Publications

Gregoire N, Chauzy A, Buyck J, Rammaert B, Couet W, Marchand S. Clinical Pharmacokinetics of Daptomycin. Clin Pharmacokinet. 2020 Dec 14. doi: 10.1007/s40262-020-00968-x. PMID: 33313994

Mainas E, Apostolopoulou O, Siopi M, Apostolidi S, Neroutsos E, Mirfendereski H, Marchand S, Couet W, Dokoumetzidis A, Valsami G, Sambatakou H, Dimopoulos G, Meletiadis J. Comparative pharmacokinetics of the three echinocandins in ICU patients. J Antimicrob Chemother. 2020 Oct 1;75(10):2969-2976. doi: 10.1093/jac/dkaa265.PMID: 32696036

Kevin Brunet, Blandine Rammaert. Mucormycosis treatment: Recommendations, latest advances, and perspectives. J Mycol Med. 2020 Sep;30(3):101007. doi: 10.1016/j.mycmed.2020.101007. Epub 2020 Jun 20.

Frédéric Tewes, Tania F. Bahamondez-Canasb, Daniel Moraga-Espinoza, Hugh D.C. Smyth, Alan B. Watts. In vivo efficacy of a dry powder formulation of ciprofloxacin-copper complex in a chronic lung infection model of bioluminescent Pseudomonas aeruginosa. European Journal of Pharmaceutics and Biopharmaceutics, Volume 152, July 2020, Pages 210-217.

Joncour A, Puyade M, Michaud A, Tourani JM, Cazenave-Roblot F, Rammaert BIs Current Initial Empirical Antibiotherapy Appropriate to Treat Bloodstream Infections in Short-Duration Chemo-Induced Febrile Neutropenia?  Support Care Cancer. 2020 Jul;28(7):3103-3111.

Wang J, Grégoire N, Marchand S, Kutter JP, Mu H, Moodley A, Couet W, Yang M. Improved Antibacterial Efficiency of Inhaled Thiamphenicol Dry Powders: Mathematical Modelling of in Vitro Dissolution Kinetic and in Vitro Antibacterial Efficacy. Eur J Pharm Sci. 2020 Jun 23:105435.

Chauzy A, Ih H, Jacobs M, Marchand S, Grégoire N, Couet W, Buyck JM. Sequential Time-Kill: A Simple Experimental Trick to Discriminate Between PK/PD Models With Distinct Heterogeneous Sub-Populations Versus Homogenous Population With Adaptive Resistance.  Antimicrob Agents Chemother. 2020 Jun 8:AAC.00788-20. 

Couet W; EPASG. Antibiotic PK/PD Modelling: A Memorial Tribute to Alan Forrest. Clin Microbiol Infect. 2020 Jun 6:S1198-743X(20)30311-6. 

Pichon M, Broutin L, Touroult-Jupin P, Cremniter J, Plouzeau C, Faure JP, Olivier R, Burucoa CFirst Detection in Helicobacter suis of a Mutation Conferring Resistance to Clarithromycin in Helicobacter pylori: Case Report and Review of the Literature.  Microb Drug Resist. 2020 Jun;26(6):677-680. 

Djenontin E, Lebeaux D, Acikgoz H, Rammaert B, Bougnoux ME, Rouzaud C, Bouyer B, Champigneulle B, Dannaoui E. Post-traumatic Curvularia Sp. Arthritis in an Immunocompetent Adult. J Mycol Med. 2020 Jun;30(2):100967.

Candon S, Rammaert B, Foray AP, Moreira B, Gallego Hernanz MP, Chatenoud L, Lortholary O. Chronic Disseminated Candidiasis During Hematological Malignancies: An Immune Reconstitution Inflammatory Syndrome With Expansion of Pathogen-Specific T Helper Type 1 Cells.  J Infect Dis. 2020 May 11;221(11):1907-1916. 

Monier A, Puyade M, Hernanz MPG, Bouchaert P, Leleu X, Tourani JM, Roblot F, Rammaert BObservational Study of Vaccination in Cancer Patients: How Can Vaccine Coverage Be Improved?  Med Mal Infect. 2020 May;50(3):263-268. 

Brunet K, Minoza A, Rammaert B, Portet-Sulla V, Hubert F, Lorenzo JC, Rodier MH, Cateau E. Invasive Candida Bovina Infection, France.  Emerg Infect Dis. 2020 Mar;26(3):626-627.

Pichon M, Pichard B, Barrioz T, Plouzeau C, Croquet V, Fotsing G, Chéron A, Vuillemin É, Wangermez M, Haineaux PA, Vasseur P, Thiebault Q, Lefèvre C, de Singly A, Cremniter J, Broutin L, Michaud A, Silvain C, Burucoa C. Diagnostic Accuracy of a Noninvasive Test for Detection of Helicobacter Pylori and Resistance to Clarithromycin in Stool by the Amplidiag H. pylori+ClariR Real-Time PCR Assay. J Clin Microbiol. 2020 Mar 25;58(4):e01787-19. 

Aranzana-Climent V, Buyck JM, Smani Y, Pachón-Diaz J, Marchand S, Couet W, Grégoire N. Semi-mechanistic PK-PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii. Clin Microbiol Infect. 2020 Jan 29. pii: S1198-743X(20)30042-2.

Frédéric Tewes, Julien Brillault, Nicolas Grégoire, Jean-Christophe Olivier, Isabelle Lamarche, Christophe Adier, Anne Marie Healy, Sandrine MarchandComparison between Colistin Sulfate Dry Powder and Solution for Pulmonary Delivery. Pharmaceutics, 2020, 12 (6), pp.557. 

Julien Brillault, Frédéric TewesControl of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones. Pharmaceutics, 2020, 12 (4), pp.E387.

Ploy MC, Andremont A, Valtier B, Le Jeunne C; et les participants à la table ronde Recherche translationnelle des Ateliers de Giens XXXV. Antibiorésistance : outils pour une recherche translationnelle efficace. Therapie. 2019 Dec 13

Magréault S, Mankikian J, Marchand S, Diot P, Couet W, Flament T, Grégoire N. Pharmacokinetics of colistin after nebulization or intravenous administration of colistin methanesulphonate (Colimycin®) to cystic fibrosis patients. Journal of Cystic Fibrosis september 2019 Sep 6

Fantin B, Poujade J, Grégoire N, Chau F, Roujansky A, Kieffer N, Berleur M, Couet W, Nordmann P. The inoculum effect of Escherichia coli expressing mcr-1 or not on colistin activity in a murine model of peritonitis. Clin Microbiol Infect. 2019 Sep 5

Chauzy A, Gaelzer Silva Torres B, Buyck J, de Jonge B, Adier C, Marchand S, Couet W, Grégoire N. Semimechanistic Pharmacodynamic Modeling of Aztreonam-Avibactam Combination to Understand Its Antimicrobial Activity Against Multidrug-Resistant Gram-Negative Bacteria. CPT Pharmacometrics Syst Pharmacol. 2019 Aug 16

Nurbaeti SN, Brillault J, Tewes F, Olivier JC. Sustained-release microparticle dry powders of chloramphenicol palmitate or thiamphenicol palmitate prodrugs for lung delivery as aerosols. Eur J Pharm Sci. 2019 Aug 1:105028.

Boisson M, Torres BGS, Yani S, Couet W, Mimoz O, Dahyot-Fizelier C, Marchand S, Grégoire N. Reassessing the dosing of cefoxitin prophylaxis during major abdominal surgery: insights from microdialysis and population pharmacokinetic modelling.J Antimicrob Chemother. 2019 Jul 1;74(7):1975-1983.

Boisson M, Corbi P, Kerforne T, Camilleri L, Debauchez M, Demondion P, Eljezi V, Flecher E, Lepelletier D, Leprince P, Nesseler N, Nizou JY, Roussel JC, Rozec B, Ruckly S, Lucet JC, Timsit JF, Mimoz O. Multicentre, open-label, randomised, controlled clinical trial comparing 2% chlorhexidine-70% isopropanol and 5% povidone iodine-69% ethanol for skin antisepsis in reducing surgical-site infection after cardiac surgery: the CLEAN 2 study protocol. BMJ Open. 2019 Jun 17;9(6):e026929.

Tewes F, Bahamondez-Canas TF, Smyth HDC. Efficacy of Ciprofloxacin and Its Copper Complex against Pseudomonas aeruginosa Biofilms. AAPS PharmSciTech. 2019 May 29;20(5):205.

Brunet T, Brunet K, Jouvion G, Cateau E, Marchand S, Rammaert B. Lichtheimia corymbifera colonization leading to pulmonary infection can be prevented with liposomal Amphotericin B in a new murine model. Antimicrob Agents Chemother. 2019 May 28

Mehta S, Aranzana-Climent V, Rammaert B, Grégoire N, Marchand S, Couet W, Buyck JM. Pre-clinical pharmacokinetic and pharmacodynamic data to support cefoxitin nebulization for the treatment of Mycobacterium abscessus. Antimicrob Agents Chemother. 2019 May 6

Carrez R, Brillault J, Grégoire N, Lamarche I, Laroche J, Couet W, Marchand S. Pulmonary Pharmacokinetics of Oseltamivir Carboxylate in Rats after Nebulization or Intravenous Administration of its Prodrug Oseltamivir Phosphate. Antimicrob Agents Chemother. 2019 Apr 8

Chauzy A, Buyck J, de Jonge BLM, Marchand S, Grégoire N, Couet W. Pharmacodynamic modelling of β-lactam/β-lactamase inhibitor checkerboard data: illustration with aztreonam-avibactam. Clin Microbiol Infect. 2019 Apr;25(4):515.e1-515.e4.

Martin C, Auboyer C, Boisson M, Dupont H, Gauzit R, Kitzis M, Leone M, Lepape A, Mimoz O, Montravers P, Pourriat JL; Steering committee of the French Society of Anaesthesia and Intensive Care Medicine (SFAR) responsible for the establishment of the guidelines. Antibioprophylaxis in surgery and interventional medicine (adult patients). Update 2017.  Anaesth Crit Care Pain Med. 2019 Mar 2.

