Antimicrobial Use Guidelines (AMUG) version 21 - UW Health

University of Wisconsin Hospital and ClinicsUWHC Guidelines For the Use of Prolonged Infusions of Beta-LactamsPlease address questions, comments, and suggestions regarding this guideline toSara Shull, Manager, Drug Policy Program at 608/262-1817.Guidelines developed by UWHC Center for Drug PolicyAuthor: Jeffrey Fish, PharmD, Brian Moilien, PharmD candidateUpdated by: Lucas Schulz, PharmDReviewed by: Barry Fox, MD, Sarah Bland, RPh, Jeffrey Fish, PharmD AntimicrobialSubcommittee, Pharmacokinetic CommitteeCoordination: Lee Vermeulen, M.S., Director, CDPApproved by P&T:Update:A. Principles and BackgroundB. ObjectivesC. GuidelineD. Dose of AntibioticE. ReferencesA. Principles and BackgroundAs a result of continuously developing antimicrobial resistance and a shortage of novelantimicrobial development, new dosing strategies have been proposed to optimize thepharmacodynamics of existing antimicrobials. Antimicrobial activity can be separated into twobroad categories: time-dependent or concentration-dependent killing. Time-dependentantimicrobials demonstrate maximum efficacy when the percent of time above the minimuminhibitory concentration (%T>MIC) is optimized. The efficacy of concentration-dependentantimicrobials is dependent on the ratio of the area under the concentration-time curve and theminimum inhibitory concentration (AUC/MIC). Piperacillin/tazobactam, cefepime and meropenemall exhibit time-dependent killing. Theoretically, prolonged and continuous infusions of betalactamsshould increase the time of antimicrobial exposure above the MIC and, as a result,improve their efficacy. Prolonged infusions have beneficial effects over continuous infusionsincluding not needing a dedicated line/catheter and usually using a lower total daily dose.Piperacillin/TazobactamKim et al. used a Monte Carlo simulation model of serum concentration-time profiles at steadystate for piperacillin/tazobactam dosed by prolonged infusion regimens, conventional intermittentdosing regimens and continuous infusions. 1 The probability of achieving 50% unbound timeabove the MIC (fT>MIC) for 470 P. aeruginosa isolates with intermittent dosing was 74.7%(3.375g every 6 hours), 79.9% (4.5g every 6 hours), and 85.6% (4.5g every 4 hours). Forprolonged infusions, probability of 50% fT> MIC was 83.3% (3.375g every 8 hours; 4-hourinfusion), 87.1% (4.5g every 8 hours; 4-hour infusion), and 89.6% (4.5g every 6 hours; 3-hourinfusion). For continuous infusions, probability of 50% fT>MIC was 82.3% for 10.125 g/day,86.5% for 13.5 g/day and 90% for 20 g/day. Prolonged and continuous infusions achievedcumulative fractions of response and probabilities of target attainment greater than thoseobserved with a 30 minute intermittent infusion. However, prolonged infusions of 3.375g every 8hours given over 4 hours achieved 50% fT>MIC in 92.8%, 40.1% and 2.7% of patients at MICs of16, 32, and 64 mcg/ml, respectively.Lodise et al. compared mortality rates and median length stay for patients receiving prolongedinfusion (over 4 hours) versus conventional infusion (over 30 minutes) of piperacillin/tazobactamin a retrospective cohort study of patients with documented P. aeruginosa infection. 2 Patientswere excluded if the P. aeruginosa was documented as being intermediate or resistant to