Can Diagnostic Delay Amplify Drug Resistance in Tuberculosis? A Critical Integrative Reflection on Bacterial Adaptation, Persistence, Within-Host Evolution, and Heteroresistance

Abstract

Background/Objectives: Drug resistance in tuberculosis remains one of the major challenges to global disease control. Traditionally, its emergence has been attributed to factors such as treatment interruption, poor adherence, and the selective pressure exerted by antimicrobial agents. However, recent advances in bacterial genetics, within-host evolution, cellular persistence, and heteroresistance suggest that relevant biological processes may develop before treatment initiation. The aim of this critical integrative reflection was to explore the biological plausibility that diagnostic delay may act as an amplifying factor for adaptive and evolutionary mechanisms potentially associated with drug resistance in Mycobacterium tuberculosis. Methods: A structured documentary search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Of the 86 documents initially identified, 29 studies were selected using predefined inclusion and exclusion criteria. The evidence was analysed through a conceptual convergence matrix, which enabled the organisation of findings into five analytical categories: diagnostic delay and programmatic determinants; mechanisms of resistance, bacterial adaptation, and clinical implications; persistence and drug tolerance; within-host evolution and genetic diversity; and heteroresistance and resistant subpopulations. In addition, four institutional reports were incorporated to contextualise the issue from a global perspective. Results: The reviewed evidence suggests that extended persistence of infection before diagnosis may favour biological opportunities for bacterial adaptation, the persistence of tolerant subpopulations, the accumulation of genetic diversity, and the emergence of variants with distinct drug susceptibility profiles. Although the available studies do not demonstrate a direct causal relationship, they support the plausibility of an evolutionary trajectory capable of influencing the dynamics of drug resistance. Conclusions: An expanded model of drug resistance in tuberculosis is proposed, in which diagnostic delay does not constitute a direct cause of resistance but rather a potential amplifying factor for biological adaptation and evolutionary change occurring before treatment initiation. This hypothesis generates new avenues for research on the interaction between timely diagnosis, bacterial evolution, and drug resistance.