Pharmacokinetics of nebulized colistin methanesulfonate in critically ill patients

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

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Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01868-15 ◽

2016 ◽

Vol 60 (3) ◽

pp. 1788-1793 ◽

Cited By ~ 24

Author(s):

M. Jacobs ◽

N. Grégoire ◽

B. Mégarbane ◽

P. Gobin ◽

D. Balayn ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Critically Ill ◽

Critically Ill Patients ◽

Published Data ◽

Intermittent Hemodialysis ◽

Dosing Regimen ◽

Icu Patients ◽

Unbound Fraction ◽

Colistin Methanesulfonate

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 andfAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests ana prioriclear and easy to follow dosing strategy for CMS in ICU-HD patients.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00554-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7240-7248 ◽

Cited By ~ 61

Author(s):

Ilias Karaiskos ◽

Lena E. Friberg ◽

Konstantinos Pontikis ◽

Konstantinos Ioannidis ◽

Vasiliki Tsagkari ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Gram Negative ◽

Link Type ◽

Colistin Methanesulfonate

ABSTRACTColistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009,http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012,http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011,http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

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Steady-State Pharmacokinetics and BAL Concentration of Colistin in Critically Ill Patients After IV Colistin Methanesulfonate Administration

CHEST Journal ◽

10.1378/chest.10-0463 ◽

2010 ◽

Vol 138 (6) ◽

pp. 1333-1339 ◽

Cited By ~ 141

Author(s):

Roberto Imberti ◽

Maria Cusato ◽

Paola Villani ◽

Livio Carnevale ◽

Giorgio A. Iotti ◽

...

Keyword(s):

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Colistin Methanesulfonate

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Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01461-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1938-1940 ◽

Cited By ~ 41

Author(s):

Mairi Ziaka ◽

Sophia L. Markantonis ◽

Marizoza Fousteri ◽

Paris Zygoulis ◽

Dimitris Panidis ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Critically Ill ◽

Intravenous Administration ◽

Critically Ill Patients ◽

External Ventricular Drain ◽

Central Nervous System Infection ◽

Intraventricular Administration ◽

Colistin Methanesulfonate

ABSTRACTColistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls,n= 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv,n= 3) or combined intravenous/intraventricular administration (EVDVcomb,n= 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%,P≤ 0.05) and in EVDVcomb compared to all other patients (P< 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.

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Population Pharmacokinetics of Colistin Methanesulfonate Sodium and Colistin in Critically Ill Patients: A Systematic Review

Pharmaceuticals ◽

10.3390/ph14090903 ◽

2021 ◽

Vol 14 (9) ◽

pp. 903

Author(s):

Mohd Shafie Zabidi ◽

Ruzilawati Abu Bakar ◽

Nurfadhlina Musa ◽

Suzana Mustafa ◽

Wan Nazirah Wan Yusuf

Keyword(s):

Plasma Concentration ◽

Critically Ill ◽

Critically Ill Patients ◽

Reference Lists ◽

Parameter Estimates ◽

Dialysis Session ◽

Loading Dose ◽

Additional Dose ◽

Comprehensive Understanding ◽

Colistin Methanesulfonate

Understanding the pharmacokinetics parameter of colistin methanesulfonate sodium (CMS) and colistin is needed to optimize the dosage regimen in critically ill patients. However, there is a scarcity of pharmacokinetics parameters in this population. This review provides a comprehensive understanding of CMS and colistin pharmacokinetics parameters in this population. The relevant studies published in English that reported on the pharmacokinetics of CMS and colistin from 2000 until 2020 were systematically searched using the PubMed and Scopus electronic databases. Reference lists of articles were reviewed to identify additional studies. A total of 252 citation titles were identified, of which 101 potentially relevant abstracts were screened, and 25 full-text articles were selected for detailed analysis. Of those, 15 studies were included for the review. This review has demonstrated vast inter-study discrepancies in colistin plasma concentration and the pharmacokinetics parameter estimates. The discrepancies might be due to complex pathophysiological changes in the population studied, differences in CMS brand used, methodology, and study protocol. Application of loading dose of CMS and an additional dose of CMS after dialysis session was recommended by some studies. In view of inter-patient and intra-patient variability in colistin plasma concentration and pharmacokinetics parameters, personalized colistin dosing for this population is recommended.

