William Couet

Unité Inserm U1077, Caen, Lower Normandy, France

Are you William Couet?

Claim your profile

Publications (94)384.4 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, dinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymuxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.
    The Lancet Infectious Diseases 02/2015; 15(2):225-234. DOI:10.1016/S1473-3099(14)70850-3 · 19.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid – BEH – Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6–8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations −4.4 to +6.3%) over the clinically relevant analytical range 0.05–20 μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4 °C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1 M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections.
    Journal of Chromatography A 11/2014; 1369. DOI:10.1016/j.chroma.2014.09.063 · 4.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin is an old antibiotic that has recently gained a considerable renew of interest for the treatment of pulmonary infections due to Multi Drug Resistant Gram-negative bacteria. Nebulization seems promising for this application but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS), but differences between intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients, have not been precisely documented. CMS and colistin concentrations were measured on two separate occasions within plasma and epithelial lining fluid (ELF) of critically ill patients (n=12) who had received 2 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) modelling and simulations. ELF colistin concentrations varied considerably (9.53 - 1137 mg/L) but were much higher than in plasma (0.15 - 0.73 mg/L) after aerosol delivery, but not after intravenous administrationof CMS.Following CMS aerosol delivery, typically 9% of the CMS dose reached the ELF, and only 1.4 % was converted into colistin pre-systemically. PK-PD analysis concluded to a much higher antimicrobial efficacy after CMS aerosol delivery than intravenous administration. These new data seem to support the use of CMS aerosol delivery for the treatment of pulmonary infections in critical care patients.
    Antimicrobial Agents and Chemotherapy 09/2014; 58(12). DOI:10.1128/AAC.03510-14 · 4.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin is an old antibiotic that has recently gained a considerable renew of interest as the last line defense therapy against Multi Drug Resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rational for a loading dose in critically ill patients. Yet faster CMS conversion was observed in healthy volunteers, but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics.
    Antimicrobial Agents and Chemotherapy 09/2014; 58(12). DOI:10.1128/AAC.03508-14 · 4.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 nebulized at a dose of 0.35mg.kg(-1) in rats and plasma concentrations were measured during 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2 and 4 h after intravenous (IV) administration and nebulization to estimate epithelial lining fluid (ELF) concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h post-dosing) were almost identical after IV infusion and nebulization. ELF concentrations were undetectable in BAL samples after IV administration, but about 1800 times higher than unbound plasma levels at respectively 2 h and 4 h after nebulization. Simultaneous pharmacokinetic modeling of plasma and ELF concentrations was performed with a model characterized by a fixed physiological volume of ELF (VELF), a passive diffusion clearance (QELF) between plasma and ELF and a nonlinear influx transfer from ELF to central compartment which was assessed by reducing the nebulized dose of colistin by 10 times (0.035mg.kg(-1)). The km was estimated at 133 μg.ml(-1) and the Vmax,in to Km ratio was equal to 2.5. 10(-3) l.h(-1).kg(-1) that is 37 times higher than QELF (6.7.10(-5) l.h(-1).kg(-1)). This study showed that with ELF concentrations higher after nebulization than after intravenous administration, for antibiotics with low permeability such as colistin nebulization offers a real interest over intravenous administration for the treatment of pulmonary infections.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(7). DOI:10.1128/AAC.02819-14 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs): ciprofloxacin (CIP), moxifloxacin (MXF) and grepafloxacin (GRX) after nebulization in rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4 and 6h after FQ intravenous administration and nebulization to estimate epithelial lining fluid (ELF) concentrations. Plasma concentrations were also measured and profiles of concentrations versus time after intravenous administration and nebulization were virtually superimposed, attesting for rapid and complete systemic absorption of FQs. ELF concentrations were systematically higher than corresponding plasma concentrations whatever the administration and averaged ELF to unbound plasma concentration ratios at post distribution equilibrium did not change significantly between the ways of administration, and were equal to 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF and 19.1 ± 10.5 for GRX. The impact of macrophage lysis on estimated ELF concentrations was significant for GRX, but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF concentrations was only performed for the latter two drugs.The model was characterized by a fixed volume of ELF (VELF), a passive diffusion clearance (QELF) and an active efflux clearance (CLout) between plasma and ELF characterizing active efflux transport systems. In conclusion, this study has demonstrated that ELF concentrations of these three FQs are several times higher than plasma concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level but no biopharmaceutical advantage of FQ nebulization was observed compared with IV.
