title: Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance.
abstract: Infections with rapidly evolving pathogens are often treated using combinations of drugs with different mechanisms of action. One of the major goal of combination therapy is to reduce the risk of drug resistance emerging during a patient's treatment. Although this strategy generally has significant benefits over monotherapy, it may also select for multidrug-resistant strains, particularly during long-term treatment for chronic infections. Infections with these strains present an important clinical and public health problem. Complicating this issue, for many antimicrobial treatment regimes, individual drugs have imperfect penetration throughout the body, so there may be regions where only one drug reaches an effective concentration. Here we propose that mismatched drug coverage can greatly speed up the evolution of multidrug resistance by allowing mutations to accumulate in a stepwise fashion. We develop a mathematical model of within-host pathogen evolution under spatially heterogeneous drug coverage and demonstrate that even very small single-drug compartments lead to dramatically higher resistance risk. We find that it is often better to use drug combinations with matched penetration profiles, although there may be a trade-off between preventing eventual treatment failure due to resistance in this way and temporarily reducing pathogen levels systemically. Our results show that drugs with the most extensive distribution are likely to be the most vulnerable to resistance. We conclude that optimal combination treatments should be designed to prevent this spatial effective monotherapy. These results are widely applicable to diverse microbial infections including viruses, bacteria, and parasites.
authors.affiliation: Program for Evolutionary Dynamics, Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138; Theoretical Biology Group, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, 9747 AG, The Netherlands;
authors.forename: Stefany
authors.initials: S
authors.lastname: Moreno-Gamez
authors.affiliation: Program for Evolutionary Dynamics, Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hill
authors.affiliation: Program for Evolutionary Dynamics, Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032;
authors.forename: Daniel I S
authors.identifier: http://orcid.org/0000-0003-1413-3907
authors.initials: DI
authors.lastname: Rosenbloom
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305;
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Petrov
authors.affiliation: Program for Evolutionary Dynamics, Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138;
authors.forename: Martin A
authors.initials: MA
authors.lastname: Nowak
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305; Department of Biology, San Francisco State University, San Francisco, CA 94132; and Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138 pennings@sfsu.edu.
authors.forename: Pleuni S
authors.identifier: http://orcid.org/0000-0001-8704-6578
authors.initials: PS
authors.lastname: Pennings
mesh_terms: D002477:Cells / Q000187:drug effects; D003141:Communicable Diseases / Q000188:drug therapy*; D003198:Computer Simulation; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology*; D004359:Drug Therapy, Combination / Q000379:methods*; D019143:Evolution, Molecular; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics
keywords: combination therapy; drug resistance; drug sanctuaries; pathogen evolution; spatial structure