Pierre-Louis Toutain

Royal Veterinary College, London, ENG, United Kingdom

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Publications (62)188.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective-To determine pharmacodynamic cutoffs with pharmacokinetic-pharmacodynamic principles and Monte Carlo simulation (MCS) for use of amoxicillin in pigs to set interpretive criteria for antimicrobial susceptibility testing. Sample-191 plasma disposition curves of amoxicillin obtained from 21 IV, 104 IM, and 66 PO administrations corresponding to 2,098 plasma concentrations. Procedures-A population model of amoxicillin disposition in pigs was developed for PO and IM administration. The MCS method was then used to determine, for various dosage regimens, the proportion of pigs achieving plasma amoxicillin concentrations greater than a selection of possible minimal inhibitory concentrations (MICs) ranging from 0.0625 to 4 mg/L for at least 40% of a 24-hour period. Results-A target attainment rate (TAR) of 90% was never achieved with the breakpoint recommended by the Clinical and Laboratory Standards Institute (0.5 mg/L) when the usual recommended dosage (20 mg/kg/d) was used. Only by dividing the orally administered daily dose into 12-hour administration intervals was a TAR > 90% achieved when the total dose was at least 40 mg/kg for a pathogen having an MIC ≤ 0.0625 mg/L. For the IM route, the TAR of 90% could only be achieved for MICs of 0.0625 and 0.125 mg/L with the use of 15 and 30 mg/kg doses, respectively. Conclusions and Clinical Relevance-Population kinetics and MCS are required to determine robust species-specific interpretive criteria (susceptible, intermediate, and resistant classifications) for antimicrobial susceptibility testing breakpoints (taking into account interanimal variability).
    American Journal of Veterinary Research 02/2014; 75(2):124-31. · 1.35 Impact Factor
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    ABSTRACT: The ability of antibiotics to combine efficacy against bacterial infections and mitigation of antibiotic resistance amplification in gut microbiota is a major challenge for antimicrobial therapy in food-producing animals. In rats we evaluated the impact of cefquinome - a fourth-generation cephalosporin - on both Klebsiella pneumonia (KP) lung infection, and intestinal flora harboring CTX-M-producing Enterobacteriaceae. Germfree rats received a fecal flora from Specific-Pathogen-Free pigs, in which a CTX-M-producing Escherichia coli strain was added. KP were inoculated in the lungs of these gnotobiotic rats, using either a low (10(5) CFU) or a high (10(9) CFU) inoculum. Without treatment, all animals infected with the low or high KP inoculum developed pneumonia and died before 120h post-challenge. In the treated groups, the low-inoculum rats received a 4-days treatment of 5 mg/kg cefquinome beginning at 24h post-challenge (pre-patent phase of the disease) and the high-inoculum rats received a 4-days treatment of 50 mg/kg cefquinome beginning when the animals expressed clinical signs of infection (patent phase of the disease). The dose of 50 mg/kg targeting the high KP inoculum cured all treated rats, with a massive amplification of CTX-M-producing Enterobacteriaceae. A dose of 5 mg/kg targeting the low KP inoculum cured all the rats and avoided the outbreak of clinical disease, without any amplification of CTX-M-producing Enterobacteriaceae. These findings might have implications for the development of new antimicrobial treatment strategies that ensure the cure of bacterial infections while avoiding the amplification of resistance genes of human concern in the gut microbiota of food-producing animals.
