrobial susceptibility testing of Mycobacterium tuberculosis produce clinically meaningful and technically reproducible results.Unfortunately, this is not always the case because mycobacteriology specialists have not followed generally accepted modern principles for the establishment of susceptibility breakpoints for bacterial and fungal pathogens.These principles specifically call for a definition of the minimum inhibitory concentrations (MICs) applicable to organisms without resistance mechanisms (also known as wild-type MIC distributions), to be used in combination with data on clinical outcomes, pharmacokinetics and pharmacodynamics.In a series of papers the authors have defined tentative wild-type MIC distributions for M. tuberculosis and hope that other researchers will follow their example and provide confirmatory data.They suggest that some breakpoints are in need of revision because they either (i) bisect the wild-type distribution, which leads to poor reproducibility in antimicrobial susceptibility testing, or (ii) are substantially higher than the MICs of wild-type organisms without supporting clinical evidence, which may result in some strains being falsely reported as susceptible.The authors recommend, in short, that susceptibility breakpoints for antituberculosis agents be systematically reviewed and revised, if necessary, using the same modern tools now accepted for all other bacteria and fungi by the scientific community and by the European Medicines Agency and the European Centre for Disease Prevention and Control.For several agents this would greatly improve the accuracy and reproducibility of antimicrobial susceptibility testing of M. tuberculosis.