Chauzy A, Nadji A, Combes JC, Defrance N, Bouhemad B, Couet W, Chavanet P. Cerebrospinal fluid pharmacokinetics of ceftaroline in neurosurgical patients with an external ventricular drain. J Antimicrob Chemother. 2019 Mar 1;74(3):675-681.

Grégoire N, Marchand S, Ferrandière M, Lasocki S, Seguin P, Vourc’h M, Barbaz M, Gaillard T, Launey Y, Asehnoune K, Couet W, Mimoz O. Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment. J Antimicrob Chemother. 2019 Jan 1;74(1):117-125.

Marchand S, Grégoire N, Couet W. Pharmacokinetics of Polymyxins in Animals. Adv Exp Med Biol. 2019;1145:89-103.

Barbara LamyDolores Remedios Serrano, Peter O’Connell, William CouetSandrine Marchand, Anne Marie Healy, Frederic Tewes. Use of leucine to improve aerodynamic properties of ciprofloxacin-loaded maltose microparticles for inhalation. Eur. J. Pharm. Res. 2019, Vol. 1, Issue 1, p. 2-11.

BGS Torres, R Awad, S Marchand, W Couet, F Tewes. In vitro evaluation of Pseudomonas aeruginosa chronic lung infection models: Are agar and calcium-alginate beads interchangeable? European Journal of Pharmaceutics and Biopharmaceutics 2019, 143, 35-43.

Brunet K, Alanio A, Lortholary O, Rammaert B. Reactivation of dormant/latent fungal infection.  J Infect. 2018 Dec;77(6):463-468.

Boisson M, Mimoz O, Hadzic M, Marchand S, Adier C, Couet W, Gregoire N. Pharmacokinetics of intravenous and nebulized gentamicin in critically ill patients. J Antimicrob Chemother. 2018 Oct

Bouchene S, Marchand S, Couet W, Friberg LE, Gobin P, Lamarche I, Grégoire N, Björkman S, Karlsson MO. A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat.  Basic Clin Pharmacol Toxicol. 2018 Oct;123(4):407-422.

Marchand S, Boisson M, Mehta S, Adier C, Mimoz O,  Grégoire N, and Couet W. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. Aminoglycosides. Antimicrob Agents Chemother. 2018 Sep.

Magréault S, Petyt C, Senneville E, Fron D, Nectoux E, Loiez C, Marchand S, Grégoire N, Couet WPharmacokinetics of colistin in a 8-year-old child with acute bone infection. Clin Microbiol Infect. 2018 Sep;24(9):1025-1026.

Chauzy A, Lamarche I, Adier C, Couet W, Marchand S. Microdialysis Study of Aztreonam-Avibactam Distribution in Peritoneal Fluid and Muscle of Rats with or without Experimental Peritonitis. Antimicrob Agents Chemother. 2018 Jul

Couet W. Pharmacokinetics/pharmacodynamics characterization of combined antimicrobial agents: a real challenge and an urgent need.  Clin Microbiol Infect. 2018 Jul;24(7):687-688.

TF Bahamondez-Canas, H Zhang, F Tewes, J Leal, HDC Smyth. PEGylation of Tobramycin Improves Mucus Penetration and Antimicrobial Activity against Pseudomonas aeruginosa Biofilms in Vitro. Mol Pharm. 2018 Apr

Nurbaeti SN, Olivier JC, Adier C, Marchand S, Couet W, Brillault J. Active Mediated Transport of Chloramphenicol and Thiamphenicol in a Calu-3 Lung Epithelial Cell Model. J Pharm Sci. 2018 Apr

Etienne M, Simon S, Antoine E, Etienne C, Blandine R, Matthieu M, Didier R, France R. Osteoarticular manifestations of Q fever: a case series and literature review. Clin Microbiol Infect. 2018 Mar

Viel A, Henri J, Bouchène S, Laroche J, Rolland JG, Manceau J, Laurentie M, Couet W, Grégoire N. A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion. Pharm Res. 2018 Mar

Grégoire M, Libois JB, Waast D, Gaborit B, Dauty M, Deslandes G, Dailly E, Touchais S, Boutoille D, Grégoire N, Couet W. Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery. Antimicrob Agents Chemother. 2018 Mar

Dahyot-Fizelier C, Marchand S, Lipman J. Is augmented renal clearance the Holy Grail of antibiotic therapy failure in ventilator-acquired pneumonia? Anaesth Crit Care Pain Med. 2018 Feb

Lamy B, Tewes F, Serrano DR, Lamarche I, Gobin P, Couet W, Healy AM, Marchand S. New aerosol formulation to control ciprofloxacin pulmonary concentration. J Control Release. 2018 Feb

Magréault S, Grégoire N, Marchand S, Couet W. Colistin Pharmacokinetics in Pediatrics. Clin Infect Dis. 2018 Feb 10;66(5):809.

Bäckman P, Arora S, Couet W, Forbes B, de Kruijf W, Paudel A. Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs. Eur J Pharm Sci. 2018 Feb 15;113:41-52.

Chauzy A., Nadji A., Combes J.C., Defrance N., Bouhemad B., Couet W., Chavanet P. Cerebrospinal fluid pharmacokinetics of ceftaroline in neurosurgical patients with an external ventricular drain. J Antimicrob Chemother. 2018.

Chauzy A., Buyck J., de Jonge B.L.M., Marchand S., Grégoire N., Couet W. Pharmacodynamic modeling of β-lactam/β-lactamase inhibitor checkerboard data: illustration with aztreonam-avibactam. Clin Microbiol Infect. 2018.

Ehrhardt C, Bäckman P, Couet W, Edwards C, Forbes B, Fridén M, Gumbleton M, Hosoya KI, Kato Y, Nakanishi T, Takano M, Terasaki T, Yumoto R. Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs. J Pharm Sci. 2017 Sep;106(9):2234-2244

Boisson M, Grégoire N, Cormier M, Gobin P, Marchand S, Couet W, Mimoz O. Pharmacokinetics of nebulized colistin methanesulfonate in critically ill patients.J Antimicrob Chemother. 2017 Jun 1. doi: 10.1093/jac/dkx167.

Grégoire N, Aranzana-Climent V, Magréault S, Marchand S, Couet W.Clinical Pharmacokinetics and Pharmacodynamics of Colistin.Clin Pharmacokinet. 2017 May 26.

Yamamoto Y, Välitalo PA, van den Berg DJ, Hartman R, van den Brink W, Wong YC, Huntjens DR, Proost JH, Vermeulen A, Krauwinkel W, Bakshi S, Aranzana-Climent V, Marchand S, Dahyot-Fizelier C, Couet W, Danhof M, van Hasselt JG, de Lange EC. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.Pharm Res. 2017 Feb;34(2):333-351.

J Brillault, F Tewes, W Couet, JC Olivier. In vitro biopharmaceutical evaluation of ciprofloxacin/metal cation complexes for pulmonary administration.Eur J Pharm Sci. 2017 Jan

Alexis Viel, Jérôme Henri, Agnès Perrin-Guyomard, Julian Laroche, William Couet, Nicolas Grégoire, Michel Laurentie. Lack of experimental evidence to support positive  strain selection during oral administration of colistin at recommended and higher dose given by gavage in weaned piglets. International Journal of Antimicrobial Agents, 2017.

Le Devendec L, Mourand G, Bougeard S, Léaustic J, Jouy E, Keita A, Couet W, Rousset N, Kempf I. Impact of colistin sulfate treatment of broilers on the presence of resistant bacteria and resistance genes in stored or composted manure. Vet Microbiol. 2016 Oct 15;194:98-106.

Gaspar MC, Grégoire N, Sousa JJ, Pais AA, Lamarche I, Gobin P, Olivier JC, Marchand S, Couet W. Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres. Eur J Pharm Sci. 2016 Oct 10;93:184-91.

Couet W. Pharmacokinetic/pharmacodynamic studies in the CMI. Clin Microbiol Infect. 2016 Oct;22(10):821.

Marchand S, Chauzy A, Dahyot-Fizelier C, Couet W. Microdialysis as a way to measure antibiotics concentration in tissues. Pharmacol Res. 2016 Sep;111:201-207.

Fleury MA, Jouy E, Eono F, Cariolet R, Couet W, Gobin P, Le Goff O, Blanquet-Diot S, Alric M, Kempf I. Impact of two different colistin dosing strategies on healthy piglet fecal microbiota.  Res Vet Sci. 2016 Aug;107:152-160.

Godet C, Laurent F, Bergeron A, Ingrand P, Beigelman-Aubry C, Camara B, Cottin V, Germaud P, Philippe B, Pison C, Toper C, Carette MF, Frat JP, Béraud G, Roblot F, Cadranel J; ACHROSCAN Study Group. CT Imaging Assessment of Response to Treatment in Chronic Pulmonary Aspergillosis. Chest. 2016 Jul;150(1):139-47.

Galindo Bedor DC, Marchand S, Lamarche I, Laroche J, Pereira de Santana D, Couet W. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 5. Oseltamivir Carboxylate. Antimicrob Agents Chemother. 2016 Jul 22;60(8):5085-7.

Maiguy-Foinard A, Genay S, Lannoy D, Barthélémy C, Lebuffe G, Debaene B, Odou P, Décaudin B. Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and intensive care units. Anaesth Crit Care Pain Med. 2016 Jun 20. pii: S2352-5568(16)30056-X.

Loupec T, Frasca D, Debaene B. Dose of sugammadex in morbidly obese patients – a reply. Anaesthesia. 2016 Jun;71(6):731-2.

Le Coz P, Carlet J, Roblot F, Pulcini C. Human resources needed to perform antimicrobial stewardship teams’ activities in French hospitals. Med Mal Infect. 2016 Jun;46(4):200-6.

Garcia M, Le Moal G, Godet C, Beraud G, Chagneau-Derrode C, Roblot F. First case report of renal improvement on tenofovir alafenamide in an HIV/hepatitis B virus-coinfected patient with adefovir-induced Fanconi’s syndrome. AIDS. 2016 Jun 1;30(9):1487-8.

Fillâtre P, Revest M, Belaz S, Robert-Gangneux F, Zahar JR, Roblot F, Tattevin P. [Pneumocystosis in non-HIV-infected immunocompromised patients]. Rev Med Interne. 2016 May;37(5):327-36.

