Aggressive chemotherapy and the selection of drug resistant pathogens.
Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible.
Center for Infectious Disease Dynamics, Departments of Biology and Entomology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
Silvie
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Huijben
Andrew S
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Bell
Derek G
DG
Sim
Danielle
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Tomasello
Nicole
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Mideo
Troy
T
Day
Andrew F
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Read
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005260:Female; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010270:Parasite Egg Count; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012641:Selection, Genetic / Q000187:drug effects*; D014774:Virulence / Q000187:drug effects
D000962:Antimalarials; D011739:Pyrimethamine