title: In vitro and murine efficacy and toxicity studies of nebulized SCC1, a methylated caffeine-silver(I) complex, for treatment of pulmonary infections.
abstract: The expanding clinical challenge of respiratory tract infections due to resistant bacteria necessitates the development of new forms of therapy. The development of a compound composed of silver coupled to a methylated caffeine carrier (silver carbene complex 1 [SCC1]) that demonstrated in vitro efficacy against bacteria, including drug-resistant organisms, isolated from patients with respiratory tract infections was described previously. The findings of current in vitro studies now suggest that bactericidal concentrations of SCC1 are not toxic to airway epithelial cells in primary culture. Thus, it was hypothesized that SCC1 could be administered by the aerosolized route to concentrate delivery to the lung while minimizing systemic toxicity. In vivo, aerosolized SCC1 delivered to mice resulted in mild aversion behavior, but it was otherwise well tolerated and did not cause lung inflammation following administration over a 5-day period. The therapeutic efficacy of SCC1 compared to that of water was shown in a 3-day prophylaxis protocol, in which mice infected with a clinical strain of Pseudomonas aeruginosa had increased survival, decreased amounts of bacteria in the lung, and a lower prevalence of bacteremia. Similarly, by using an airway infection model in which bacteria were impacted in the airways by agarose beads, the administration of SCC1 was significantly superior to water in decreasing the lung bacterial burden and the levels of bacteremia and markers of airway inflammation. These observations indicate that aerosolized SCC1, a novel antimicrobial agent, warrants further study as a potential therapy for bacterial respiratory tract infections.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1002, USA. cannon_c@kids.wustl.edu
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hogue
authors.forename: Ravy K
authors.initials: RK
authors.lastname: Vajravelu
authors.forename: George H
authors.initials: GH
authors.lastname: Capps
authors.forename: Aida
authors.initials: A
authors.lastname: Ibricevic
authors.forename: Khadijah M
authors.initials: KM
authors.lastname: Hindi
authors.forename: Aysegul
authors.initials: A
authors.lastname: Kascatan-Nebioglu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walter
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Wiley J
authors.initials: WJ
authors.lastname: Youngs
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity*; D002110:Caffeine / Q000031:analogs & derivatives*; D002460:Cell Line; D004195:Disease Models, Animal; D008297:Male; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D018030:Silver Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D000900:Anti-Bacterial Agents; D018030:Silver Compounds; C030011:carbene; D002110:Caffeine; D008697:Methane