    Antimicrobial Agents and Chemotherapy 01/2014; · 4.57 Impact Factor
  • Aude A. Ferran, Pierre-Louis Toutain, Alain Bousquet-Melou
    International Journal of Antimicrobial Agents. 01/2014;
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    ABSTRACT: We measured serum dBPA in non-pregnant and pregnant female rhesus monkeys, fetuses and amniotic fluid. dBPA was administered by a daily oral bolus or sc implantation of Silastic capsules; both resulted in daily average serum unconjugated dBPA concentrations of <1 ng/ml. We observed lower serum concentrations of unconjugated dBPA in pregnant females relative to pre-pregnancy values, and generally lower concentrations in fetal serum than in maternal serum. Differences in pharmacokinetics of dBPA were evident between pre-pregnancy, early and late pregnancy, likely reflecting changes in maternal, fetal and placental physiology. The serum ratio of conjugated to unconjugated dBPA after continuous sc release of dBPA was similar to values reported in human biomonitoring studies and markedly lower than with oral administration, suggesting oral bolus exposure is not an appropriate human exposure model. We report elsewhere that there were numerous adverse effects on fetuses exposed to very low serum dBPA in these studies.
    Reproductive Toxicology 01/2014; · 3.14 Impact Factor
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    ABSTRACT: For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of 'oral' exposures. It is now widely used - and in some cases required - by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, gavage exposures avoid these interactions, leading to dramatic differences in absorption, bioavailability and metabolism with implications for toxicokinetic assumptions and models. Additionally, there are well acknowledged complications associated with gavage, such as perforation of the esophagus that diminish its value in toxicological experiments. Finally, the gavage protocol itself can induce stress responses by the endocrine system and confound the assessment of EDCs. These serious flaws have not been taken into account in interpreting results of EDC research. We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic. We conclude that gavage may be preferred over other routes for some environmental chemicals in some circumstances, but it does not appropriately model human dietary exposures for many chemicals. Because it avoids exposure pathways, is stressful, and thus interferes with endocrine responses, gavage should be abandoned as the default route of administration for hazard assessments of EDCs.
    Environmental health : a global access science source. 01/2014; 13(1):46.
  • Environmental Health Perspectives 12/2013; 121(11-12):A323-A324. · 7.26 Impact Factor
  • Pierre-Louis Toutain
    The Veterinary Journal 09/2013; · 2.42 Impact Factor
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    ABSTRACT: Classical pharmacokinetic/pharmacodynamic studies of antimicrobial agents performed by combining plasma concentrations and minimum inhibitory concentrations (MICs) are often predictive of the activity of a drug against targeted pathogens located at infectious sites closely connected to circulating blood. However, these studies do not predict the impact of parenteral antimicrobial treatment on intestinal bacteria, which could be responsible for transmission of resistance between species or in the environment. The aim of this study was to assess the differential antibacterial activity of a fluoroquinolone against lung and gut bacteria. Plasma and intestinal concentrations of marbofloxacin were assessed in pigs following intramuscular administration, and the in vitro relationship between marbofloxacin concentrations and mean bacterial inoculum growth in standard broth and in sterilised intestinal contents was modelled. It was shown that the increased intestinal exposure to marbofloxacin compared with plasma in pigs was compensated by reduced marbofloxacin activity against Escherichia coli in the contents of the digestive tract compared with in broth. These results showed that marbofloxacin doses used to target pathogens at the lung level would similarly affect the bacterial population of the same size and with a similar MIC located in the small intestine. However, it was shown that the bactericidal activity of marbofloxacin was increased 4- to 7-fold with low (10(5)CFU/mL) compared with high (10(8)CFU/mL) inoculum sizes. This result suggests that much lower marbofloxacin doses than those classically used would potentially eradicate low pulmonary pathogenic inocula while having a minimal impact on the large gut microbiota.
    International journal of antimicrobial agents 08/2013; · 3.03 Impact Factor
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    ABSTRACT: BACKGROUND: Bisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher than expected BPA plasma concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG). OBJECTIVES: Using dogs as a valid model, plasma concentrations of BPA were compared over a 24-h period after intravenous, orogastric and sublingual administrations, in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability. METHODS: Six dogs were sublingually administered with BPA at 0.05 mg/kg and 5mg/kg. The time course of plasma BPA concentrations was compared with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20mg/kg BPA dose administrated by orogastric gavage. RESULTS: The data indicated that the systemic bioavailability of BPA deposited sublingually was high (70-90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastro-intestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after oral dosing enabling the two pathways of absorption to be easily distinguished. CONCLUSIONS: These findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa by the sublingual route. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastro-intestinal tract.
