1117. Tazobactam Pharmacokinetic/Pharmacodynamic Target Attainment in Healthy Volunteers and Critically-Ill Hospitalized Patients

Background Pharmacokinetic/pharmacodynamic (PK/PD) targets and attainment are well described for beta-lactams; however, are rarely considered for beta-lactamase inhibitors. Recent evidence suggests that tazobactam (TAZ) target exposures to restore piperacillin bacteriostatic and 1 log 10 bactericidal activity against Enterobacterales are fT> the piperacillin/tazobactam (TZP) MIC of 64% and 77%, respectively. The aim of this study was to evaluate TAZ probability of target attainment (PTA) of a 500 mg every 6-hour dose of tazobactam using population PK data in both healthy volunteers and hospitalized patients. Methods PK exposures in 1,000 patients with varying degrees of renal function were simulated using a previously described TAZ PK model developed with data from critically ill infected patients. An identical one-compartment structural model describing TAZ PK using mean population parameters observed in phase 1 PK studies was also used to simulate exposures in healthy volunteers. All simulated patients received 500 mg of TAZ as an intravenous infusion over 30 minutes or as a 3-hour extended-infusion. Results The table displays PTA results for patients with an estimated creatinine clearance of 60 mL/min. Based on healthy volunteer data, the highest TZP MIC where ~90% PTA was achieved for bacteriostasis was 1 mg/L and was 0.25 mg/L for bactericidal activity. These were only achieved with extended infusion administration of TAZ. In the cohort of hospitalized patients, >90% PTA of TAZ exposures associated with both bacteriostasis and 1 log kill were achieved up to a MIC of 2 for intermittent infusion and up to 4 mg/L for extended infusion, due to decreased TAZ clearance in hospitalized patients. These values are significantly lower than the CLSI TZP susceptibility breakpoint of 16 mg/L, and PTA rates were lower at increased creatinine clearances. Conclusion fT>TZP MIC target attainment is poor with maximal package insert tazobactam doses given with piperacillin, even when administered as an extended infusion. These findings have serious implications for the role of TZP in beta-lactamase producing Enterobacterales, including ESBLs, and suggest the current susceptibility breakpoints are 4-32 fold higher than those supported by PK/PD data. Disclosures Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Emily Heil, PharmD, MS, BCIDP, Nothing to disclose

Influence of Concentration and Temperature on Stability of Imipenem Focused on Solutions for Extended Infusion

Background Imipenem remains active against most Gram-positive and Gram-negative organisms. This study aimed to evaluate chemical stability of imipenem in 2 commonly used concentrations when stored in 3 various temperatures. Methods Imipenem injection powder was used to prepare 5 mL and 10 mg/mL of imipenem in .9% sodium chloride solution. Prepared solutions in PVC bags were stored at 25°C, 30°C, and 40°C. The solutions were investigated over 0, 1, 2, 3, 4, and 6 hours using HPLC analysis. The association between drug stability, temperature, and concentration was determined. Results The 5 mg/mL solutions of brand A and B imipenem mL were stable for 6 hours at 25°C, 30°C, and 40°C, respectively. For 10 mg/mL, the solution of brand A was stable for 3 hours and brand B was stable for 6 hours at 25°C. Also, brand A and B imipenem solutions at the concentration of 10 mg/mL were stable for less than 1 hour at 30°C and 40°C. Conclusion The stability of imipenem injection solution was affected by temperature and concentration. Increasing in temperature and drug concentration resulted in decreased stability of imipenem. Suitable temperature and drug concentration should be concerned when this drug is given by extended infusion.

Administration and Therapeutic Drug Monitoring of β-lactams and Vancomycin in Critical Care Units in Colombia: The ANTIBIOCOL Study

Therapeutic drug monitoring (TDM) and continuous infusion strategies are effective interventions in clinical practice, but these practices are still largely unknown in Colombia, especially in the critical care setting. This study aims to describe the practices involved in the administration and TDM of β-lactams and vancomycin reported by specialists in critical care in Colombia and to explore the factors that are related to the use of extended infusion. An online nationwide survey was applied to 153 specialists, who were selected randomly. A descriptive, bivariate analysis and a logistic regression model were undertaken. In total, 88.9% of the specialists reported TDM availability and 21.57% reported access to results within 6 h. TDM was available mainly for vancomycin. We found that 85.62% of the intensivists had some type of institutional protocol; however, only 39.22% had a complete and socialized protocol. The odds of preferring extended infusions among those who did not have institutional protocols were 80% lower than those with complete protocols, OR 0.2 (95% CI: 0.06−0.61). The most important perceived barriers to performing continuous infusions and TDM were the lack of training and technologies. This pioneering study in Colombia could impact the quality of care and outcomes of critically ill patients in relation to the threat of antimicrobial resistance.

Population Pharmacokinetics of Vancomycin and Meropenem in Pediatric Extracorporeal Membrane Oxygenation Support

Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target.Design: Prospective, multicentric, population PK analysis.Setting: Two hospitals with pediatric intensive care unit.Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support.Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of >400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% > 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30–550) ml/min/1.73 m2. The median dose was 13.6 (range 10–15) mg/kg every 6–12 h and 40 mg/kg every 8–12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin.Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.