Antibiotic Resistance: The Ongoing Era’s Crisis, and How to Stay Ahead
Keywords:
Antibiotic Resistance, Antibiotics, Cellular Mechanisms, Bacteriophage Therapy, Antimicrobial Peptides, CRISPR, Monoclonal Antibodies, Nanotechnology, Pharmacokinetics of Antimicrobial Agents, Pharmacodynamics of Antimicrobial AgentsAbstract
Antibiotics have been crucial in reshaping the treatment of bacterial infections in the modern era of medicine, significantly reducing mortality rates and improving public health outcomes. Their overuse and misuse, however, have led to the emergence of antibiotic resistance, now a growing global public health threat. Antibiotic resistance arises through various genetic mechanisms, including mutations, horizontal gene transfer, and selective pressure, which enable bacteria to adapt and survive despite the presence and usage of antibiotics. The early emergence of resistance in the 1940s and 1950s is particularly historically significant for antibiotics, underscoring the importance of responsible antibiotic stewardship in combating resistance.
Despite significant advances in alternative therapies, such as bacteriophage therapy, antimicrobial peptides, monoclonal antibodies, CRISPR gene editing, and nanotechnology, a major gap persists in the literature: pharmacokinetics (PK), pharmacodynamics (PD), and the therapeutic index (TI) of antibiotics are underexplored. This review synthesizes the historical development, underlying cellular mechanisms, and recent advances in emerging therapeutic strategies while drawing attention to these overlooked PK/PD aspects. By integrating both treatment innovations and pharmacological models, this review informs future research directions aimed at optimizing treatment efficacy and addressing the escalating challenge of antibiotic resistance.
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References
Al-Humadi HW, Al-Saigh RJ, Al-Humadi AW. Addressing the Challenges of Tuberculosis: A Brief Historical Account. Frontiers in Pharmacology [Internet]. 2017 Sep 26 [cited 2020 Jul 14];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626940/
AMR Review [Internet]. Amr-review.org. 2016 [cited 2025 Aug 9]. Available from: https://amr-review.org
Ates A, Tastan C, Ermertcan S. CRISPR-Cas9-Mediated Targeting of Multidrug Resistance Genes in Methicillin-Resistant Staphylococcus aureus. The CRISPR Journal [Internet]. 2024 Nov 8; Available from: https://doi.org/10.1089/crispr.2024.0001
Bankar NJ, Ugemuge S, Ambad RS, Hawale DV, Timilsina DR. Implementation of Antimicrobial Stewardship in the Healthcare Setting. Cureus [Internet]. 2022 Jul 8;14(7). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9357433/
Bjedov I. Stress-Induced Mutagenesis in Bacteria. Science [Internet]. 2003 May 30;300(5624):1404–9. Available from: https://doi.org/10.1126/science.1082240
Burmeister AR. Horizontal Gene Transfer. Evolution, Medicine, and Public Health [Internet]. 2015 Jul 29;2015(1):193–4. Available from: https://doi.org/10.1093/emph/eov018
Centers for Disease Control and Prevention. Core Elements of Hospital Antibiotic Stewardship Programs [Internet]. Antibiotic Prescribing and Use. 2024. Available from: https://www.cdc.gov/antibiotic-use/hcp/core-elements/hospital.html
Ceri H, Olson ME, Stremick C, Read RR, Morck D, Buret A. The Calgary Biofilm Device: New Technology for Rapid Determination of Antibiotic Susceptibilities of Bacterial Biofilms. Journal of Clinical Microbiology [Internet]. 1999;37(6):1771–6. Available from: https://doi.org/10.1128/jcm.37.6.1771-1776.1999
Chambers HF, DeLeo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Reviews Microbiology [Internet]. 2009 Sep;7(9):629–41. Available from: https://doi.org/10.1038/nrmicro2200
