Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 2. Colistin

Abstract

The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (V ELF ), a passive diffusion clearance (Q ELF ) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg ؊1 ). The k m was estimated to be 133 g ml ؊1 , and the V max, in -to-K m ratio was equal to 2.5 ؋ 10 ؊3liter h ؊1 kg ؊1 , which was 37 times higher than the Q ELF (6.7 ؋ 10 ؊5 liter h ؊1 kg ؊1 ). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.T reatment of lung infections by administration of antimicrobial agents using the pulmonary route presents potential clinical use, since it may afford higher drug concentrations at the site of infection with a reduction of systemic exposure (1, 2). Consequently, increased use of inhaled antibiotics, such as tobramycin, aztreonam, or colistin methansulfonate (CMS), has been observed to treat lung infections (3, 4).CMS is the inactive prodrug of colistin (5), which is a multicomponent cationic polypeptide that belongs to the class of polymyxins, comprised mainly of colistin A and colistin B (6). It is an old antibiotic that was abandoned in the 1970s due to its adverse effects (7). During the last 15 years, it has occasionally been used as "salvage" therapy for the treatment of infections engendered by multidrug-resistant bacteria, due to the lack of new antibiotics (8). When CMS was developed, controlled clinical trials and determination of pharmacokinetic and pharmacodynamic (PK/PD) properties were not required by drug-regulating agencies (6). However, the understanding of colistin pharmacokinetics after CMS intravenous (i.v.) administration to critically ill patients is progressing (9-13). But CMS is also nebulized for the treatment of pulm...

Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin

“…However, this potential advantage may vary between compounds and could be much greater for antibiotics with a weak rather than a strong ability to permeate membranes, as recently shown for colistin (2) in comparison with ciprofloxacin or moxifloxacin (3). The aim of this study was to confirm this hypothesis by investigating the pulmonary pharmacokinetics (PK) of tobramycin (TOB), another antibiotic with a weak ability to permeate membranes that is clinically available for pulmonary administration, by using the same standardized protocol as before (2).…”

“…A first group of anesthetized rats received a 3-mg · kg Ϫ1 bolus dose of TOB (TOB sulfate solution, 50 mg · ml Ϫ1 , Nebcine; Erempharma) by the tail vein. A second group of anesthetized rats received the same dose of TOB (100 l) by intratracheal NEB under anesthesia (2,3). In the two groups, bronchoalveolar lavage (BAL) fluid and blood samples were collected 0.25, 0.5, 1, 2.5, and 4 h after TOB administration (four or five rats per sampling time) (2,3).…”

“…Animal experiments were approved by the Poitou Charentes Ethic Committee (COMETHEA) and registered by the French Ministry of Higher Education and Research (01733.01). Male Sprague-Dawley rats (n ϭ 50, 300 to 350 g; Janvier Laboratories, Le Genest-St-Isle, France) were used and housed as previously described (2). A first group of anesthetized rats received a 3-mg · kg Ϫ1 bolus dose of TOB (TOB sulfate solution, 50 mg · ml Ϫ1 , Nebcine; Erempharma) by the tail vein.…”

“…A second group of anesthetized rats received the same dose of TOB (100 l) by intratracheal NEB under anesthesia (2,3). In the two groups, bronchoalveolar lavage (BAL) fluid and blood samples were collected 0.25, 0.5, 1, 2.5, and 4 h after TOB administration (four or five rats per sampling time) (2,3). The TOB assay used was adapted from a previously described method (6).…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…Then again, the i.v. dose given in this study may have been too low at 0.35 mg/kg, as doses of at least 1 mg/kg were used previously (172). Given the higher rate of adverse effects with nebulization of formed colistin, as discussed below in this review, and the high concentrations of formed colistin in the lungs after inhalation of CMS, CMS should almost certainly be used in clinical practice.…”