Lemaire X, Bonnet E, Castan B, Forestier E, Lescure FX, Roblot F, Pulcini C. Management of non-necrotizing cellulitis in France. Med Mal Infect. 2016 May 26. pii: S0399

Marchand S, Grégoire N, Brillault J, Lamarche I, Gobin P, Couet W. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 4. Aztreonam. Antimicrob Agents Chemother. 2016 Apr 22;60(5):3196-8.

Loupec T, Frasca D, Rousseau N, Faure JP, Mimoz O, Debaene B. Appropriate dosing of sugammadex to reverse deep rocuronium-induced neuromuscular blockade in morbidly obese patients. Anaesthesia. 2016 Mar;71(3):265-72.

Jacobs M, Grégoire N, Couet W, Bulitta JB. Distinguishing Antimicrobial Models with Different Resistance Mechanisms via Population Pharmacodynamic Modeling. PLoS Comput Biol. 2016 Mar 11;12(3):e1004782.

Roblot F, Robin S, Chubilleau C, Giraud J, Bouffard B, Ingrand P. Vaccination coverage in French 17-year-old young adults: an assessment of mandatory and recommended vaccination statuses. Epidemiol Infect. 2016 Feb;144(3):612-7.

Tewes F, Brillault J, Lamy B, O’Connell P, Olivier JC, Couet W, Healy AM. Ciprofloxacin-Loaded Inorganic-Organic Composite Microparticles To Treat Bacterial Lung Infection. Mol Pharm. 2016 Jan 4;13(1):100-12.

Jacobs M, Grégoire N, Mégarbane B, Gobin P, Balayn D, Marchand S, Mimoz O, Couet W. Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis. Antimicrob Agents Chemother. 2016 Jan 4;60(3):1788-93.

Tewes F, Gobbo OL, Ehrhardt C, Healy AM. Amorphous Calcium Carbonate Based-Microparticles for Peptide Pulmonary Delivery. ACS Appl Mater Interfaces. 2016 Jan 20;8(2):1164-75.

Kabran FA, Okpekon TA, Roblot F, Séon-Méniel B, Leblanc K, Bories C, Champy P, Yolou SF, Loiseau PM, Djakouré LA, Figadère B, Maciuk A. Bioactive phloroglucinols from Mallotus oppositifolius. Fitoterapia. 2015 Dec;107:100-104.

Ratajczak-Enselme M, Gregoire N, Estebe J-P, Dollo G, Chevanne F, Bec D, Ecoffey C, Couet W, Le Corre P. Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep. Reg Anesth Pain Med. 2015 Dec;40(6):681–6.

Guechi Y, Pichot A, Frasca D, Rayeh-Pelardy F, Lardeur J-Y, Mimoz O. Assessment of noninvasive acoustic respiration rate monitoring in patients admitted to an Emergency Department for drug or alcoholic poisoning. J Clin Monit Comput. 2015 Dec;29(6):721–6.

Mimoz O, Lucet J-C, Kerforne T, Pascal J, Souweine B, Goudet V, Mercat A, Bouadma L, Lasocki S, Alfandari S, Friggeri A, Wallet F, Allou N, Ruckly S, Balayn D, Lepape A, Timsit J-F. Skin antisepsis with chlorhexidine-alcohol versus povidone iodine-alcohol, with and without skin scrubbing, for prevention of intravascular-catheter-related infection (CLEAN): an open-label, multicentre, randomised, controlled, two-by-two factorial trial. Lancet. 2015 Nov 21;386(10008):2069–77.

Godet C, Laurent F, Beraud G, Toper C, Camara B, Philippe B, Germaud P, Cottin V, Beigelman-Aubry C, Khalil A, Blouin P, Pouriel M, Roblot F, Bergeron A, Cadranel J. Phenotyping chronic pulmonary aspergillosis by cluster analysis. Eur Respir J. 2015 Nov;46(5):1509–12.

Marchand S, Gregoire N, Brillault J, Lamarche I, Gobin P, Couet W. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin. Antimicrob Agents Chemother. 2015 Oct;59(10):6646–7.

Marchand S, Bouchene S, de Monte M, Guilleminault L, Montharu J, Cabrera M, Gregoire N, Gobin P, Diot P, Couet W, Vecellio L. Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys. Pharm Res. 2015 Oct;32(10):3403–14.

Gaspar MC, Sousa JJS, Pais AACC, Cardoso O, Murtinho D, Serra MES, Tewes F, Olivier J-C. Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy. Eur J Pharm Biopharm. 2015 Oct;96:65–75.

Hutchinson PJ, Jalloh I, Helmy A, Carpenter KLH, Rostami E, Bellander B-M, Boutelle MG, Chen JW, Claassen J, Dahyot-Fizelier C, Enblad P, Gallagher CN, Helbok R, Hillered L, Le Roux PD, Magnoni S, Mangat HS, Menon DK, Nordstrom C-H, O’Phelan KH, Oddo M, Perez Barcena J, Robertson C, Ronne-Engstrom E, Sahuquillo J, Smith M, Stocchetti N, Belli A, Carpenter TA, Coles JP, Czosnyka M, Dizdar N, Goodman JC, Gupta AK, Nielsen TH, Marklund N, Montcriol A, O’Connell MT, Poca MA, Sarrafzadeh A, Shannon RJ, Skjoth-Rasmussen J, Smielewski P, Stover JF, Timofeev I, Vespa P, Zavala E, Ungerstedt U. Consensus statement from the 2014 International Microdialysis Forum. Intensive Care Med. 2015 Sep;41(9):1517–28.

Pham D-D, Gregoire N, Couet W, Gueutin C, Fattal E, Tsapis N. Pulmonary delivery of pyrazinamide-loaded large porous particles. Eur J Pharm Biopharm. 2015 Aug;94:241–50.

Drouet M, Chai F, Barthelemy C, Lebuffe G, Debaene B, Decaudin B, Odou P. Endothelial Cell Toxicity of Vancomycin Infusion Combined with Other Antibiotics. Antimicrob Agents Chemother. 2015 Aug;59(8):4901–6.

de Luca A, Parizel A, Fromont G, Roblot P, Roblot F, Gambert-Abdel Rahman C, Hankard R. High procalcitonin and thrombocytopenic purpura in a case of Kikuchi-Fujimoto disease. Arch Pediatr. 2015 Jun;22(6):602-4.

Payen DM, Guilhot J, Launey Y, Lukaszewicz AC, Kaaki M, Veber B, Pottecher J, Joannes-Boyau O, Martin-Lefevre L, Jabaudon M, Mimoz O, Coudroy R, Ferrandiere M, Kipnis E, Vela C, Chevallier S, Mallat J, Robert R. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med. 2015 Jun;41(6):975–84.

Leone M, Bechis C, Baumstarck K, Ouattara A, Collange O, Augustin P, Annane D, Arbelot C, Asehnoune K, Baldesi O, Bourcier S, Delapierre L, Demory D, Hengy B, Ichai C, Kipnis E, Brasdefer E, Lasocki S, Legrand M, Mimoz O, Rimmele T, Aliane J, Bertrand P-M, Bruder N, Klasen F, Friou E, Levy B, Martinez O, Peytel E, Piton A, Richter E, Kamel T, Vogler M-C, Wallet F, Boufi M, Allaouchiche B, Constantin J-M, Martin C, Jaber S, Lefrant J-Y. Erratum to: Outcome of acute mesenteric ischemia in the intensive care unit: a retrospective, multicenter study of 780 cases. Intensive Care Med. 2015 May;41(5):966–8.

Amaro MI, Tewes F, Gobbo O, Tajber L, Corrigan OI, Ehrhardt C, Healy AM. Formulation, stability and pharmacokinetics of sugar-based salmon calcitonin-loaded nanoporous/nanoparticulate microparticles (NPMPs) for inhalation. Int J Pharm. 2015 Apr 10;483(1–2):6–18.

Perez M, Decaudin B, Foinard A, Barthelemy C, Debaene B, Lebuffe G, Odou P. Compatibility of medications during multi-infusion therapy: A controlled in vitro study on a multilumen infusion device. Anaesth Crit Care Pain Med. 2015 Apr;34(2):83–8.

Matzneller P, Gobin P, Lackner E, Zeitlinger M. Feasibility of microdialysis for determination of protein binding and target site pharmacokinetics of colistin in vivo. J Clin Pharmacol. 2015 Apr;55(4):431–7.

Leone M, Bechis C, Baumstarck K, Ouattara A, Collange O, Augustin P, Annane D, Arbelot C, Asehnoune K, Baldesi O, Bourcier S, Delapierre L, Demory D, Hengy B, Ichai C, Kipnis E, Brasdefer E, Lasocki S, Legrand M, Mimoz O, Rimmele T, Aliane J, Bertrand P-M, Bruder N, Klasen F, Friou E, Levy B, Martinez O, Peytel E, Piton A, Richter E, Toufik K, Vogler M-C, Wallet F, Boufi M, Allaouchiche B, Constantin J-M, Martin C, Jaber S, Lefrant J-Y. Outcome of acute mesenteric ischemia in the intensive care unit: a retrospective, multicenter study of 780 cases. Intensive Care Med. 2015 Apr;41(4):667–76.

Godet C, Goudet V, Laurent F, Le Moal G, Gounant V, Frat J-P, Cateau E, Roblot F, Cadranel J. Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review. Mycoses. 2015 Mar;58(3):173–80.

Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, Mouton JW, Paterson DL, Tam VH, Theuretzbacher U, Tsuji BT, Turnidge JD. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015 Feb;15(2):225–34.

Drouet M, Chai F, Barthelemy C, Lebuffe G, Debaene B, Decaudin B, Odou P. Influence of vancomycin infusion methods on endothelial cell toxicity. Antimicrob Agents Chemother. 2015 Feb;59(2):930–4.

Barham AS, Tewes F, Healy AM. Moisture diffusion and permeability characteristics of hydroxypropylmethylcellulose and hard gelatin capsules. Int J Pharm. 2015 Jan 30;478(2):796–803.

Mimoz O, Montravers P, Paiva J-A. Continuous administration of linezolid in pneumonia: what is the level of proof? Intensive Care Med. 2015 Jan;41(1):157–9.

Jayle CPM, Allain G, Ingrand P, Laksiri L, Bonnin E, Hajj-Chahine J, Mimoz O, Corbi P. Flail chest in polytraumatized patients: surgical fixation using Stracos reduces ventilator time and hospital stay. Biomed Res Int. 2015;2015:624723.

