Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. Aminoglycosides

Abstract

Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.

Preclinical Pharmacokinetic and Pharmacodynamic Data To Support Cefoxitin Nebulization for the Treatment of Mycobacterium abscessus

“…administration and reflecting the relative increased FOX exposure within ELF after NEB, was close to a thousand (TA of 1,113). This high TA is consistent with values previously reported under similar experimental conditions: 242, 2,673, 874, and 162 for TOB (11), ATM (10), AMK, and GEN (12), which are all antibiotics with low membrane permeability precluding oral administration. By comparison, for ciprofloxacin (CIP) and moxifloxacin (MXF), two fluoroquinolone antibiotics with high membrane permeability allowing oral administration, the ratio of AUC u,ELF after NEB versus that after i.v.…”

“…Antimicrobial Agents and Chemotherapy independent of the route of administration (8)(9)(10)(11)(12). This characteristic, which was confirmed in the present study (AUC u,plasma of 103 h·g/ml after i.v.…”

“…and 104 h·g/ml after NEB treatment), does not reflect the clinical setting, with only a small fraction of the dose being absorbed after aerosolization. This can be illustrated by comparing results obtained after nebulization of GEN in rats (12) and patients (13). Comparison of AUC u,plasma values in patients indicates that GEN systemic exposure was close to 5% after NEB compared with i.v.…”

“…The effect of initial FOX concentration on time to nadir would not be the same in the presence of one and two subpopulations. The supplementary intermediate FOX concentrations used for this second time-kill set of experiments (12,20,30,45,75,115, and 175 mg/liter), the frequency of CFU determinations (every day instead of every 2 days), and the experiment duration (increased from 8 to 11 days) were selected in order to allow discrimination between one-and two-population models.…”

“…However, numerous complementary experiments would be necessary to confirm the potential therapeutic advantage of FOX NEB for the treatment of M. abscessus infections. concentrations of 12,20,30,45,75,115, and 175 mg/liter and a growth control using a protocol similar to that explained above. Numbers of CFU were determined daily for up to 11 days.…”