Interaction of Ceftazidime and Clindamycin with Extracorporeal Life Support

Abstract

Background:

Ceftazidime and clindamycin are commonly prescribed to critically ill patients who require extracorporeal life support such as ECMO and CRRT. The effect of ECMO and CRRT on the disposition of ceftazidime and clindamycin is currently unknown.

Methods:

Ceftazidime and clindamycin extraction were studied with ex vivo ECMO and CRRT circuits primed with human blood. The percent recovery of these drugs over time was calculated to determine the degree of interaction between these drugs and circuit components.

Results:

Neither ceftazidime nor clindamycin exhibited measurable interactions with the ECMO circuit. In contrast, CRRT cleared 100% of ceftazidime from the experimental circuit within the first 2 h. Clearance of clindamycin from the CRRT circuit was slower, with about 20% removed after 6 h.

Conclusion:

Clindamycin and ceftazidime dosing adjustments are likely required in patients who are supported with CRRT, and future studies to quantify these adjustments should consider the pathophysiology of the patient in combination with the clearance due to CRRT. Dosing adjustments to account for adsorption to ECMO circuit components are likely unnecessary and should focus instead on the pathophysiology of the patient and changes in volume of distribution. These results will help improve the safety and efficacy of ceftazidime and clindamycin in patients requiring ECMO and CRRT.

INTRODUCTION

Patients who are supported by extracorporeal life support (ECLS) devices such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are at high risk for infection.(1,2) Antibiotics are the mainstay of treatment, but optimal dosing for most antimicrobials is unknown because ECLS can significantly alter drug disposition.(3,4) Drug disposition in patients on ECLS can be altered in the following ways: 1) drug adsorption to components of the ECLS circuit; 2) drug clearance by the hemofilter; and 3) increased volume of distribution due to exogenous fluids used to prime the circuit as well as inflammation, edema, and altered protein binding caused by the circuit and underlying critical illness. The extent of drug extraction by the circuit depends on both circuit components and drug physicochemical properties (e.g., molecular weight, protein binding, lipophilicity). Lipophilic and highly protein-bound drugs are more likely to adsorb to circuit components, while hydrophilic unbound drugs are more likely to be cleared by the hemofilter.

Ceftazidime and clindamycin are commonly prescribed to combat serious infections, and are often given to patients supported by ECLS.(5) Ceftazidime is a broad spectrum beta-lactam antibiotic especially useful against Pseudomonas aeruginosa.(6) Clindamycin is a versatile lincosamide antibiotic especially useful against serious gram-positive infections, including but not limited to toxic/septic shock, pneumonia, bacteremia and septic arthritis caused by Methicillin-resistant Staphylococcus aureus (MRSA) and for patients with beta-lactam allergy.(7) Effective treatment requires sustained tissue concentrations,(8) but overdosing risks serious toxicities.(9) Toxicities of ceftazidime include hepatic injury, neurotoxicity, lactic acidosis, acute kidney injury and cytopenias.(10) Adverse effects of clindamycin include infection with Clostridioides difficile, hypersensitivity reactions, dermatologic pathology like Stevens-Johnson syndrome and toxic epidermal necrolysis, acute kidney injury, and hypotension.(11) Ceftazidime, is hydrophilic and minimally protein bound, suggesting that it is readily filtered by CRRT but less likely to be adsorbed by circuit components. In contrast, clindamycin, is moderately lipophilic and protein bound, making adsorption to circuit components more likely. Thus, there is an urgent need to understand the degree to which ceftazidime and clindamycin interact with ECLS circuits.

The interactions between individual drugs and ECLS circuits have been studied primarily in ex vivo experiments in which a drug is injected into a blood-primed ECLS circuit and concentrations measured over time.(12–16) This method enables an assessment of drug clearance by the hemofilter and the degree to which drug adsorbs to the circuit components, including the impact of surface coatings.(16,17) In this study, we performed ex vivo ECMO and CRRT experiments to quantify the interaction of clindamycin and ceftazidime in ECLS in order to determine the extent of extraction and impact on optimal dosing.