Godet C, Le Goff J, Beby-Defaux A, Robin M, Raffoux E, Arnulf B, Roblot F, Frat JP, Maillard N, Tazi A, Bergeron A. Human metapneumovirus pneumonia in patients with hematological malignancies. J Clin Virol. 2014 Dec;61(4):593–6.

Grégoire N, Mimoz O, Mégarbane B, Comets E, Chatelier D, Lasocki S, Gauzit R, Balayn D, Gobin P, Marchand S, Couet W. New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale. Antimicrob Agents Chemother. 2014 Dec;58(12):7324-30.

Boisson M, Jacobs M, Gregoire N, Gobin P, Marchand S, Couet W, Mimoz O. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother. 2014 Dec;58(12):7331–9.

Mercier T, Tissot F, Gardiol C, Corti N, Wehrli S, Guidi M, Csajka C, Buclin T, Couet W, Marchetti O, Decosterd LA. High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate. J Chromatogr A. 2014 Nov 21;1369:52–63.

Lasocki S, Chudeau N, Papet T, Tartiere D, Roquilly A, Carlier L, Mimoz O, Seguin P, Malledant Y, Asehnoune K, Hamel JF. Prevalence of iron deficiency on ICU discharge and its relation with fatigue: a multicenter prospective study. Crit Care. 2014 Sep 30;18(5):542.

Asehnoune K, Seguin P, Allary J, Feuillet F, Lasocki S, Cook F, Floch H, Chabanne R, Geeraerts T, Roger C, Perrigault PF, Hanouz JL, Lukaszewicz AC, Biais M, Boucheix P, Dahyot-Fizelier C, Capdevila X, Mahe PJ, Le Maguet P, Paugam-Burtz C, Gergaud S, Plaud B, Constantin JM, Malledant Y, Flet L, Sebille V, Roquilly A. Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial. Lancet Respir Med. 2014 Sep;2(9):706–16.

Garcia M, Le Moal G, Dupuis A, Rochette N, Roblot F, Venisse N. Plasma exchange significantly affects darunavir exposure. J Antimicrob Chemother. 2014 Aug;69(8):2296–7.

Million M, Roblot F, Carles D, D’Amato F, Protopopescu C, Carrieri MP, Raoult D. Reevaluation of the risk of fetal death and malformation after Q Fever. Clin Infect Dis. 2014 Jul 15;59(2):256–60.

Gontijo AVL, Gregoire N, Lamarche I, Gobin P, Couet W, Marchand S. Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 2. Colistin. Antimicrob Agents Chemother. 2014 Jul;58(7):3950–6.

Gontijo AVL, Brillault J, Gregoire N, Lamarche I, Gobin P, Couet W, Marchand S. Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, moxifloxacin, and grepafloxacin. Antimicrob Agents Chemother. 2014 Jul;58(7):3942–9.

Conte B, Zoric L, Bonada G, Debaene B, Ripart J. Reversal of a rocuronium-induced grade IV anaphylaxis via early injection of a large dose of sugammadex. Can J Anaesth. 2014 Jun;61(6):558–62.

Le Maguet P, Roquilly A, Lasocki S, Asehnoune K, Carise E, Saint Martin M, Mimoz O, Le Gac G, Somme D, Cattenoz C, Feuillet F, Malledant Y, Seguin P. Prevalence and impact of frailty on mortality in elderly ICU patients: a prospective, multicenter, observational study. Intensive Care Med. 2014 May;40(5):674–82.

Roquilly A, Seguin P, Mimoz O, Feuillet F, Rosenczweig E, Chevalier F, Loutrel O, Malledant Y, Sebille V, Asehnoune K. Risk factors for prolonged duration of mechanical ventilation in acute traumatic tetraplegic patients–a retrospective cohort study. J Crit Care. 2014 Apr;29(2):313.e7-13.

Laribi S, Kansao J, Borderie D, Collet C, Deschamps P, Ababsa R, Mouniam L, Got L, Leon A, Thoannes H, Santin A, Kouyoumdjian J-C, Dahyot-Fizelier C, Millet C, Golmard J-L, Beaudeux J-L. S100B blood level measurement to exclude cerebral lesions after minor head injury: the multicenter STIC-S100 French study. Clin Chem Lab Med. 2014 Apr;52(4):527–36.

Gras G, Buzele R, Parienti JJ, Debiais F, Dinh A, Dupon M, Roblot F, Mulleman D, Marcelli C, Michon J, Bernard L. Microbiological diagnosis of vertebral osteomyelitis: relevance of second percutaneous biopsy following initial negative biopsy and limited yield of post-biopsy blood cultures. Eur J Clin Microbiol Infect Dis. 2014 Mar;33(3):371-5.

Roblot F, Le Moal G, Kauffmann-Lacroix C, Bastides F, Boutoille D, Verdon R, Godet C, Tattevin P. Pneumocystis jirovecii pneumonia in HIV-negative patients: a prospective study with focus on immunosuppressive drugs and markers of immune impairment. Scand J Infect Dis. 2014 Mar;46(3):210–4.

Vitorino C, Almeida A, Sousa J, Lamarche I, Gobin P, Marchand S, Couet W, Olivier J-C, Pais A. Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: in vitro vs. in vivo studies. Eur J Pharm Biopharm. 2014 Feb;86(2):133–44.

Swaminathan J, Gobbo OL, Tewes F, Healy AM, Ehrhardt C. Encapsulation into PEG-liposomes does not improve the bioavailability of pulmonary delivered salmon calcitonin. J Aerosol Med Pulm Drug Deliv. 2014 Feb;27(1):1–11.

de Castro WV, Marchand S, Lamarche I, Couet W. Effect of experimentally induced hypovolemia on ertapenem tissue distribution using microdialysis in rats. Eur J Pharm Sci. 2014 Jan 23;51:45–50.

Tewes F, Ehrhardt C, Healy AM. Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung. Eur J Pharm Biopharm. 2014 Jan;86(1):98–104.

Seguin P, Laviolle B, Dahyot-Fizelier C, Dumont R, Veber B, Gergaud S, Asehnoune K, Mimoz O, Donnio P-Y, Bellissant E, Malledant Y. Effect of oropharyngeal povidone-iodine preventive oral care on ventilator-associated pneumonia in severely brain-injured or cerebral hemorrhage patients: a multicenter, randomized controlled trial. Crit Care Med. 2014 Jan;42(1):1–8.

Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, Mouton JW, Paterson DL, Tam VH, Theuretzbacher U, Tsuji BT, Turnidge JD. Consistent global approach on reporting of colistin doses to promote safe and effective use. Clin Infect Dis. 2014 Jan;58(1):139–41.

Salama A, Fichou N, Allard M, Dubreil L, De Beaurepaire L, Viel A, Jegou D, Bosch S, Bach J-M. MicroRNA-29b modulates innate and antigen-specific immune responses in mouse models of autoimmunity. PLoS One. 2014;9(9):e106153.

Frasca D, Dahyot-Fizelier C, Adier C, Mimoz O, Debaene B, Couet W, Marchand S. Metronidazole and hydroxymetronidazole central nervous system distribution: 2. cerebrospinal fluid concentration measurements in patients with external ventricular drain. Antimicrob Agents Chemother. 2014;58(2):1024–7.

Frasca D, Dahyot-Fizelier C, Adier C, Mimoz O, Debaene B, Couet W, Marchand S. Metronidazole and hydroxymetronidazole central nervous system distribution: 1. microdialysis assessment of brain extracellular fluid concentrations in patients with acute brain injury. Antimicrob Agents Chemother. 2014;58(2):1019–23.

Loupec T, Petitpas F, Kalfon P, Mimoz O. Subglottic secretion drainage in prevention of ventilator-associated pneumonia: mind the gap between studies and reality. Crit Care. 2013 Dec 9;17(6):R286.

Timsit J-F, Bouadma L, Mimoz O, Parienti J-J, Garrouste-Orgeas M, Alfandari S, Plantefeve G, Bronchard R, Troche G, Gauzit R, Antona M, Canet E, Bohe J, Herrault M-C, Schwebel C, Ruckly S, Souweine B, Lucet J-C. Jugular versus femoral short-term catheterization and risk of infection in intensive care unit patients. Causal analysis of two randomized trials. Am J Respir Crit Care Med. 2013 Nov 15;188(10):1232–9.

Bianco S, Tewes F, Tajber L, Caron V, Corrigan OI, Healy AM. Bulk, surface properties and water uptake mechanisms of salt/acid amorphous composite systems. Int J Pharm. 2013 Nov 1;456(1):143–52.

Tewes F, Paluch KJ, Tajber L, Gulati K, Kalantri D, Ehrhardt C, Healy AM. Steroid/mucokinetic hybrid nanoporous microparticles for pulmonary drug delivery. Eur J Pharm Biopharm. 2013 Nov;85(3 Pt A):604–13.

Gaspar MC, Couet W, Olivier JC, Pais AA, Sousa JJ. Pseudomonas aeruginosa infection in cystic fibrosis lung disease and new perspectives of treatment: a review. Eur J Clin Microbiol Infect Dis. 2013 Oct;32(10):1231-52.

Payen J-F, Genty C, Mimoz O, Mantz J, Bosson J-L, Chanques G. Prescribing nonopioids in mechanically ventilated critically ill patients. J Crit Care. 2013 Aug;28(4):534.e7-12.

Marchand S, Lauda M, Le Moal G, Gobin P, Couet W, Roblot F. Pharmacokinetics of daptomycin in a patient with severe renal failure not receiving dialysis. Antimicrob Agents Chemother. 2013 Jun;57(6):2898–9.

Jacolot A, Judel C, Louchahi K, Tod M, Marchand S, Petitjean O, Mimoz O. How to solve the problem of spontaneous bacterial clearance when testing new antibiotic treatment: results on experimental pneumonia due to a derepressed cephalosporinase-producing Enterobacter cloacae. Fundam Clin Pharmacol. 2013 Jun;27(3):239–43.

Dahyot-Fizelier C, Frasca D, Gregoire N, Adier C, Mimoz O, Debaene B, Couet W, Marchand S. Microdialysis study of cefotaxime cerebral distribution in patients with acute brain injury. Antimicrob Agents Chemother. 2013 Jun;57(6):2738–42.

