title: Effect of oxygen limitation on the in vitro activity of levofloxacin and other antibiotics administered by the aerosol route against Pseudomonas aeruginosa from cystic fibrosis patients.
abstract: Studies have demonstrated that thickened mucous layers in the lungs of cystic fibrosis (CF) patients contain areas of low oxygen tension. These microaerophilic environments may reduce the activity of aerosol antibiotics used in the management of chronic infection in CF. The aim of this study was to compare the MICs of levofloxacin, tobramycin, amikacin, and aztreonam against Pseudomonas aeruginosa under reference and anaerobic conditions and evaluate the in vitro pharmacodynamics of levofloxacin under aerobic and hypoxic testing conditions. The MICs for 114 isolates of P. aeruginosa from CF patients were determined in cation-adjusted Mueller Hinton broth alone or supplemented with 1% potassium nitrate for anaerobic testing. Levofloxacin time-kill curves were performed under aerobic and hypoxic conditions using strains of P. aeruginosa with elevated efflux pump overexpression and/or target mutations. The MICs of nonmucoid or mucoid P. aeruginosa isolates to levofloxacin incubated under aerobic and anaerobic conditions were similar. In contrast, anaerobic incubation resulted in higher MICs for tobramycin, amikacin, and aztreonam among nonmucoid or mucoid isolates, with > or =4-fold increase in MICs for over 40% of the isolates. Time-kill curves performed in aerobic and hypoxic environments with levofloxacin concentrations attained in CF sputum demonstrated similar activity, approaching a maximum bactericidal effect within 10 min of exposure. Together, these results indicate that the activity of some antibiotics against P. aeruginosa is significantly reduced under conditions relevant to the CF lung environment. In contrast, levofloxacin maintains activity against P. aeruginosa under anaerobic or hypoxic conditions similar to those found in CF microaerophilic environments.
authors.affiliation: Mpex Pharmaceuticals, Inc., San Diego, CA 92121-1309, USA. pking@mpexpharma.com
authors.forename: Paula
authors.initials: P
authors.lastname: King
authors.forename: Diane M
authors.initials: DM
authors.lastname: Citron
authors.forename: David C
authors.initials: DC
authors.lastname: Griffith
authors.forename: Olga
authors.initials: O
authors.lastname: Lomovskaya
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000332:Aerobiosis; D000336:Aerosols; D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000150:complications*; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability; D015242:Ofloxacin / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D013997:Time Factors
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D015242:Ofloxacin; D010100:Oxygen