Flukloxacilin je polosyntetické betalaktamové antibiotikum ze skupiny isoxazolylpenicilinů. Od oxacilinu se liší připojením jednoho atomu fluoru a chloru na benzenové jádro, což zlepšuje vstřebávání z GIT a prodlužuje jeho biologický poločas. Jeho biologická dostupnost je 54-79 %, distribuční objem 0,14 ± 0,14 l/kg, vazba na plazmatické bílkoviny dosahuje 92-95 %. Metabolizován je jen asi z 10 %, vylučuje se ze 75 % ledvinami glomerulární filtrací i tubulární sekrecí s poločasem 0,75-1,14 h. Dávkování se dle závažnosti stavu a charakteristik pacienta pohybuje od 500 mg každých 8 hodin p. o. až po 2 g co 4 h i. v., celková denní dávka by neměla překročit 12 g. Terapeutické monitorování by mohlo optimalizovat dávkování u pacientů se zvýšenou renální clearance a u onemocnění způsobených méně citlivými patogeny, mělo by být založeno na stanovení jeho volné frakce.
Flucloxacillin is a semi-synthetic betalactam antibiotic from the group of isoxazolylpenicillins. It differs from oxacillin by the attachment of one fluorine-chlorine atom to the benzene nucleus which improves absorption from the GIT and prolongs its biological half-life. Its bioavailability is 54-79 %, volume of distribution is 0.14 ± 0.14 l/kg, and plasma protein binding is 92-95%. It is only about 10 % metabolised, 75 % excreted by the kidneys via glomerular filtration and tubular secretion with a half-life of 0.75-1.14 h. Dosage ranges from 500 mg every 8 h PO to 2 g every 4 h IV, depending on the severity of the condition and patient characteristics, the total daily dose should not exceed 12 g. Therapeutic monitoring could optimize dosing in patients with increased renal clearance and in diseases caused by less sensitive pathogens, and should be based on determination of its free fraction.
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Byla zavedena a validována jednoduchá metoda s použitím kapalinové chromatografie a tandemové hmotnostní spektrometrie (LC-MS/MS) pro stanovení kolistinu A a kolistinu B v plazmě. Extrakce proteinů z plazmy byla provedena pomocí 1 ml kazet Oasis HLB a chromatografická separace byla provedena na koloně Arion® Polar C18 (250 × 4,6 mm; 5 mm) při 35 °C. Mobilní fáze se skládala z vody obsahující 0,1 % kyseliny mravenčí a methanolu obsahujícího 0,1 % kyseliny mravenčí v poměru 40 : 60 (v/v), při průtoku 0,8 ml/minutu. Eluent byl detekován v režimu pozitivních iontů pomocí ionizace elektrosprejem s následujícími iontovými přechody m/z: kolistin A 585,55 → 101,05; kolistin B 578,5 → 101,15; a IS 602,4 → 101,1; 120,15; 86,15. Byly provedeny testy krátkodobé stability kolistinu a CMS, a to při pokojové teplotě a 37 °C, kdy se stabilita obou složek se zvyšující se teplotou snižuje. Předložený příspěvek je součástí studie Pharmacokinetics of Colistin in Critically Ill Patients With Extracorporeal Membrane Oxygenation (COL-ECMO2022), v níž budou prezentovány další výsledky.
A simple liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the determination of colistin A and colistin B in human plasma was developed and validated. Plasma extraction was performed using Oasis HLB 1 ml cartridges, analysis was performed using Arion® Polar C18 (250×4,6mm; 5mm) column at 35°C. Mobile phases consisted of water containing 0,1% formic acid and methanol containing 0,1% formic acid (40:60, v/v) delivered at a flow rate of 0,8 ml/minute. Eluent was detected in the positive ion mode using electrospray ionization at the following transitions of mass to charge (m/z): colistin A 585,55 → 101,05; colistin B 578,5 → 101,15; and IS 602,4 → 101,1; 120,15; 86,15. Short-term stability tests of colistin and CMS were performed, at room temperature and 37°C, where the stability of both components decreases with increasing temperature. The presented paper is part of the Pharmacokinetics of Colistin in Critically Ill Patients With Extracorporeal Membrane Oxygenation (COL-ECMO2022) study in which further results will be presented.
- MeSH
- chemické techniky analytické * metody přístrojové vybavení MeSH
- chromatografie kapalinová metody přístrojové vybavení MeSH
- hydrolýza MeSH
- kolistin * krev MeSH
- lidé MeSH
- methansulfonáty krev MeSH
- stabilita proteinů MeSH
- statistika jako téma MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinická studie MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Colistin is a lipopeptide antibiotic administered as an inactive prodrug-colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment. METHODS AND ANALYSIS: The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of St. Anne's University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals. TRIAL REGISTRATION NUMBERS: EudraCT Number 2022-000291-19; NCT05542446.