    Antimicrobial Agents and Chemotherapy 05/2014; 58(7). DOI:10.1128/AAC.02818-14 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0–τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml−1. This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.
    Antimicrobial Agents and Chemotherapy 02/2014; 58(2). DOI:10.1128/AAC.01760-13 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification-evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10 h and maintained for 48 h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller(®) pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 12/2013; DOI:10.1016/j.ejpb.2013.12.004 · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study explored CSF metronidazole and hydroxy-metronidazole distribution in brain-injured patients.Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8h. CSF and blood samples were collected at steady-state over 8 h and metronidazole and hydroxy-metronidazole concentrations were assayed by HPLC. A non-compartmental analysis was performed.Metronidazole distributes extensively within CSF with a mean CSF over unbound plasma AUC0-τ ratio equal to 86 ± 16 %. Yet concentrations profiles in CSF were mostly flat compared with plasma profiles. Hydroxy-metronidazole concentrations were much lower than those of metronidazole both in plasma and CSF with a corresponding CSF over unbound plasma AUC0-τ ratio equal to 79 ± 16 %.This study was the first one to describe in details the pharmacokinetics of metronidazole and hydroxy -metronidazole in CSF.
    Antimicrobial Agents and Chemotherapy 11/2013; DOI:10.1128/AAC.01762-13 · 4.57 Impact Factor
  • Clinical Infectious Diseases 10/2013; 58(1). DOI:10.1093/cid/cit680 · 9.42 Impact Factor
  • Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A248-A249. DOI:10.1016/j.annfar.2013.07.465 · 0.84 Impact Factor
  • Annales Françaises d Anesthésie et de Réanimation 09/2013; 32:A75-A76. DOI:10.1016/j.annfar.2013.07.154 · 0.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypovolemia is a common event in critical care patients that may affect drug distribution and elimination. In order to better understand this issue the effect of hypovolemia on the plasma protein binding and tissue distribution of ertapenem was investigated in rats using microdialysis. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Ertapenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced in 6 rats by removing 40% of the initial blood volume over 30 min. Ertapenem was infused intravenously at a dose of 40 mg,kg(-1) over 30 min, and microdialysis samples were collected for 310 min. The unbound concentration profiles in muscle and blood were virtually superimposed in both groups except at early time points. The ratios of the area under the concentration-time curve (AUC) for tissue to the AUC for blood were 0.7± 0.2 and 0.8 ± 0.2 for control and hypovolemic rats, respectively. Hypovolemia induced a 40% decrease in the clearance of ertapenem, with no statistically significant alteration of its volume of distribution. This study showed that ertapenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. Unbound concentrations of ertapenem in blood and muscle were always virtually identical.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 08/2013; DOI:10.1016/j.ejps.2013.08.017 · 2.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cystic fibrosis (CF) is a complex inherited disease which affects many organs, including the pancreas and liver, gastrointestinal tract and reproductive system, sweat glands and, particularly, the respiratory system. Pseudomonas aeruginosa is the main cause of chronic airway infection. In order to reduce morbidity and mortality due to lung infection by P. aeruginosa, aerosol antibiotics have been used to achieve high local concentrations in the airways and to reduce systemic toxicity. In the course of this review, the current treatments to control CF lung infections by P. aeruginosa are presented. Some innovative aerosol formulations such as liposomes and microspheres are herein reviewed, which may improve the efficiency of anti-pseudomonal agents, and ensure patients' compliance to treatments, by reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy, preventing the occurrence of bacterial resistance and/or reducing adverse effects due to their controlled-release properties.
