Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.

Section: Discussionmentioning

confidence: 56%

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Landersdorfer

Nguyen

Lieu

et al. 2017

“…The use of a CMS loading dose to hasten the attainment of therapeutic colistin concentrations has been previously proposed (8,11,27,54,55). It should be noted that the reported disposition of formed colistin following CMS administration shows substantial variance; a recent report on the disposition of CMS/colistin in critically ill patients has described the rapid formation of colistin following CMS administration (55).…”

Section: Discussionmentioning

confidence: 99%

“…The volume and temperature of the central reservoir were 80 ml and 37°C, respectively, and cation-adjusted Mueller-Hinton broth was circulated at a rate of 4.8 ml/h to achieve an elimination half-life of 11.6 h. Viable counting was performed on drug-free and drug-containing (6.6 mg/liter polymyxin B base) plates at 0, 0.5, 1, 2, 4, 8,11,13,23,25,26,28,47,49,50,52,71,73,74,76, and 96 h. The PAPs were performed at 0, 23, 47, 71, and 96 h on polymyxin B-containing plates (1.7, 3.3, and 6.6 mg/liter polymyxin B base). Polymyxin B and colistin concentrations were measured using a previously described and validated liquid chromatography-tandem mass spectrometry assay (29).…”

Section: Methodsmentioning

confidence: 99%

“…The two clinically used polymyxins, colistin and polymyxin B, differ substantially in clinical pharmacokinetics (PK) due to differences in administered form. Although colistin and polymyxin B have long been regarded as equivalent, clinical studies in critically ill patients have revealed considerable differences in their PK (5)(6)(7)(8)(9)(10)(11)(12). Given the importance of polymyxins as last-line therapy, developing innovative dosage regimens for polymyxins will be critical to maintaining their efficacy against MDR pathogens.…”

mentioning

confidence: 99%

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Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Cheah

Tsuji

et al. 2016

dInfections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused >4 log 10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log 10 CFU/ ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

“…However, in clinical practice colistin is administered in the form of an inactive prodrug, colistin methanesulfonate (CMS), which subsequently converts to colistin in vivo (5), while polymyxin B is parenterally administered in its pharmacologically active sulfate salt form (6). They substantially differ in their plasma pharmacokinetic (PK) properties following intravenous administration in critically ill patients (2,(7)(8)(9)(10)(11). In patients with cystic fibrosis, the maximum plasma concentration (C max, Plasma ) of formed colistin following parenteral CMS (150 mg colistin base activity) ranged from 0.40 to 0.77 mg/liter (12).…”

mentioning

confidence: 99%

Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model

Lin

Zhou

Onufrak

et al. 2017

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R 2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.