Helena Colom-Codina1,2, Ariadna Padullés-Zamora3,4, Erika Esteve-Pitarch5,1, Víctor Daniel Gumucio-Sanguino6, Sara Cobo-Sacristán1,7, Evelyn Shaw8,9,10, Kristel Maisterra-Santos6, Joan Sabater-Riera6, Xosé L Pérez-Fernandez6, Raül Rigo-Bonnin11, Fe Tubau-Quintano12,13, Jordi Carratalà8,14. 1. Farmacoteràpia, Farmacogenètica i Tecnologia Farmacèutica, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 2. Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, Faculty of Barcelona, University of Barcelona, Barcelona, Spain. 3. Farmacoteràpia, Farmacogenètica i Tecnologia Farmacèutica, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. apadulles@bellvitgehospital.cat. 4. Department of Pharmacy, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, C/Feixa Llarga s/n., 08907, Barcelona, Spain. apadulles@bellvitgehospital.cat. 5. Department of Pharmacy, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain. 6. Department of Intensive Care Medicine, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 7. Department of Pharmacy, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, C/Feixa Llarga s/n., 08907, Barcelona, Spain. 8. Department of Infectious Diseases, Hospital Universitari de Bellvitge. Hospitalet de Llobregat, Barcelona, Spain. 9. Epidemiologia de les infeccions bacterianes, Patologia Infecciosa i Transplantament, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 10. Spanish Network for Research in Infectious Diseases, Instituto de Salud Carlos III, Madrid, Spain. 11. Department of Clinical Laboratory, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain. 12. Department of Microbiology, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. 13. Department of Microbiology, CIBERES-Instituto de Salud Carlos III, Madrid, Spain. 14. Infeccions respiratòries i en l'hoste immunocompromès, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Abstract
BACKGROUND AND OBJECTIVES: Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. RESULTS: We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [β = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. CONCLUSION: Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.
BACKGROUND AND OBJECTIVES: Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. RESULTS: We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [β = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. CONCLUSION: Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.
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