Piperacillin Pharmacokinetics in a Pediatric Patient With Primary Hyperoxaluria Receiving High-Dose Continuous Dialysis Post Liver-Kidney Transplant

Introduction

Continuous kidney replacement therapy, or CKRT, is a type of continuous dialysis typically used to support patients with severe acute kidney injury (AKI), intoxications, or fluid overload.¹ Patients who receive CKRT are often oligoanuric, but CKRT can be used in non-oligoanuric patients for supplemental toxin removal.¹ Extracorporeal clearance (CL_EC), or solute removal via CKRT, is possible when the solute is smaller than the pore size of the CKRT filter (molecular weight [MW] <35 kDa using modern CKRT filters²), has a low volume of distribution (V_d), and is not highly bound to plasma proteins. The solutes removed include toxins that accumulate with kidney dysfunction and some medications, including many antibiotics. Antibiotics are commonly administered to children receiving CKRT, as sepsis is a leading cause of AKI requiring CKRT,³ and the presence of an indwelling hemodialysis catheter predisposes to infection. However, there is a paucity of data regarding antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) in children receiving CKRT, especially in patients who are non-oligoanuric.⁴

Piperacillin-tazobactam (PTZ) is a beta-lactam/beta lactamase inhibitor combination commonly used in critically ill children given its broad-spectrum activity, which includes anaerobic and antipseudomonal coverage.⁵ Piperacillin (PIP), the active antimicrobial component, has a MW of 518 Da and is approximately 30% protein bound,⁶ rendering it susceptible to CL_EC via CKRT. Optimal bactericidal activity of PIP depends on the percentage of time that free PIP concentrations are above the minimum inhibitory concentration, or MIC (% fT > MIC). A lack of consensus about precise PD targets exists due to limited data associated with clinical outcomes, but typically, more stringent PD targets are recommended for critically ill patients.⁷ Expert reviews have suggested that targets such as 100% fT > 1xMIC and 100% fT > 4xMIC could be necessary for maximum efficacy of PIP and minimum emergence of resistance.^7,8

Previous studies in adults have quantified the effects of CKRT on PIP PK. A review reported a median additional CL_EC of 1.43 L/hr, which contributed to a 66% increase in total clearance (CL) while on CKRT (median body CL = 2.76 L/hr). This review suggested that the use of continuous infusions could help attain stringent PD targets in the setting of this additional CL_EC.⁹

Pediatric data on PIP PK/PD in patients supported with CKRT are comparatively limited, with only 3 published reports to our knowledge. In a PIP PK and dose optimization study of 32 critically ill children receiving CKRT, Thy et al¹⁰ created a population PK model to simulate different dosing regimens. Because only 53% of the patients were anuric, and 25% had urine output (UOP) >0.3 mL/kg/hr, they could only assess the effect of residual renal function on PIP PD target attainment (TA) to an oliguric threshold of 0.5 mL/kg/hr. Through simulating different levels of UOP up to 0.5 mL/kg/hr, they recommended using higher doses with continuous infusions for patients with modest residual renal function. A second population PIP PK study in critically ill children by Butragueño-Laiseca et al¹¹ included 13 (41% of total included) patients on CKRT. Only 3 of those patients had any residual UOP. Using the model that they created, they recommended PIP drug monitoring and either intermittent or continuous infusion dosing regimens for patients on CKRT. Finally, a case study on PIP PK in a child with liver failure who received concomitant molecular adsorbent recirculating system therapy and CKRT reported on PIP PK for 1 cycle of CKRT alone.¹² The authors found an increase in CL from baseline to during CKRT alone (2.0 L/hr vs 3.0 L/hr, 50% increase) and adequate TA on CKRT alone. Residual UOP was not reported. This last case report is the only one of the 3 articles that reported using free PIP concentrations. Measuring free concentrations directly obviates the need to rely on an assumption of a fixed percentage of protein binding, which is known to fluctuate in the context of critical illness.¹³ Thus, there is a knowledge gap regarding free PIP PK in critically ill children receiving CKRT with significant residual kidney function.