Dahyot-Fizelier C, Debaene B, Mimoz O. [Management of infection risk in asplenic patients]. Ann Fr Anesth Reanim. 2013 Apr;32(4):251-6.

Roger PM, Garo B, Roblot F, Bernard E. Implication of antibiotic referents in complex bone and joint infections. Med Mal Infect. 2013 Apr;43(4):159-62.

Goudet V, Timsit J-F, Lucet J-C, Lepape A, Balayn D, Seguin S, Mimoz O. Comparison of four skin preparation strategies to prevent catheter-related infection in intensive care unit (CLEAN trial): a study protocol for a randomized controlled trial. Trials. 2013 Apr 27;14:114.

Boisson M, Gregoire N, Couet W, Mimoz O.Colistin in critically ill patients. Minerva Anestesiol. 2013 Feb;79(2):200-8.

Foinard A, Decaudin B, Barthelemy C, Debaene B, Odou P. The impact of multilumen infusion devices on the occurrence of known physical drug incompatibility: a controlled in vitro study. Anesth Analg. 2013 Jan;116(1):101–6.

Doan TV, Grégoire N, Lamarche I, Gobin P, Marchand S, Couet W, Olivier JC. A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin.  Eur J Pharm Sci. 2013 Jan 23;48(1-2):223-30.

Ayraud-Thévenot S, Huart C, Mimoz O, Taouqi M, Laland C, Bousseau A, Castel O. Control of multi-drug-resistant Acinetobacter baumannii outbreaks in an intensive care unit: feasibility and economic impact of rapid unit closure. J Hosp Infect. 2012 Dec;82(4):290-2.

Timsit J-F, Mimoz O, Mourvillier B, Souweine B, Garrouste-Orgeas M, Alfandari S, Plantefeve G, Bronchard R, Troche G, Gauzit R, Antona M, Canet E, Bohe J, Lepape A, Vesin A, Arrault X, Schwebel C, Adrie C, Zahar J-R, Ruckly S, Tournegros C, Lucet J-C. Randomized controlled trial of chlorhexidine dressing and highly adhesive dressing for preventing catheter-related infections in critically ill adults. Am J Respir Crit Care Med. 2012 Dec 15;186(12):1272–8.

Gobbo OL, Zurek M, Tewes F, Ehrhardt C, Cremillieux Y. Manganese: a new contrast agent for lung imaging? Contrast Media Mol Imaging. 2012 Dec;7(6):542–6.

Frasca D, Dahyot-Fizelier C, Couet W, Debaene B, Mimoz O, Marchand S. Brain microdialysis distribution study of cefotaxime in a patient with traumatic brain injury. Br J Anaesth. 2012 Nov;109(5):830-1. doi: 10.1093/bja/aes369.

Mimoz O. Chlorhexidine is better than aqueous povidone iodine as skin antiseptic for preventing surgical site infections. Infect Control Hosp Epidemiol. 2012 Sep;33(9):961–2.

Robert R, Mehaud J-E, Timricht N, Goudet V, Mimoz O, Debaene B. Benefits of an early cooling phase in continuous renal replacement therapy for ICU patients. Ann Intensive Care. 2012 Aug 23;2(1):40.

Seguin P, Roquilly A, Mimoz O, Le Maguet P, Asehnoune K, Biederman S, Carise E, Malledant Y. Risk factors and outcomes for prolonged versus brief fever: a prospective cohort study. Crit Care. 2012 Aug 13;16(4):R150.

Béraud G, Le Moal G, Elsendoorn A, Tattevin P, Godet C, Alfandari S, Couet W, Roblot P, Roblot F. A survey on the use of gentamicin in infective endocarditis. Eur J Clin Microbiol Infect Dis. 2012 Jul;31(7):1413-8.

Foinard A, Decaudin B, Barthelemy C, Debaene B, Odou P. Impact of physical incompatibility on drug mass flow rates: example of furosemide-midazolam incompatibility. Ann Intensive Care. 2012 Jul 13;2(1):28.

Semoun O, Marchand S, Gregoire N, Lamarche I, Adier C, Laroche L, Goldschmidt P, Couet W. Modeling approach to characterize intraocular doripenem pharmacokinetics after intravenous administration to rabbits, with tentative extrapolation to humans. Antimicrob Agents Chemother. 2012 Jul;56(7):3531–4.

Motamed C, Devys J-M, Debaene B, Billard V. Influence of real-time Bayesian forecasting of pharmacokinetic parameters on the precision of a rocuronium target-controlled infusion. Eur J Clin Pharmacol. 2012 Jul;68(7):1025–31.

Mimoz O, Petitpas F, Gregoire N, Gobin P, Marchand S, Couet W. Colistin distribution in the peritoneal fluid of a patient with severe peritonitis. Antimicrob Agents Chemother. 2012 Jul;56(7):4035–6.

Baginski L, Gobbo OL, Tewes F, Salomon JJ, Healy AM, Bakowsky U, Ehrhardt C. In vitro and in vivo characterisation of PEG-lipid-based micellar complexes of salmon calcitonin for pulmonary delivery. Pharm Res. 2012 Jun;29(6):1425–34.

Mimoz O, Benard T, Gaucher A, Frasca D, Debaene B. Accuracy of respiratory rate monitoring using a non-invasive acoustic method after general anaesthesia. Br J Anaesth. 2012 May;108(5):872-5.

Petitpas F, Kerforne T, Lacroix C, Mimoz O. Comment on ‘a novel approach to confirming nasogastric tube placement in the ED’. Am J Emerg Med. 2012 May;30(4):631–2.

Parienti J-J, du Cheyron D, Timsit J-F, Traore O, Kalfon P, Mimoz O, Mermel LA. Meta-analysis of subclavian insertion and nontunneled central venous catheter-associated infection risk reduction in critically ill adults. Crit Care Med. 2012 May;40(5):1627–34.

Mimoz O, Gregoire N, Poirel L, Marliat M, Couet W, Nordmann P. Broad-spectrum β-lactam antibiotics for treating experimental peritonitis in mice due to Klebsiella pneumoniae producing the carbapenemase OXA-48. Antimicrob Agents Chemother. 2012 May;56(5):2759–60.

Godet C, Meurice J-C, Roblot F, Kauffmann-Lacroix C, Verdaguer M, Frat J-P, Cadranel J. Efficacy of nebulised liposomal amphotericin B in the attack and maintenance treatment of ABPA. Eur Respir J. 2012 May;39(5):1261–3.

Veinstein A, Debouverie O, Gregoire N, Goudet V, Adier C, Robert R, Couet W. Lack of effect of extracorporeal membrane oxygenation on tigecycline pharmacokinetics. J Antimicrob Chemother. 2012 Apr;67(4):1047–8.

Quenot J-P, Milesi C, Cravoisy A, Capellier G, Mimoz O, Fourcade O, Gueugniaud P-Y. Intrahospital transport of critically ill patients (excluding newborns) recommendations of the Societe de Reanimation de Langue Francaise (SRLF), the Societe Francaise d’Anesthesie et de Reanimation (SFAR), and the Societe Francaise de Medecine d’Urgence (SFMU). Ann Intensive Care. 2012 Feb 3;2(1):1.

Lannoy D, Decaudin B, Simon N, Barthelemy C, Debaene B, Odou P. The impact on drug mass flow rate of interrupting and resuming carrier fluid flow: an in vitro study on a very low dead-space volume infusion set. Anesth Analg. 2012 Feb;114(2):328–32.

Couet W, Grégoire N, Marchand S, Mimoz O. Colistin pharmacokinetics: the fog is lifting. Clin Microbiol Infect. 2012 Jan;18(1):30-9.

Pichereau S, Pantrangi M, Couet W, Badiou C, Lina G, Shukla SK, Rose WE. Simulated antibiotic exposures in an in vitro hollow-fiber infection model influence toxin gene expression and production in community-associated methicillin-resistant Staphylococcus aureus strain MW2. Antimicrob Agents Chemother. 2012 Jan;56(1):140–7.

Kerforne T, Petitpas F, Frasca D, Goudet V, Robert R, Mimoz O. Ultrasound-guided peripheral venous access in severely ill patients with suspected difficult vascular puncture. Chest. 2012 Jan;141(1):279–80.

Baginski L, Tewes F, Buckley ST, Healy AM, Bakowsky U, Ehrhardt C. Investigations into the fate of inhaled salmon calcitonin at the respiratory epithelial barrier. Pharm Res. 2012 Jan;29(1):332–41.

Jacolot A, Judel C, Chaumais M-C, Louchahi K, Nicolas P, Marchand S, Petitjean O, Mimoz O. Animal model methodology: immunocompetent or leucopenic rats, which is the best? Results from a model of experimental pneumonia due to derepressed cephalosporinase-producing Enterobacter cloacae. Chemotherapy. 2012;58(2):129–33.

Spapen HD, Honore PM, Gregoire N, Gobin P, de Regt J, Martens GA, Pierard D, Couet W. Convulsions and apnoea in a patient infected with New Delhi metallo-β-lactamase-1 Escherichia coli treated with colistin. J Infect. 2011 Dec;63(6):468–70.

Elsendoorn A, Agius G, Le Moal G, Aajaji F, Favier A-L, Wierzbicka-Hainault E, Beraud G, Flusin O, Crance J-M, Roblot F. Severe ear chondritis due to cowpox virus transmitted by a pet rat. J Infect. 2011 Nov;63(5):391–3.

Tewes F, Gobbo OL, Amaro MI, Tajber L, Corrigan OI, Ehrhardt C, Healy AM. Evaluation of HPbetaCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery. Mol Pharm. 2011 Oct 3;8(5):1887–98.

Frasca D, Dahyot-Fizelier C, Catherine K, Levrat Q, Debaene B, Mimoz O. Accuracy of a continuous noninvasive hemoglobin monitor in intensive care unit patients. Crit Care Med. 2011 Oct;39(10):2277–82.

Tod M, Goutelle S, Clavel-Grabit F, Nicolas G, Charpiat B. Quantitative prediction of cytochrome P450 (CYP) 2D6-mediated drug interactions. Clin Pharmacokinet. 2011 Aug;50(8):519–30.

