Simplifying Piperacillin/Tazobactam (TZP) Dosing: Pharmacodynamics (PD) of Utilizing 4.5g Doses for Patients with Normal and Impaired Renal Function

Background: Various TZP doses (2.25, 3.325, and 4.5g) are used for regimens based on patient creatinine clearance (CrCl). The ability to stock a single TZP strength or unify the preparation to a single concentration would simplify dosage preparation, reduce cost due to waste, and potentially minimize administration errors. We aimed to assess the utility of using TZP 4.5g in designing dosing regimens that would maintain PD exposure across the renal function range.

Methods: A 5,000-patient Monte Carlo simulation was conducted using Crystal Ball (Oracle, Inc.) to determine the probability of achieving 50% free time above the MIC (fT>MIC) for the piperacillin component of TZP. Pharmacokinetic data from 2 previous studies were used for the simulation. Proposed new dosing regimens, all using 4.5g and varying infusion durations, were simulated and compared with recommended regimens listed in TZP prescribing information over CrCl ranges of 120 mL/min down to hemodialysis (HD). The probability of target attainment (PTA) at the susceptibility breakpoint (16 μg/mL) and area under the concentration-time curve (AUC) of these regimens were compared.

Results: PTA and AUC results of each simulated TZP regimen are provided in the Table.

Simulated CrCL Range (mL/min)	Dosing Regimen (infusion duration)	PTA at MIC = 16 μg/mL (%)	AUC, mean ± SD (μg·h/mL)
40 - 120	4.5g q6h (0.5h)*	76.0	1121 ± 743
	4.5g q6h (3h)**	99.3	1121 ± 743
20-39	3.375g q6h (0.5h)*	98.1	1434 ± 772
	4.5g q8h (0.5h)	96.4	1425 ± 761
	4.5g q8h (3h)**	99.1	1474 ± 802
1-19	2.25g q6h (0.5h)*	95.8	1543 ± 975
	4.5g q12h (0.5h)	91.6	1548 ± 984
	4.5g q12h (3h)**	95.8	1567 ± 997
	4.5g q24h (3h)	56.3	787 ± 505
HD (post-dialysis)	2.25g q8h (0.5h)*	99.9	1152 ± 161
	4.5g q12h (0.5h)	99.7	1568 ± 226
	4.5g q12h (3h)**	100	1591 ± 236
	4.5g q24h (3h)	17.1	793 ± 118

^* TZP dose per current prescribing information

^** Proposed TZP dose based on PTA and AUC analyses

Conclusion: TZP regimens designed around the 4.5g dose and 3h prolonged infusions provided similar or better PTA at MIC = 16 μg/mL compared with current prescribing guidelines, without increasing daily AUC exposure across the simulated CrCl range. These findings support the use of a single TZP dose in patients with varied degrees of kidney function to simplify dosing regimens, reduce cost, and minimize errors.