Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

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Colistin is often administered by inhalation and/or the parenteral route for the treatment of respiratory infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. However, limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to guide the optimization of dosage regimens of inhaled colistin. In the present study, PK of colistin in epithelial lining fluid (ELF) and plasma was determined following intratracheal delivery of a single dose of colistin solution in neutropenic lung-infected mice. The antimicrobial efficacy of intratracheal delivery of colistin against three P. aeruginosa strains (ATCC 27853, PAO1, and FADDI-PA022; MIC of 1 mg/liter for all strains) was examined in a neutropenic mouse lung infection model. Dose fractionation studies were conducted over 2.64 to 23.8 mg/kg of body weight/day. The inhibitory sigmoid model was employed to determine the PK/PD index that best described the antimicrobial efficacy of pulmonary delivery of colistin. In both ELF and plasma, the ratio of the area under the unbound concentration-time profile to MIC (fAUC/MIC) was the PK/PD index that best described the antimicrobial effect in mouse lung infection (R 2 ϭ 0.60 to 0.84 for ELF and 0.64 to 0.83 for plasma). The fAUC/MIC targets required to achieve stasis against the three strains were 684 to 1,050 in ELF and 2.15 to 3.29 in plasma. The histopathological data showed that pulmonary delivery of colistin reduced infection-caused pulmonary inflammation and preserved the integrity of the lung epithelium, although colistin introduced mild pulmonary inflammation in healthy mice. This study showed pulmonary delivery of colistin provides antimicrobial effects against MDR P. aeruginosa lung infections superior to those of parenteral administrations. For the first time, our results provide important preclinical PK/PD information for optimization of inhaled colistin therapy.

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics/Pharmacodynamics of Pulmonary Delivery of Colistin against Pseudomonas aeruginosa in a Mouse Lung Infection Model

Lin

Zhou

Cheah

et al. 2017

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“…Although passive diffusion was described as the dominant transport mechanism for drug absorption from rat lungs (33,34), a number of transporters have been described in lung tissue that could interfere with the disposition of inhaled drugs (35). Colistin is probably not a glycoprotein P (P-gp) substrate (36), but it may have an affinity for organic cation transporters (OCTs) and peptide transporters (PEPT) (37). Both transporters, which belong to the superfamily of solute-linked carriers (SLC), have been identified in lung tissues (35).…”

Section: Discussionmentioning

confidence: 99%

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

Gontijo

Grégoire

Lamarche

et al. 2014

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...

“…200 l of 0.9% (wt/ vol) saline (control) or LPS (P. aeruginosa, 3 mg/kg of body weight in saline) at 0, 6, and 24 h. At 4 h after the last administration, mice (n ϭ 6) were intravenously administered a 50-l dose of [ 14 C]sucrose (2 Ci in saline), plasma and brain samples were collected at 5 min postdose, and radioactivity in plasma and brain was determined using liquid scintillation counting (Tri-Carb 2800 TR; PerkinElmer, Boston, MA) (9). The brain-to-plasma (B:P) ratio of [ 14 C]sucrose at 5 min was calculated using the following formula: (number of disintegrations per minute [dpm] per gram of brain tissue)/(number of dpm per milliliter of plasma).…”

Section: Chemicalsmentioning

confidence: 99%

“…Plasma and brain samples (n ϭ 4) were harvested 0.5 h later, and the concentrations of colistin in brain homogenate and plasma were determined by HPLC to obtain B:P ratios (24). These B:P ratios were compared to those obtained following administration of LPS from S. enterica under the same experimental conditions (9).…”

Section: Chemicalsmentioning

confidence: 99%

“…Indeed, we have demonstrated that systemic administration to mice of lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, from Salmonella enterica (as a model of bacterium-induced inflammation) leads to BBB dysfunction (9). One proposed mechanism for the decreased paracellular integrity of the BBB in response to LPS involves elevated plasma concentrations of cytokines, especially tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and interleukin-6 (IL-6).…”

mentioning

confidence: 99%

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Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Jin

Nation

et al. 2013

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The aim of this study was to use in vitro and in vivo models to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS from Pseudomonas aeruginosa, the brain-to-plasma ratio of [ 14 C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS from Salmonella enterica, LPS from P. aeruginosa had no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P > 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS from P. aeruginosa or S. enterica and claudin-5 expression was measured by Western blotting. S. enterica LPS significantly (P < 0.05) reduced claudin-5 expression at a concentration of 7.5 g/ml. In contrast, P. aeruginosa LPS decreased (P < 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 g/ml). Coadministration of therapeutic concentrations of colistin ameliorated the S. enterica LPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least between P. aeruginosa and S. enterica, and can be ameliorated by colistin.T he blood-brain barrier (BBB) is formed by specialized endothelial cells of cerebral microvessels. Unlike endothelial cells in other organs, the layer of endothelial cells lining the cerebral microvessels constitutes a physical barrier between blood and brain tissue by a complex network of tight junctions (TJs) (1). The TJs consist of transmembrane proteins spanning the intercellular cleft; these proteins include occludin, claudins (particularly claudin-5) (2), and several cytoplasmic proteins, such as zonula occludens (3). Under normal conditions, these TJ proteins seal the paracellular route of the BBB, thus preventing the movement of relatively small hydrophilic molecules from the blood into the brain, ensuring homeostatic regulation of the central nervous system (CNS) (4).Alterations to TJ proteins and increases in BBB permeability are observed during various disease states, including peripheral hyperalgesia, bacterial meningitis, systemic inflammation, and sepsis (5-8). Indeed, we have demonstrated that systemic administration to mice of lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, from Salmonella enterica (as a model of bacterium-induced inflammation) leads to BBB dysfunction (9). One proposed mechanism for the decreased paracellular integrity of the BBB in response to LPS involves elevated plasma c...