Charani E, Holmes A. Antibiotic Stewardship—Twenty Years in the Making. Antibiotics [Internet]. 2019 Jan 24;8(1):7. Available from: https://www.mdpi.com/2079-6382/8/1/7
Chen CH, Lu TK. Development and Challenges of Antimicrobial Peptides for Therapeutic Applications. Antibiotics [Internet]. 2020 Jan 13;9(1):24. Available from: https://doi.org/10.3390/antibiotics9010024
Cleveland Clinic. Antibiotic Resistance [Internet]. Cleveland Clinic. 2023. Available from: https://my.clevelandclinic.org/health/articles/21655-antibiotic-resistance
de Vor L, van Dijk B, van Kessel K, Kavanaugh JS, de Haas C, Aerts PC, et al. Human monoclonal antibodies against Staphylococcus aureus surface antigens recognize in vitro and in vivo biofilm. eLife [Internet]. [cited 2022 May 4];11:e67301. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751199/
Doak TG, Doerder FP, Jahn CL, Herrick G. A proposed superfamily of transposase genes: transposon-like elements in ciliated protozoa and a common “D35E” motif.. Proceedings of the National Academy of Sciences [Internet]. 1994 Feb 1 [cited 2024 Dec 6];91(3):942–6. Available from: https://doi.org/10.1073/pnas.91.3.942
Eissing T. A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks. Frontiers in Physiology [Internet]. 2011 [cited 2019 Aug 3];2. Available from: https://doi.org/10.3389/fphys.2011.00004
FLEMING A. THE DISCOVERY OF PENICILLIN. British Medical Bulletin [Internet]. 1944;2(1):4–5. Available from: https://doi.org/10.1093/oxfordjournals.bmb.a071032
Gordillo Altamirano FL, Barr JJ. Phage Therapy in the Postantibiotic Era. Clinical Microbiology Reviews [Internet]. 2019 Jan 16;32(2). Available from: https://doi.org/10.1128/cmr.00066-18
Huan Y, Kong Q, Mou H, Yi H. Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Frontiers in Microbiology [Internet]. 2020 Oct 16;11. Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2020.582779/full
Hutchings MI, Truman AW, Wilkinson B. Antibiotics: past, Present and Future. Current Opinion in Microbiology [Internet]. 2019 Oct;51(1):72–80. Available from: https://www.sciencedirect.com/science/article/pii/S1369527419300190
Karanika S, Paudel S, Grigoras C, Kalbasi A, Mylonakis E. Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs. Antimicrobial Agents and Chemotherapy [Internet]. 2016 May 31;60(8):4840–52. Available from: https://doi.org/10.1128/aac.00825-16
Khafaja S, Salameh Y, Boutros CF, Awad C, Faour K, Tfaily N, et al. Increased rate of multidrug-resistant gram-negative bacterial infections in hospitalized immunocompromised pediatric patients. Frontiers in Cellular and Infection Microbiology [Internet]. 2025 Jan 6;14. Available from: https://doi.org/10.3389/fcimb.2024.1382500
Klumpp J, Fouts DE, Sozhamannan S. Next generation sequencing technologies and the changing landscape of phage genomics. Bacteriophage [Internet]. 2012 Jul;2(3):190–9. Available from: https://doi.org/10.4161/bact.22111
Lade H, Kim JS. Bacterial Targets of Antibiotics in Methicillin-Resistant Staphylococcus aureus. Antibiotics [Internet]. 2021 Apr 7;10(4):398. Available from: https://doi.org/10.3390/antibiotics10040398
Landecker H. Antibiotic Resistance and the Biology of History. Body & Society [Internet]. 2016 Jul 8;22(4):19–52. Available from: https://doi.org/10.1177/1357034x14561341
Livermore DM. Antibiotic resistance in staphylococci. International Journal of Antimicrobial Agents [Internet]. 2000 Nov [cited 2020 Jan 7];16:3–10. Available from: https://doi.org/10.1016/s0924-8579(00)00299-5
Lonsdale DO, Kipper K, Baker EH, Barker CIS, Oldfield I, Philips BJ, et al. β-Lactam antimicrobial pharmacokinetics and target attainment in critically ill patients aged 1 day to 90 years: the ABDose study. Journal of Antimicrobial Chemotherapy [Internet]. 2020 Sep 29;75(12):3625–34. Available from: https://doi.org/10.1093/jac/dkaa363
