Adequacy of beta-lactam antibiotic dosing in critically ill children on continuous renal replacement therapy: A pilot study. Diaz F 1,2, Benner KW 3, Sewell K 1, Daniel L 4, Kalra Y 1, Sims PJ 3, Gorman GS 3. 1 Department of Pediatrics, University of Alabama at Birmingham, Birmingham Alabama. 2 Pediatric Intensive Care Unit, Clínica Alemana de Santiago, Chile. 3 Samford University, McWhorter School of Pharmacy, Birmingham Alabama. 4 Children’s of Alabama, Birmingham, Alabama. Objective Determine the adequacy of standard dosing regimen of beta-lactam antibiotics in critically ill children on continuous renal replacement therapy (CRRT) using calculated pharmacokinetic parameters. Methods Design: prospective observational study. Setting: 22 bed pediatric intensive care unit of an academic center Inclusion criteria: patients admitted to PICU, 28 days old to 18 years old on CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Data collection: Demographic and clinical data were registered. No interventions were done. Pharmacokinetic Study: Four blood samples were taken after drug administration according to their posology (table1): Beta-lactam antibiotics concentrations were determined at each time point using high- performance liquid chromatography connected to UV spectrophotometry (HPLC-UV). Semi-natural log plots of concentration versus time were used to estimate various pharmacokinetic (PK) parameters including: clearance, volume of distribution, half-life, initial concentration, elimination rate constant and time above minimal inhibitory concentration (MIC). Adequacy of therapy was determined according to current recommendations for time above MIC for susceptible, intermediate and resistant Pseudomonas spp. Data are shown as median and interquartile range. Results Eight patients were included (Table 2). Median age: 6 ( ) years old, median weight: 22.6( ) kg, male 13%. All patients were on mechanical ventilation, had sepsis and 62.5 % had multi-organ failure. 14 series of serum samples were obtained: MEM, n = 2; TZP, n = 3; FEP, n = 8; CAZ, n = 1. Overall serum concentrations remained above four times the MIC for Pseudomonas spp. for the recommended time in 14.3% of studies. Table 3 shows data for each antibiotic and different cut-off recommendations. Table 4 shows PK data for each study. Conclusions This pilot study shows the importance of antibiotic PK studies in critically ill children on CRRT. Standard dosing of antibiotics can be insufficient to treat resistant microorganisms due to pathophysiologic changes of acute illness and extracorporeal therapies. All patients treated with FEP maintained sufficient plasma levels for susceptible strains while 75% and 0% had sufficient exposure for intermediate and resistant exposure, respectively. TZP was impacted by CRRT to the greatest degree where no patients had sufficient coverage. Additional data would be needed for the other antibiotics tested. Future studies should focus on beta-lactam therapeutic drug monitoring protocols and PK studies to titrate therapy in this population. AntibioticPK studies Susceptible MIC=8 µg/mL Intermediate MIC = 16 µg/mL Resistant MIC= 32 µg/mL CEFEPIME (FEP)8860 MEROPENEM(MEM)2211 PIP-TAZO (TZP)3000 CEFTAZIDIME (CAZ)1100 Table 2. Demographic and clinical data of included patients. Table 3. PK studies of beta-lactam and carbapenem achieving recommended time above the MIC for susceptible, intermediate and resistant Pseudomonas spp. in critically ill children on CRRT. Table 1. Blood sample time points for pharmacokinetic study according to drug posology Table 4. PK values of various beta-lactams after initial (early) and second (late) dosing cycles in pediatric patients on CRRT. Drug Patient/P hase K e (hr - 1 ) ½ Life (hr) C 0 (µg/mL) V d (L/Kg) * Cl (L/hr)/Kg * FEP 1/Late /Early /Late /Early /Late /Late /Early /Late MEM 5/Early /Late CAZ 8/Early TZP Tazobactam 7/Early /Late /Early TZP Piperacillin 7/Early /Late /Early * Body Weight adjusted