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1. Impact of imipenem concentration in lung perfusate and tissue biopsy during clinical ex-vivo lung perfusion of high-risk lung donors

Author

Anna Teresa Mazzeo, Luca Brazzi, Vito Fanelli, Tiziana Musso, Luciana Mascia, Lorena Baietto, Paolo Solidoro, Antonio D'Avolio, Stefano Balzano, Paola Cappello, Francesco Giuseppe Derosa, V. Marco Ranieri, Lorenzo Del Sorbo, Massimo Boffini, Andrea Costamagna, Sara Scutera, Mauro Rinaldi, Fanelli V., Del Sorbo L., Boffini M., Costamagna A., Balzano S., Musso T., Scutera S., Cappello P., Mazzeo A., Solidoro P., Baietto L., D'Avolio A., Derosa F.G., Brazzi L., Mascia L., Rinaldi M., and Marco Ranieri V.

Subjects
medicine.medical_specialty, Imipenem, Biopsy, medicine.medical_treatment, Primary Graft Dysfunction, Pharmacokinetic, Gastroenterology, Ventilation-perfusion scan, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Internal medicine, Escherichia coli, medicine, Ventilation-perfusion scan, Lung transplantation, Imipenem, Pharmacokinetics, Pneumonia, Cytokines, Humans, Lung transplantation, Pharmacokinetics, Antibiotic prophylaxis, Lung, Cytokine, medicine.diagnostic_test, business.industry, Ventilation/perfusion scan, Respiratory infection, 030208 emergency & critical care medicine, Organ Preservation, Pneumonia, medicine.disease, Tissue Donors, Perfusion, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Cytokines, business, medicine.drug
Abstract

Background Normothermic ex-vivo lung perfusion (EVLP) limits organ donor shortage by potentially using high-risk donor lungs. Microbial burden reduction has been demonstrated after EVLP using antibiotic prophylaxis with imipenem. However, no data have been published on the clinical consequences of the potential residual bacterial burden. Methods Imipenem concentration was measured every hour (T0 to T6) in the lung perfusate and at the end of EVLP (Tf) in biopsies. The antimicrobial activity of perfusate at T1 and Tf against E. coli and K. pneumoniae was evaluated. Lungs were distinguished: no bacterial species in recipients and donors (donor-/recipient-); bacterial species isolated from donors and not from recipients (donor+/recipient-); same bacterial species in both recipients and donors (donor+/recipient+). Interleukin 6 (IL-6) and IL-8 concentrations in lung perfusate, clinical pulmonary infection score (CPIS) and primary graft dysfunction (PGD) were evaluated. Results Imipenem concentration in perfusate decreased over time. T1 and Tf perfusates exhibited bactericidal activity against E. coli and K. pneumoniae. Overall, T1 perfusates yielded higher bactericidal titers (BTs) than Tf. The donor+/recipient+ group (26% of cases) had higher IL-6 and IL-8 in perfusate and higher CPIS. Conclusions Recipients with the same bacterial species isolated in their donors had higher risk of pulmonary inflammation and early post-transplant pneumonia. Improvements in antimicrobial strategies during EVLP are warranted to minimize the consequences of donor associated respiratory infection.

Published
2020

2. Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: Lessons from the DALI Study

