Origin and Proliferation of Multiple- Drug Resistance in Bacterial Pathogens The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Chang, Hsiao-Han, Ted Cohen, Yonatan H. Grad, William P. Hanage, Thomas F. O’Brien, and Marc Lipsitch. 2015. “Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens.” Microbiol. Mol. Biol. Rev. 79 (1) (February 4): 101–116. doi:10.1128/ mmbr.00039-14. Published Version doi:10.1128/MMBR.00039-14 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:26882169 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA crossmark Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens Hsiao-Han Chang,a Ted Cohen,a,b Yonatan H. Grad,a,c William P. Hanage,a Thomas F. O’Brien,d Marc Lipsitcha,e Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USAa; Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USAb; Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USAc; The World Health Organization Collaborating Centre for Surveillance of Antimicrobial Resistance, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USAd; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USAe SUMMARY ..................................................................................................................................................102 INTRODUCTION ............................................................................................................................................102 THE EXCESS OF MDR IN BACTERIA.........................................................................................................................102 Streptococcus pneumoniae................................................................................................................................102 Enterobacteriaceae........................................................................................................................................102 Neisseria gonorrhoeae.....................................................................................................................................102 Mycobacterium tuberculosis...............................................................................................................................103 Staphylococcus aureus ....................................................................................................................................103 MECHANISMS LEADING TO EXCESS MDR .................................................................................................................104 Explanations for the Origin of MDR Strains ..............................................................................................................104 Single biochemical mechanism conferring resistance to multiple drugs..............................................................................104 (i) Testable predictions ..............................................................................................................................104 (ii) Practical implications ............................................................................................................................105 Genetic linkage ........................................................................................................................................105 (i) Examples .........................................................................................................................................105 (ii) Testable predictions .............................................................................................................................105 (iii) Practical implications ............................................................................................................................105 Highly mutable or recombinogenic bacterial lineages ................................................................................................106 (i) Examples .........................................................................................................................................107 (ii) Complexities .....................................................................................................................................107 (iii) Testable predictions .............................................................................................................................107 (iv) Practical implications............................................................................................................................107 Multidrug therapy with accelerated treatment failure in resistant infections..........................................................................107 (i) Example ..........................................................................................................................................108 (ii) Testable predictions .............................................................................................................................108 (iii) Practical implications ............................................................................................................................108 Explanations for the Proliferation of MDR Strains.........................................................................................................108 Associated linkage selection...........................................................................................................................108 (i) Examples .........................................................................................................................................108 (ii) Testable predictions .............................................................................................................................109 (iii) Practical implications ............................................................................................................................109 Bystander selection ....................................................................................................................................109 (i) Examples .........................................................................................................................................109 (ii) Testable predictions .............................................................................................................................110 (iii) Practical implications ............................................................................................................................110 Positive epistasis between drug resistance determinants or between resistance determinants and genetic background............................110 (i) Examples .........................................................................................................................................110 (ii) Testable predictions .............................................................................................................................110 (iii) Practical implications ............................................................................................................................110 Niche differentiation: aggregation of multiple drug selection pressures within specific populations..................................................111 (continued) Published 4 February 2015 Citation Chang H-H, Cohen T, Grad YH, Hanage WP, O’Brien TF, Lipsitch M. 4 February 2015. Origin and proliferation of multiple-drug resistance in bacterial pathogens. Microbiol Mol Biol Rev doi:10.1128/MMBR.00039-14. Address correspondence to Marc Lipsitch, [email protected]. Copyright © 2015, American Society for Microbiology. All Rights Reserved. doi:10.1128/MMBR.00039-14 March 2015 Volume 79 Number 1 Microbiology and Molecular Biology Reviews mmbr.asm.org 101 Chang et al. (i) Examples .........................................................................................................................................111 (ii) Testable predictions .............................................................................................................................111 (iii) Practical implications ............................................................................................................................111 Importation of MDR strains and geographic source-sink dynamics ...................................................................................111 (i) Example ..........................................................................................................................................111 (ii) Testable predictions .............................................................................................................................111 (iii) Practical implications ............................................................................................................................111 CONCLUSIONS .............................................................................................................................................111