HETERORESISTANCE: THE HIDDEN DRIVER OF ‘SUSCEPTIBLE-BUT-FAILS’ INFECTIONS AND RAPID EVOLUTION TO FIXED RESISTANCE, A PUBLIC HEALTH ISSUE
Main Article Content
Keywords
Heteroresistance, hVISA, colistin, Klebsiella pneumoniae, Acinetobacter baumannii, population analysis profiling (PAP), antimicrobial stewardship
Abstract
Antimicrobial heteroresistance (HR)—reproducible minority subpopulations that grow at antibiotic concentrations inhibiting the dominant clone—offers a unifying explanation for “susceptible-but-fails” infections and for rapid, on-therapy evolution to fixed resistance. We narratively reviewed evidence (1997–30 Sept 2025) across MEDLINE, Embase and Web of Science on definitions, epidemiology, mechanisms, detection, clinical impact and translational tools for HR. HR is best established for glycopeptide heteroresistance in Staphylococcus aureus (hVISA) and for polymyxin HR in carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, where links to persistent bacteraemia, treatment modification and on-therapy emergence of high-level resistance recur despite MICs that read “susceptible.” Mechanistically, unstable architectures (gene amplification, regulatory toggling, plasmid copy-number variation) and early fixed mutations generate minority survival, with spatial drug gradients and biofilms amplifying selection in vivo. Emerging triage solutions—semi-automated PAP derivatives, direct-from-specimen ddPCR/WGS, and machine-learning assisted image/genome analysis—can increase sensitivity at scale if validated and explicitly positioned as screening, not diagnosis. We propose HR-aware stewardship triggers (high-risk organism–drug pairs; persistent bacteraemia at 48–72 h) coupled to PK/PD verification, source control and mechanism-aware therapy, and call for prospective, assay-anchored trials testing HR-guided strategies with time-to-clearance and failure endpoints.
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9. Heidarian S, Guliaev A, Nicoloff H, Hjort K, Andersson DI. High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes. PLoS biology. 2024 Jan 4;22(1):e3002457.
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16. Jo J, Ko KS. Tigecycline heteroresistance and resistance mechanism in clinical isolates of Acinetobacter baumannii. Microbiology spectrum. 2021 Oct 31;9(2):e01010-21.
17. Jo J, Kwon KT, Ko KS. Multiple heteroresistance to tigecycline and colistin in Acinetobacter baumannii isolates and its implications for combined antibiotic treatment. Journal of Biomedical Science. 2023 Jun 7;30(1):37.
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19. Napier BA, Band V, Burd EM, Weiss DS. Colistin heteroresistance in Enterobacter cloacae is associated with cross-resistance to the host antimicrobial lysozyme. Antimicrobial Agents and Chemotherapy. 2014 Sep;58(9):5594-7.
20. Band VI, Satola SW, Burd EM, Farley MM, Jacob JT, Weiss DS. Carbapenem-resistant Klebsiella pneumoniae exhibiting clinically undetected colistin heteroresistance leads to treatment failure in a murine model of infection. MBio. 2018 May 2;9(2):10-128.
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22. Hartman BJ, Tomasz AL. Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus. Antimicrobial agents and chemotherapy. 1986 Jan;29(1):85-92.
23. Eagle H, Musselman AD. The rate of bactericidal action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms. The Journal of experimental medicine. 1948 Jul 1;88(1):99-131.
24. Walsh TR, Bolmström A, Qwärnström A, Ho P, Wootton M, Howe RA, MacGowan AP, Diekema D. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. Journal of clinical microbiology. 2001 Jul 1;39(7):2439-44.
25. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, Andersen LP, Goossens H, Glupczynski Y. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013 Jan 1;62(1):34-42.
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27. Charretier Y, Diene SM, Baud D, Chatellier S, Santiago-Allexant E, Van Belkum A, Guigon G, Schrenzel J. Colistin heteroresistance and involvement of the PmrAB regulatory system in Acinetobacter baumannii. Antimicrobial agents and chemotherapy. 2018 Sep;62(9):10-128.
28. Hjort K, Nicoloff H, Andersson DI. Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica. Molecular microbiology. 2016 Oct;102(2):274-89.
