Beyond historical breakpoints: Recalibrating antifungal pharmacokinetic-pharmacodynamic targets to match evolving minimum inhibitory concentration distributions

Pharmacokinetic-pharmacodynamic (PK-PD) targets underpin antifungal dosing and therapeutic drug monitoring (TDM), but most were derived from animal models, small clinical cohorts, and wild-type susceptibility distributions that no longer reflect contemporary resistance. Static thresholds such as voriconazole trough ranges or echinocandin area under the curve/minimum inhibitory concentration (MIC) ratios improved outcomes in susceptible populations but are increasingly brittle against resistant phenotypes. Rising azole resistance in Aspergillus fumigatus , driven both by long-term therapy and agricultural fungicide exposure, and the global epidemiological shift in candidemia toward Candida glabrata and Candidozyma auris have reshaped the MIC landscape. Clinical paradoxes now emerge: Breakthrough infections despite “therapeutic” drug levels, toxicity when escalating doses to chase higher MICs, and poor outcome prediction once FKS mutations undermine echinocandin activity. This review synthesizes historical foundations of antifungal PK-PD targets, highlights how evolving MIC distributions deform the probability of target attainment, and analyzes why genotype rather than MIC alone predicts clinical failure in C. glabrata . It critiques the limitations of current breakpoints, explores special populations in which PK variability magnifies risk, and emphasizes how diagnostic and methodological gaps perpetuate miscalibration. Moving forward, recalibration should link surveillance to modeling through minimal interoperable datasets, embed real-time PK-PD dashboards in TDM laboratories, and incorporate genotype-informed decision rules. Region-specific MIC distributions, site- and biofilm-aware targets, combination PK-PD indices, and next-generation antifungals such as rezafungin and ibrexafungerp must be integrated into new frameworks.