title: Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia.
abstract: BACKGROUND
  Aminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs.
  
  
  METHODS
  Nebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points.
  
  
  RESULTS
  Median (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) microg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) microg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm.
  
  
  CONCLUSIONS
  PDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01021436.
authors.affiliation: Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Paris-Pierre-et-Marie-Curie, 75651 Paris Cedex 13, France. charles-edouard.luyt@psl.aphp.fr
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.forename: Marc
authors.initials: M
authors.lastname: Clavel
authors.forename: Kalpalatha
authors.initials: K
authors.lastname: Guntupalli
authors.forename: Jay
authors.initials: J
authors.lastname: Johannigman
authors.forename: John I
authors.initials: JI
authors.lastname: Kennedy
authors.forename: Christopher
authors.initials: C
authors.lastname: Wood
authors.forename: Kevin
authors.initials: K
authors.lastname: Corkery
authors.forename: Dennis
authors.initials: D
authors.lastname: Gribben
authors.forename: Jean
authors.initials: J
authors.lastname: Chastre
mesh_terms: D000336:Aerosols; D000583:Amikacin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003428:Cross Infection / Q000188:drug therapy*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D007440:Intubation / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D012121:Respiration, Artificial / Q000379:methods*
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D000583:Amikacin