Rethinking “Antimicrobial Resistance”: Focusing on Patients instead of Pathogenic Organisms
Main Article Content
Abstract
Antimicrobial resistance (AMR) has received widespread attention in the press and considerable resources from governments and global organizations, and that has resulted in many new drugs but not in better outcomes for patients. To achieve better outcomes, researchers and regulators should focus more on a drug’s meaningful clinical benefit to patients and less on the in vitro study of the drug’s ability to inhibit the growth of pathogenic organisms. That requires putting resistance in the context of overall infections and the impact of the human immune response to develop medical interventions that improve the lives of patients.
Keywords:
Antimicrobial resistance, clinical outcomes, immune response, patient-centered care, drug efficacy
Article Details
How to Cite
POWERS III, John H.; ZUCKERMAN, Diana M..
Rethinking “Antimicrobial Resistance”: Focusing on Patients instead of Pathogenic Organisms.
Medical Research Archives, [S.l.], v. 13, n. 3, mar. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6291>. Date accessed: 06 apr. 2025.
doi: https://doi.org/10.18103/mra.v3i3.6291.
Section
Editorial
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. O’Neill J. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. 2014. Accessed May 27, 2024. https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf
2. Pezzani MD, Tornimbene B, Pessoa-Silva C, et al. Methodological quality of studies evaluating the burden of drug-resistant infections in humans due to the WHO Global Antimicrobial Resistance Surveillance System target bacteria. Clin Microbiol Infect. Jan 13 2021;doi:10.1016/j.cmi.2021.01.004
3. Watkins RR, Du B, Isaacs R, Altarac D. Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial. Clin Infect Dis. May 01 2023;76(Suppl 2):S210-S214. doi:10.1093/cid/ciad097
4. US Food and Drug Administration. Antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases: Guidance for Industry. https://www.fda.gov/files/drugs/published/Antibacterial-Therapies-for-Patients-With-an-Unmet-Medical-Need-for-the-Treatment-of-Serious-Bacterial-Diseases.pdf
5. Lawandi A, Kadri S, Powers III JH. Focusing on antimicrobial resistant infections –are we missing the forest for the trees and the patients for pathogens? Frontiers in Antibiotics. 2023;2(December) doi:https://doi.org/10.3389/frabi.2023.1329081
6. Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov. Dec 19 2023;9(1):465. doi:10.1038/s41420-023-01766-7
7. Yaw LK, Robinson JO, Ho KM. A comparison of long-term outcomes after meticillin-resistant and meticillin-sensitive Staphylococcus aureus bacteraemia: an observational cohort study. Lancet Infect Dis. Oct 2014;14(10):967-75. doi:10.1016/S1473-3099(14)70876-X
8. Doshi P. Defining antibiotic effectiveness and resistance: how a private party may soon rule judgments over susceptibility testing. BMJ. Jan 06 2016;352:h6849. doi:10.1136/bmj.h6849
9. Tamma PD, Powers JH. Do patient data really support the clinical and laboratory standards institute recommendation for lowering third-generation cephalosporin interpretive breakpoints? Clin Infect Dis. Aug 2013;57(4):624-5. doi:10.1093/cid/cit308
10. Tamma PD, Wu H, Gerber JS, et al. Outcomes of children with enterobacteriaceae bacteremia with reduced susceptibility to ceftriaxone: do the revised breakpoints translate to improved patient outcomes? Pediatr Infect Dis J. Sep 2013;32(9):965-9. doi:10.1097/INF.0b013e31829043b3
11. Kadri SS, Adjemian J, Lai YL, et al. Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents. Clin Infect Dis. Jul 2018;doi:10.1093/cid/ciy378
12. Vostal A, Grance M, Powers III JH, et al. Demographics, epidemiology, mortality, and difficult-to-treat resistance patterns of bacterial bloodstream infections in the global US Military Health System from 2010-2019: a retrospective cohort study. BMJ Open. Mar 2025;15(3):e094861. doi: 10.1136/bmjopen-2024-094861.
13. US Centers for Disease Control and Prevention Management of Multidrug-Resistant Organisms in Healthcare Settings: MDRO Definition. https://www.cdc.gov/infection-control/hcp/mdro-management/background.html#:~:text=MDRO%20Definition,of%20antimicrobial%20agents%20(1).
14. Kadri SS, Lai YLE, Ricotta EE, et al. External Validation of Difficult-to-Treat Resistance Prevalence and Mortality Risk in Gram-Negative Bloodstream Infection Using Electronic Health Record Data From 140 US Hospitals. Open Forum Infect Dis. Apr 2019;6(4):ofz110. doi:10.1093/ofid/ofz110
15. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. Jun 4 2002;136(11):834-44.