Because blood flow rates are typically much faster than dialysis fluid flow rates in CKRT, the total effluent flow (Q_ef) is the main driver of solute removal in CKRT¹ and can affect antibiotic CL_EC. Q_ef can be considered the overall dialysis dose, and the standard pediatric dialysis dose is around 2000 mL/hr/1.73 m².¹⁴ High-dose or high-intensity dialysis involves an effluent flow rate significantly above that standard. The aforementioned studies also do not elucidate the potential effect of high Q_ef on PIP CL or TA. Therefore, there also remains a knowledge gap in PIP PK regarding the effects of high-dose dialysis in the setting of preserved intrinsic kidney function.

This case study describes the unique PK/PD of free PIP in a child receiving high- dose CKRT for oxalate CL after combined liver-kidney transplant for primary hyperoxaluria who had intrinsic kidney function from the new allograft. We report CL, V_d, and TA, by estimating the percent time free PIP concentrations remain above 1x MIC (fT > 1xMIC) and 4x MIC (fT > 4xMIC).

Case Report

Methods

PK/PD Analysis.

We analyzed free PIP concentrations immediately postoperatively and through the end of PTZ treatment, a period that spanned 7 days. Free PIP concentrations were measured from residual blood samples obtained from clinical samples through a random scavenged opportunistic sampling strategy.²⁰ Samples were stored at 4°C and centrifuged within 7 days for plasma extraction. Plasma was stored at −80°C until free drug was isolated with ultrafiltration, and free concentrations were measured by using a high-performance liquid chromatography assay previously validated by our group.²⁰

PIP doses and free concentrations were entered into a precision dosing software, MwPharm++ (Mediware, Prague, Czech Republic), to estimate concentration vs time profiles as well as CL and central volume of distribution (V₁). To conduct the PK modeling for this patient, a previously published population PK model describing PIP in critically ill children,²¹ adapted for free PIP by assuming 30% protein binding, was used because there is no available published model with free PIP concentrations at this time. Weight and post-menstrual age (PMA) are included as covariates in this model, and allometric scaling was used to scale the median body weight of 14 kg to 70 kg for use in MwPharm++. PMA was included as a maturation sigmoidal function , though this was not influential on this patient’s CL because he was significantly older than the maturation half-life (TM₅₀) of 61 weeks.²¹ Intercompartmental CL (Q) and peripheral compartment V_d (V₂) were fixed to the population mean established by the model and adapted to free concentrations (Q = 13 L/hr/70 kg^0.75 and V₂ = 11.37 L/70 kg).

Analysis of the observed free concentrations was completed by using Bayesian estimation with an assay error of 5%, aligning with the test-retest variability of our clinical laboratory. Concentration vs time profiles were generated and used to find the CL and V₁ for each period on and off CKRT (Figure A). Serial fits were obtained by inputting all PIP doses prior to the period of interest, then fitting the concentration-time profile using only the concentrations available during the period of interest. Time-weighted arithmetic means of PK parameters were then calculated as based on the time the patient spent in each period to determine average PK parameters for time on- and off-circuit. These fits were also used to assess PD TA as % fT > 1xMIC and % fT > 4xMIC. The empiric selected MIC was 8 mg/L—the Clinical Laboratory and Standards Institute PIP breakpoint for Enterobacterales—because no bacteria were cultured from the patient.²²

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Results

Twenty-two free PIP concentrations were analyzed from scavenged plasma samples, 17 of which were obtained when the patient was receiving CKRT. The concentration-vs-time profile for the entire study period is displayed in Figure B. Each period on and off CKRT was analyzed individually, and the PK results are summarized in Table 1. Average urine outputs and albumin levels on each study day are reported in Table 2. The weighted mean PIP CL for all cycles when the patient was on CKRT was 5.59 L/hr (13.1 L/hr/70 kg^0.75). The weighted mean PIP CL for all cycles off CKRT was 3.36 L/hr (7.88 L/hr/70 kg^0.75). Thus, mean CL_EC was 2.23 L/hr, increasing total CL by 66% while on CKRT vs while off CKRT (Table 3). This CL_EC was 40% of total patient CL while on CKRT and 51% of the total dialysis dose of ∼4.4 L/hr.