    Environmental Health Perspectives 06/2013; · 7.26 Impact Factor
  • Peter Lees, Pierre-Louis Toutain
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    ABSTRACT: The presence of horse meat in food products destined for human consumption and labelled as beef has raised several concerns of public interest. This review deals solely with one aspect of these concerns; samples of equine tissue from horses destined for the human food chain have tested positive for the non-steroidal anti-inflammatory drug, phenylbutazone. The safety of some or all such foods for human consumers is a major concern, because it was shown many years ago that phenylbutazone therapy in humans can be associated with life threatening blood dyscrasias. As an initial basis for assessing the potential toxicity of foods containing phenylbutazone and its metabolites, this article reviews (1) the pharmacokinetic, pharmacodynamic, metabolic and toxicological profiles of phenylbutazone, with particular reference to horses and humans; (2) toxicity data in laboratory animals; (3) phenylbutazone residues in food producing species, and (4) as a preliminary assessment, the potential hazard associated with the consumption of horse meat containing phenylbutazone and its metabolites. Since phenylbutazone cannot be classified as a carcinogenic substance in humans, and noting that blood dyscrasias in humans are likely to be dose and treatment duration-dependent, the illegal and erratic presence of trace amount residues of phenylbutazone in horse meat is not a public health issue.
    The Veterinary Journal 05/2013; · 2.42 Impact Factor
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    ABSTRACT: The widespread human exposure to bisphenol A (BPA), a xenoestrogen interfering with developmental processes, raises the question of the mechanisms determining fetal exposure to BPA. A physiological model was developed in ewes to determine whether the pregnancy-associated physiological changes and the metabolic specificities of the feto-placental unit can influence BPA toxicokinetic (TK) and fetal exposure to BPA. In a first longitudinal study, BPA was infused i.v. (2 mg/(kg.d) for 1 day) into ewes before breeding, at early and late gestation stages and after lambing. In a second study, BPA and BPA-glucuronide (BPA-G) were infused i.v. into pregnant ewes or to fetuses at 4 month of gestational age. BPA and its metabolites were assayed in maternal and fetal plasma and amniotic fluid sampled at steady state and after the end of the infusion. The pregnancy status did not modify the TK parameters of BPA and of BPA-G. Five percent of the BPA dose infused into the pregnant ewe was transferred across the placenta to the fetus. The feto-placental unit was very efficient in metabolizing BPA into conjugated compounds. Those metabolites remained trapped in the feto-placental compartment leading to a high fetal exposure to BPA conjugates. Taking into account a body weight adjustment, the ovine fetus in late pregnancy is exposed to a BPA dose similar to that of its mother. In contrast to its mother, the fetus exhibits much higher and sustained exposure to BPA metabolites without evidence of their hydrolysis.
    Biology of Reproduction 05/2013; · 4.03 Impact Factor
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    ABSTRACT: We compared the prevalence of pathogenic and extended-spectrum beta-lactamase (ESBL) - producing Escherichia coli in effluents of a municipal wastewater treatment plant (WWTP) receiving wastewater from a slaughterhouse. A total of 1248 isolates were screened for the presence of virulence genes associated with enterohemorrhagic E. coli (EHEC) (stx1, stx2, and eae) and extraintestinal pathogenic E. coli (ExPEC) (sfa/focDE, kpsMT K1, hlyA, papEF, afa/draBC, clbN, f17A and cnf). The prevalence of atypical enteropathogenic E. coli (EPEC) was 0.7%, 0.2% and 0.5% in city wastewater, slaughterhouse wastewater and in the treated effluent, respectively. One stx1a and stx2b-positive E. coli isolate was detected in city wastewater. The prevalence of ExPEC was significantly higher in city wastewater (8.4%), compared to slaughterhouse wastewater (1.2%). Treatment in the WWTP did not significantly impact the prevalence of ExPEC in the outlet effluent (5.0%) compared to city wastewater. Moreover, the most potentially pathogenic ExPEC were isolated from city wastewater and from the treated effluent. ESBL-producing E. coli was also mainly detected in city wastewater (1.7%), compared to slaughterhouse wastewater (0.2%), and treated effluent (0.2%). One ESBL-producing E. coli, isolated from city wastewater, was eae-β1 positive. These results showed that pathogenic and/or ESBL-producing E. coli were mainly detected in human wastewater, and at a lesser extend in animal wastewater. Treatment failed to eliminate these strains which were discharged into the river, and then these strains could be transmitted to animals and humans via the environment.
