Journal Article

Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance

Petrov, Dmitri A., Moreno-Gamez, Stefany, Pennings, Pleuni S., Hill, Alison L., Nowak, Martin A., Rosenbloom, Daniel I. S.

2015

Overview

Significance The evolution of drug resistance is a major health threat. In chronic infections with rapidly mutating pathogens—including HIV, tuberculosis, and hepatitis B and C viruses—multidrug resistance can cause even aggressive combination drug treatment to fail. Oftentimes, individual drugs within a combination do not penetrate equally to all infected regions of the body. Here we present a mathematical model suggesting that this imperfect penetration can dramatically increase the chance of treatment failure by creating regions where only one drug from a combination reaches a therapeutic concentration. The resulting single-drug compartments allow the pathogen to evolve resistance to each drug sequentially, rapidly causing multidrug resistance. More broadly, our model provides a quantitative framework for reasoning about trade-offs between aggressive and moderate drug therapies. 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Biological Sciences / body regions / Cells - drug effects / Communicable Diseases - drug therapy / Computer Simulation / Drug resistance / Drug Resistance, Multiple - genetics / Drug Resistance, Multiple - physiology / Drug therapy / Drug Therapy, Combination - methods / drugs / evolution / Evolution, Molecular / hepatitis B / Human immunodeficiency virus / Humans / Infections / mathematical models / Models, Biological / Multidrug resistant organisms / multiple drug resistance / Parasites / Pathogens / Pharmacokinetics / Physical Sciences / PNAS Plus / Public health / tuberculosis