Tewes F, Krafft MP, Boury F. Dynamical and rheological properties of fluorinated surfactant films adsorbed at the pressurized CO2-H2O interface. Langmuir. 2011 Jul 5;27(13):8144–52.

Elsendoorn A, Robert R, Culos A, Roblot F, Burucoa C. Catabacter hongkongensis Bacteremia with fatal septic shock. Emerg Infect Dis. 2011 Jul;17(7):1330–1.

Doan TV, Couet W, Olivier JC. Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery. Int J Pharm. 2011 Jul 29;414(1-2):112-7.

Couet W, Grégoire N, Gobin P, Saulnier PJ, Frasca D, Marchand S, Mimoz O. Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers. Clin Pharmacol Ther. 2011 Jun;89(6):875-9. doi: 10.1038/clpt.2011.48. Epub 2011 May 4. PMID: 21544080

Renauld V, Goudet V, Mouton-Faivre C, Debaene B, Dewachter P. Case Report: perioperative immediate hypersensitivity involves not only allergy but also mastocytosis. Can J Anaesth. 2011 May;58(5):456–9.

Loupec T, Nanadoumgar H, Frasca D, Petitpas F, Laksiri L, Baudouin D, Debaene B, Dahyot-Fizelier C, Mimoz O. Pleth variability index predicts fluid responsiveness in critically ill patients. Crit Care Med. 2011 Feb;39(2):294–9.

Mimoz O, Chauvet S, Gregoire N, Marchand S, Le Guern M-E, Saleh A, Couet W, Debaene B, Levy RH. Nefopam pharmacokinetics in patients with end-stage renal disease. Anesth Analg. 2010 Nov;111(5):1146–53.

Marchand S, Gobin P, Brillault J, Baptista S, Adier C, Olivier J-C, Mimoz O, Couet W. Aerosol therapy with colistin methanesulfonate: a biopharmaceutical issue illustrated in rats. Antimicrob Agents Chemother. 2010 Sep;54(9):3702–7.

Marchand S, Lamarche I, Gobin P, Couet W. Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses. J Antimicrob Chemother. 2010 Aug;65(8):1753–8.

Marchand S, Frat J-P, Petitpas F, Lemaitre F, Gobin P, Robert R, Mimoz O, Couet W. Removal of colistin during intermittent haemodialysis in two critically ill patients. J Antimicrob Chemother. 2010 Aug;65(8):1836–7.

Dahyot-Fizelier C, Timofeev I, Marchand S, Hutchinson P, Debaene B, Menon D, Mimoz O, Gupta A, Couet W. Brain microdialysis study of meropenem in two patients with acute brain injury. Antimicrob Agents Chemother. 2010 Aug;54(8):3502–4.

Gregoire N, Raherison S, Grignon C, Comets E, Marliat M, Ploy M-C, Couet W. Semimechanistic pharmacokinetic-pharmacodynamic model with adaptation development for time-kill experiments of ciprofloxacin against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010 Jun;54(6):2379–84.

Gobin P, Lemaitre F, Marchand S, Couet W, Olivier J-C. Assay of colistin and colistin methanesulfonate in plasma and urine by liquid chromatography-tandem mass spectrometry. Antimicrob Agents Chemother. 2010 May;54(5):1941–8.

Dahyot-Fizelier C, Lefeuvre S, Laksiri L, Marchand S, Sawchuk RJ, Couet W, Mimoz O. Kinetics of imipenem distribution into the peritoneal fluid of patients with severe peritonitis studied by microdialysis. Clin Pharmacokinet. 2010 May;49(5):323–34.

Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology. 2010 Apr;112(4):1013–22.

Mimoz O. Preoperative skin cleansing with chlorhexidine-alcohol reduces surgical site infection after clean-contaminated surgery compared with povidone-iodine. Evid Based Nurs. 2010 Apr;13(2):36–7.

Frasca D, Marchand S, Petitpas F, Dahyot-Fizelier C, Couet W, Mimoz O. Pharmacokinetics of ertapenem following intravenous and subcutaneous infusions in patients. Antimicrob Agents Chemother. 2010 Feb;54(2):924–6.

Duvaldestin P, Kuizenga K, Saldien V, Claudius C, Servin F, Klein J, Debaene B, Heeringa M. A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia. Anesth Analg. 2010 Jan 1;110(1):74–82.

Brillault J, De Castro WV, Couet W. Relative contributions of active mediated transport and passive diffusion of fluoroquinolones with various lipophilicities in a Calu-3 lung epithelial cell model. Antimicrob Agents Chemother. 2010 Jan;54(1):543–5.

Frasca D, Dahyot-Fizelier C, Mimoz O. Prevention of central venous catheter-related infection in the intensive care unit. Crit Care. 2010;14(2):212.

Decaudin B, Dewulf S, Lannoy D, Simon N, Secq A, Barthelemy C, Debaene B, Odou P. Impact of multiaccess infusion devices on in vitro drug delivery during multi-infusion therapy. Anesth Analg. 2009 Oct;109(4):1147–55.

Brillault J, De Castro WV, Harnois T, Kitzis A, Olivier J-C, Couet W. P-glycoprotein-mediated transport of moxifloxacin in a Calu-3 lung epithelial cell model. Antimicrob Agents Chemother. 2009 Apr;53(4):1457–62.

Marchand S, Frasca D, Dahyot-Fizelier C, Breheret C, Mimoz O, Couet W. Lung microdialysis study of levofloxacin in rats following intravenous infusion at steady state. Antimicrob Agents Chemother. 2008 Sep;52(9):3074–7.

Tewes F, Brillault J, Couet W, Olivier J-C. Formulation of rifampicin-cyclodextrin complexes for lung nebulization. J Control Release. 2008 Jul 14;129(2):93–9.

Tod M, Lagneau F, Jullien V, Mimoz O. A physiological model to evaluate drug kinetics in patients with hemorrhagic shock followed by fluid resuscitation. Application to amoxicillin-clavulanate. Pharm Res. 2008 Jun;25(6):1431–9.

Lefeuvre S, Marchand S, Pariat C, Lamarche I, Couet W. Microdialysis study of imipenem distribution in the peritoneal fluid of rats with experimental acute pancreatitis. Antimicrob Agents Chemother. 2008 Apr;52(4):1516–8.

Venisse N, Gregoire N, Marliat M, Couet W. Mechanism-based pharmacokinetic-pharmacodynamic models of in vitro fungistatic and fungicidal effects against Candida albicans. Antimicrob Agents Chemother. 2008 Mar;52(3):937–43.

Karjagin J, Lefeuvre S, Oselin K, Kipper K, Marchand S, Tikkerberi A, Starkopf J, Couet W, Sawchuk RJ. Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock.  Clin Pharmacol Ther. 2008 Mar;83(3):452-9.

Lefeuvre S, Venisse N, Marchand S, Bachelet M, Couet W. A simple and sensitive liquid chromatography-tandem mass spectrometry assay for the quantification of ertapenem in microdialysate. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Feb 1;862(1–2):242–5.

Brillault J, Lam TI, Rutkowsky JM, Foroutan S, O’Donnell ME. Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells. Am J Physiol Cell Physiol. 2008 Jan;294(1):C88-96.

Dahyot C, Marchand S, Bodin M, Debeane B, Mimoz O, Couet W. Application of basic pharmacokinetic concepts to analysis of microdialysis data: illustration with imipenem muscle distribution. Clin Pharmacokinet. 2008;47(3):181–9.

Thesis

Directors: William Couet and Julien Buyck

Summary

Due to the lack of new antibiotics facing the increasing emergence of resistances, it is important to understand the mechanism and dynamics of these phenomenon. Lipopolysaccharide (LPS) is the polymyxin main target and the most contributing component to polymyxin resistance. Plasmid-mediated colistin resistance MCR-1 (Mobile Colistin Resistance) carrying by Escherichia coli and Klebsiella pneumoniae encodes a phosphoethanolamine transferase leads to the addition of phosphoethanolamine to lipid A of LPS. However, chromosomally-encoded LPS-modifying phosphoethanolamine transferase and loss of LPS are the two primary mechanisms that have been described in colistin-resistant Acinetobacter baumannii to date. Polymyxin-resistance occurred during polymyxin treatment, but the mechanism and dynamics how these strains acquired resistance is poorly understood. Sequential time-kill (TK) were developed as an alternative approach to discriminate heterogenous subpopulations (S/R) versus adaptive resistance (AR) during colistin and polymyxin B exposure.
In this thesis we:
1. Confirm that sequential TK could discriminate between a single homogenous population of bacteria without or with adaptation (AR) and two independent subpopulations with different antibiotic susceptibilities (S/R) demonstrated by pharmacokinetics/pharmacodynamics (PK/PD) modelling.
2. Determine the molecular impact of MCR-1 in the progressive adaptation of E. coli and K. pneumoniae over chromosomal genes involved to LPS modification by using the sequential TK approach.
3. Determine the mechanisms involved in polymyxin resistance in two clinical strains of A. baumannii, isolated from a patient before and after treated with colistin.
These studies not only provide a simple approach to discriminate between two PK/PD models, but also an indication that the MCR-1 presence favor another resistance mechanism leading to high-level resistance to polymyxin. By the similar approach, we determine how colistin-susceptible and resistant A. baumannii isolates respond under polymyxin pressure, including the genes involved. Furthermore, polymyxin B showed a lower capacity to induce high-level of resistance than colistin for all bacterial species.
Keywords: colistin, polymyxin B, E. coli, K. pneumoniae, A. baumannii, sequential time-kill

Directors: Sandrine Marchand and Frédéric Tewes

Summary
Pseudomonas aeruginosa (PA) and Acinetobacter baumannii (A. baumannii) are responsible for chronic lung infections often associated with the development of biofilms, i.e. bacterial aggregates trapped in a self-produced matrix of anionic polymers such as alginate or DNA. Within these biofilms, bacteria are protected from cationic antibiotics (ATB) such as tobramycin (TOB) and colistin (COL), in part through their interaction with matrix polymers, which reduce their diffusion. The main objectives of this thesis were first to develop a lung biofilm model that mimics those found in chronic lung infections of patients with cystic fibrosis (CF), one of the main lung diseases for which biofilms develop. Then use this model to evaluate a new ATB delivery system made of lipid nanoparticles developed to treat lung biofilms. In CF patients, PA forms biofilms consisting of aggregates (5-100 μm) enclosed in their pulmonary mucus. An in vitro lung biofilm model composed of polymers present in vivo (alginate, mucins, DNA) and consisting of PA trapped in alginate beads has been developed and evaluated using COL and TOB. This model was refined by evaluating the effect of the size of the beads and the growth medium in which they were dispersed. Changing the size of the beads from 60 to 1200 μm and using a dispersion medium simulating the composition of mucus further decreased the effectiveness of TOB in this model. For high TOB concentrations, smallcolony variants (SCV) of PA, also found in the CF patient, were observed in the model, suggesting a good mimicry of the conditions in vivo. In this model, COL efficacy was less impacted than that of TOB, and prevented the appearance of SCV. Pegylated lipid nanoparticles loaded with COL and containing a lipophilic adjuvant to COL such as Farnesol (FAR) have been developed to increase its effectiveness against biofilms. Encapsulation of COL improved its efficiency by two in the lung biofilm model PA developed, but also restored the sensitivity to COL of a resistant A. baumannii and improved its efficiency in an abiotic adherent biofilm model with A. baumannii.