    Water Research 05/2013; 47(13):4719-4729. · 4.66 Impact Factor
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    ABSTRACT: Objective-To measure florfenicol concentrations in ovine tear fluid after IM and SC administration and determine minimum inhibitory concentrations (MICs) of florfenicol against field isolates of Mycoplasma organisms potentially involved in infectious keratoconjunctivitis. Animals-9 healthy adult Lacaune ewes. Procedures-Animals received an IM and SC administration of florfenicol (20 mg/kg) in a 2-way crossover design. Samples of blood and tear fluid were collected before and for 24 hours after administration. Concentrations of florfenicol in plasma and tear fluid were measured via high-performance liquid chromatography. The MIC of florfenicol for various Mycoplasma strains cultured from sheep and goats was determined via an agar dilution method. Results-Mean florfenicol concentration in tear fluid for the 24-hour period was significantly higher after IM administration (0.70 μg/mL) than after SC administration (0.22 μg/mL) and was maintained for a longer duration. The lacrimal fluid-to-plasma concentration ratio was not different between the 2 routes of administration, with mean values of 40.2% and 32.5% after IM and SC administration, respectively. The MIC for Mycoplasma agalactiae, Mycoplasma conjunctivae, and Mycoplasma mycoides isolates ranged from 0.5 to 8 μg of florfenicol/mL. Two strains of M agalactiae could be considered resistant to florfenicol. Conclusions and Clinical Relevance-Florfenicol readily penetrated the preocular tear fluid of sheep after IM and SC administration. For both routes of administration, doses > 20 mg/kg would be necessary to achieve tear fluid concentrations of florfenicol greater than the MICs for most strains of Mycoplasma organisms.
    American Journal of Veterinary Research 02/2013; 74(2):268-74. · 1.35 Impact Factor
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    ABSTRACT: The objective of this study was to document the effect of social ranking on the internal exposure of pigs to an antibiotic (Fosfomycin) administered either in food or in drinking water. Signs of aggression were recorded at the feeder and drinker. The interindividual variability explained by the social rank was even greater when the test antibiotic was given in food despite the fact that the water consumption was less variable than the food intake. The range of plasma concentrations after administration of fosfomycin either in food or drinking water leads to a number of pigs in the treated group being exposed to rather low and highly variable concentrations of fosfomycin and not able to maintain adequate plasma concentrations above the typical minimum inhibitory concentration (MIC). Social rank clearly influences the level of exposure of pigs to fosfomycin both in food and drinking. However, its administration in drinking water is likely to be the best option to optimize antibiotic efficacy.
    Research in Veterinary Science 01/2013; · 1.77 Impact Factor
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    ABSTRACT: The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T(4) concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T(4) plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.
    Endocrinology 11/2012; · 4.72 Impact Factor
  • Peter Lees, Pierre-Louis Toutain
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    ABSTRACT: This review provides a summary of those pharmacokinetic properties of veterinary drugs relevant to marker residues, marker tissues, and residue depletion rates. The scientific literature in this field is very extensive and there is also a wealth of data available on the websites of various regulatory jurisdictions. Therefore, this review is limited to selected examples, cited to illustrate general principles. The areas considered are: (1) the relationship of dose to plasma concentration through the pharmacokinetic properties, area under plasma concentration-time curve, bioavailability, and clearance; (2) the critical dependence of drug pharmacokinetics and residue depletion on product formulation; (3) disease state and population pharmacokinetics; and (4) the requirement for residue depletion studies for generic products shown to be bioequivalent to pioneer products.
