Abstract:To assess the difference in the fate of the antibiotic colistin (COLI) after its pulmonary delivery as a powder or a solution, we developed a COLI powder and evaluated the COLI pharmacokinetic properties in rats after pulmonary administration of the powder or the solution. The amorphous COLI powder prepared by spray drying was characterized by a mass median aerodynamic diameter and fine particle fraction of 2.68 ± 0.07 µm and 59.5 ± 5.4%, respectively, when emitted from a Handihaler®. After intratracheal admin… Show more
“… 31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35 , 36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin – and the expression of these transporters might be different between species. 34 …”
Section: Inhaled Sodium Colistimethatementioning
confidence: 99%
“…Tewes et al found a lower exposure of the pulmonary epithelial lining fluid to colistin after intratracheal administration of SCM powder to rats, compared to SCM solution. 36 However, they attributed this difference to faster systemic absorption of the drug after the inhalation of powder and, as mentioned above, the PK of SCM absorption might be different in humans. Even using the same formulation, the PK could be different, depending on the delivery system (ie, the design of the nebulizer), although Ratjen et al found no significant differences in sputum colistin concentrations with two different nebulizers.…”
Section: Inhaled Sodium Colistimethatementioning
confidence: 99%
“…These studies agree, however, that high levels of colistin exposure are achieved in epithelial lining fluid (ELF) and sputum after inhalation, and that these levels are much higher than after intravenous administration. 29,31,[34][35][36][37][38] Systemic exposure after SCM inhalation is low. Concentrations of SCM and colistin can be on the order of 100 to 1000 times higher in the ELF than in plasma after administration of aerosolized SCM.…”
Section: Pereira MCmentioning
confidence: 99%
“…31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35,36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin -and the expression of these transporters might be different between species. 34 The substantial pulmonary exposure and minimal systemic exposure observed after inhalation of SCM in humans imply that this route should be effective in maximizing the antibacterial effect in the respiratory system, while also minimizing toxicity.…”
International guidelines on the treatment of bronchiectasis indicate that the use of inhaled antibiotics is effective, especially in symptomatic chronic bronchial infection (CBI) due to
Pseudomonas aeruginosa
(PA). To date, however, no such treatment has been approved by regulatory agencies. Of the inhaled antibiotics on the market, colistimethate sodium (colistin) is one of the most used in many countries, either in its nebulized presentation or as dry powder. Among the characteristics of this antibiotic, it is worth noting that its main target is the lipopolysaccharide in the outer membrane of the cell wall of gram-negative bacteria and that it has a low rate of resistance to PA (<1%). Most observational studies have shown that the use of colistin in patients with bronchiectasis and CBI due to PA results in a decrease in both the number and severity of exacerbations, an improvement in quality of life, a decrease in sputum volume and purulence, and a high rate of PA eradication, although there are no clear differences with respect to other inhaled antibiotics. However, the lack of randomized clinical trials (RCT) with positive results for its main variable (exacerbations) in an intention-to-treat analysis has prevented its approval by regulatory agencies as a formal indication for use in bronchiectasis. The PROMIS program, made up of two RCT with identical methodology, is currently underway. The first of these RCT (already concluded) has demonstrated a clearly positive effect on the group randomized to colistin in its main variable (number of annual exacerbations), while the results of the second are still pending. This review presents exhaustive information on the pharmacological and microbiological characteristics of colistin, the results of the studies carried out to date, and the future challenges associated with this treatment.
“… 31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35 , 36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin – and the expression of these transporters might be different between species. 34 …”
Section: Inhaled Sodium Colistimethatementioning
confidence: 99%
“…Tewes et al found a lower exposure of the pulmonary epithelial lining fluid to colistin after intratracheal administration of SCM powder to rats, compared to SCM solution. 36 However, they attributed this difference to faster systemic absorption of the drug after the inhalation of powder and, as mentioned above, the PK of SCM absorption might be different in humans. Even using the same formulation, the PK could be different, depending on the delivery system (ie, the design of the nebulizer), although Ratjen et al found no significant differences in sputum colistin concentrations with two different nebulizers.…”
Section: Inhaled Sodium Colistimethatementioning
confidence: 99%
“…These studies agree, however, that high levels of colistin exposure are achieved in epithelial lining fluid (ELF) and sputum after inhalation, and that these levels are much higher than after intravenous administration. 29,31,[34][35][36][37][38] Systemic exposure after SCM inhalation is low. Concentrations of SCM and colistin can be on the order of 100 to 1000 times higher in the ELF than in plasma after administration of aerosolized SCM.…”
Section: Pereira MCmentioning
confidence: 99%
“…31 In contrast, a much higher systemic bioavailability (46 to 64%) have been observed in rat models after intratracheal administration. 35,36 The reason for this difference is unclear, but it has been speculated that the diffusion of colistin across the bronchial epithelium is not only mediated by passive diffusion and that specific drug transporters might be implicated in the absorption of colistin -and the expression of these transporters might be different between species. 34 The substantial pulmonary exposure and minimal systemic exposure observed after inhalation of SCM in humans imply that this route should be effective in maximizing the antibacterial effect in the respiratory system, while also minimizing toxicity.…”
International guidelines on the treatment of bronchiectasis indicate that the use of inhaled antibiotics is effective, especially in symptomatic chronic bronchial infection (CBI) due to
Pseudomonas aeruginosa
(PA). To date, however, no such treatment has been approved by regulatory agencies. Of the inhaled antibiotics on the market, colistimethate sodium (colistin) is one of the most used in many countries, either in its nebulized presentation or as dry powder. Among the characteristics of this antibiotic, it is worth noting that its main target is the lipopolysaccharide in the outer membrane of the cell wall of gram-negative bacteria and that it has a low rate of resistance to PA (<1%). Most observational studies have shown that the use of colistin in patients with bronchiectasis and CBI due to PA results in a decrease in both the number and severity of exacerbations, an improvement in quality of life, a decrease in sputum volume and purulence, and a high rate of PA eradication, although there are no clear differences with respect to other inhaled antibiotics. However, the lack of randomized clinical trials (RCT) with positive results for its main variable (exacerbations) in an intention-to-treat analysis has prevented its approval by regulatory agencies as a formal indication for use in bronchiectasis. The PROMIS program, made up of two RCT with identical methodology, is currently underway. The first of these RCT (already concluded) has demonstrated a clearly positive effect on the group randomized to colistin in its main variable (number of annual exacerbations), while the results of the second are still pending. This review presents exhaustive information on the pharmacological and microbiological characteristics of colistin, the results of the studies carried out to date, and the future challenges associated with this treatment.
“…Nebulization of high doses of CMS results in high lung tissue colistin concentrations with correspondingly low plasma colistin concentrations (< 2 µg/mL) (Figure 6c) suggesting limited diffusion into the systemic compartment [26,28,41,42,[75][76][77][78][79][80][81][82]. After the initial CMS nebulization of 2 million IU (Figure 8a,b), CMS and colistin plasma concentrations show quite similar pharmacokinetic profiles [79]: an early peak concentration for CMS (30 min), a delayed peak concentration for colistin (3 h) and a slow and progressive decrease in concentrations over the following hours.…”
Section: Pharmacokinetics Of Nebulized Colistimethate Sodiummentioning
Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.
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