Mathias S, Wippermann A, Raab N, Zeh N, Handrick R, Gorr I, et al. Unraveling what makes a monoclonal antibody difficult‐to‐express: From intracellular accumulation to incomplete folding and degradation via ERAD. Biotechnology and Bioengineering [Internet]. 2019 Nov 15;117(1):5–16. Available from: https://doi.org/10.1002/bit.27196
Mc Dermott PF, Walker RD, White DG. Antimicrobials: Modes of Action and Mechanisms of Resistance. International Journal of Toxicology [Internet]. 2003 Mar;22(2):135–43. Available from: https://journals.sagepub.com/doi/10.1080/10915810305089
Nathwani D, Raman G, Sulham K, Gavaghan M, Menon V. Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis. Antimicrobial Resistance and Infection Control. 2014;3(1):32. Available from: https://doi.org/10.1186/2047-2994-3-32
National Institute of Allergy and Infectious Diseases. Causes of Antimicrobial (Drug) Resistance | NIH: National Institute of Allergy and Infectious Diseases [Internet]. Nih.gov. 2011. Available from: https://www.niaid.nih.gov/research/antimicrobial-resistance-causes
Pienaar E, Linderman JJ, Kirschner DE. Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas. PLoS ONE [Internet]. 2018 May 10;13(5). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944939/
Quinn R. Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative. American Journal of Public Health [Internet]. 2013 Mar;103(3):426–34. Available from: https://doi.org/10.2105/ajph.2012.300693
Roberts MG, Burgess S, Toombs-Ruane LJ, Benschop J, Marshall JC, French NP. Combining mutation and horizontal gene transfer in a within-host model of antibiotic resistance. Mathematical Biosciences [Internet]. 2021 Sep 1;339:108656. Available from: https://www.sciencedirect.com/science/article/pii/S0025556421000882
Robinson DA, Enright MC. Evolutionary Models of the Emergence of Methicillin-Resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy [Internet]. 2003 Nov 24 [cited 2019 Jun 20];47(12):3926–34. Available from: https://doi.org/10.1128/aac.47.12.3926-3934.2003
Rr Y, Jr R, Jl S. The Mechanism of Action of Penicillin. Penicillin Acylates the Active Site of Bacillus Stearothermophilus D-alanine Carboxypeptidase [Internet]. The Journal of biological chemistry. 1980. Available from: https://pubmed.ncbi.nlm.nih.gov/7372662/
Song X, Liu P, Liu X, Wang Y, Wei H, Zhang J, et al. Dealing with MDR bacteria and biofilm in the post-antibiotic era: Application of antimicrobial peptides-based nano-formulation. Materials Science and Engineering: C [Internet]. 2021 Sep [cited 2022 Jan 1];128:112318. Available from: https://doi.org/10.1016/j.msec.2021.112318
Wang Q, Wang M, Yang Q, Feng L, Zhang H, Wang R, et al. The role of bacteriophages in facilitating the horizontal transfer of antibiotic resistance genes in municipal wastewater treatment plants. Water Research [Internet]. 2024 Nov 9;268:122776. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0043135424016750
World Health Organization. Guidelines on core components of infection prevention and control programmes at the national and acute health care facility level [Internet]. www.who.int. 2016. Available from: https://www.who.int/publications/i/item/9789241549929
Yang L. The Future of Gene Drive Technology: Dual Challenges of Biosafety and Ecological Risk. GMO Biosafety Research [Internet]. 2024;15(2). Available from: https://ecoevopublisher.com/index.php/gmo/article/html/3823/policy
Zhang Y, Lin S, Fu J, Zhang W, Shu G, Lin J, et al. Nanocarriers for combating biofilms: Advantages and challenges. Journal of Applied Microbiology [Internet]. 2022 May 27 [cited 2025 Apr 30];133(3):1273–87. Available from: https://doi.org/10.1111/jam.15640
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