    Drug Testing and Analysis 08/2012; 4 Suppl 1:34-9. · 3.17 Impact Factor
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    Environmental Health Perspectives 01/2012; 120(1):a15. · 7.26 Impact Factor
  • Peter Lees, Pierre-Louis Toutain
    11/2011: pages 61 - 109; , ISBN: 9781118067208
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    ABSTRACT: A model of thyroidectomized sheep intravenously supplemented with thyroid hormone (TH) was developed to mimic endogenous TH exposure and to analyze the impact on plasma TH homeostasis of xenobiotic interference with TH binding to plasma proteins. TH was displaced from plasma protein binding sites by using phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on steady state free and total plasma TH concentrations between the in vivo situation and an in vitro system. While PBZ increased free TH in vitro, PBZ administration in vivo produced an immediate reduction in both total and free plasma TH. The decrease in the total TH was consistent with a PBZ-induced displacement of TH from its plasma binding proteins, leading to an increase in total TH plasma clearance. However, this reduction in total TH was not expected to be accompanied by a parallel decrease in free plasma TH since the free TH is determined by the clearance of the free plasma TH. This suggested that PBZ may also have interfered with the clearance mechanisms of free TH. It can be concluded that our thyroidectomized sheep model enables a dual action of a xenobiotic on plasma TH to be distinguished, namely a displacement of TH from its binding proteins leading to a decrease in the total plasma concentration, which is not relevant to thyroid function versus an interference with the intrinsic TH clearance leading to a change in the free plasma TH, which has a major impact in terms of thyroid disruption.
    General and Comparative Endocrinology 09/2011; 174(2):225-31. · 2.82 Impact Factor
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    ABSTRACT: To explore different ciprofloxacin dosage regimens for the treatment of intensive care unit (ICU) patients with respect to clinical outcome and the development of bacterial resistance for the major Gram-negative pathogens. A population pharmacokinetic model was first developed on ciprofloxacin serum concentrations obtained in 102 ICU patients. Then, based on this model, pharmacokinetic-pharmacodynamic Monte Carlo simulations (MCSs) were carried out to explore the appropriateness of different ciprofloxacin dosage regimens in ICU patients. The defined targets were free AUC(24)/MIC ≥90 h (as a predictor of clinical outcome) and T(MSW) ≤20% (as a predictor of selecting resistance), where T(MSW) is the time spent within the mutant selection window over 24 h. Two simulation trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used MIC breakpoints given by the Antibiogram Committee of the French Microbiology Society in order to treat the 'worst-case' scenario. Trial 1 showed that for Pseudomonas aeruginosa and Acinetobacter baumannii, the common dosage regimens of 400 mg twice or three times a day did not achieve the desired target attainment rates (TARs) with respect to T(MSW), while suboptimal TARs were found for AUC(24)/MIC. Trial 2 showed that ≤ 18% of patients reached the target of T(MSW) ≤ 20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose. Based on the mutant selection window concept, our simulations truly question the use of ciprofloxacin for the treatment of P. aeruginosa and A. baumannii infections in ICU patients due to the potential for developing resistance.
    Journal of Antimicrobial Chemotherapy 06/2011; 66(8):1798-809. · 5.34 Impact Factor

Publication Stats

666 Citations
188.75 Total Impact Points

Institutions

  • 2012–2013
    • Royal Veterinary College
      • Department of Veterinary Basic Sciences
      London, ENG, United Kingdom
  • 2006–2013
    • French National Institute for Agricultural Research
      Lutetia Parisorum, Île-de-France, France
    • L’Institut national de la recherche agronomique (Toulouse)
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2002–2013
    • École Nationale Vétérinaire de Toulouse
      • UMR 1225 IHAP - Interactions hôtes - agents pathogènes
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2009
    • Technical University of Denmark
      København, Capital Region, Denmark