title: Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa.
abstract: OBJECTIVE
  Multidrug-resistant Pseudomonas aeruginosa (MDRP) is becoming a serious problem in hospitals, especially in patients on ventilators. Recent data demonstrate that colistin may be effective for these patients, although limited in vitro and in vivo data are available. Our aim was to identify further characteristics of colistin for the therapy of pneumonia caused by MDRP.
  
  
  METHODS
  The effects of colistin on clinical strains of MDRP were examined by susceptibility test, time-kill assay, lipopolysaccharide (LPS)-blocking assay and a mouse pneumonia model, alone or in combination with other antibiotics. For the pneumonia model, mice were intranasally infected with bacteria and kept in hyperoxic conditions to mimic ventilator-associated pneumonia.
  
  
  RESULTS
  As a single agent, colistin exhibited the strongest activity of the antimicrobial agents tested. In combination, maximum synergy was observed with colistin plus rifampicin. As expected, co-incubation of bacterial culture supernatants with colistin significantly reduced LPS activities with an associated decrease in cellular cytotoxicity. In the pneumonia model, intranasal, but not intravenous, colistin combined with rifampicin produced maximum survival protection. Pharmacokinetic analysis of colistin demonstrated the superiority of intranasal administration, judging from the compartmentalized high concentration and the long half-life in the lungs. Moreover, colistin therapy significantly decreased both production of inflammatory cytokines and LPS activity, even at a dose effecting no change in the bacterial burden in the lung.
  
  
  CONCLUSIONS
  These data strongly suggest that colistin may be an important option for combination therapy against critical MDRP infections. For pneumonia especially, intranasal colistin with rifampicin may be beneficial not only for synergistic antibacterial activity, but also for blocking LPS.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Aoki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Choichiroh
authors.initials: C
authors.lastname: Miyazaki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D003091:Colistin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D003091:Colistin