MATERIALS AND METHODS

We evaluated extraction of ceftazidime and clindamycin from blood-primed ECMO and CRRT circuits. Drug was dosed to achieve ceftazidime or clindamycin therapeutic plasma concentrations of 70 to 120 mg/L and 10 to 15 mg/L, respectively.(18,19)

Extracorporeal Membrane Oxygenation (ECMO) Setup

ECMO experiments were performed as previously reported.(20) Briefly, ECMO Complete Circuits (ceftazidime: n=3; clindamycin: n=3) comprised: a hollow-fiber oxygenator(21) (Quadrox-iD, Maquet, Hirrlingen, Germany); a reservoir (Viaflex 1000 mL, Baxter, Deerfield, IL); tubing (Sorin Smart Perfusion Pack, LivaNova, London, UK or Custom Perfusion System, Medtronic, Minneapolis, MN); a centrifugal pump (Rotaflow Pump, Maquet); and a hemofilter (Sorin DHF 0.2, Arvada, CO) (Table 1). ECMO Oxygenator Circuits (ceftazidime: n=4; clindamycin: n=3) were identical except that they did not include a hemofilter. Circuits were assembled as depicted in Figure 1A using the specified tubing (Table 1). Circuits were then filled with expired human blood and plasma purchased from the American Red Cross as a mixture comprising the following: 0.5 to 1 unit thawed human plasma frozen within 24 hours after phlebotomy, 1.5 to 2 units human red blood cells (adenine saline added leukocytes reduced; Run 1 contained 1 unit), Plasma-Lyte A crystalloid (~300–600 mL; Baxter Healthcare, Deerfield, IL), heparin sulfate (500 units), tromethamine (2 g), sodium bicarbonate (7 mEq), calcium gluconate (650 mg), and 12.5 g human serum albumin, for a total fluid volume of 1000 to 1600 mL. Additional tromethamine and carbon dioxide were introduced as needed to maintain physiologic pH (7.2–7.5). To limit the impact on hospital blood bank supply, we used recently expired blood products from the American Red Cross. Fluid flow through the ECMO circuit was maintained at 1.0 L/min using a HT110 bypass flow meter with H8XL flowsensor (Transonic, Davis, CA). Temperature of the human blood mixture was maintained at 37 °C with an ECMO Water Heater (Cincinnati Sub-Zero, Cincinnati, OH) connected to the Quadrox-iD integrated heat exchanger.

Table 1.

ECMO and CRRT Circuit Components and Parameters

	ECMO Circuits
ECMO Ceftazidime Circuits	Oxygenator: Quadrox iD Adulta		Pump: Rotaflow		Tubingd	Hemofilter: Sorin DHF 0.2g	Reservoird	# of Doses
	Biolineb	Softlinec	Biolineb	Softlinec
Run 1	X		X		Medtronic (uncoated)	X	Medtronic (uncoated)	1
Run 2	X		X		Medtronic Cortivae	X	Medtronic Cortivae	1
Run 3	X		X		Medtronic Cortivae	X	Medtronic Cortivae	3
Run 4		X	X		Sorin Smart-Xf		Viaflex	3
Run 5		X	X		Sorin Smart-Xf		Viaflex	3
Run 6	X		X		Medtronic Cortivae		Medtronic Cortivae	3
Run 7	X			X	Sorin Smart-Xf		Viaflex	3
ECMO Clindamycin Circuits	Oxygenator		Pump		Tubing	Hemofilter	Reservoir	# of Doses
Run 1–3	Quadrox iD Adulta Biolineb		Rotaflow Biolineb		Medtronicd Cortivae		Medtronicd Cortivae	1
	CRRT Circuits
CRRT Ceftazidime Circuits: Run 1–3	System				Hemofilter		Temp Control	Reservoir
	Baxter PrisMax				HF1000h		TherMax bagi	EXACTAMIX EVAj
	PBP (mL/h)		BFR (mL/min)		PFR (mL/h)		DIA (mL/h)	REP (mL/h)
	700		150		0		1000	300
CRRT Clindamycin Circuits: Run 1–3	System				Hemofilter		Temp Control	Reservoir
	Baxter PrisMax				HF1000h		TherMax bagi	EXACTAMIX EVAj
	PBP (mL/h)		BFR (mL/min)		PFR (mL/h)		DIA (mL/h)	REP (mL/h)
	300		80		0		400	100

