The evolution of diverse antimicrobial responses in vancomycin-intermediateStaphylococcus aureusand its therapeutic implications

Abstract

ABSTRACTStaphylococcus aureuscauses serious clinical infections, including bacteremia and endocarditis. When clinicians suspect these diseases, they prescribe broad-spectrum antibiotics like vancomycin and then adjust treatment based on antimicrobial susceptibility test results. However, these results reflect the infection’s state before treatment and do not account for any potential changes in its antibiotic response arising from intervening evolution. Thus, an initial test may indicate that the infection is susceptible to a particular drug, but this recommendation may be tentative. In this study, we aimed to understand how treatment effectiveness changes over time by accounting for evolution. First, we evolved 18 methicillin-susceptibleS. aureus(MSSA) populations under increasing vancomycin concentrations until they reached intermediate resistance levels. We then sequenced their complete genomes to characterize the mutational paths to their evolved vancomycin-intermediate states. Lastly, we subjected these evolved populations to seven antibiotics used to treat MSSA infections and compared drug susceptibilities between the evolved lines and their common ancestor. Mutations in several genes responsible for regulating the cell membrane stress response and cell-wall biosynthesis appeared in parallel among the evolved vancomycin-intermediateS. aureus(VISA) populations, and these lines were repeatedly cross-resistant to daptomycin. These observations align with previous clinical findings, reinforcing the role of these genes in mediating resistance. In contrast, the populations exhibited diverse responses to other antibiotics. Most lines were susceptible to meropenem, gentamicin, and nafcillin, but several replicates were also resistant. We accounted for this diversity by deriving likelihood estimates that express a population’s probability of exhibiting a drug response following vancomycin treatment. Our findings support using antistaphylococcal penicillins (e.g., nafcillin) as a first-line treatment for MSSA, even in light of intermediate vancomycin resistance. They also emphasize the inherent uncertainty and risk that evolution poses to effective therapies, attributes one cannot account for by susceptibility tests alone. Instead, clinicians must consider infections as evolving systems that may take several different paths, with implications on their potential sensitivities to other drugs.