    European Journal of Clinical Microbiology 04/2013; DOI:10.1007/s10096-013-1876-y · 3.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CNS antibiotics distribution was mainly described from cerebrospinal fluid data, only few data exit on brain extracellular fluid concentrations. The aim of this study was to describe brain distribution of cefotaxime by microdialysis in patients with acute brain injury, treated for a lung infection (2g/8h). Microdialysis probes were inserted into healthy brain tissue of five critical care patients. Plasma and unbound brain concentrations were determined at steady state by high performance liquid chromatography. In vivo recoveries were determined individually using retrodialysis by drug. Non compartmental and compartmental pharmacokinetics analyses were performed. Unbound cefotaxime brain concentrations were much lower than corresponding plasma concentrations with a mean cefotaxime unbound brain to plasma areas under the curve ratio equal to 26.1 ± 12.1%. This result was in accordance with the brain input to brain output clearances ratio (CLin,brain/CLout,brain). Unbound brain concentrations were then simulated at two dosing regimens (4g every 6h or 8h) and the time over the minimal inhibitory concentrations (T>MIC) was estimated for breakpoints of suceptible and resistant Steptococcus pneumoniae strains. T>MIC was higher than 90% of the dosing interval for both dosing regimen for suceptible strains and only for 4 g every 6h for resistant ones.In conclusion, brain distribution of cefotaxime was well described by microdialysis in patients and was limited.
    Antimicrobial Agents and Chemotherapy 04/2013; 57(6). DOI:10.1128/AAC.02570-12 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pharmacokinetics of daptomycin has been described in patients with normal renal function (1, 2) or under hemodialysis (3), but not in patients with severe impaired renal function not receiving hemodialysis.…
    Antimicrobial Agents and Chemotherapy 04/2013; 57(6). DOI:10.1128/AAC.00230-13 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin is a re-emerging old antibiotic that is used as a salvage treatment against multidrug-resistant Gramnegative infections. Because it is administrated as an inactive prodrug, colistin methanesulfonate (CMS) that undergoes rapid hydrolyze to colistin, pharmacokinetic studies using biological assays are unreliable. With the recent development of new assays using high performance liquid chromatography (HPLC) accurate pharmacokinetic of CMS and formed colistin is now available in various populations. This article aims to update previous reports on pharmacodynamics, pharmacokinetics, safety and clinical use of colistin, with a special focus on data useful to treat critically ill patients.
    Minerva anestesiologica 12/2012; · 2.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A rifampicin-hydroxypropyl-beta-cyclodextrin (RIF-HPCD) complex solution and two RIF-loaded PLGA microspheres with slow or fast release rates were nebulized into the rat lungs for a comparative biopharmaceutical evaluation. A pharmacokinetic model was applied to model systemic RIF concentrations and to predict the RIF concentrations in the lung epithelial lining fluid (ELF). With intravenous RIF and nebulized RIF-HPCD, plasma profiles and predicted RIF ELF profiles were superimposed indicating that RIF diffused almost instantaneously through the broncho-alveolar barrier. Five hours post administration RIF ELF predicted concentrations were in agreement with experimental concentrations determined using the broncho-alveolar lavage (BAL) sampling method. Microsphere formulations resulted in different plasma concentration profiles, demonstrating RIF sustained release. The PK model predicted the ELF concentrations to be much higher with microspheres than with nebulized and IV RIF, over a prolonged time period, which was confirmed by BAL sampling. In conclusion this work demonstrated the benefit of using sustained-release microspheres administered as aerosols to maintain, over a prolonged time period, high levels of pulmonary concentrations of drugs characterized by a rapid absorption through the broncho-alveolar barrier. Moreover, PK modeling was a useful tool to build concentration-versus-time profiles in non-readily accessible ELF compartment and to assess the biopharmaceutical properties of aerosol formulations for lung delivery.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2012; 48(1-2). DOI:10.1016/j.ejps.2012.10.024 · 2.61 Impact Factor
  • BJA British Journal of Anaesthesia 11/2012; 109(5):830-1. DOI:10.1093/bja/aes369 · 4.24 Impact Factor
  • Source
    09/2012; 13(1). DOI:10.1186/2050-6511-13-S1-A74

Publication Stats

1k Citations
384.40 Total Impact Points


  • 2008–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1999–2014
    • Université de Poitiers
      Poitiers, Poitou-Charentes, France
  • 2012
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 2011–2012
    • Centre Hospitalier Universitaire de Poitiers
      Poitiers, Poitou-Charentes, France
  • 2010
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2008–2009
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2006
    • The University of Manchester
      Manchester, England, United Kingdom