Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 Ϯ 12.1 g · h/ml and 13.3 Ϯ 3.5 g · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor ϭ 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL lung ) was added to the model for these animals (CL lung ϭ 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

Section: Poppk Of Ciprofloxacin In Biofilm Pneumoniamentioning

confidence: 99%

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Torres

Helfer

Bernardes

et al. 2017

“…Following a short sedation period with isoflurane (3%; air at 550 ml min Ϫ1 ), a volume of 100 l of colistin at a dose of 0.35 mg kg Ϫ1 (mean colistin base dose) was instilled between the vocal cords by using a nebulizer (Penn Century Inc., Philadelphia, PA) as previously described (18,26). Arterial blood samples were then collected before administration and 0.25, 0.5, 1, 2, 3, and 4 h after administration.…”

Section: Methodsmentioning

confidence: 99%

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

Gontijo

Grégoire

Lamarche

et al. 2014

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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...

“…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).…”

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confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Marchand

Grégoire

Brillault

et al. 2015

Self Cite

The aim of this study was to determine the biopharmaceutical characteristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (i.v.) bolus or intratracheal nebulization (3 mg · kg ؊1 ), and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. The ratio of the TOB concentration in ELF to the plasma area under the curve (AUC) was more than 200 times as high after NEB as after i.v. bolus administration, indicating that TOB nebulization offers a biopharmaceutical advantage over i.v. administration. Much higher intrapulmonary antibiotic concentrations may be achieved after nebulization (NEB) than after systemic administration, which may be of value for the treatment of pulmonary infections (1). 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).Transepithelial transport across Calu-3 monolayers was tested to determine the apparent ability of TOB to permeate membranes (P app ) (4, 5). 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). A Waters Alliance 2695 separation module coupled with a Waters Micromass Quattro micro API tandem mass spectrometer was used. Chromatographic separation was done with an X bridge C 18 column (5.0 m, 150 by 2.1 mm [inside diameter]; Waters, St-Quentin en Yvelines, France) with a mobile phase composed of 0.1% (vol/vol) formic acid in water and 0.1% formic acid in acetonitrile (75:25, vol/vol) at a flow rate of 0.2 ml · min Ϫ1 . Quantification was performed in the positive-ion mode with multiple-reaction monitoring of m/z transitions 468.2 ¡ 163.1 for TOB and 448.2 ¡ 160.2 for sisomycin, the internal standard. The intraday and interday variabilities in plasma and BAL fluid were determined at three concentratio...