Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection

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.

[1]  Melissa Carter,et al.  Sialic acid: a preventable signal for pneumococcal biofilm formation, colonization, and invasion of the host. , 2009, The Journal of infectious diseases.

[2]  Jo Leonardi-Bee,et al.  Impact of Neuraminidase Inhibitor Treatment on Outcomes of Public Health Importance During the 2009–2010 Influenza A(H1N1) Pandemic: A Systematic Review and Meta-Analysis in Hospitalized Patients , 2012, The Journal of infectious diseases.

[3]  C. Beauchemin,et al.  Modelling the emergence of influenza drug resistance: The roles of surface proteins, the immune response and antiviral mechanisms , 2017, PloS one.

[4]  E. D. Kilbourne.  Influenza Pandemics of the 20 th Century , 2005 .

[5]  Larisa V. Gubareva,et al.  Surveillance for Neuraminidase Inhibitor Resistance among Human Influenza A and B Viruses Circulating Worldwide from 2004 to 2008 , 2008, Antimicrobial Agents and Chemotherapy.

[6]  Larisa V. Gubareva,et al.  Comparison of the Activities of Zanamivir, Oseltamivir, and RWJ-270201 against Clinical Isolates of Influenza Virus and Neuraminidase Inhibitor-Resistant Variants , 2001, Antimicrobial Agents and Chemotherapy.

[7]  Andreas Handel,et al.  A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead , 2011, BMC public health.

[8]  A. Perelson,et al.  Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection , 2009, Journal of Virology.

[9]  Frank Klawonn,et al.  Analysis of Practical Identifiability of a Viral Infection Model , 2016, PloS one.

[10]  Alan S. Perelson,et al.  Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus , 2010, Journal of Virology.

[11]  M. Jordana,et al.  Influenza Infection Leads to Increased Susceptibility to Subsequent Bacterial Superinfection by Impairing NK Cell Responses in the Lung , 2010, The Journal of Immunology.

[12]  J. Xie,et al.  Mechanisms of Severe Mortality-Associated Bacterial Co-infections Following Influenza Virus Infection , 2017, Front. Cell. Infect. Microbiol..

[13]  F. Hayden,et al.  Antiviral combinations for severe influenza , 2014, The Lancet Infectious Diseases.

[14]  J. Rehg,et al.  Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor. , 2002, The Journal of infectious diseases.

[15]  A. Moscona.  Neuraminidase inhibitors for influenza. , 2005, The New England journal of medicine.

[16]  R. Webster,et al.  Competitive Fitness of Oseltamivir-Sensitive and -Resistant Highly Pathogenic H5N1 Influenza Viruses in a Ferret Model , 2010, Journal of Virology.

[17]  A. Perelson,et al.  Kinetics of Coinfection with Influenza A Virus and Streptococcus pneumoniae , 2013, PLoS pathogens.

[18]  E. D. Kilbourne.  Influenza Pandemics of the 20th Century , 2006, Emerging infectious diseases.

[19]  Stephen H. D. Jackson,et al.  Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. , 2003, British journal of clinical pharmacology.

[20]  Ronald Gieschke,et al.  Population Pharmacokinetics of Oseltamivir When Coadministered With Probenecid , 2008, Journal of clinical pharmacology.

[21]  Arjun Srinivasan,et al.  Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients--North Carolina, 2009. , 2011, The Journal of infectious diseases.

[22]  Alan S. Perelson,et al.  Viral kinetic modeling: state of the art , 2014, Journal of Pharmacokinetics and Pharmacodynamics.

[23]  F. Hayden,et al.  Perspectives on antiviral use during pandemic influenza. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[24]  C. Beauchemin,et al.  A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression , 2015, Antimicrobial Agents and Chemotherapy.

[25]  J. McCullers.  Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza. , 2004, The Journal of infectious diseases.

[26]  John J. Treanor,et al.  Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza , 2000 .

[27]  Robert Schechter,et al.  Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[28]  Laetitia Canini,et al.  Population modeling of influenza A / H 1 N 1 viral kinetics and symptom dynamics , 2010 .

[29]  R. Eggo,et al.  Influenza Interaction with Cocirculating Pathogens, and Its Impact on Surveillance, Pathogenesis and Epidemic Profile: A Key Role for Mathematical Modeling , 2017, bioRxiv.

[30]  Andreas Handel,et al.  Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread , 2007, PLoS Comput. Biol..

[31]  I. Mcnicholl,et al.  Neuraminidase Inhibitors: Zanamivir and Oseltamivir , 2001, The Annals of pharmacotherapy.

