Abstract
Background: N-acetylcysteine (NAC) is investigated as an antibiotic adjunct, but acidity, formulation and experimental context complicate interpretation. We evaluated comparative in-vitro evidence while distinguishing biofilm prevention, established-biofilm treatment and resistance evolution. Methods: MEDLINE/PubMed, Embase, Scopus and Web of Science were searched through August 2026, with supplementary searching. Extraction distinguished NAC preparation and exposure pH, medium, hydrodynamics, NAC-alone controls, treatment intent and interaction methodology. Results were synthesized by experimental context, regimen, phase and endpoint without pooling or whole-study efficacy voting. Results: Fifty-five studies were included: 7 evaluated combination exposure during formation only, 37 after establishment only, 9 both, and 2 resistance evolution. NAC-alone arms were documented in 39 studies, partial or formulation-specific in 9, and not identified in 7. Only two studies included a continuous-flow model. Selected combinations improved biofilm-associated outcomes, but intrinsic-acidic and neutralized preparations, biomass and viability endpoints, and planktonic versus biofilm interaction tests were not interchangeable. Liposomal and catheter-lock findings differed by dose matching, isolate and control set. Polymyxin findings varied with organism, resistance background, medium and exposure; rifampicin-alone and rifampicin-containing multidrug comparators addressed different questions. Conclusions: NAC is a context-dependent experimental adjunct, not an established class-wide antibiotic potentiator. The evidence does not support clinical antibiotic dose reduction or routine NAC combination therapy. Translation requires controlled final exposure pH, matched monotherapy and formulation controls, clinically relevant background regimens, viable-burden and regrowth outcomes, and resistance monitoring.