title: Preclinical advantages of intramuscularly administered peptide A3-APO over existing therapies in Acinetobacter baumannii wound infections.
abstract: OBJECTIVE
  The designer antibacterial peptide A3-APO is efficacious in mouse models of Escherichia coli and Acinetobacter baumannii systemic infections. Here we compare the efficacy of the peptide with that of imipenem and colistin in A. baumannii wound infections after burn injury.
  
  
  METHODS
  CD-1 mice were inflicted with burn wounds and different inocula of A. baumannii, isolated from an injured soldier, were placed into the wound sites. The antibiotics were given intramuscularly (im) one to five times. Available free peptide in the blood and the systemic toxicity of colistin and A3-APO were studied in healthy mice.
  
  
  RESULTS
  While toxicity of colistin was observed at 25 mg/kg bolus drug administration, the lowest toxic dose of A3-APO was 75 mg/kg. In the A. baumannii blast injury models, 5 mg/kg A3-APO improved survival and reduced bacterial counts in the blood as well as in the wounds and improved wound appearance significantly better than any other antibiotic treatment. The free peptide concentration in the blood did not reach 1 µg/mL.
  
  
  CONCLUSIONS
  Peptide A3-APO, with an intramuscular therapeutic index of 15, is more efficacious and less toxic than any existing burn injury infection therapy modality against multidrug-resistant Gram-negative pathogens. A3-APO administered by the im route probably binds to a biopolymer that promotes the peptide's biodistribution.
authors.affiliation: Department of Dermatology, Venerology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Ostorhazi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Rozgonyi
authors.forename: Andras
authors.initials: A
authors.lastname: Sztodola
authors.forename: Ferenc
authors.initials: F
authors.lastname: Harmos
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Dora
authors.initials: D
authors.lastname: Szabo
authors.forename: Daniel
authors.initials: D
authors.lastname: Knappe
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Marco
authors.initials: M
authors.lastname: Cassone
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000302:isolation & purification; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002056:Burns / Q000150:complications*; D003091:Colistin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007273:Injections, Intramuscular; D051379:Mice; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010949:Plasma / Q000737:chemistry; D016896:Treatment Outcome; D014946:Wound Infection / Q000188:drug therapy* / Q000382:microbiology
chemical_list: C539766:A3-APO peptide; D000900:Anti-Bacterial Agents; D010455:Peptides; D015378:Imipenem; D003091:Colistin
references.citation: Peptides. 2008 Nov;29(11):1878-86
references.pmid: 18721837
references.citation: Antimicrob Agents Chemother. 2007 Jan;51(1):376-8
references.pmid: 17043112
references.citation: Expert Rev Anti Infect Ther. 2010 Jun;8(6):703-16
references.pmid: 20521897
references.citation: J Pharm Sci. 1992 Aug;81(8):731-5
references.pmid: 1403714
references.citation: Clin Microbiol Infect. 2002 Nov;8(11):687-93
references.pmid: 12445005
references.citation: Curr Opin Microbiol. 2004 Oct;7(5):466-76
references.pmid: 15451501
references.citation: J Med Chem. 2007 Jul 12;50(14):3334-9
references.pmid: 17569519
references.citation: J Orthop Res. 2009 Aug;27(8):1008-15
references.pmid: 19173261
references.citation: Biochemistry. 2001 Mar 13;40(10):3016-26
references.pmid: 11258915
references.citation: Antimicrob Agents Chemother. 2006 Sep;50(9):3146-9
references.pmid: 16940114
references.citation: J Antimicrob Chemother. 2002 Mar;49(3):455-65
references.pmid: 11864945
references.citation: Curr Med Chem. 2009;16(30):3996-4002
references.pmid: 19747127
references.citation: Clin Infect Dis. 2007 Aug 15;45(4):409-15
references.pmid: 17638186
references.citation: Proteomics. 2004 Apr;4(4):1195-203
references.pmid: 15048999
references.citation: Clin Infect Dis. 2003 May 15;36(10):1268-74
references.pmid: 12746772
references.citation: Infect Control Hosp Epidemiol. 2007 Jun;28(6):720-2
references.pmid: 17520547
references.citation: Protein Sci. 2008 Jul;17(7):1249-55
references.pmid: 18413862
references.citation: J Trauma. 2009 Apr;66(4 Suppl):S138-44
references.pmid: 19359957
references.citation: Drugs. 2009 Oct 1;69(14):1879-901
references.pmid: 19747006
references.citation: J Infect Dev Ctries. 2010 Mar 29;4(3):164-7
references.pmid: 20351457
references.citation: BMC Infect Dis. 2007 Aug 14;7:95
references.pmid: 17697345
references.citation: Infect Control Hosp Epidemiol. 2010 Jul;31(7):716-21
references.pmid: 20486855
references.citation: Curr Pharm Des. 2003;9(16):1277-87
references.pmid: 12769736
references.citation: Pharmacology. 2008;81(2):79-91
references.pmid: 17940348
references.citation: Rapid Commun Mass Spectrom. 2004;18(5):588-9
references.pmid: 14978805
references.citation: Int J Antimicrob Agents. 2010 Apr;35(4):357-61
references.pmid: 20031377
references.citation: Antimicrob Agents Chemother. 2006 Nov;50(11):3856-60
references.pmid: 17065624
references.citation: Ann Surg. 2007 May;245(5):803-11
references.pmid: 17457175
references.citation: Burns. 1995 May;21(3):181-4
references.pmid: 7794498
references.citation: J Med Chem. 2005 Aug 11;48(16):5349-59
references.pmid: 16078852
references.citation: J Vet Pharmacol Ther. 2005 Aug;28(4):349-54
references.pmid: 16050814
references.citation: Vet Microbiol. 2001 Oct 1;82(4):347-59
references.pmid: 11506928
references.citation: Infect Immun. 1997 Jun;65(6):2160-7
references.pmid: 9169746
references.citation: Burns. 2010 Jun;36(4):522-7
references.pmid: 19864072
references.citation: J Pept Sci. 2005 Nov;11(11):697-706
references.pmid: 16059966
references.citation: Lancet Infect Dis. 2001 Oct;1(3):156-64
references.pmid: 11871492
references.citation: Biopolymers. 2011;96(2):126-9
references.pmid: 20564029
references.citation: Nature. 2002 Jan 24;415(6870):389-95
references.pmid: 11807545