ArticleProceedings of the National Academy of Sciences of the United States of America2015
Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers.
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Who cites it
83 citing papers in PubMed, 156 citations in OpenAlex.
- High concordance in plasma and CSF HIV-1 drug resistance mutations despite high cases of CSF viral escape in individuals with HIV-associated cryptococcal meningitis in Botswana.The Journal of antimicrobial chemotherapy · 2022Trial
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- The effect of the fitness gradient on fixation probability.Nature communications · 2026Article
- Environmental cues shape extracellular vesicles biogenesis and function in Streptococcus pneumoniae.BMC microbiology · 2026Article
- Enhancing antiretroviral delivery to secondary lymph nodes by targeting CD169 + macrophages with HIV-mimicking nanoparticles.Scientific reports · 2025Article
- Survival mechanism of pancreatic tumor bacteria and their ability to metabolize chemotherapy drugs.Microbiology spectrum · 2025Article
- Heterogeneous Antiretroviral Drug Exposure in Male and Female Genital Tract Tissues.The Journal of infectious diseases · 2025Article
- Fitness seascapes are necessary for realistic modeling of the evolutionary response to drug therapy.Science advances · 2025Article
- A nomogram for predicting unfavorable outcomes of antituberculosis treatment among individuals with AIDS combined with pulmonary tuberculosis in China.Frontiers in immunology · 2025Article
- High concordance of human immunodeficiency virus-1 genotypic drug resistance generated from paired cerebrospinal fluid and plasma in antiretroviral therapy -naive or -experienced patients.Frontiers in microbiology · 2025Article
- Azole Combinations and Multi-Targeting Drugs That Synergistically InhibitJournal of fungi (Basel, Switzerland) · 2024Review
- Modelling HIV-1 control and remission.NPJ systems biology and applications · 2024Review
- The many dimensions of combination therapy: How to combine antibiotics to limit resistance evolution.Evolutionary applications · 2024Article
- Modeling spatial evolution of multi-drug resistance under drug environmental gradients.PLoS computational biology · 2024Article
- Building pyramids against the evolutionary emergence of pathogens.Proceedings. Biological sciences · 2024Article
- Diverse mutant selection windows shape spatial heterogeneity in evolving populations.PLoS computational biology · 2024Article
- Pathogen non-planktonic phases within the urinary tract impact early infection and resistance evolution.The ISME journal · 2024Article
- Long term management of people with post-tuberculosis lung disease.The Korean journal of internal medicine · 2024Review
- Modeling spatial evolution of multi-drug resistance under drug environmental gradients.bioRxiv : the preprint server for biology · 2023Article
23 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.