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

Abstract

Introduction: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01021436.

Figure 1

The pulmonary delivery drug system. (a) Clinical in the 'on-vent configuration' and (b) with the hand-held device.

Figure 2

Day 3 serum amikacin concentrations before (0), and at hours 0.5, 1, 3, 6, 9, 12, 13 and 24 after starting the first aerosol. Results are expressed as medians (interquartile range). Black arrows indicate the timing of aerosols.

Figure 3

Day 3 amikacin concentration in the alveolar epithelial lining fluid (ELF) of the 28 assessable patients. The dotted line corresponds to 128 μg/mL, which is 10-fold the critical 90% minimum inhibitory concentration (MIC₉₀) for Pseudomonas aeruginosa. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.

Figure 4

Day 3 amikacin concentration in the tracheal aspirates of the 19 assessable patients. H1 to H6 corresponds to the first six hours following the first aerosol, H7 to H12 to the next six hours (before the second aerosol of the day), H13 to H18 to the six hours following the second nebulization, and H19 to H24 to the last six hours of the day, before next aerosol. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.

Figure 5

Serum amikacin trough concentrations during the study from day 1 (D1) to D10 with the corresponding number of patients. T-bars represent the 10th and 90th percentiles; the horizontal line in the box is the median; the lower and upper limits of the box represent the 25th and 75th percentiles, respectively. Circles represent outliers.