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The Pharmacology of Bacterial Persistence: From Antibiotic Tolerance to Antimicrobial Resistance

Maria Cristina Caroleo1,2, Maria Pisano2, Erika Cione3

  • 1CRUISE Research Center, Science of Health Department, University Magna Graecia, 88100 Catanzaro, Italy.

Antibiotics (Basel, Switzerland)
|July 27, 2026
PubMed

Insights

Bacterial persister cells, though susceptible to antibiotics, can cause persistent infections. New strategies should focus on preventing persister cells to reduce relapses and the development of antimicrobial resistance (AMR).

Area of Science:

  • Pharmacology
  • Microbiology
  • Infectious Diseases

Background:

  • Persistent infections involve recurrent treatment failures and relapses, unexplained by standard antibiotic susceptibility testing.
  • Bacterial persister cells are genetically susceptible but phenotypically tolerant subpopulations that survive antibiotic exposure via reversible physiological adaptations.
  • Conventional resistance paradigms do not fully account for the clinical reality of persistent infections.

Purpose of the Study:

  • To propose a pharmacological framework linking antimicrobial exposure, bacterial tolerance, persistence, relapse, and antimicrobial resistance (AMR).
  • To operationalize persistence prevention exposure (PPE) using various antimicrobial exposure metrics.
  • To advocate for a shift in antimicrobial therapy models.

Main Methods:

  • A structured narrative review of scientific literature and surveillance data.
  • Utilized databases such as PubMed/MEDLINE, ClinicalTrials.gov, CDC, and WHO/GLASS.
  • Followed the Scale for the Assessment of Narrative Review Articles (SANRA) framework.

Main Results:

  • Bacterial resistance, tolerance, and persistence are pharmacologically distinct phenotypes.
  • Persistence occurs without an elevated minimum inhibitory concentration (MIC) and is influenced by factors like antimicrobial exposure, target penetration, biofilms, intracellular location, and host stress.
  • Introduced concepts like persistence prevention exposure (PPE), minimum duration for killing (MDK), persister fraction, and minimum biofilm eradication concentration (MBEC).

Conclusions:

  • Antimicrobial therapy must evolve beyond MIC suppression to include prevention and eradication of persister cell reservoirs.
  • Preventing bacterial persistence may decrease infection relapse rates and reduce the need for repeated antibiotic courses.
  • Targeting bacterial persistence could mitigate the evolutionary pathways leading to stable antimicrobial resistance (AMR).
Keywords:
MBECMDK99PK/PDVBNCantibiotic toleranceantimicrobial resistancebacteriophage therapybiofilmpersister cellstherapeutic drug monitoring

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