William Couet

Federal University of São João del-Rei, São José del Rey, Minas Gerais, Brazil

Are you William Couet?

Claim your profile

Publications (86)349.61 Total impact

  • [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; · 4.57 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; · 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). · 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; · 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; · 4.57 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; · 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; · 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; · 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; · 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; · 2.82 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; · 2.61 Impact Factor
  • BJA British Journal of Anaesthesia 11/2012; 109(5):830-1. · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colistin appears more and more frequently as a last line defense therapy against nosocomial infections due to multi-resistant Gram-negative bacteria (8).…
    Antimicrobial Agents and Chemotherapy 04/2012; 56(7):4035-6. · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to determine the penetration of doripenem administered intravenously into the rabbit aqueous and vitreous humors. Nineteen New Zealand White rabbits received a 20-mg dose of doripenem intravenously over 60 min. Specimens of aqueous humor, vitreous humor, and blood were obtained 30 min (n = 5), 1 h (n = 5), 2 h (n = 5), and 3 h (n = 4) after the beginning of the infusion and analyzed by high-performance liquid chromatography (HPLC). A pharmacokinetic (PK) model was developed to fit the experimental data. Doripenem concentrations in aqueous humor were lower than those in plasma ultrafiltrates at all sampling times, with an average aqueous humor-to-plasma ultrafiltrate area under the concentration-time curve ratio estimated as 8.3%. A pharmacokinetic model with peripheral elimination described the data adequately and was tentatively used to predict concentration-versus-time profiles and pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients under various dosing regimens. In conclusion, systematically administered doripenem does not seem to be a promising approach for the treatment of intraocular infections, especially since it could not be detected in the vitreous humor. However, this study has provided an opportunity to develop a new PK modeling approach to characterize the intraocular distribution of doripenem administered intravenously to rabbits, with tentative extrapolation to humans.
    Antimicrobial Agents and Chemotherapy 04/2012; 56(7):3531-4. · 4.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A lethal peritonitis model was induced in mice with a Klebsiella pneumoniae isolate producing the carbapenemase OXA-48. Administration of a single dose (up to 100 mg/kg) of the antibiotic piperacillin-tazobactam, imipenem-cilastatin, ertapenem, or cefotaxime had little or no impact on lethality. Ceftazidime had the highest efficacy in vivo, which mirrored its in vitro activity; this was not the case for carbapenems. Therefore, ceftazidime may be recommended for the treatment of infections due to OXA-48 producers if they do not coproduce an extended-spectrum β-lactamase or a plasmid-mediated AmpC cephalosporinase.
    Antimicrobial Agents and Chemotherapy 02/2012; 56(5):2759-60. · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin is a re-emerging old antibiotic that is used to treat multidrug-resistant infections in critically ill patients. It corresponds to a mixture of at least 30 different compounds administered as inactive derivatives. Therefore, colistin pharmacokinetics are quite difficult to investigate and complex to predict. However specific chromatographic methods have been made available in recent years, leading to a series of modern pharmacokinetic studies after intravenous administration of the prodrug to critical-care patients; these have been conducted by a few groups and have only been recently published. The objective of this article was to conduct a critical review of these very informative modern pharmacokinetic studies and to provide prospective thoughts.
    Clinical Microbiology and Infection 01/2012; 18(1):30-9. · 4.58 Impact Factor
  • Journal of Antimicrobial Chemotherapy 12/2011; 67(4):1047-8. · 5.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: US and European guidelines recommend a daily divided gentamicin dose (3 mg/kg in two or three equally divided doses) for the treatment of infective endocarditis caused by staphylococci or enterococci, but once-daily dosing (3 mg/kg/day) is recommended for streptococcal endocarditis. However, studies have recommended the use of higher doses of gentamicin (4 or ≥5 mg/kg/day) administered once-daily. A survey was conducted in France by mailing a questionnaire to the 595 members of the French Infectious Disease Society regarding their gentamicin prescription patterns in infective endocarditis, focusing on the dosing regimen. The survey was answered by 137 physicians (23%). The proportions of physicians following guideline-based regimens were similar for each organism (30.9%, 38.8%, and 39.4% for staphylococci, enterococci, and streptococci, respectively [p=0.26]). In contrast, the proportions of physicians following literature-based regimens were significantly different for each organism (59.6%, 42.5%, and 27.7% for staphylococci, enterococci, and streptococci, respectively [p<0.001]). The number of years practicing and the type of practice (university vs. non-university hospital) did not influence the gentamicin dose or regimen. Although adherence to published guidelines for gentamicin administration in patients with infective endocarditis was poor, a large proportion of physicians who did not follow those guidelines used literature-based regimens.
    European Journal of Clinical Microbiology 10/2011; 31(7):1413-8. · 3.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There has been a resurgence of interest in the use of colistin for the treatment of multidrug-resistant Gram-negative bacterial infections. A more favorable infection outcome is observed when colistin is used in combination with carbapenems. We present a patient with severe New Delhi metallo-β-lactamase-1 Escherichia coli infection who developed convulsions rapidly followed by acute respiratory muscle weakness and apnoea during treatment with colistin and meropenem. Chromatographic assay showed a "trough" colistin level that was approximately fourfold higher than previously reported maximum steady-state colistin plasma levels in critically ill patients. The patient's renal clearance never necessitated dose adjustments, suggesting that the observed high plasma colistin level might be due to impaired non renal elimination. Although meropenem itself has very low neurotoxic potential, its concomitant use with colistin may have elicited colistin neurotoxicity.
    The Journal of infection 07/2011; 63(6):468-70. · 4.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1-h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine-related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min-close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half-life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data.
    Clinical Pharmacology &#38 Therapeutics 06/2011; 89(6):875-9. · 6.85 Impact Factor

Publication Stats

845 Citations
349.61 Total Impact Points


  • 2013
    • Federal University of São João del-Rei
      São José del Rey, Minas Gerais, Brazil
  • 2008–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2012
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 1999–2012
    • Université de Poitiers
      Poitiers, Poitou-Charentes, France
  • 2011
    • Free University of Brussels
      • Department of Intensive Care Medicine
      Brussels, BRU, Belgium
  • 2010
    • University of Limoges
      Limages, Limousin, France
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2006
    • Centre Hospitalier Universitaire de Poitiers
      Poitiers, Poitou-Charentes, France
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2000–2001
    • Leiden University
      • Leiden Amsterdam Center for Drug Research
      Leiden, South Holland, Netherlands
  • 1998
    • Roswell Park Cancer Institute
      • Department of Biomathematics
      Buffalo, New York, United States