title: Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection.
abstract: Influenza pandemics and seasonal outbreaks have shown the potential of Influenza A virus (IAV) to enhance susceptibility to a secondary infection with the bacterial pathogen Streptococcus pneumoniae (Sp). The high morbidity and mortality rate revealed the poor efficacy of antiviral drugs and vaccines to fight IAV infections. Currently, the most effective treatment for IAV is by antiviral neuraminidase inhibitors. Among them, the most frequently stockpiled is Oseltamivir which reduces viral release and transmission. However, effectiveness of Oseltamivir is compromised by the emergence of resistant IAV strains and secondary bacterial infections. To date, little attention has been given to evaluate how Oseltamivir treatment strategies alter Influenza viral infection in presence of Sp coinfection and a resistant IAV strain emergence. In this paper we investigate the efficacy of current approved Oseltamivir treatment regimens using a computational approach. Our numerical results suggest that the curative regimen (75 mg) may yield 47% of antiviral efficacy and 9% of antibacterial efficacy. An increment in dose to 150 mg (pandemic regimen) may increase the antiviral efficacy to 49% and the antibacterial efficacy to 16%. The choice to decrease the intake frequency to once per day is not recommended due to a significant reduction in both antiviral and antibacterial efficacy. We also observe that the treatment duration of 10 days may not provide a clear improvement on the antiviral and antibacterial efficacy compared to 5 days. All together, our in silico study reveals the success and pitfalls of Oseltamivir treatment strategies within IAV-Sp coinfection and calls for testing the validity in clinical trials.
authors.affiliation: Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre for Infection Research, Helmholtz Centre for Infection Research Braunschweig, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boianelli
authors.affiliation: Immune Regulation, Helmholtz Centre for Infection ResearchBraunschweig, Germany; Infection Immunology, Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke-UniversityMagdeburg, Germany.
authors.forename: Niharika
authors.initials: N
authors.lastname: Sharma-Chawla
authors.affiliation: Immune Regulation, Helmholtz Centre for Infection ResearchBraunschweig, Germany; Infection Immunology, Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke-UniversityMagdeburg, Germany.
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
authors.affiliation: Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre for Infection Research, Helmholtz Centre for Infection Research Braunschweig, Germany.
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Hernandez-Vargas
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D060085:Coinfection / Q000188:drug therapy*; D003198:Computer Simulation; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000472:pathogenicity; D007251:Influenza, Human / Q000150:complications / Q000188:drug therapy*; D008962:Models, Theoretical; D009439:Neuraminidase / Q000187:drug effects; D053139:Oseltamivir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011008:Pneumococcal Infections / Q000150:complications / Q000188:drug therapy*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase
keywords: Oseltamivir treatment; PK/PD model; S. pneumoniae coinfection; microbial resistance; population modeling; viral dynamic model; viral infection