title: Anti-staphylococcal activity resulting from epithelial lining fluid (ELF) concentrations of amikacin inhale administered via the pulmonary drug delivery system.
abstract: BACKGROUND
  Amikacin inhale (BAY41-6551), a unique drug-device combination of a specially formulated drug solution and a pulmonary drug delivery system device (AMK-I) is currently under phase III study as an adjunctive therapy to IV antibiotics for the treatment of Gram-negative pneumonia in mechanically ventilated patients. While the epidemiology of nosocomial pneumonia is predominated by Gram-negative pathogens such as Pseudomonas aeruginosa and the Enterobacteriaceae, Staphylococcus aureus is increasingly recognized as a pathogen of concern for these pulmonary based infections. Since the aminoglycosides are historically quite active against S. aureus the use of adjunctive AMK-I may enhance bacterial eradication. Herein, we aimed to characterize the in vitro pharmacodynamic (PD) profile of human-simulated ELF exposures of AMK-I against both methicillin-sensitive (MSSA) and -resistant (MRSA) S. aureus.
  
  
  METHODS
  An in vitro model was used to simulate the resultant ELF pharmacokinetic profile of amikacin after the administration of AMK-I 400 mg q12h. The antibacterial activity of this regimen was tested against 7 S. aureus isolates that display MIC profiles encountered clinically (4 MRSA; MIC range 4-64, 3 MSSA; MIC range 8-16 mg/L). Experiments were conducted over 24 h and samples were taken throughout this period to assess the bacterial density in both control and treatments.
  
  
  RESULTS
  The mean ± SD inoculum 0 h bacterial density was 6.4 ± 0.09 which increased to 8.6 ± 0.19 log10CFU/mL in the control models by the end of 24 h experiments. Simulated ELF concentrations of AMK-I resulted in a rapid, 5 log10declined in CFU over the initial 12 h for all MRSA and MSSA isolates. After 12 h, all bacterial counts remained below the limit of detection (LOD, 1.7 log10CFU/mL) and no regrowth was evident at the end of the study.
  
  
  CONCLUSIONS
  AMK-I produced an ELF exposure profile that was rapidly bactericidal against S. aureus displaying typical MICs to amikacin irrespective of their phenotypic profile to methicillin. While the Gram-negative organisms are the target pathogens for AMK-I in the ongoing clinical trials, these data suggest that this adjunctive regimen may also have the potential to eradicate both MSSA and MRSA from lower airway which needs to be further evaluated in randomized-controlled clinical trials.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.
authors.forename: Islam M
authors.initials: IM
authors.lastname: Ghazi
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Grupper
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT, 06102, USA. david.nicolau@hhchealth.org.|Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA. david.nicolau@hhchealth.org.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000583:Amikacin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology*; D006801:Humans; D008168:Lung / Q000382:microbiology; D009330:Nebulizers and Vaporizers; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin
keywords: Inhaled amikacin; Pharmacodynamics; S. aureus