Author

Roberts, J. A., Stove, V., De Waele, J. J., Sipinkoski, B., McWhinney, B., Ungerer, J. P. J., Akova, M., Bassetti, M., Dimopoulos, G., Kaukonen, K. -M., Koulenti, D., Martin, C., Montravers, P., Rello, J., Rhodes, A., Starr, T., Wallis, S. C., Lipman, J., Paul, S., Ribas, A. M., DeCrop, L., Spapen, H., Wauters, J., Dugernier, T., Jorens, P., Dapper, I., De Backer, D., Taccone, F. S., Ruano, L., Afonso, E., Alvarez-Lerma, F., Gracia-Arnillas, M. P., Fernández, F., Feijoo, N., Bardolet, N., Rovira, A., Garro, P., Colon, D., Castillo, C., Fernado, J., Lopez, M. J., Fernandez, J. L., Arribas, A. M., Teja, J. L., Ots, E., Montejo, J. C., Catalan, M., Prieto, I., Gonzalo, G., Galvan, B., Blasco, M. A., Meyer, E., Nogal, F. D., Vidaur, L., Sebastian, R., Garde, P. M., Velasco Mdel, M., Crespo, R. Z., Esperatti, M., Torres, A., Baldesi, O., Dupont, H., Mahjoub, Y., Lasocki, S., Constantin, J. M., Payen, J. F., Albanese, J., Malledant, Y., Pottecher, J., Lefrant, J. Y., Jaber, S., Joannes-Boyau, O., Orban, C., Ostermann, M., McKenzie, C., Berry, W., Smith, J., Lei, K., Rubulotta, F., Gordon, A., Brett, S., Stotz, M., Templeton, M., Ebm, C., Moran, C., Pettilä, V., Xristodoulou, A., Theodorou, V., Kouliatsis, G., Sertaridou, E., Anthopoulos, G., Choutas, G., Rantis, T., Karatzas, S., Balla, M., Papanikolaou, M., Myrianthefs, P., Gavala, A., Fildisis, G., Koutsoukou, A., Kyriakopoulou, M., Petrochilou, K., Kompoti, M., Michalia, M., Clouva-Molyvdas, F. M., Gkiokas, G., Nikolakopoulos, F., Psychogiou, V., Malliotakis, P., Akoumianaki, E., Lilitsis, E., Koulouras, V., Nakos, G., Kalogirou, M., Komnos, A., Zafeiridis, T., Chaintoutis, C., Arvaniti, K., Matamis, D., Kydona, C., Gritsi-Gerogianni, N., Giasnetsova, T., Giannakou, M., Soultati, I., Chytas, I., Antoniadou, E., Antipa, E., Lathyris, D., Koukoubani, T., Paraforou, T., Spiropoulou, K., Bekos, V., Spring, A., Kalatzi, T., Nikolaou, H., Laskou, M., Strouvalis, I., Aloizos, S., Kapogiannis, S., Soldatou, O., Adembri, C., Villa, G., Giarratano, A., Raineri, S. M., Cortegiani, A., Montalto, F., Strano, M. T., Ranieri, V. M., Sandroni, C., De Pascale, G., Molin, A., Pelosi, P., Montagnani, L., Urbino, R., Mastromauro, I., DeRosa, F. G., Cardoso, T., Afonso, S., Gonçalves-Pereira, J., Baptista, J. P., Özveren, A., Roberts JA, Lipman J, Starr T, Wallis SC, Paul S, Ribas AM, De Waele JJ, DeCrop L, Spapen H, Wauters J, Dugernier T, Jorens P, Dapper I, De Backer D, Taccone FS, Rello J, Ruano L, Afonso E, Alvarez-Lerma F, Gracia-Arnillas MP, Fernández F, Feijoo N, Bardolet N, Rovira A, Garro P, Colon D, Castillo C, Fernado J, Lopez MJ, Fernandez JL, Arribas AM, Teja JL, Ots E, Montejo JC, Catalan M, Prieto I, Gonzalo G, Galvan B, Blasco MA, Meyer E, Nogal FD, Vidaur L, Sebastian R, Garde PM, Velasco Mdel M, Crespo RZ, Esperatti M, Torres A, Montravers P, Baldesi O, Dupont H, Mahjoub Y, Lasocki S, Constantin JM, Payen JF, Martin C, Albanese J, Malledant Y, Pottecher J, Lefrant JY, Jaber S, Joannes-Boyau O, Orban C, Ostermann M, McKenzie C, Berry W, Smith J, Lei K, Rubulotta F, Gordon A, Brett S, Stotz M, Templeton M, Rhodes A, Ebm C, Moran C, Kaukonen KM, Pettilä V, Dimopoulos G, Koulenti D, Xristodoulou A, Theodorou V, Kouliatsis G, Sertaridou E, Anthopoulos G, Choutas G, Rantis T, Karatzas S, Balla M, Papanikolaou M, Myrianthefs P, Gavala A, Fildisis G, Koutsoukou A, Kyriakopoulou M, Petrochilou K, Kompoti M, Michalia M, Clouva-Molyvdas FM, Gkiokas G, Nikolakopoulos F, Psychogiou V, Malliotakis P, Akoumianaki E, Lilitsis E, Koulouras V, Nakos G, Kalogirou M, Komnos A, Zafeiridis T, Chaintoutis C, Arvaniti K, Matamis D, Kydona C, Gritsi-Gerogianni N, Giasnetsova T, Giannakou M, Soultati I, Chytas I, Antoniadou E, Antipa E, Lathyris D, Koukoubani T, Paraforou T, Spiropoulou K, Bekos V, Spring A, Kalatzi T, Nikolaou H, Laskou M, Strouvalis I, Aloizos S, Kapogiannis S, Soldatou O, Bassetti M, Adembri C, Villa G, Giarratano A, Raineri SM, Cortegiani A, Montalto F, Strano MT, Ranieri VM, Sandroni C, De Pascale G, Molin A, Pelosi P, Montagnani L, Urbino R, Mastromauro I, DeRosa FG, Cardoso T, Afonso S, Gonçalves-Pereira J, Baptista JP, Akova M, Özveren A, Hôpital Nord [CHU - APHM], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Roberts, J.A., Stove, V., De Waele, J.J., Sipinkoski, B., McWhinney, B., Ungerer, J.P.J., Akova, M., Bassetti, M., Dimopoulos, G., Kaukonen, K.-M., Koulenti, D., Martin, C., Montravers, P., Rello, J., Rhodes, A., Starr, T., Wallis, S.C., Lipman, J., Paul, S., Ribas, A.M., DeCrop, L., Spapen, H., Wauters, J., Dugernier, T., Jorens, P., Dapper, I., De Backer, D., Taccone, F.S., Ruano, L., Afonso, E., Alvarez-Lerma, F., Gracia-Arnillas, M.P., Fernández, F., Feijoo, N., Bardolet, N., Rovira, A., Garro, P., Colon, D., Castillo, C., Fernado, J., Lopez, M.J., Fernandez, J.L., Arribas, A.M., Teja, J.L., Ots, E., Montejo, J.C., Catalan, M., Prieto, I., Gonzalo, G., Galvan, B., Blasco, M.A., Meyer, E., Nogal, F.D., Vidaur, L., Sebastian, R., Garde, P.M., Velasco Mdel, M., Crespo, R.Z., Esperatti, M., Torres, A., Baldesi, O., Dupont, H., Mahjoub, Y., Lasocki, S., Constantin, J.M., Payen, J.F., Albanese, J., Malledant, Y., Pottecher, J., Lefrant, J.Y., Jaber, S., Joannes-Boyau, O., Orban, C., Ostermann, M., McKenzie, C., Berry, W., Smith, J., Lei, K., Rubulotta, F., Gordon, A., Brett, S., Stotz, M., Templeton, M., Ebm, C., Moran, C., Pettilä, V., Xristodoulou, A., Theodorou, V., Kouliatsis, G., Sertaridou, E., Anthopoulos, G., Choutas, G., Rantis, T., Karatzas, S., Balla, M., Papanikolaou, M., Myrianthefs, P., Gavala, A., Fildisis, G., Koutsoukou, A., Kyriakopoulou, M., Petrochilou, K., Kompoti, M., Michalia, M., Clouva-Molyvdas, F.M., Gkiokas, G., Nikolakopoulos, F., Psychogiou, V., Malliotakis, P., Akoumianaki, E., Lilitsis, E., Koulouras, V., Nakos, G., Kalogirou, M., Komnos, A., Zafeiridis, T., Chaintoutis, C., Arvaniti, K., Matamis, D., Kydona, C., Gritsi-Gerogianni, N., Giasnetsova, T., Giannakou, M., Soultati, I., Chytas, I., Antoniadou, E., Antipa, E., Lathyris, D., Koukoubani, T., Paraforou, T., Spiropoulou, K., Bekos, V., Spring, A., Kalatzi, T., Nikolaou, H., Laskou, M., Strouvalis, I., Aloizos, S., Kapogiannis, S., Soldatou, O., Adembri, C., Villa, G., Giarratano, A., Raineri, S.M., Cortegiani, A., Montalto, F., Strano, M.T., Ranieri, V.M., Sandroni, C., De Pascale, G., Molin, A., Pelosi, P., Montagnani, L., Urbino, R., Mastromauro, I., DeRosa, F.G., Cardoso, T., Afonso, S., Gonçalves-Pereira, J., Baptista, J.P., Özveren, A., and İç Hastalıkları

