Tracheal aspirates for amikacin concentration determinations were collected on day 3 from 19 patients at 69 time points (Figure (Figure4).4). Median amikacin concentrations for the four six-hour periods (H1 to H6, H7 to H12, H13 selleck chemicals Perifosine to H18 and H19 to H24) were: 1517.5 (793 to 3430), 477 (100 to 1605.5), 1948 (288.25 to 6412.5) and 472 (241.5 to 1825.5) ��g/mL, respectively.Figure 3Day 3 amikacin concentration in the alveolar epithelial lining fluid (ELF) of the 28 assessable patients. The dotted line corresponds to 128 ��g/mL, which is 10-fold the critical 90% minimum inhibitory concentration (MIC90) for Pseudomonas aeruginosa …Figure 4Day 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 …Patients were exposed to the study drug for a median of 7 (3 to 9) days. Figure Figure55 shows the trough serum amikacin concentrations during the study period. Values on day 1 (before any nebulization) were not null because the limits of detection varied from one center to another. Mean creatinine levels fluctuated between 53 and 106 ��mol/L with no apparent trend.Figure 5Serum 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 …

Among the 64 unexpected adverse events reported in our study, one episode of worsening renal failure was possibly due to nebulized amikacin. The patient, who developed septic shock and was receiving many concomitant nephrotoxic medications, developed acute renal failure requiring continuous renal replacement therapy and aerosol discontinuation. The investigator deemed this severe adverse event possibly attributable to nebulized amikacin. Another patient experienced an episode of bronchospasm that resolved after discontinuing the amikacin and nebulizing bronchodilators.DiscussionIn this study, we were able to demonstrate that amikacin, delivered by PDDS aerosolization, achieved high concentrations in the lower respiratory tract, in zones corresponding to radiographic infiltrate location, with low systemic absorption. Moreover, amikacin concentrations in ELF were more than 10-fold higher than the MIC90 of microorganisms usually responsible for nosocomial pneumonia (8 ��g/mL for P. aeruginosa) [16]; and the observed amikacin concentrations exceeded Batimastat the MIC90 of Acinetobacter species by four-fold [17].