Pneumococcal pneumonia often occurs secondary to influenza infection and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. Peramivir is a novel, intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. We investigated the efficacy of peramivir for modulating the severity of secondary pneumococcal pneumonia.
Methods
CBA/JNCrlj mice, infected with influenza virus and superinfected with Streptococcus pneumoniae, were treated with either intravenous peramivir (single or multiple doses of 60 mg/kg/day) or oral oseltamivir at doses of 10 or 40 mg/kg/day in divided doses. The survival rate, viable bacterial count and virus titre in the lungs, as well as cytokine/chemokine concentration and histopathological findings were compared between both groups.
Results
The median duration of survival of coinfected mice was significantly prolonged by treatment with multiple doses of peramivir, relative to mice treated with oseltamivir at either dose. Viable bacterial counts and virus titres in the lungs were significantly reduced by intravenous peramivir treatment compared with no treatment or oral oseltamivir treatment. The production of inflammatory cytokines/chemokines was also significantly suppressed by multiple dosing of peramivir compared with oseltamivir. Increased survival appeared to be mediated by decreased inflammation, manifested as lower levels of inflammatory cells and proinflammatory cytokines in the lungs and less severe histopathological findings. The lungs of mice treated with multiple doses of peramivir showed mild inflammatory changes compared to oseltamivir.
Conclusions
This study demonstrated that a multiple-dose regimen of intravenous peramivir was more efficacious than a single peramivir dose or multiple doses of oseltamivir for improving outcomes in pneumococcal pneumonia following influenza virus infection in mice.
References
1.
HoyertD.L., XuJ.Deaths: preliminary data for 2011.Natl Vital Stat Rep2012; 61: 1–51.
2.
HsuJ., SantessoN., MustafaR.Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies.Ann Intern Med2012; 156: 512–524.
3.
ChemalyR.F., TorresH.A., AguileraE.A.Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study.Clin Infect Dis2007; 44: 964–967.
4.
HernánM.A., LipsitchM.Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials.Clin Infect Dis2011; 53: 277–279.
5.
MuthuriS.G., MylesP.R., VenkatesanS., Leonardi-BeeJ., Nguyen-Van-TamJ.S.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.J Infect Dis2013; 207: 553–563.
6.
YangS.G., CaoB., LiangL.R.Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus.PLoS ONE2012; 7: e29652.
7.
LouieJ.K., YangS., AcostaM.Treatment with neuraminidase inhibitors for critically ill patients with influenza A(H1N1)pdm09.Clin Infect Dis2012; 55: 1198–1204.
8.
YuH., LiaoQ., YuanY.Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China.BMJ2010; 341: c4779.
9.
HarperS.A., BradleyJ.S., EnglundJ.A.Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis2009; 48: 1003–1032.
10.
BantiaS., KelloggD., ParkerC., UpshawR., IlyushinaN.A., BabuY.S.A single intramuscular injection of neuraminidase inhibitor peramivir demonstrates antiviral activity against novel pandemic A/California/04/2009 (H1N1) influenza virus infection in mice.Antiviral Res2011; 90: 17–21.
11.
YunN.E., LindeN.S., ZacksM.A.Injectable peramivir mitigates disease and promotes survival in ferrets and mice infected with the highly virulent influenza virus, A/Vietnam/1203/04 (H5N1).Virology2008; 374: 198–209.
12.
Centers for Disease Control and Prevention.Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009.MMWR Morb Mortal Wkly Rep2009; 58: 433–435.
13.
BirnkrantD., CoxE.The Emergency Use Authorization of peramivir for treatment of 2009 H1N1 influenza.N Engl J Med2009; 361: 2204–2207.
14.
HernandezJ.E., AdigaR., ArmstrongR.Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States.Clin Infect Dis2011; 52: 695–706.
15.
KohnoS., KidaH., MizuguchiM.Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients.Antimicrob Agents Chemother2011; 55: 2803–2812.
16.
KohnoS., KidaH., MizuguchiM., ShimadaJ.Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.Antimicrob Agents Chemother2010; 54: 4568–4574.
17.
KohnoS., YenM.Y., CheongH.J.Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection.Antimicrob Agents Chemother2011; 55: 5267–5276.
18.
SorbelloA., JonesS.C., CarterW.Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus.Clin Infect Dis2012; 55: 1–7.
