Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an...

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Bibliographic Details
Published in:PLoS computational biology 2016-04, Vol.12 (4), p.e1004857-e1004857
Main Authors: Gjini, Erida, Brito, Patricia H
Format: Article
Language:English
Subjects:
Anti-infective agents
Anti-Infective Agents - administration & dosage
Anti-Infective Agents - therapeutic use
Antibiotics
Antimicrobial agents
Bacteria
Bacterial infections
Biology and Life Sciences
Clinical outcomes
Computational Biology
Computer Simulation
Dosage and administration
Drug dosages
Drug resistance
Drug Resistance, Microbial
Evolution
Host-Pathogen Interactions - drug effects
Host-Pathogen Interactions - immunology
Humans
Immune response
Immune system
Infection - drug therapy
Infection - immunology
Infections
Mathematical models
Medicine and Health Sciences
Microbial drug resistance
Models, Immunological
Observations
Pathogens
Prevention
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Summary:Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. We use mathematical modelling of within-host infection dynamics to study the interplay between pathogen-dependent host immune responses and antibiotic treatment. We compare classical (fixed dose and duration) and adaptive (coupled to pathogen load) treatment regimes, exploring systematically infection outcomes such as time to clearance, immunopathology, host immunization, and selection of resistant bacteria. Our analysis and simulations uncover effective treatment strategies that promote synergy between the host immune system and the antimicrobial drug in clearing infection. Both in classical and adaptive treatment, we quantify how treatment timing and the strength of the immune response determine the success of moderate therapies. We explain key parameters and dimensions, where an adaptive regime differs from classical treatment, bringing new insight into the ongoing debate of resistance management. Emphasizing the sensitivity of treatment outcomes to the balance between external antibiotic intervention and endogenous natural defenses, our study calls for more empirical attention to host immunity processes.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1004857