16. Murray CJL, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. Feb 12 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0
17. Kadri SS, Strich JR, Swihart BJ, et al. Attributable mortality from extensively drug-resistant gram-negative infections using propensity-matched tracer antibiotic algorithms. Am J Infect Control. Sep 2019;47(9):1040-1047. doi:10.1016/j.ajic.2019.01.010
18. Chin V, Samia NI, Marchant R, et al. A case study in model failure? COVID-19 daily deaths and ICU bed utilisation predictions in New York state. Eur J Epidemiol. Aug 2020;35(8):733-742. doi:10.1007/s10654-020-00669-6
19. Abat C, Rolain JM, Dubourg G, Fournier PE, Chaudet H, Raoult D. Evaluating the Clinical Burden and Mortality Attributable to Antibiotic Resistance: The Disparity of Empirical Data and Simple Model Estimations. Clin Infect Dis. Aug 15 2017;65(suppl_1):S58-S63. doi:10.1093/cid/cix346
20. Abat C, Fournier PE, Jimeno MT, Rolain JM, Raoult D. Extremely and pandrug-resistant bacteria extra-deaths: myth or reality? Eur J Clin Microbiol Infect Dis. Sep 2018;37(9):1687-1697. doi:10.1007/s10096-018-3300-0
21. Baquero F. Threats of antibiotic resistance: an obliged reappraisal. Int Microbiol. Nov 2021;24(4):499-506. doi:10.1007/s10123-021-00184-y
22. Diallo OO, Baron SA, Dubourg G, et al. Major discrepancy between factual antibiotic resistance and consumption in South of France: analysis of 539,037 bacterial strains. Sci Rep. Oct 26 2020;10(1):18262. doi:10.1038/s41598-020-75158-7
23. Ghosh M, Iarikov D, Qi XK, et al. Flexible Development Programs for Antibacterial Drugs to Address Unmet Medical Needs. Emerg Infect Dis. Nov 2024;30(11):2227-2230. doi:10.3201/eid3011.231416
24. Doshi P, Hur P, Jones M, et al. Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011. JAMA Intern Med. Oct 2017;177(10):1-8. doi:10.1001/jamainternmed.2017.3820
25. Morlock R, Rose J, Powers JH. Perspectives of US Adults on Antimicrobial Trials With Noninferiority Designs. JAMA Netw Open. May 01 2023;6(5):e2316297. doi:10.1001/jamanetworkopen.2023.16297
26. Doshi P, Spence O, Kuzucan A, Powers JH. Communication of Nonefficacy Benefits of New Drugs Approved on the Basis of Noninferiority Trials Alone: Cohort Study of FDA and Sponsor Communication, 2011-2017. JAMA Intern Med. 05 2019;179(5):719-721. doi:10.1001/jamainternmed.2018.7040
27. Powers JH, Evans SR, Kesselheim AS. Studying new antibiotics for multidrug resistant infections: are today's patients paying for unproved future benefits? BMJ. Feb 2018;360:k587.
28. Crasta K, Daly CG, Mitchell D, Curtis B, Stewart D, Heitz-Mayfield LJ. Bacteraemia due to dental flossing. J Clin Periodontol. Apr 2009;36(4):323-32. doi:10.1111/j.1600-051X.2008.01372.x
29. Martins CC, Lockhart PB, Firmino RT, et al. Bacteremia following different oral procedures: Systematic review and meta-analysis. Oral Dis. Apr 2024;30(3):846-854. doi:10.1111/odi.14531
30. Powers JH. Scientific Evidence, Regulatory Decision Making, and Incentives for Therapeutics in Infectious Diseases: The Example of Cefiderocol. Clin Infect Dis. Jun 15 2021;72(12):e1112-e1114. doi:10.1093/cid/ciaa1795
31. Mitra-Majumdar M, Powers JH, Brown BL, Kesselheim AS. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227. doi:10.1136/bmjmed-2022-000227
32. Deak D, Outterson K, Powers JH, Kesselheim AS. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015. Ann Intern Med. May 31 2016; doi:10.7326/M16-0291
33. US Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence; Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical
34. Upjohn v Finch. United States Court of Appeals for the Sixth Circuit. February 27, 1970 1970;No. 19926 422 F.2d 944; 1970 U.S. App. LEXIS 10524
35. World Medical Association. Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/