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Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01733-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3284-3294 ◽

Cited By ~ 466

Author(s):

S. M. Garonzik ◽

J. Li ◽

V. Thamlikitkul ◽

D. L. Paterson ◽

S. Shoham ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Creatinine Clearance ◽

Replacement Therapy ◽

Critically Ill ◽

Critically Ill Patients ◽

Multidrug Resistant ◽

Parameter Estimates ◽

Highly Active ◽

Dosing Regimens ◽

Colistin Methanesulfonate

ABSTRACTWith increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m2. Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥1.0 mg/liter.

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Comparison of Intrapulmonary and Systemic Pharmacokinetics of Colistin Methanesulfonate (CMS) and Colistin after Aerosol Delivery and Intravenous Administration of CMS in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03510-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7331-7339 ◽

Cited By ~ 78

Author(s):

Matthieu Boisson ◽

Matthieu Jacobs ◽

Nicolas Grégoire ◽

Patrice Gobin ◽

Sandrine Marchand ◽

...

Keyword(s):

Critically Ill ◽

Intravenous Administration ◽

Critically Ill Patients ◽

Multidrug Resistant ◽

Pharmacokinetic Analysis ◽

Pulmonary Infections ◽

Aerosol Delivery ◽

Epithelial Lining Fluid ◽

Colistin Methanesulfonate ◽

Critical Care Patients

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n= 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.

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Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients

Pharmaceutics ◽

10.3390/pharmaceutics14010031 ◽

2021 ◽

Vol 14 (1) ◽

pp. 31

Author(s):

Wasan Katip ◽

Suriyon Uitrakul ◽

Peninnah Oberdorfer

Keyword(s):

Acinetobacter Baumannii ◽

Critically Ill ◽

Critically Ill Patients ◽

Cohort Analysis ◽

University Hospital ◽

Loading Dose ◽

Carbapenem Resistant ◽

Significant Difference ◽

Pre Treatment ◽

Colistin Methanesulfonate

Carbapenem-resistant Acinetobacter baumannii (CRAB) is one of the most common causes of nosocomial infections in critically ill patients. Colistin methanesulfonate (CMS), an inactive prodrug, has been considered as a last-resort treatment for CRAB infection in critically ill patients. The objective of this study was to assess 30-day survival and nephrotoxicity in critically ill patients who received non-loading dose (LD) versus LD of CMS for CRAB infection treatment. Between 2012 and 2017, this retrospective cohort analysis was performed at Chiang Mai University Hospital (CMUH), focusing on critically ill patients with CRAB infection who received either non-LD or LD of CMS. A total of 383 patients met the criteria for inclusion. At the 30th day of treatment, the survival rate of patients in the LD CMS group was 1.70 times (adjusted HR) of those in the non-LD group (95% CI = 1.17–2.50, p = 0.006). Clinical response was significantly higher in the LD CMS group than non-LD CMS group (aHR, 1.35, 95% CI, 1.01–1.82, p = 0.046). In addition, a microbiological response—eradication of pre-treatment isolated pathogens in post-treatment cultures—in patients with LD CMS was 1.57 times that of patients with non-LD CMS (95% CI, 1.15–2.15, p = 0.004). Additionally, there was a significant difference in nephrotoxicity between LD CMS and non-LD CMS (aHR, 1.57, 95% CI, 1.14–2.17, p = 0.006). Based on these results, LD CMS should be used to increase the opportunity of patients to achieve favourable outcomes. However, LD CMS was found associated with an increase in nephrotoxicity, so renal function should be closely monitored when LD colistin was administered.

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Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06426-11 ◽

2012 ◽

Vol 56 (8) ◽

pp. 4241-4249 ◽

Cited By ~ 141

Author(s):

Ami F. Mohamed ◽

Ilias Karaiskos ◽

Diamantis Plachouras ◽

Matti Karvanen ◽

Konstantinos Pontikis ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Half Life ◽

Equilibrium Dialysis ◽

Compartment Model ◽

Pharmacokinetic Data ◽

Loading Dose ◽

Content Type ◽

Colistin Methanesulfonate

ABSTRACTA previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from anin vitrostudy onPseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

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