[32]  Andrew Hughes,et al.  Model-based drug discovery: implementation and impact. , 2013, Drug discovery today.

[33]  Hana M. Dobrovolny,et al.  Assessing Mathematical Models of Influenza Infections Using Features of the Immune Response , 2013, PloS one.

[34]  Alan S. Perelson,et al.  Effects of Aging on Influenza Virus Infection Dynamics , 2014, Journal of Virology.

[35]  Gilles Clermont,et al.  A Dynamical Model of Human Immune Response to Influenza a Virus Infection , 2006 .

[36]  A. Shahangian,et al.  Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice. , 2009, The Journal of clinical investigation.

[37]  M. Nowak,et al.  Virus dynamics: Mathematical principles of immunology and virology , 2001 .

[38]  Alan S. Perelson,et al.  Impact of Different Oseltamivir Regimens on Treating Influenza A Virus Infection and Resistance Emergence: Insights from a Modelling Study , 2014, PLoS Comput. Biol..

[39]  Laetitia Canini,et al.  Population Modeling of Influenza A/H1N1 Virus Kinetics and Symptom Dynamics , 2010, Journal of Virology.

[40]  J. McCullers,et al.  Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. , 2009, The Journal of infectious diseases.

[41]  K. Walters,et al.  Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses , 2011, mBio.

[42]  D. E. Rogers,et al.  Studies on influenza in the pandemic of 1957-1958. II. Pulmonary complications of influenza. , 1959, The Journal of clinical investigation.

[43]  J. McCullers.  Insights into the Interaction between Influenza Virus and Pneumococcus , 2006, Clinical Microbiology Reviews.

[44]  M. Meyer-Hermann,et al.  Innate Immune System Dynamics to Influenza Virus , 2012 .

[45]  T. Moran,et al.  Type I Interferon Induction during Influenza Virus Infection Increases Susceptibility to Secondary Streptococcus pneumoniae Infection by Negative Regulation of γδ T Cells , 2012, Journal of Virology.

[46]  A. Perelson,et al.  Kinetics of Influenza A Virus Infection in Humans , 2006, Journal of Virology.

[47]  M. Lipsitch,et al.  Antiviral usage for H1N1 treatment: pros, cons and an argument for broader prescribing guidelines in the United States , 2009, PLoS currents.

[48]  T. Eissing,et al.  A pharma perspective on the systems medicine and pharmacology of inflammation. , 2015, Mathematical biosciences.

[49]  S. Goerdt,et al.  Macrophage activation and polarization: nomenclature and experimental guidelines. , 2014, Immunity.

[50]  Michael Meyer-Hermann,et al.  Modeling Influenza Virus Infection: A Roadmap for Influenza Research , 2015, Viruses.

[51]  Alan S. Perelson,et al.  Modeling Within-Host Dynamics of Influenza Virus Infection Including Immune Responses , 2012, PLoS Comput. Biol..

[52]  C. Beauchemin,et al.  Neuraminidase inhibitors for treatment of human and avian strain influenza: A comparative modeling study. , 2011, Journal of theoretical biology.

[53]  Y. Kuang,et al.  Modeling the interaction of cytotoxic T lymphocytes and influenza virus infected epithelial cells. , 2010, Mathematical biosciences and engineering : MBE.

[54]  K. Yanagihara,et al.  The Effect of Intravenous Peramivir, Compared with Oral Oseltamivir, on the Outcome of Post-Influenza Pneumococcal Pneumonia in Mice , 2015, Antiviral therapy.

[55]  G. Taylor,et al.  Structural basis for Streptococcus pneumoniae NanA inhibition by influenza antivirals zanamivir and oseltamivir carboxylate. , 2011, Journal of molecular biology.

[56]  Niall Johnson,et al.  Updating the Accounts: Global Mortality of the 1918-1920 "Spanish" Influenza Pandemic , 2002, Bulletin of the history of medicine.

[57]  J. McCullers.  The co-pathogenesis of influenza viruses with bacteria in the lung , 2014, Nature Reviews Microbiology.

[58]  N. J. White,et al.  Pharmacokinetics of High-Dose Oseltamivir in Healthy Volunteers , 2008, Antimicrobial Agents and Chemotherapy.

[59]  Anthony S Fauci,et al.  Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. , 2008, The Journal of infectious diseases.

[60]  F Y Aoki,et al.  Early administration of oral oseltamivir increases the benefits of influenza treatment. , 2003, The Journal of antimicrobial chemotherapy.