mGem: Antibiotic tolerance across the growth-rate continuum in chronic human infections

Antibiotic failure is frequently attributed to genetic resistance, yet many chronic infections persist despite clinical isolates remaining susceptible to antibiotics. Antibiotic tolerance offers an alternative explanation, but is commonly interpreted through persisters, dormancy, and growth arrest. We argue this theory is incomplete. In vitro studies consistently demonstrate that growth rate strongly influences antibiotic susceptibility, while bacteria in chronic human infections occupy a broad continuum of growth states. However, experimental models of tolerance largely examine rapidly growing or growth-arrested bacteria and rarely encompass the substantially slower growth rates found in chronic infection. We propose that tolerance can emerge from stochastic growth-rate heterogeneity within clonal populations without requiring transition into dormancy. Thus, understanding tolerance requires defining how antibiotic survival changes across the growth-rate continuum. Further studies directly examining antibiotic tolerance at slow growth rates representative of chronic infection are needed to understand tolerance during human infection.