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An analogous situation also occurs in cancer therapy, where cell lineages within a tumor compete for access to space and nutrients. There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which simply removes the competitively more able susceptible cell lineages, allowing drug-resistant lineages to kill the host (Gatenby, 2009; Gatenby et al., 2009). Mouse experiments support this: Conventionally treated mice died of drug-resistant tumors, but less aggressively treated mice survived (Gatenby et al., 2009). Elsewhere, we and others have also argued that by concentrating on malaria control rather than vector control, selection for insecticide-resistant mosquitoes can be managed and even eliminated, obviating the need for an insecticide discovery pipeline (Koella et al., 2009; Read et al., 2009; Gourley et al., 2011). In all this, the key issue is to impose only the selection needed to achieve health gains and no more.

There is widespread agreement that stewardship of antimicrobials means restricting their use to only those patients who need them. We suggest that a similar default philosophy of sparing use should apply at the within-host level to patient treatment regimens. Overwhelming chemical force may at times be required, but we need to be very clear about when and why that is. Aggressive chemotherapy will, under a wide range of circumstances, spread resistance.

ACKNOWLEDGMENTS

Our arguments benefited from discussion with V. Barclay, C. Bergstrom, S. Bonhoeffer, N. Colegrave, M. Ferdig, A. Griffin, J. Hansen, J. Juliano, M. Laufer, B. Levin, J. Lloyd Smith, M. Mackinnon, S. Meshnick, N. Mideo, S. Nee, R. Paul, J. de Roode, P. Schneider, F. Taddei, and A. Wargo, not all of whom agree with our conclusions. We thank J. Antonovics, A. Bell, K. Foster, M. Greischar, S. Reece, and an anonymous referee for comments on the manuscript and members of the Research and Policy in Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, for stimulating discussion. Award R01GM089932 from the National Institute of General Medical Sciences supported the empirical work reported here; work under Awards R01AI089819 and U19AI089676 from the National Institute of Allergy and Infectious Diseases contributed to conceptual development. This work greatly benefited from a Fellowship to A.F.R. at the Wissenschaftskolleg zu Berlin.



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