Table 1.PK and Target Attainment Results From Each Period On and Off CKRT^*

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Table 2.Urine Output and Albumin Concentrations^*

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Table 3.Comparisons of CL Provided by CKRT^*

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The weighted mean PIP V₁ was larger while the patient was on CKRT vs off CKRT (18.25 L/70 kg vs 15.89 L/70 kg). Of note, the PIP V₁ for the first period off CKRT, immediately postoperatively, was elevated (18.20 L/70 kg) as compared with the estimated V₁ during other periods off CKRT (14.28 and 13.18 L/70 kg). The patient’s net intake for the first period off CKRT was +4760.6 mL (366.2 mL/hr). PD results are summarized in Table 1. fT > 1xMIC approached or achieved 100% for all periods analyzed. fT > 4xMIC while the patient was on CKRT was 60% as compared with 97% when off CKRT.

Discussion

This case report of a child receiving high-dose CKRT after combined liver-kidney transplant demonstrates that CKRT was associated with higher PIP CL and decreased PD TA. For a target of 100% fT > 1xMIC, the target was achieved while off CKRT and nearly achieved while on CKRT. However, % fT > 4xMIC was much lower than 100% (60.3%) while on CKRT. Because the patient had immediate kidney allograft function post transplant, he had antibiotic elimination from both intrinsic kidney function and from CKRT in the form of CL_EC. This additional CL_EC explains the lower PD TA for on-circuit periods. However, CL_EC was only 40% of total patient CL while on CKRT, suggesting that the majority of PIP elimination was from the patient’s newly transplanted kidneys despite high-dose dialysis.

Because the dialysis dose (Q_ef) is the primary driver of solute removal in CKRT, and this patient was receiving a dose approximately 4½ times that of standard pediatric CKRT, it is interesting to note that PIP CL_EC was approximately half of the dialysis dose received (2.23 L/hr vs 4.4 L/hr). CL_EC in CKRT is sometimes estimated as the unbound fraction (f_u) multiplied by the Q_ef because only free solutes can pass through the CKRT filter. PIP has an f_u of ∼70% (∼30% protein binding), suggesting that CL_EC would be expected as ∼70% of the Q_ef. The discrepancy between the observed and predicted CL_EC may exist because of decreased PIP availability for extracorporeal elimination due to intrinsic renal elimination. It also could be due to the limitations of using a predominantly diffusive, rather than convective, form of solute removal for CKRT CL,^1,18,23 as this patient was prescribed continuous veno-venous hemodialysis. This modality very effectively removes small molecules like oxalate, but less effectively clears molecules of middle MW (MW in the 500–50,000 Da range). With PIP’s MW of 518 Da, it is considered a middle MW molecule despite being on the “small” end of the middle-MW range. Thus, PIP was perhaps less susceptible to CL_EC than would be expected from the prescribed effluent flow and degree of protein binding alone.

One additional change in PK/PD parameters in this patient over time is worth noting. PIP V₁ was likely elevated in the immediate postoperative period while the patient was off CKRT owing to the volume of fluids given immediately after the operation and the absence of much output (overall net fluid balance approximately +4.7 L during post CKRT period #1). This increase in V₁ did not appear to affect TA while the patient was off CKRT given the high percentage of fT > 1xMIC for all 3 off-CRKT periods. It is known that a larger V_d with a constant CL can increase half-life and thus time over MIC.^24,25

Comparing these patient data directly to existing reports of PIP PK on CKRT is challenging in part because of differences in data reported and patients included. For example, Butragueño-Laiseca et al¹¹ reported only 3 patients with residual kidney function and did not explore the impact of residual diuresis. The case report by Tang-Girdwood et al¹² did not report UOP. While Thy et al¹⁰ reported the impact of residual kidney function, they did not include UOP values for each patient or evaluations of UOPs above an oliguric level. In addition, the reports by Thy et al¹⁰ and Butragueño-Laiseca et al¹¹ do not compare the CL on CKRT to the CL off CKRT for the patients in their studies, because their research is focused on PIP PK modeling.

