Quantifying the therapeutic requirements and potential for combination therapy to prevent bacterial coinfection during influenza.
Secondary bacterial infections (SBIs) exacerbate influenza-associated disease and mortality. Antimicrobial agents can reduce the severity of SBIs, but many have limited efficacy or cause adverse effects. Thus, new treatment strategies are needed. Kinetic models describing the infection process can help determine optimal therapeutic targets, the time scale on which a drug will be most effective, and how infection dynamics will change under therapy. To understand how different therapies perturb the dynamics of influenza infection and bacterial coinfection and to quantify the benefit of increasing a drug's efficacy or targeting a different infection process, I analyzed data from mice treated with an antiviral, an antibiotic, or an immune modulatory agent with kinetic models. The results suggest that antivirals targeting the viral life cycle are most efficacious in the first 2 days of infection, potentially because of an improved immune response, and that increasing the clearance of infected cells is important for treatment later in the infection. For a coinfection, immunotherapy could control low bacterial loads with as little as 20 % efficacy, but more effective drugs would be necessary for high bacterial loads. Antibiotics targeting bacterial replication and administered 10 h after infection would require 100 % efficacy, which could be reduced to 40 % with prophylaxis. Combining immunotherapy with antibiotics could substantially increase treatment success. Taken together, the results suggest when and why some therapies fail, determine the efficacy needed for successful treatment, identify potential immune effects, and show how the regulation of underlying mechanisms can be used to design new therapeutic strategies.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. amber.smith@stjude.org.
Amber M
AM
Smith
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology; D060085:Coinfection / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000382:microbiology / Q000821:virology
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents
Antibiotics; Antivirals; Coinfection; Combination therapy; Immunotherapy; Influenza; Kinetic modeling; Pneumococcus
J Infect Dis. 2004 Aug 1;190(3):519-26
15243927
J Infect Dis. 2003 Mar 15;187(6):1000-9
12660947
J Infect Dis. 2012 Feb 1;205(3):458-65
22158564
J Immunol. 2010 Feb 15;184(4):2048-56
20083661
PLoS Pathog. 2013 Mar;9(3):e1003238
23555251
J Infect Dis. 2013 Oct 15;208(8):1281-5
23852122
Nat Rev Microbiol. 2014 Apr;12(4):252-62
24590244
Infect Immun. 2006 Dec;74(12):6707-21
16982840
J Infect Dis. 2002 Aug 1;186(3):341-50
12134230
Immunol Cell Biol. 2016 Jan;94(1):101-8
26134269
J Infect Dis. 2014 May 1;209(9):1459-68
24273183
JAMA. 2004 Sep 15;292(11):1333-40
15367555
Infect Immun. 2015 Oct;83(10):3764-70
26216421
J Clin Invest. 1959 Jan;38(1 Part 2):213-65
13620784
Influenza Other Respir Viruses. 2013 Jan;7 Suppl 1:63-75
23279899
J Immunol. 2013 Sep 1;191(5):2047-52
23964104
J Infect Dis. 2011 Nov;204(9):1358-66
21900488
J Virol. 2010 Jul;84(14):7105-13
20444902
Antivir Ther. 2011;16(2):123-35
21447860
Comp Med. 2007 Feb;57(1):82-9
17348295
Future Microbiol. 2012 May;7(5):609-24
22568716
J Interferon Cytokine Res. 2015 Jun;35(6):474-9
25713979
Nat Med. 2008 May;14(5):558-64
18438414
Pediatr Infect Dis J. 2004 Jan;23(1 Suppl):S87-97
14730275
Curr Top Microbiol Immunol. 2014;385:327-56
25027822
J Theor Biol. 2011 May 7;276(1):106-16
21300073
PLoS Comput Biol. 2011 Feb;7(2):e1001081
21379324
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10948-53
12960399
J Immunol. 2013 Aug 1;191(3):1250-9
23804714
Sci Rep. 2016 Dec 15;6:38703
27974820
J Leukoc Biol. 2001 Jan;69(1):50-6
11200067
J Virol. 2006 Aug;80(15):7590-9
16840338
J Antimicrob Chemother. 2003 Jan;51(1):123-9
12493796
J Infect Dis. 2015 Aug 1;212(3):445-52
25649173
J Infect Dis. 2009 Feb 1;199(3):311-9
19113989
Nat Rev Immunol. 2008 Jul;8(7):533-44
18551128
Lancet. 2000 Mar 4;355(9206):827-35
10711940
PLoS One. 2013;8(3):e57483
23478252
Blood. 1999 Apr 1;93(7):2395-403
10090951
J Virol. 2012 Sep;86(17):9035-43
22674997
J Math Biol. 2010 May;60(5):711-26
19633852
J Infect Dis. 2008 Oct 1;198(7):962-70
18710327
Curr Opin Immunol. 2015 Jun;34:59-67
25723597
N Engl J Med. 2009 Dec 24;361(26):2582-3
20032332
Cell Microbiol. 2015 Mar;17(3):303-17
25293394
Lancet Infect Dis. 2006 May;6(5):303-12
16631551
PLoS One. 2015 Mar 04;10(3):e0118369
25738736