title: Beneficial antimicrobial effect of the addition of an aminoglycoside to a β-lactam antibiotic in an E. coli porcine intensive care severe sepsis model.
abstract: This study aimed to determine whether the addition of an aminoglycoside to a ß-lactam antibiotic increases the antimicrobial effect during the early phase of Gram-negative severe sepsis/septic shock. A porcine model was selected that considered each animal's individual blood bactericidal capacity. Escherichia coli, susceptible to both antibiotics, was given to healthy pigs intravenously during 3 h. At 2 h, the animals were randomized to a 20-min infusion with either cefuroxime alone (n = 9), a combination of cefuroxime+tobramycin (n = 9), or saline (control, n = 9). Blood samples were collected hourly for cultures and quantitative polymerase chain reaction (PCR). Bacterial growth in the organs after 6 h was chosen as the primary endpoint. A blood sample was obtained at baseline before start of bacterial infusion for ex vivo investigation of the blood bactericidal capacity. At 1 h after the administration of the antibiotics, a second blood sample was taken for ex vivo investigation of the antibiotic-induced blood killing activity. All animals developed severe sepsis/septic shock. Blood cultures and PCR rapidly became negative after completed bacterial infusion. Antibiotic-induced blood killing activity was significantly greater in the combination group than in the cefuroxime group (p<0.001). Growth of bacteria in the spleen was reduced in the two antibiotic groups compared with the controls (p<0.01); no difference was noted between the two antibiotic groups. Bacterial growth in the liver was significantly less in the combination group than in the cefuroxime group (p<0.05). High blood bactericidal capacity at baseline was associated with decreased growth in the blood and spleen (p<0.05). The addition of tobramycin to cefuroxime results in increased antibiotic-induced blood killing activity and less bacteria in the liver than cefuroxime alone. Individual blood bactericidal capacity may have a significant effect on antimicrobial outcome.
authors.affiliation: Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Skorup
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Maudsdotter
authors.affiliation: Section of Anesthesiology & Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Miklós
authors.initials: M
authors.lastname: Lipcsey
authors.affiliation: Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Castegren
authors.affiliation: Section of Clinical Chemistry, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Ann-Beth
authors.initials: AB
authors.lastname: Jonsson
authors.affiliation: Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Sjölin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology; D058491:Bacterial Load; D002444:Cefuroxime / Q000494:pharmacology*; D003422:Critical Care; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D008297:Male; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D013154:Spleen / Q000187:drug effects / Q000382:microbiology; D013552:Swine; D014031:Tobramycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D014031:Tobramycin