Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Abdul-Aziz, M. H.; Lipman, J.; Akova, M.; Bassetti, M.; De Waele, J. J.; Dimopoulos, G.; Dulhunty, J.; Kaukonen, K. -M.; Koulenti, D.; Martin, C.; Montravers, P.; Rello, J.; Rhodes, A.; Starr, T.; Wallis, S. C.; Roberts, J. A.; Paul, S.; Ribas, A. M.; De Crop, L. D.; Spapen, H.; Wauters, J.; Dugernier, T.; Jorens, P.; Dapper, I.; De Backer, D. D.; Taccone, F. S.; Ruano, L.; Afonso, E.; Alvarez-Lerma, F.; Gracia-Arnillas, M. P.; Fernandez, 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, M. M. M.; Crespo, R. Z.; Esperatti, M.; Torres, A.; Baldesi, O.; Dupont, H.; Mahjoub, Y.; Lasocki, S.; Constantin, J. M.; Payen, J. C.; 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.; Pettila, 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.; Marco Ranieri, V.; Sandroni, C.; De Pascale, G. D.; Molin, A.; Pelosi, P.; Montagnani, L.; Urbino, R.; Mastromauro, I.; De Rosa, F. G.; Cardoso, T.; Afonso, S.; Goncalves-Pereira, J.; Baptista, J. P.; Ozveren, A.

doi:10.1093/jac/dkv288

Objectives: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged- infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT≥MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of ≥ 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025]. Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.