29. Babiker A, Lohsen S, Van Riel J, Hjort K, Weiss DS, Andersson DI, Satola S. Heteroresistance to piperacillin/tazobactam in Klebsiella pneumoniae is mediated by increased copy number of multiple β-lactamase genes. JAC-Antimicrobial Resistance. 2024 Apr;6(2):dlae057.
30. Lee H, Hsu FF, Turk J, Groisman EA. The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. Journal of bacteriology. 2004 Jul 1;186(13):4124-33.
31. Zheng JX, Lin ZW, Sun X, Lin WH, Chen Z, Wu Y, Qi GB, Deng QW, Qu D, Yu ZJ. Overexpression of OqxAB and MacAB efflux pumps contributes to eravacycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae. Emerging microbes & infections. 2018 Dec 1;7(1):1-1.
32. Napier BA, Band V, Burd EM, Weiss DS. Colistin heteroresistance in Enterobacter cloacae is associated with cross-resistance to the host antimicrobial lysozyme. Antimicrobial Agents and Chemotherapy. 2014 Sep;58(9):5594-7.
33. Martino F, Petroni A, Menocal MA, Corso A, Melano R, Faccone D. New insights on mcr-1-harboring plasmids from human clinical Escherichia coli isolates. Plos one. 2024 Feb 26;19(2):e0294820.
34. Elitas M. Isoniazid killing of Mycobacterium smegmatis NADH pyrophosphatase mutant at single-cell level using microfluidics and time-lapse microscopy. Scientific reports. 2017 Sep 7;7(1):10770.
35. Eilertson B, Maruri F, Blackman A, Herrera M, Samuels DC, Sterling TR. High proportion of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrobial agents and chemotherapy. 2014 Jun;58(6):3270-5.
36. van Hal SJ, Paterson DL. Systematic review and meta-analysis of the significance of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Antimicrobial agents and chemotherapy. 2011 Jan;55(1):405-10.
37. Satola SW, Farley MM, Anderson KF, Patel JB. Comparison of detection methods for heteroresistant vancomycin-intermediate Staphylococcus aureus, with the population analysis profile method as the reference method. Journal of clinical microbiology. 2011 Jan;49(1):177-83.
38. Castro BE, Berrio M, Vargas ML, Carvajal LP, Millan LV, Rios R, Hernandez AK, Rincon S, Cubides P, Forero E, Dinh A. Detection of heterogeneous vancomycin intermediate resistance in MRSA isolates from Latin America. Journal of Antimicrobial Chemotherapy. 2020 Sep 1;75(9):2424-31.
39. Zhang S, Sun X, Chang W, Dai Y, Ma X. Systematic review and meta-analysis of the epidemiology of vancomycin-intermediate and heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. PloS one. 2015 Aug 19;10(8):e0136082.
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Dec 02, 2025
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Kalpana Kuntal, Nishtha Singh, Sufia Talib, & Nandaputhra Das S. (2025). HETERORESISTANCE: THE HIDDEN DRIVER OF ‘SUSCEPTIBLE-BUT-FAILS’ INFECTIONS AND RAPID EVOLUTION TO FIXED RESISTANCE, A PUBLIC HEALTH ISSUE. Journal of Population Therapeutics and Clinical Pharmacology, 32(10), 1754-1764. https://doi.org/10.53555/rk6wft87
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Author Biographies
Kalpana Kuntal
Department of Microbiology, King George's Medical University, Uttar Pradesh, Lucknow, India
Nishtha Singh
Hind Institute of Medical Sciences, Microbiology, Lucknow
Sufia Talib
Medical Officer, Department of Medical Health and Family Welfare, Uttar Pradesh, India
Nandaputhra Das S
Junior Resident, Department of Microbiology, King George’s Medical University, Lucknow, India.
How to Cite
Kalpana Kuntal, Nishtha Singh, Sufia Talib, & Nandaputhra Das S. (2025). HETERORESISTANCE: THE HIDDEN DRIVER OF ‘SUSCEPTIBLE-BUT-FAILS’ INFECTIONS AND RAPID EVOLUTION TO FIXED RESISTANCE, A PUBLIC HEALTH ISSUE. Journal of Population Therapeutics and Clinical Pharmacology, 32(10), 1754-1764. https://doi.org/10.53555/rk6wft87