- MeSH
- antibakteriální látky farmakokinetika MeSH
- COVID-19 * MeSH
- kolistin terapeutické užití MeSH
- kritický stav terapie MeSH
- lidé MeSH
- mimotělní membránová oxygenace * MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
AIMS: The aim of this pharmacokinetic study was to describe and quantify population pharmacokinetics of three antibiotics, cefazolin, ampicillin, and ciprofloxacin, used as antibacterial prophylaxis during cardiovascular surgery with the use of extracorporeal circulation (ECC). METHODS: Adult patients undergoing cardiac surgery with ECC were enrolled to this prospective, pharmacokinetic study. An intravenous bolus of 2 g of ampicillin, 2 g of cefazolin or 400 mg of ciprofloxacin was administered 60-30 min before surgery. Blood samples were collected at 15, 30, 45, 60, 120 and 180 min after the administration and at the end of the surgery. Plasma concentrations of the antibiotics were measured using HPLC methods. Serum concentration-time profiles were analyzed using nonlinear mixed-effects modeling approach. RESULTS: A total of 54 patients were enrolled into the study, 20 with ampicillin, 25 cefazolin and 9 ciprofloxacin. For all antibiotics, population pharmacokinetic models have been successfully developed. CONCLUSION: We identified estimated glomerular filtration rate (eGFR) as the main factor determining the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target in ampicillin or cefazolin and body weight in ciprofloxacin prophylaxis during cardiac surgery with ECC support.
- MeSH
- ampicilin MeSH
- antibakteriální látky terapeutické užití MeSH
- antibiotická profylaxe metody MeSH
- cefazolin * farmakokinetika terapeutické užití MeSH
- ciprofloxacin MeSH
- dospělí MeSH
- kardiochirurgické výkony * MeSH
- lidé MeSH
- mimotělní oběh MeSH
- prospektivní studie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Flukloxacilin je polosyntetické betalaktamové antibiotikum ze skupiny isoxazolylpenicilinů. Od oxacilinu se liší připojením jednoho atomu fluoru a chloru na benzenové jádro, což zlepšuje vstřebávání z GIT a prodlužuje jeho biologický poločas. Jeho biologická dostupnost je 54-79 %, distribuční objem 0,14 ± 0,14 l/kg, vazba na plazmatické bílkoviny dosahuje 92-95 %. Metabolizován je jen asi z 10 %, vylučuje se ze 75 % ledvinami glomerulární filtrací i tubulární sekrecí s poločasem 0,75-1,14 h. Dávkování se dle závažnosti stavu a charakteristik pacienta pohybuje od 500 mg každých 8 hodin p. o. až po 2 g co 4 h i. v., celková denní dávka by neměla překročit 12 g. Terapeutické monitorování by mohlo optimalizovat dávkování u pacientů se zvýšenou renální clearance a u onemocnění způsobených méně citlivými patogeny, mělo by být založeno na stanovení jeho volné frakce.
Flucloxacillin is a semi-synthetic betalactam antibiotic from the group of isoxazolylpenicillins. It differs from oxacillin by the attachment of one fluorine-chlorine atom to the benzene nucleus which improves absorption from the GIT and prolongs its biological half-life. Its bioavailability is 54-79 %, volume of distribution is 0.14 ± 0.14 l/kg, and plasma protein binding is 92-95%. It is only about 10 % metabolised, 75 % excreted by the kidneys via glomerular filtration and tubular secretion with a half-life of 0.75-1.14 h. Dosage ranges from 500 mg every 8 h PO to 2 g every 4 h IV, depending on the severity of the condition and patient characteristics, the total daily dose should not exceed 12 g. Therapeutic monitoring could optimize dosing in patients with increased renal clearance and in diseases caused by less sensitive pathogens, and should be based on determination of its free fraction.
The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.
Kolistin je úzkospektré baktericidní antibiotikum ze skupiny lipopeptidů, účinné pouze proti gram-negativním patogenům. Pacientům je podáván ve formě proléčiva - kolistin methansulfonátu, jehož spontánní hydrolýzou dochází k uvolnění vlastního účinného kolistinu. Stabilita kolistin methansulfonátu je závislá na koncentraci, teplotě, pH i složení nosného roztoku. V klinické praxi pak jeho stabilita sehrává roli v případě inhalačního či intravenózního podávání; v případě terapeutického monitorování léčiv je zásadní správné uchovávání vzorků a zvolený typ zkumavek a laboratorních pomůcek. Cílem tohoto přehledového článku je upozornit na jednotlivé rizikové momenty používání kolistinu a jeho terapeutického monitorování.
Colistin, a lipopeptide antibacterial agent, has a narrow-spectrum bactericidal activity only against gram-negative bacteria. It is administered as an inactive prodrug - colistin methanesulphonate, which is spontaneously converted to the active colistin. Its stability is concentration-, temperature-, and pH-dependent; moreover, the type of the carrier solution also plays a role. The stability of the colistin prodrug solutions has several implications for clinical practice, whether in intravenous or inhalation administration. Appropriate storage and properly selected type of test tubes and laboratory equipment are essential in therapeutic drug monitoring procedures. The aim of this paper is to emphasize several aspects for safe and effective colistin use and therapeutic monitoring.
- MeSH
- chemické jevy MeSH
- fyzikální jevy MeSH
- hodnocení léčiv MeSH
- kolistin * farmakologie terapeutické užití MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- stabilita léku MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