Directors: Sandrine Marchand and Blandine Rammaert

Summary
Pulmonary mucormycosis are life-threatening invasive fungal infections affecting immunocompromised patients. First-line treatment is based on liposomal amphotericin B (AmB). Despite treatment, mortality remains high. The aim of this thesis was to optimize preventive and curative treatments of pulmonary mucormycosis. This thesis was divided in 2 axes, curative and preventive, themselves divided in two parts.The first aim of preventive axis was to study reactivation of mucormycosis. This concept was described in a first publication. Fungi can remain latent after an asymptomatic primary infection. After a latency period, they may be reactivated in the event of major immune deficiency leading to symptomatic infection. A mouse model was developed to reproduce this concept and assess AmB as decolonizing treatment. Decolonization using AmB was effective to prevent the disease.In the second part of this axis, the role of corticosteroids in infection pathophysiology was studied. An ex vivo model was developed to expose mouse alveolar macrophages to an infection-triggering dose of corticosteroids. In this model, corticosteroids were administered to naive mice, and then alveolar macrophages were collected by bronchoalveolar lavage. Alterations induced by corticosteroids on alveolar macrophages co-incubated with fungal spores were then studied in vitro. Corticosteroids decreased alveolar macrophage capacity to control fungal growth through phagocytosis and oxidative burst alterations.In the first part of curative axis, an acute pulmonary mucormycosis model was developed to study physiopathology of this infection. This model will be used to explore fungal-host-antifungal relationship.In the second part of this axis, in vitro combinations using AmB and several compounds were evaluated in order to improve AmB efficacy. These combinations were tested by checkerboard assays on several strains of Mucorales. After screening of 20 compounds (antibiotics, antifungal agents, terpene alcohols, surfactants), a candidate was identified, PEG15HS, which decreased AmB minimum inhibitory concentrations.

Directors: William Couet and Julien Buyck

Summary

Mycobacterium abscessus is rapidly growing non-tuberculous mycobacteria responsible for difficult-to-treat pulmonary infections in humans. Current recommended treatment is associated with high treatment failure and emergence of resistance to most of the antibiotics.  Also, with only a few new antibiotic drugs active against multidrug-resistant bacteria approved every year, it is important to optimize the use of already existing antibiotics using biopharmaceutical approach like Pharmacokinetic/pharmacodynamic (PK/PD). In pulmonary infections, direct administration of low permeability drugs such as cefoxitin (FOX) and amikacin (AMK) into lungs as therapeutic aerosols should increase their efficiency and minimize whole body exposure responsible for adverse effects, particularly in the case of prolonged treatments. Moreover, the use of antibiotics in combination may reduce the risk of resistance. Several points have been addressed in this thesis:

  1. Biopharmaceutical studies of AMK and FOX: It was shown that after nebulization of AMK and FOX, pulmonary concentrations were almost 1000-fold higher than after intravenous administration for both antibiotics, making them a good candidate for nebulization.
  2. Pharmacokinetic/pharmacodynamic (PK/PD) study of cefoxitin: a semi-mechanistic PK/PD model was developed from in vitro time kill-kinetics assay data, enabling identification of concentration-effect relationships for two bacterial sub-populations while taking into account the unstability degradation of cefoxitin.
  3. PK/PD study of bi-combination: Using a mechanism-based mathematical model and data obtained from time kill-kinetics study, it was shown that the combined effect of AMK and FOX was additive to synergistic at different concentration.
  4. Bi-or tri-combinations: several tri-combinations including AMK, FOX and a 3rd antibiotic (including clarithromycin, linezolid, clofazimine, ciprofloxacin, moxifloxacin, rifampicin and rifabutin) were tested against reference strain, clarithromycin resistance-clinical isolate (Ma1611) and multidrug-resistance-clinical isolate (T28). All tri-combinations were active against reference strain. Similar observation was made with Ma1611 except combination with clofazimine and clarithromycin. Any combination was active against T28. Bi-combinations with highest concentrations of FOX and rifamycins were effective against T28. The synergy between FOX and fluoroquinolones or rifamycins suggests a potent role of these combinations that may warrant further optimization of treatment regimen for the treatment of M. abscessus pulmonary infections.
  5. Tri-combination including AMK, FOX and moxifloxacin (MXF) up to 21 days against clarithromycin-resistance clinical isolate has shown no importance of using MXF as tri-combination was not more effective than the bi-combination of AMK and FOX.

pdf available here

Directors: Sandrine Marchand and Julien Brillault

Summary

In the face of the shortage of new anti-infectives and the ever-increasing emergence of multi-resistant infectious agents, it is essential to make better use of the therapeutic arsenal at our disposal. This may involve the use of new routes of administration in order to act more effectively locally. To treat lung infections, inhalation or nebulisation appear to be a good option. It has been shown previously that rather hydrophilic molecules were good candidates for this route of administration because the pulmonary epithelium was not very permeable to them and that the active drug was sequestered in the lung. On the other hand, for lipophilic compounds that diffuse rapidly through the epithelium, pulmonary administration is of little therapeutic interest. The situation becomes more complex in the case of prodrug nebulization and/or when efflux pumps are involved in the pulmonary distribution of anti-infectives. In order to better characterize the role of efflux pumps in the pulmonary distribution of anti-infectives in vitro and their impact in vivo, the pulmonary distribution of several anti-infectives was evaluated according to a standardized protocol in rats, allowing measurement and comparison of free plasma and pulmonary epithelial fluid (ELF) concentrations after systemic and intratracheal administration. The first study focuses on the pulmonary distribution of oseltamivir, an anti-viral active against influenza, which is administered as a prodrug (oseltamivir phosphate (OP)). It has been shown in vitro that OP (non-active) is a substrate for efflux pumps and that this active transport is characterized in vivo by higher local concentrations of OP in ELF than in plasma regardless of the route of administration (intravenous or nebulization). However, these high pulmonary prodrug concentrations have little effect on pulmonary concentrations of the active molecule (oseltamivir carboxylate (OC)), due to low local conversion to the active compound and pulmonary permeability of the OC. The second study presents the case of oxazolidinones (linezolide and tedizolide) used to treat Gram-positive infections for which in vivo studies in humans had previously shown local concentrations (ELF) higher than plasma concentrations after oral administration. These data were found in rats according to our standardized protocol and supplemented with post-nebulization data, suggesting a major role for transporters in the pulmonary diffusion of tedizolide. However, membrane permeability and in vitro inhibition studies conducted in a cellular model (NCI-H441) were unable to demonstrate the role of these efflux transporters on high pulmonary concentrations. Other explanations have been considered such as protein binding in ELF or intracellular penetration of active compound. In conclusion, these in vivo and in vitro studies on 4 active compounds have allowed us to improve our knowledge of the parameters that govern the pulmonary diffusion of anti-infectives such as permeability and affinity for efflux transporters and to show the complexity of extrapolation in vitro/in vivo.

pdf available here

Directors: Nicolas Grégoire and Julien Buyck

Summary

Fighting against multidrug-resistant bacteria is a major priority set by World Health Organisation, since it is forecasted that multi-drug-resistant bacteria will be responsible for more deaths than cancer by 2050. In the current context, with only a few new antibiotic drugs active against multidrug-resistant bacteria approved every year, it is of importance to optimize the use of already available antibiotics. It is with this goal in mind, that semi-mechanistic models used to analyse results from PK/PD studies of antibiotics, can be developed. These mathematical tools enable quantification of concentration-effect relationships of drugs, used alone or in combination, in order to optimize their efficacy, prevent bacterial resistance, thus lengthening the period of usability of antibiotics. In this work, after a presentation of the methods used to study PK/PD of antibiotics alone and in combination, results from two projects are presented:

  1. A study of cefoxitin PK/PD against a Mycobacterium abscessus strain. Firstly, it was shown that after nebulisation of cefoxitin, pulmonary concentrations were 1000-fold higher than after intravenous administration, making cefoxitin a good candidate for nebulisation. In a second part, a semi-mechanistic PK/PD model was developed from in vitro data, enabling identification of concentration-effect relationships for two bacterial sub-populations while taking into account degradation of cefoxitin.
  2. A study of the PK/PD of polymyxin B and minocycline association against a polymyxin B resistant Acinetobacter baumannii strain. This in vitro study incorporates data from time-kill experiments with quantification of a bacterial sub-population resistant to polymyxin B, enriched by complementary experiments providing information on the characteristics of this resistant sub-population. This data was analysed by semi-mechanistic PK/PD modelling, which made possible quantification of the strength of interaction between the two drugs and to form hypotheses about the mechanisms of the observed interaction.


Keywords: cefoxitin, polymyxin B, minocycline, Mycobacterium abscessus, Acinetobacter baumannii, PK/PD modelling, pharmacokinetics, pharmacodynamics, combination.