Regardless, some comparisons regarding TA are apparent. The report by Tang Girdwood et al¹² found that CKRT provides a 50% increase in PIP CL while on CKRT vs off CKRT (3.0 L/hr vs 2.0 L/hr) in a 13-year-old, 42-kg patient with liver failure. This result is comparable to the 66% increase in PIP CL discussed in this article. Tang Girdwood et al¹² reported nearly 100% fT > 4xMIC for a MIC of 16 mg/L while on CKRT despite receiving a lower dose of 80 mg/kg every 8 hours while on CKRT and 48 mg/kg every 8 hours while off, which does not align with the 60% fT > 4xMIC for a MIC of 8 mg/L reported here. This discrepancy can be attributed to our patient’s significant kidney function and high dialysis dose. Thy et al¹⁰ simulated TA for a 15-kg patient on CKRT receiving 100 mg/kg of PTZ every 8 hours with a residual UOP of 0.5 mL/kg/hr and found approximately 75% fT > 4xMIC for a MIC of 8 mg/L. Butragueño-Laiseca et al¹¹ similarly reported PD TA of 78% fT > 4xMIC for a MIC of 8 mg/L in a simulated patient on CKRT weighing 10 to 30 kg and receiving 100 mg/kg of PTZ every 8 hours, though they could not explore the effect of residual kidney function. The TA for the patient in this study is lower, likely owing to both high-intensity CKRT and robust kidney function.

Because this was a single-patient case study, we cannot make broad generalizations regarding appropriate PTZ dosing in this patient population. That said, we simulated 3 dosing regimens that would achieve 100% fT > 4xMIC for on-circuit periods, assuming no change in CKRT or kidney CL: 110 mg/kg PTZ (98 mg/kg PIP) every 4 hours as a 30-minute infusion, 160 mg/kg PTZ (142 mg/kg PIP) every 6 hours as a 3-hour infusion, or 220 mg/kg/day PTZ (196 mg/kg PIP) as a continuous infusion. Concentration-time profiles for these simulated dosing regimens are available in Supplemental Figure A through C.

Limitations

This case study has limitations. Only 5 of the 22 concentrations were obtained when the patient was off CKRT. This is mainly because the patient was only off CKRT for short periods (mean of 9 hours vs mean of 38 hours on CKRT), but the paucity of data could result in less accurate estimates of PIP CL. Because this is a single-patient case report, we also cannot perform statistical inferential testing to examine the impact of patient- and CKRT-specific parameters in predicting PIP PK. We assume a fixed percentage of binding in the de Cock model used here, which may inaccurately represent the actual protein binding of PIP in this patient owing to his critical illness and fluctuating albumin levels. In addition, we did not collect urine or effluent PIP concentrations because the case study was subsumed under a parent study that only involved collection of scavenged opportunistic blood samples. Because piperacillin is known to have renal, hepatic, and extracorporeal clearance,^7,26,27 the absence of urine and effluent samples limited our ability to precisely quantify the contribution of each. Finally, because we do not have a validated assay for tazobactam at our institution, we could not perform tazobactam PK, which would have enriched this case report.

However, this report has strengths as well, especially owing to the unique nature of the patient case. To our knowledge, this is the first analysis of free PIP concentrations in a critically ill pediatric patient undergoing high-dose continuous dialysis. His significant intrinsic kidney function also adds to the novelty of the PK/PD results. The 17 free PIP concentrations available while the patient was on CKRT likely allowed for accurate estimates of PK parameters during those periods, as evidenced by the good fits of the observed concentrations while on CKRT.

Conclusions

This case report contributes valuable PIP PK data from a distinctive patient case to the sparse existing CKRT PK literature. We provide information about the potential effects of both the high dialysis dose and residual UOP above an oligoanuric level as is typically seen in children on CKRT. Clinical monitoring of free PIP concentrations may be warranted to better inform dosing in patients supported with CKRT, particularly given the discordance between dialysis dose and antibiotic elimination seen here. More frequent PIP dosing or prolonged or continuous infusions may be necessary to achieve stringent PD targets in this population, though more research is needed. Further analysis should be completed by using free PIP concentration data directly from critically ill pediatric patients receiving CKRT, including those with residual kidney function.