19.
LeVineA.M., KoeningsknechtV., StarkJ.M.Decreased pulmonary clearance of S. pneumoniae following influenza A infection in mice.J Virol Methods2001; 94: 173–186.
20.
McCullersJ.A.Insights into the interaction between influenza virus and pneumococcus.Clin Microbiol Rev2006; 19: 571–582.
21.
Broug-HolubE., ToewsG.B., van IwaardenJ.F.Alveolar macrophages are required for protective pulmonary defenses in murine Klebsiella pneumonia: elimination of alveolar macrophages increases neutrophil recruitment but decreases bacterial clearance and survival.Infect Immun1997; 65: 1139–1146.
22.
MorensD.M., TaubenbergerJ.K., FauciA.S.Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.J Infect Dis2008; 198: 962–970.
ColamussiM.L., WhiteM.R., CrouchE., HartshornK.L.Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria.Blood1999; 93: 2395–2403.
26.
ShahangianA., ChowE.K., TianX.Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice.J Clin Invest2009; 119: 1910–1920.
27.
NakamuraS., DavisK.M., WeiserJ.N.Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice.J Clin Invest2011; 121: 3657–3665.
28.
SmithM.W., SchmidtJ.E., RehgJ.E., OrihuelaC.J., McCullersJ.A.Induction of pro- and anti-inammatory molecules in a mouse model of pneumococcal pneumonia after influenza.Comp Med2007; 57: 82–89.
29.
SunK., MetzgerD.W.Inhibition of pulmonary antibacterial defense by interferon-during recovery from influenza infection.Nat Med2008; 14: 558–564.
30.
McCullersJ.A.Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza.J Infect Dis2004; 190: 519–526.
31.
McCullersJ.A., BartmessK.C.Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae.J Infect Dis2003; 187: 1000–1009.
32.
KarlströmA., BoydK.L., EnglishB.K., McCullersJ.A.Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza.J Infect Dis2009; 199: 311–319.
33.
YamayaM., ShinyaK., HatachiY.Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells.J Pharmacol Exp Ther2010; 333: 81–90.
34.
SatoK., SugaM., AkaikeT.Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice.Am J Respir Crit Care Med1998; 157: 853–857.
35.
MinJ.Y., JangY.J.Macrolide therapy in respiratory viral infections.Mediators Inflamm2012; 2012: 649570.
36.
KitanoM., ItohY., KodamaM.Efficacy of single intravenous injection of peramivir against influenza B virus infection in ferrets and cynomolgus macaques.Antimicrob Agents Chemother2011; 55: 4961–4970.
37.
SekiM., YanagiharaK., HigashiyamaY.Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice.Eur Respir J2004; 24: 143–149.
38.
WardP., SmallI., SmithJ., SuterP., DutkowskiR.Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic.J Antimicrob Chemother2005; 55: i5–i21.
39.
FalagasM.E., KoletsuiP.K., VouloumanouE.K.Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials.J Antimicrob Chemother2010; 65: 1330–1346.
40.
BantiaS., ArnoldC.S., ParkerC.D., UpshawR., ChandP.Anti-influenza virus activity of peramivir in mice with single intramuscular injection.Antiviral Res2006; 69: 39–45.
41.
BoltzD.A., IlyushinaN.A., ArnoldC.S., BabuY.S., WebsterR.G., GovorkovaE.A.Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice.Antiviral Res2008; 80: 150–157.
42.
KitanoM., KodamaM., ItohY.Efficacy of repeated intravenous injection of peramivir against influenza A (H1N1) 2009 virus infection in immunosuppressed mice.Antimicrob Agents Chemother2013; 57: 2286–2294.
43.
IsonM.G., HuiD.S., ClezyK.A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults.Antivir Ther2013; 18: 651–661.
44.
NicholsonK.G., AokiF.Y., OsterhausA.D.Efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.Lancet2000; 355: 1845–1850.
45.
TreanorJ.J., HaydenF.G., VroomanP.S.Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.JAMA2000; 283: 1016–1024.
46.
South East Asia Infectious Disease Clinical Research Network.Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomized controlled trial.BMJ2013; 346: f3039.
47.
LeeN., HuiD.S., ZuoZ.A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza A and B infections.Clin Infect Dis2013; 57: 1511–1519.
