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Therapeutic Drug Monitoring-Based Dose Optimisation of Piperacillin and Meropenem: a Randomised Controlled Trial
Study Question: Does a therapeutic drug monitoring (TDM) based approach to piperacillin/tazobactam (PTZ) and meropenem (MEM) result in higher attainment of pharmacokinetic/ pharmacodynamic (PK/PD) targets?
Study Description: This prospective, partially-blinded trial randomized patients with an estimated glomerular filtration rate (eGFR) >80 mL/min to PTZ or MEM by conventional dosing (CD) (4g PTZ extended interval (EI) over 3 hours given every 6 hours, 1g MEM EI over 3 hours every 8 hours) or TDM guided dosing for 7 days. In the TDM group, the antibiotic regimen was adjusted to achieve target trough concentrations >64 mg/L for PTZ and >8 mg/L for MEM for wild-type Pseudomonas spp. until the causative organism was known. The PK/PD target of this study was 100% fT>4MIC (percentage of time during dosing interval free drug concentrations exceed 4x MIC) and blood samples were collected daily: mid-dose for the first 3 days then trough levels for the last 4 days. The first regimen modification increased dosing frequency to every 4 hours (PTZ) or every 6 hours (MEM). If the target was not attained after this modification, the second regimen modification increased the dose by 50%. No further adjustments were made if the target was not attained.
Results: A total of 41 patients were included (PTZ: TDM n = 15, CD n = 13; MEM: TDM n = 6, CD n = 7) and 3 patients did not complete study protocol. A majority of patients were treated for pneumonia (78%). Patient characteristics were similar between groups [median (IQR) for weight 76 kg (67–88); APACHE II score 18 (13–24)]. Patients in the TDM had numerically lower baseline median concentrations than CD, and fewer TDM patients achieved 100% fT>4MIC (9% vs. 20%) on day 1. The TDM-based approach increased target attainment within the first 72 hours (fT>4MIC 57.9% vs. 15.8%, p = 0.007 and fT>MIC 94.7% vs. 68.4%, p = 0.045). The median fT>4MIC was significantly increased by TDM from 44.5% to 86% and 90% on days 2 and 3, respectively (p = 0.012). There were no adverse events or differences in the rates of clinical failure (p = 0.41).
Conclusion(s): TDM with dose adaptation yielded a higher target attainment for 100% fT>4MIC and 100% fT>MIC in patients with normal kidney function.
Perspective: CD does not reach target attainment in many patients. Whether TDM leads to improved outcomes remains to be determined.