Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) combinations: should we monitor the BLI concentration?
Amaury O’Jeanson, Elisabet I. Nielsen, Lena E. Friberg
Department of Pharmacy, Uppsala University, Uppsala, Sweden
Introduction: In order to restore the activity of β-lactam (BL) drugs against β-lactamase-producing bacteria, several combinations of a BL and a β-lactamase inhibitor (BLI) have been marketed in recent years [1,2]. A broad consensus exists to support the use of therapeutic drug monitoring (TDM) of BL antibiotics [3] and this is nowadays recommended in clinical practice, especially for patients with high risk of an ‘atypical’ pharmacokinetic profile. However, there is limited insights on the impact of the accompanying BLI drug in the current practice of TDM with BL antibiotics.
Objectives: The aim of this study was to use a population pharmacokinetic-pharmacodynamic simulation framework developed for five BL/BLI combinations to evaluate whether the BLI is present in effective concentration at the site of infection and assess if TDM of BLI drugs could be of interest in clinical practice.
Methods: Five marketed BL/BLI combinations were selected: ceftazidime-avibactam (CAZ-AVI) [4], ceftolozane-tazobactam (CET-TAZ) [5], imipenem-relebactam (IMI-REL) [6], meropenem-vaborbactam (MER-VAB) [7] and piperacillin-tazobactam (PIP-TAZ) [8]. Population PK models and tissue penetration ratios were extracted from the literature and implemented in R for each compound (both BLs & BLIs) using the mrgsolve package [9]. Individual drug concentration-time profiles were predicted for a one-week treatment period in various organs (blood, lung, abdomen, kidney and prostate) for two simulated populations: a typical renal clearance (TRC) patient population with a creatinine clearance (CrCL) of 80 mL/min and an augmented renal clearance (ARC) population (CrCL 200 mL/min). Simulated patients received standard of care dose regimens as laid out in the EMA summary of product characteristics (SmPC). Dosing regimens were the same for TRC and ARC patients as no specific dosing regimens exist for the ARC population in the SmPCs. Probabilities of target attainment (PTA) at the site of infection were derived, using PD targets from EUCAST [10–14], for the BL alone, the BLI alone and the combination with the condition that both targets should be met at the same time. PD targets were: 50% fT>MIC for CAZ and 50% fT>CT for AVI (with CT 1 mg/L); 30% fT>MIC for CET and 20% fT>CT for TAZ; 6.5% fT>MIC for IMI and fAUC0-24h/MIC≥5.2 h for REL; 45% fT>MIC for MER and fAUC0-24h/MIC≥35 h for VAB; 40% fT>MIC for PIP and 40% fT>CT for TAZ.
Results: With the exception of IMI-REL, for which overall adequate PTAs were achieved, the accompanying BLI compounds (AVI, TAZ and VAB) were found to be responsible of lowering the PTA for the BL/BLI combination in both simulated populations. For example, in TRC patients treated with CAZ-AVI for a pneumonia infection (with MICCAZ/AVI 4 mg/L), PTA was 98.9% for CAZ, 75.6% for AVI and 74.2% for the combination. ARC patients treated with CET-TAZ for a complicated urinary tract infection (MICCET/TAZ 2 mg/L) had an estimated PTA of 99.9% for CET, but a PTA of 88.9% for TAZ and the combination. BLI drugs that have earlier been suggested to be time-dependent (AVI and TAZ) had overall lower PTA than BLIs suggested to be concentration-dependent (REL and VAB), for which PD targets (fAUC/MIC) were more easily met. Since BL and BLI compounds are mostly renally cleared, PTAs were in general lower in the ARC population. To compare with the previous example of TRC patients with a pneumonia infection treated by CAZ-AVI: in the ARC patient population PTAs were 92.2% for CAZ, 43.3% for AVI and 38.1% for the combination. As the PD target was assumed to be independent of the site of infection, PTA for each compound was linked to its tissue penetration. For example, in TRC patients treated with PIP-TAZ for a bacterial infection with a MICCAZ/AVI of 4 mg/L: PTA for TAZ was 79.4% in the case of complicated intra-abdominal infection, 46.3% in prostatitis, 95.7% in pneumonia and 96.5% in bacteraemia.
Conclusions: These findings would suggest that adhering to SmPC for AVI, TAZ and VAB might result in ineffective BLI concentrations at the site of infection, which in turn could explain therapeutic failure due to non-prevented BL degradation. Therefore, TDM of the BLI could be of interest in clinical practice. However, rather than recommending that the current TDM practice should be extended to BLI drugs (a highly technical and financial challenge), an alternative could be to develop specific PD targets for different sites of infection.
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