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10. Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria

Author

Kristoffersson, Anders N., Rognås, Viktor, Brill, Margreke JE, Dishon-Benattar, Y, Durante-Mangoni, E, Daitch, V, Skiada, A, Lellouche, J, Nutman, A, Kotsaki, A, Andini, R, Eliakim-Raz, N, Bitterman, R, Antoniadou, A, Karlsson, M O, Theuretzbacher, U, Leibovici, L, Daikos, G L, Mouton, J W, Carmeli, Y, Paul, M, Friberg, Lena E., Kristoffersson, Anders N., Rognås, Viktor, Brill, Margreke JE, Dishon-Benattar, Y, Durante-Mangoni, E, Daitch, V, Skiada, A, Lellouche, J, Nutman, A, Kotsaki, A, Andini, R, Eliakim-Raz, N, Bitterman, R, Antoniadou, A, Karlsson, M O, Theuretzbacher, U, Leibovici, L, Daikos, G L, Mouton, J W, Carmeli, Y, Paul, M, and Friberg, Lena E.

Abstract

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Published
2020
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27. Posters

Author

Frutos, F., Nuñez, C., Garrido, P., Lorenzo, J. M., Aranda, M., Revuelta, P., Chinea, C., Rico, M., Ibáñez-Nolla, J., León-Regidor, M. A., Díaz-Boladeras, R. M., García-Hernández, F., Nolla-Salas, M., Sirvent, J. M., Torres, A., El-Ebiary, M., Castro, P., de Batlle, J., de Velasco, J. G., Alvarez, A., Bonet, A., Thomas, M. L., McLure, H. A., Soni, N., Roberts, A. P., Azadian, B. F., Tibby, S. M., Cheema, I. U., Cox, S., Gransden, W. R., Murdoch, I. A., Tayoro, J., Legras, A., Dequin, P. F., Hazouard, E., Perrotin, D., Anglès, R., de Latorre, F. J., Ferrer, A., Palomar, M., Burgueńo, M. J., Bosque, M. D., Pont, T., Bermejo, B., Melgar, J. L., Chamorro, C., Romera, M. A., Borrallo, J. M., de Luna, R. Ruiz, De la Calle, N., Sousa-Dias, C., Paiva, J. A., Pereira, A. Costa, Ribeiro, T., Gomes, J., Carmo, E., Gaspar, I., Simões, I., Monteiro, E., Neves, J. L., Abecasis, P., Álvarez-Lerma, F., de la Cal, M. A., Insausti J., Olaechea, P., Anđelić, N., Ćosić, O., Risović, M., Todorović, K., Đukić, V., Karamarković, A., Ricart, A., Garrigosa, F., Prieto, A. Diaz, Casanovas, T., Rodriguez, P., Avila, F. J., Pujol, M., Ariza, X., Shunko, E., Polishchuk, O., Kostiuk, O., Poluliakh, O., Nys, M., Damas, P., Ledoux, D., De Mol, P., Melin, P., Lamy, M., Ivanović, D., Radonić, R., Gaŝparović, V., Merkler, M., Gjuraŝin, M., van ’t Veen, A., Gommers, D., Mouton, J. W., Kluytmans, J. A. J. W., Lachmann, B., Adnet, F., Bekka, R., Vicaut, E., Lapostolle, F., Giraudeaux, V., Bismuth, C., Baud, F., Young, S. P., Haj, M. A., Robbie, L. A., Adey, G., Croll, A. M., Booth, N. A., Bennett, B., Santos, J. A., Ormaechea, E., Barcons, M., Quintana, E., Rialp, G., Bak, E., Puzo, C., Coll, P., Net, A., Blazková, M., Ŝteparová, P., Nejdlová, H., Jelínková, L., Winkelhoferová, H., Rokyta, R., Matejovic, M., Ŝrámck, V., Novák, I., Blinzler, L., Franz-Kilian, K., Benda, N., Heuser, D., Lerma, F. Alvarez, Maladorno, D., Hager, H., Richelo, B., Teller, S., Berkowicz, C., O’Brien, D., Leighton, A., Dougnac, A., Hernandez, G., Angus, D., Ojeda, M., Castro, J., Labarca, E., Castillo, L., Andresen, M., Bugedo, G., Diaz, O., Arriagada, D., Dagnino, J., Spanish Study Group of Surveillance of ICU-Acquired Infection, Spanish Study Group of Surveillance of ICU-acquired Infection., and Ro 4S-2081 Study Group

Published
1996
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34. How to:EUCAST recommendations on the screening procedure E.Def 10.1 for the detection of azole resistance in Aspergillus fumigatus isolates using four-well azole-containing agar plates

Author

Guinea, J., Verweij, P. E., Meletiadis, J., Mouton, J. W., Barchiesi, F., Arendrup, M. C., Arikan-Akdagli, S., Castanheira, M., Chryssanthou, E., Friberg, N., Järv, H., Klimko, N., Kurzai, O., Lagrou, K., Lass-Flörl, C., Mares, M., Matos, T., Moore, C. B., Muehlethaler, K., Rogers, T. R., Andersen, C. T., Velegraki, A., Guinea, J., Verweij, P. E., Meletiadis, J., Mouton, J. W., Barchiesi, F., Arendrup, M. C., Arikan-Akdagli, S., Castanheira, M., Chryssanthou, E., Friberg, N., Järv, H., Klimko, N., Kurzai, O., Lagrou, K., Lass-Flörl, C., Mares, M., Matos, T., Moore, C. B., Muehlethaler, K., Rogers, T. R., Andersen, C. T., and Velegraki, A.

Abstract

Background: The emergence of azole-resistant Aspergillus fumigatus isolates is a matter of significant concern in Europe, with countries reporting resistance rates (which can be as high as 30%) in hospitalized patients. Consequently, the treatment guidelines in The Netherlands, the country with the highest documented prevalence of azole-resistant A. fumigatus, has just been revised to now recommend initial therapy with combination therapy until the susceptibility pattern is known. Therefore, susceptibility testing of clinically relevant isolates has been strongly recommended in the ESCMID-EFISG aspergillosis guidelines. Furthermore, mixed azole-susceptible and azole-resistant (isogenic as well as non-isogenic) infections have been reported to occur, which implies that colonies of clinical cultures may harbour various phenotypes of azole susceptibility. Objectives: The EUCAST-AFST (European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing) has released a new screening method document (E.Def 10.1) for the detection of azole-resistant A. fumigatus isolates and updated the QC tables for antifungal susceptibility testing with associated QC endpoints. This review described in detail how to perform the screening test. Sources: This “How to document” is based on the EUCAST azole agar screening method document E.Def 10.1 and the QC tables for antifungal susceptibility testing document, v 2.0 (available at http://www.eucast.org/ast_of_fungi/qcafsttables/) Contents: The method is based on the inoculation of azole-containing and azole-free agars and visual determination of fungal growth after one and two days of incubation. It can easily be implemented in routine laboratories of clinical microbiology and has been validated for simultaneous testing of up to five A. fumigatus colonies using itraconazole and voriconazole (mandatory), and posaconazole (optional). Implications: This easy-to-use screening procedure for the detecti

Published
2019

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