Directors: William Couet and Nicolas Grégoire

Summary

The rapid increase in antibiotic resistance during the last decades and the few numbers of recently approved new antibiotics lead to a significant interest to drug combinations. Among these combinations, the β-lactam-β-lactamase inhibitor combination, such as aztreonam-avibactam (ATM-AVI), is one strategy that aims to overcome the resistance due to β-lactamases production, one of the most relevant mechanisms of resistance in Gram-negative bacteria. However, drug interactions can be complex. To better understand the PK/PD of ATM-AVI, two issues have been addressed in this thesis: i. ATM-AVI PK at the infection site. A microdialysis study performed in rats with or without peritonitis showed that ATM and AVI distribution in intraperitoneal fluid was rapid and that concentrations at the target site could be predicted from blood concentrations.ii. PD interaction between ATM and AVI. Checkerboard experiments analyzed with an Emax model have been used to characterize AVI effect on ATM MIC in terms of efficacy and potency in the presence of various multi-drug resistant strains. A PK/PD model was developed based on in vitro data to describe the time-course of ATM-AVI combined effect and to investigate the individual contribution of each of the AVI effects to the combined activity. According to the modeling results, the combined bactericidal activity was mainly explained by AVI enhancing effect, even though AVI demonstrated high efficiency to prevent ATM hydrolysis.

Directors: Sandrine Marchand and Frederic Tewes

Summary

Ciprofloxacin (CIP) is an antibiotic that has been clinically trialed for the treatment of P. aeruginosa (PA) lung infections by aerosolization. However, CIP is rapidly systemically absorbed after lung delivery, increasing the risk for subtherapeutic concentrations and resistant bacteria selection. The aim of this study was to develop an inhalable dry powder (DP) of CIP which would allow the concentration of CIP in the lung epithelial lining fluid (ELF) to be controlled to provide a more efficient effect against extracellular PA. CIP can form complexes with cations (Ca2+,…) reducing its intestinal permeability. While these interactions prove a limitation in terms of oral delivery, it was envisaged as beneficial to slowdown CIP absorption through the lung. This work includes two main parts. First, a proof of concept study that has shown the ability to precisely control the CIP apparent permeability across a pulmonary epithelium model thanks to a Ca−CIP interaction, while keeping antibacterial activity. In this study, CaCO3-based particles were developed to deliver CIP as (CIP-Ca)2+ complex to the lung by a DP inhaler. A second study allowed validating the concept in vivo in healthy rats. In this study, two types of inhalable microparticles loaded with the low-affinity CIP-calcium complex (CIP-Ca)2+ or with the high-affinity CIP-copper complex(CIP-Cu)2+ were developed. Then, ELF and plasma pharmacokinetics of CIP were studied after intratracheal delivery of these particles and of a CIP solution. The dry powder loaded with (CIP-Cu)2+ allowed a 100-times higher pulmonary ELF CIP exposure to be obtained compared to the intratracheal administration of a CIP solution.

Directors:  Jean-Christophe Olivier  and Julien Brillault.

Summary

The rapid emergence of resistant bacteria and the lack of new efficient treatments lead to re-use old forgotten, but still effective, antimicrobials. In particular, chloramphenicol (CHL) and thiamphenicol (THA) have been proposed to treat multidrug-resistant pulmonary bacterial infections. Their direct administration into the lungs as therapeutic aerosols should increase their efficiency and minimize whole body exposure responsible for adverse effects, particularly in the case of prolonged treatments. The purpose of these PhD. works was to perform biopharmaceutical studies and to develop an effective aerosol formulation for lung delivery. The membrane permeability of CHL and THA was evaluated in vitro in the Calu-3 bronchial epithelial cell model and pharmacokinetic (PK) studies were carried out in rats after intratracheal and intravenous administration. In vitro membrane permeability of CHL was high, but intermediate for THA. Both compounds were shown to be substrates of membrane efflux transporters. In agreement with these findings, the PK studies showed that the administration route had no impact in the case of CHL and a moderate one in the case of THA. Therefore, in order to prolong lung exposure to CHL and THA, nanoparticle-based formulations with sustained release properties were formulated using the palmitate ester prodrugs of CHL and THA. To ease administration, nanoparticles were included in microsphere-based dry powder for inhalation. These powders showed an optimal content, satisfactory aerodynamic properties and sustained drug release, which make them promising formulations for lung delivery of CHL and THA as aerosols.

pdf (in french) available here

Directors:  Nicolas Grégoire and Jérôme Henri.

Summary

Colistin is an old antibiotic used in human and veterinary medicine. However, as less and less antibiotics are discovered, colistin is considered as a last-line antibiotic to fight against multi-drug resistant bacteria in human. In order to preserve the efficacy of colistin, two issues were investigated in this thesis:(i) Risks of selection of bacteria resistant to colistin, in conjunction with the discovery by the end of 2015 of a plasmid-mediated resistance gene (mcr-1). Thus, the impact of oral use of colistin in pigs was assessed in vivo and no selection was observed in our experimental conditions. Similarly, the use of colistin in human medicine for selective digestive decontamination was studied thanks to human flora‐associated rats. Preliminary results were also neither in favour of a selective effect of colistin.(ii) development of a physiologically-based pharmacokinetic model (PBPK) in pigs for the systemic use of colistin and its prodrug, the colistimethate sodium (CMS). This model provided a further insight into CMS and colistin tissue distribution, especially in kidneys where toxic effects are frequent. As a model application, the withdrawal period after use of CMS in pigs was estimated. Then, we used the ability of PBPK models to carry out intra and inter-species extrapolations in order to adapt this model in adults and children and eventually predict the plasmatic concentrations of colistin during a treatment with CMS.

pdf (in french) available here

Directors:  Olivier Mimoz and Nicolas Grégoire.

Summary

Ventilator-associated pneumonia (VAP) is associated with high mortality. Nebulization of antibiotics improves outcome of patient with VAP. However, pharmacokinetic data concerning colistin and gentamicin allowing for optimal dosing regimen recommendation are lacking.We compared systemic and pulmonary concentrations of colistin (administered as an inactive prodrug, colistin methanesulfonate or CMS) and gentamicin according to the route of administration (nebulization and intravenous infusion) in critically ill patients with VAP.Intra-pulmonary concentrations of colistin and gentamicin were 10 to 40-fold and 50 to 70-fold much higher after nebulization than after the same dose by intravenous route, respectively. Nebulization has also the theoretical potential advantage to improve patients’ safety in relation to the colistin biodisponibility lower than 10%.With high intra-pulmonary concentrations and very low systemic absorption, CMS and gentamicin nebulization may be good alternatives to intravenous infusion for VAP treatment.

Directors: William Couet and Nicolas Grégoire

Summary

Antibiotics are among the most commonly prescribed drugs, however optimal dosages are not yet well defined. The aim of this thesis was to develop pharmacokinetic (PK) and pharmacokinetic-pharmacodynamics (PK/PD) models that characterize the course of antimicrobial drug concentrations and effects over time, with an emphasis on the development of resistance. These models were applied to optimize dosing regimens of antimicrobial therapies.<br/>A population PK model for colistin and its prodrug, colistin methanesulfonate (CMS) was developed in critically ill patients receiving colistin by nebulization and/or undergoing an intermittent hemodialysis (HD). Results predicted clear benefits of using aerosol delivery of 2MIU CMS dose for the treatment of pulmonary infections. For patients with HD session dosing regimen of CMS should be 1.5 MIU twice daily with an additional dose of 1.5 MIU after each HD session.<br/>An assessment of the performances of different PK-PD models by using a simulation approach have shown the importance of longer study designs and of complementary microbiological data to predict accurately bacterial resistance development.<br/> A semi-mechanistic PK/PD model that incorporates mutation rate and adaptive resistance development of a bioluminescent strain of Pseudomonas aeruginosa against colistin was developed based on in-vitro data. A high, quick and partially reversible resistance was described. These results confirm that the first 24 h of treatment are critical in the management of infections, that colistin alone cannot eradicate completely the mutants of Pseudomonas aeruginosa that were selected during the experiments and that combination therapies seem necessary.

pdf (in french) available here

Directors: Sandrine Marchand and Claire Dahyot

Summary

To exert their effect while avoiding adverse events, drugs must reach sufficient concentrations in their site of action. Antibiotics are used for treating infection that bacterial target is in the cerebrospinal fluid (CSF) or brain extracellular fluid (ECF) which is also a target for adverse events. Drug distribution in the brain and CSF may be limited by the presence of the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB). In addition, efflux mechanisms may decrease tissue concentrations of drugs.To optimize the use of antibiotics and reduce adverse events, it is important to obtain tissue pharmacokinetics. Collecting ECF samples via brain microdialysis and CSF samples via external ventricular drain in critically ill patients allow comparison of free drug concentrations. This work is a study of the distribution in plasma, CSF and ECF of two antibiotics, cefotaxime and metronidazole.Patients (after a head injury or stroke) were treated with cefotaxime and metronidazole for pneumonia. Four pharmacokinetic studies were performed at equilibrium by brain microdialysis (n = 11) for collecting ECF or CSF samples (n = 9) by an external ventricular drain. The results showed that metronidazole distributes extensively in both ECF and CSF while the diffusion of cefotaxime was limited, probably due to efflux transporters.

pdf (in french) available here

Directors: Sandrine Marchand and Julien Brillault

Summary

The aim of this study was to investigate the efficiency of intrapulmonary administration and the biopharmaceutical parameters regulating the pulmonary diffusion following nebulization. We examined whether certain efflux pumps were present in an in vitro model of rat lung cells and whether these efflux pumps could be beneficial by increasing lung concentrations in vivo. Fluoroquinolones and colistin were the molecules used as reference. These different molecules allowed an overview of the intrapulmonary diffusion characteristics of antibiotics. The in vivo study with fluoroquinolones showed that their lung concentrations are higher than in plasma, probably due to glycoprotein-P. The presence of this efflux pump was confirmed in the model with rat lung cells. The in vivo study with colistin showed that a slow diffusion may confer an advantage for nebulization over intravenous administration. In conclusion, the nebulization molecules passing slowly (colistin) across the tissues may be advantageous, whereas for others, with a fast passage across the barrier (fluoroquinolones), the pulmonary route may not provide an advantage over the intravenous administration. Moreover, the results showed that a slow permeability across the lung (colistin) may confer an advantage for the antibiotic nebulization, while affinity by transporters (fluoroquinolones) is beneficial for both nebulization and intravenous administration.

pdf (in french) available here


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