Underscoring interstrain variability and the impact of growth conditions on associated antimicrobial susceptibilities in preclinical testing of novel antimicrobial drugs.

In the era of multidrug resistant (MDR) organisms, reliable efficacy testing of novel antimicrobials during developmental stages is of paramount concern prior to introduction in clinical trials. Unfortunately, interstrain variability is often underappreciated when appraising the efficacy of innovative antimicrobials as preclinical testing of a limited number of standardized strains in unvarying conditions does not account for the vastness and potential for hyperdiversity among and within microbial populations. In this review, the importance of accounting for interstrain variability's potential to impact breadth of novel drug efficacy evaluation in the early stages of drug development will be discussed. Additionally, testing under varying microenvironmental conditions that may influence drug efficacy will be discussed. Biofilm growth, the influence of polymicrobial growth, mechanisms of antimicrobial resistance, pH, anaerobic conditions, and other virulence factors are some of critical issues that require more attention and standardization during preclinical drug efficacy evaluation. Furthermore, potential solutions for addressing this issue in pre-clinical antimicrobial development are proposed via centralization of microbial characterization and drug target databases, testing of a large number of clinical strains, inclusion of mutator strains in testing and the use of growth parameter mathematical models for testing.