36. Powers JH. Noninferiority and equivalence trials: deciphering 'similarity' of medical interventions. Stat Med. Feb 10 2008;27(3):343-52. doi:10.1002/sim.3138
37. 112th United States Congress. Generating Antibiotic Incentives Now (GAIN) Act. https://www.gpo.gov/fdsys/pkg/BILLS-112s1734is/pdf/BILLS-112s1734is.pdf
38. Yahav D, Tau N, Shepshelovich D. Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria. Clin Infect Dis. Jun 01 2021;72(11):1968-1974. doi:10.1093/cid/ciaa457
39. Sinha MS, Powers JH, Kesselheim AS. The Wrong Cure: Financial Incentives for Unimpressive New Antibiotics. J Infect Dis. May 20 2021;223(9):1506-1509. doi:10.1093/infdis/jiaa536
2. Pezzani MD, Tornimbene B, Pessoa-Silva C, et al. Methodological quality of studies evaluating the burden of drug-resistant infections in humans due to the WHO Global Antimicrobial Resistance Surveillance System target bacteria. Clin Microbiol Infect. Jan 13 2021;doi:10.1016/j.cmi.2021.01.004
3. Watkins RR, Du B, Isaacs R, Altarac D. Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial. Clin Infect Dis. May 01 2023;76(Suppl 2):S210-S214. doi:10.1093/cid/ciad097
4. US Food and Drug Administration. Antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases: Guidance for Industry. https://www.fda.gov/files/drugs/published/Antibacterial-Therapies-for-Patients-With-an-Unmet-Medical-Need-for-the-Treatment-of-Serious-Bacterial-Diseases.pdf
5. Lawandi A, Kadri S, Powers III JH. Focusing on antimicrobial resistant infections –are we missing the forest for the trees and the patients for pathogens? Frontiers in Antibiotics. 2023;2(December) doi:https://doi.org/10.3389/frabi.2023.1329081
6. Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov. Dec 19 2023;9(1):465. doi:10.1038/s41420-023-01766-7
7. Yaw LK, Robinson JO, Ho KM. A comparison of long-term outcomes after meticillin-resistant and meticillin-sensitive Staphylococcus aureus bacteraemia: an observational cohort study. Lancet Infect Dis. Oct 2014;14(10):967-75. doi:10.1016/S1473-3099(14)70876-X
8. Doshi P. Defining antibiotic effectiveness and resistance: how a private party may soon rule judgments over susceptibility testing. BMJ. Jan 06 2016;352:h6849. doi:10.1136/bmj.h6849
9. Tamma PD, Powers JH. Do patient data really support the clinical and laboratory standards institute recommendation for lowering third-generation cephalosporin interpretive breakpoints? Clin Infect Dis. Aug 2013;57(4):624-5. doi:10.1093/cid/cit308
10. Tamma PD, Wu H, Gerber JS, et al. Outcomes of children with enterobacteriaceae bacteremia with reduced susceptibility to ceftriaxone: do the revised breakpoints translate to improved patient outcomes? Pediatr Infect Dis J. Sep 2013;32(9):965-9. doi:10.1097/INF.0b013e31829043b3
11. Kadri SS, Adjemian J, Lai YL, et al. Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents. Clin Infect Dis. Jul 2018;doi:10.1093/cid/ciy378
12. Vostal A, Grance M, Powers III JH, et al. Demographics, epidemiology, mortality, and difficult-to-treat resistance patterns of bacterial bloodstream infections in the global US Military Health System from 2010-2019: a retrospective cohort study. BMJ Open. Mar 2025;15(3):e094861. doi: 10.1136/bmjopen-2024-094861.
13. US Centers for Disease Control and Prevention Management of Multidrug-Resistant Organisms in Healthcare Settings: MDRO Definition. https://www.cdc.gov/infection-control/hcp/mdro-management/background.html#:~:text=MDRO%20Definition,of%20antimicrobial%20agents%20(1).
14. Kadri SS, Lai YLE, Ricotta EE, et al. External Validation of Difficult-to-Treat Resistance Prevalence and Mortality Risk in Gram-Negative Bloodstream Infection Using Electronic Health Record Data From 140 US Hospitals. Open Forum Infect Dis. Apr 2019;6(4):ofz110. doi:10.1093/ofid/ofz110
15. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, enterococcus, gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. Jun 4 2002;136(11):834-44.