Subjects
Male, validity, validation proce, International Cooperation, Settore MED/41 - Anestesiologia, drug protein binding, Gastroenterology, law.invention, Plasma, Staphylococcus infection, Critically ill patients, Interquartile range, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antibiotics, antibiotic therapy, Pharmacology (medical), Pharmacology & Pharmacy, Glycopeptides, Hypoalbuminaemia, ICU, Pharmacokinetics, Adult, Aged, Anti-Bacterial Agents, Chromatography, Critical Illness, Female, Humans, Middle Aged, Protein Binding, Teicoplanin, Young Adult, Drug Monitoring, Microbiology (medical), Infectious Diseases, clinical article, medicine.diagnostic_test, drug dose regimen, critical illne, Medicine (all), article, clinical trial, General Medicine, trough time concentration, drug protein binding variability, Intensive care unit, Glycopeptides, Antibiotics, Critically ill patients, Pharmacokinetics, Hypoalbuminaemia, ICU, 3. Good health, antiinfective agent, drug distribution, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, priority journal, multicenter study (topic), Vancomycin, blood sampling, Critically ill patient, Human, medicine.drug, medicine.medical_specialty, high performance liquid chromatography, area under the curve, ultraviolet spectroscopy, mid dose concentration, chemistry, Glycopeptide, Microbiology, teicoplanin, adult, enterococcal infection, young adult, Adult, drug clearance, Therapeutic index, Internal medicine, Anti-Bacterial Agent, medicine, steady state, Dosing, business.industry, drug half life, Antibiotic, recommended drug dose, calibration, Surgery, multicenter study, Therapeutic drug monitoring, drug blood level, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, free plasma drug concentration, business, metabolism
Abstract

The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6(11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (rho=0.79, P = 0.0021) and trough (rho = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Published
2014
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