Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia

Abstract

IntroductionAminoglycosides 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.MethodsNebulized 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.ResultsMedian (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) μg/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) μg, 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.ConclusionsPDDS 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.Trial RegistrationClinicalTrials.gov Identifier: NCT01021436.

Ventilator-Integrated Jet Nebulization Systems: Tidal Volume Control and Efficiency of Synchronization

“…Indeed, the gas and thus the aerosol delivered at the end of insufflation do not reach the deep part of the lungs. 7,15 An ideal algorithm would start nebulization immediately before the start of insufflation (this concerns only fully controlled ventilation) for the nebulizer flow to be highest at the beginning of insufflation. As the particle sizes produced by jet nebulizers decrease with increasing nebulizer flow, such an algorithm would allow production of the finest droplets at the beginning of inspiration, thus favoring distal lung deposition.…”

Defining Antibiotic Dosing in Lung Infections

“…Luyt et al 46 similarly showed favorable amikacin concentrations in ELF in a study of 28 mechanically ventilated patients with gram-negative VAP. In this study, patients received nebulized amikacin through an advanced nebulizer system as an adjunct to IV therapy.…”

“…PK studies reporting antibiotic concentrations in the lung compartments using nebulization are becoming increasingly reported. 45,46 Athanassa et al 45 evaluated 20 critically ill patients with ventilator-associated tracheobronchitis treated with nebulized colistin. After the first nebulization, the median ELF concentrations were 6.7 and 2.0 mg/L at 1 and 8 hours, respectively.…”

“…The median peak amikacin concentration in the ELF (976 mg/L) was far higher than that observed in serum (0.85 mg/L). 46 With the advancement of this antibiotic delivery system, nebulization may prove to be an effective alternative method of administration to improve antibiotic concentrations in the lung tissue. However, issues relating to appropriate dose selection in the context of pathogen susceptibility need to be considered.…”

“…However, issues relating to appropriate dose selection in the context of pathogen susceptibility need to be considered. 45 Further, TDM to prevent any local or systemic unwanted effects 46 as well as use of a specially formulated antibiotic solutions for inhalation and delivery devices should be considered. 46 …”