16. Murray CJL, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. Feb 12 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0
17. Kadri SS, Strich JR, Swihart BJ, et al. Attributable mortality from extensively drug-resistant gram-negative infections using propensity-matched tracer antibiotic algorithms. Am J Infect Control. Sep 2019;47(9):1040-1047. doi:10.1016/j.ajic.2019.01.010
18. Chin V, Samia NI, Marchant R, et al. A case study in model failure? COVID-19 daily deaths and ICU bed utilisation predictions in New York state. Eur J Epidemiol. Aug 2020;35(8):733-742. doi:10.1007/s10654-020-00669-6
19. Abat C, Rolain JM, Dubourg G, Fournier PE, Chaudet H, Raoult D. Evaluating the Clinical Burden and Mortality Attributable to Antibiotic Resistance: The Disparity of Empirical Data and Simple Model Estimations. Clin Infect Dis. Aug 15 2017;65(suppl_1):S58-S63. doi:10.1093/cid/cix346
20. Abat C, Fournier PE, Jimeno MT, Rolain JM, Raoult D. Extremely and pandrug-resistant bacteria extra-deaths: myth or reality? Eur J Clin Microbiol Infect Dis. Sep 2018;37(9):1687-1697. doi:10.1007/s10096-018-3300-0
21. Baquero F. Threats of antibiotic resistance: an obliged reappraisal. Int Microbiol. Nov 2021;24(4):499-506. doi:10.1007/s10123-021-00184-y
22. Diallo OO, Baron SA, Dubourg G, et al. Major discrepancy between factual antibiotic resistance and consumption in South of France: analysis of 539,037 bacterial strains. Sci Rep. Oct 26 2020;10(1):18262. doi:10.1038/s41598-020-75158-7
23. Ghosh M, Iarikov D, Qi XK, et al. Flexible Development Programs for Antibacterial Drugs to Address Unmet Medical Needs. Emerg Infect Dis. Nov 2024;30(11):2227-2230. doi:10.3201/eid3011.231416
24. Doshi P, Hur P, Jones M, et al. Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011. JAMA Intern Med. Oct 2017;177(10):1-8. doi:10.1001/jamainternmed.2017.3820
25. Morlock R, Rose J, Powers JH. Perspectives of US Adults on Antimicrobial Trials With Noninferiority Designs. JAMA Netw Open. May 01 2023;6(5):e2316297. doi:10.1001/jamanetworkopen.2023.16297
26. Doshi P, Spence O, Kuzucan A, Powers JH. Communication of Nonefficacy Benefits of New Drugs Approved on the Basis of Noninferiority Trials Alone: Cohort Study of FDA and Sponsor Communication, 2011-2017. JAMA Intern Med. 05 2019;179(5):719-721. doi:10.1001/jamainternmed.2018.7040
27. Powers JH, Evans SR, Kesselheim AS. Studying new antibiotics for multidrug resistant infections: are today's patients paying for unproved future benefits? BMJ. Feb 2018;360:k587.
28. Crasta K, Daly CG, Mitchell D, Curtis B, Stewart D, Heitz-Mayfield LJ. Bacteraemia due to dental flossing. J Clin Periodontol. Apr 2009;36(4):323-32. doi:10.1111/j.1600-051X.2008.01372.x
29. Martins CC, Lockhart PB, Firmino RT, et al. Bacteremia following different oral procedures: Systematic review and meta-analysis. Oral Dis. Apr 2024;30(3):846-854. doi:10.1111/odi.14531
30. Powers JH. Scientific Evidence, Regulatory Decision Making, and Incentives for Therapeutics in Infectious Diseases: The Example of Cefiderocol. Clin Infect Dis. Jun 15 2021;72(12):e1112-e1114. doi:10.1093/cid/ciaa1795
31. Mitra-Majumdar M, Powers JH, Brown BL, Kesselheim AS. Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 2022;1(1):e000227. doi:10.1136/bmjmed-2022-000227
32. Deak D, Outterson K, Powers JH, Kesselheim AS. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration-Approved Antibiotics, 2010-2015. Ann Intern Med. May 31 2016; doi:10.7326/M16-0291
33. US Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence; Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical
34. Upjohn v Finch. United States Court of Appeals for the Sixth Circuit. February 27, 1970 1970;No. 19926 422 F.2d 944; 1970 U.S. App. LEXIS 10524
35. World Medical Association. Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/
36. Powers JH. Noninferiority and equivalence trials: deciphering 'similarity' of medical interventions. Stat Med. Feb 10 2008;27(3):343-52. doi:10.1002/sim.3138
37. 112th United States Congress. Generating Antibiotic Incentives Now (GAIN) Act. https://www.gpo.gov/fdsys/pkg/BILLS-112s1734is/pdf/BILLS-112s1734is.pdf
38. Yahav D, Tau N, Shepshelovich D. Assessment of Data Supporting the Efficacy of New Antibiotics for Treating Infections Caused by Multidrug-resistant Bacteria. Clin Infect Dis. Jun 01 2021;72(11):1968-1974. doi:10.1093/cid/ciaa457
39. Sinha MS, Powers JH, Kesselheim AS. The Wrong Cure: Financial Incentives for Unimpressive New Antibiotics. J Infect Dis. May 20 2021;223(9):1506-1509. doi:10.1093/infdis/jiaa536