Aggressive chemotherapy and the selection of drug resistant pathogens

PLoS Pathog. 2013 Sep;9(9):e1003578. doi: 10.1371/journal.ppat.1003578. Epub 2013 Sep 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antimalarials / administration & dosage*
  • Antimalarials / adverse effects
  • Antimalarials / pharmacology
  • Antimalarials / therapeutic use
  • Clone Cells
  • Dose-Response Relationship, Drug
  • Drug Resistance*
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Female
  • Malaria / blood
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Mice, Inbred C57BL
  • Models, Biological*
  • Parasite Egg Count
  • Plasmodium chabaudi / drug effects*
  • Plasmodium chabaudi / genetics
  • Plasmodium chabaudi / growth & development
  • Plasmodium chabaudi / pathogenicity
  • Pyrimethamine / administration & dosage
  • Pyrimethamine / adverse effects
  • Pyrimethamine / pharmacology
  • Pyrimethamine / therapeutic use
  • Selection, Genetic / drug effects*
  • Virulence / drug effects

Substances

  • Antimalarials
  • Pyrimethamine