^aPolymethylpentene fibers

^bBioline coating: covalently bonded recombinant human albumin and heparin

^cSoftline coating: amphiphilic polymer coating (glycerol-poly[ethylene glycol]-ricinoleate)

^dPolyvinyl chloride

^eCortiva BioActive coating: heparin covalently attached to electrostatically adsorbed copolymer

^fSmart-X coating: tribloc copolymer (polycaprolactone-polydimethylsiloxane-polycaprolactone)

^gpolyethersulfone fibers

^hPolyarylEtherSulfone fibers, plasticized polyvinyl chloride tubing

ⁱEthylene vinyl acetate

^jPolyurethane

PBP: pre-blood pump flow rate; BFR: blood flow rate; PFR: patient fluid removal flow rate; DIA: dialysate volumetric flow rate; REP: replacement fluid flow rate.

Figure 1.

Schematic of ECMO and CRRT ex vivo circuit configurations: A. ECMO circuit experiments demonstrating a Complete Circuit configuration including reservoir, pump, hemofilter, and oxygenator. Oxygenator Circuits do not include a hemofilter. B. CRRT circuit experiments. PBP=pre-blood pump, EFF=effluent, DIA=dialysate, REP=replacement fluid.

Continuous Renal Replacement Therapy (CRRT) Setup

Triplicate CRRT experiments were conducted using the Baxter (Baxter Healthcare, Deerfield, IL) PrisMax system with HF1000 filter as previously described.(20) The HF1000 filter was chosen because it is commonly used in children on CRRT. We acknowledge that other filters could clear drugs differently. Briefly, a 500 mL EXACTAMIX EVA (Baxter Healthcare) reservoir bag was filled with blood mixture consisting of: 1 unit human red blood cells (adenine saline added leukocytes reduced [~300 ml]), ~0.4 units thawed human plasma frozen within 24 hours after phlebotomy (125 ml), Plasma-Lyte A crystalloid (~150 ml), heparin sulfate (350 units), tromethamine (1.5 g), sodium bicarbonate (7 mEq), calcium gluconate (180 mg), and human serum albumin (6.25 g). Physiologic pH was maintained with tromethamine. PrisMax was then connected to the reservoir and primed with human blood mixture. The reservoir rested on an orbital shaker at 80 RPM. Temperature was maintained at 37 °C by the Thermax heat exchanger. The continuous venovenous hemodiafiltration (CVVHDF) modality was chosen as this is the treatment of choice for critically ill patients at our institution. Components and dialysis prescriptions are presented in Table 1.

Control Setup

Control experiments for both ceftazidime and clindamycin (n=3) were incubated in water bath at 37 °C with periodic gentle mixing to determine drug degradation in human blood mixture throughout the experiment. 50 mL of blood solution were drawn from the ECMO circuit before drug administration and dispensed into polypropylene centrifuge tubes (229426, CELLTREAT, Pepperell, MA).

Drug Administration and Sample Collection

For ECMO circuits, drug was administered to the circuit at the arterial limb via a 3-way stopcock downstream of the sampling port (Figure 1A). To determine the impact of multiple doses, drug administration was repeated at 24 h and again at 32 h for five of the seven ceftazidime ECMO circuits (Table 1). For ceftazidime circuits, blood samples were collected at 1, 5, 15, and 30 minutes and 1, 2, 3, 4, 6, 10, and 24 h after the first administration. For Runs 3 through 7, samples were also collected at 1, 5, 15, and 30 min and 1, 2, 4, 6, 8 h after the second administration, and at 1, 5, 15, and 30 minutes and 1, 6, 7, 8 h after the third administration. For clindamycin ECMO circuits, samples were collected at 1, 5, 15, and 30 min and 1, 2, 3, 4, 6, 8, and 24 h after administration. Control blood was collected five minutes later than ECMO samples.

For CRRT circuits, drug was administered via the access line immediately downstream of the reservoir (Figure 1B). Blood and effluent samples were collected at the following time points after drug administration: 1, 5, 15, and 30 minutes, and 1, 2, 3, 4 and 6 h from the pre-filter sampling port and the post-filter effluent sampling port, respectively (Figure 1B).

For both ECMO and CRRT experiments, blood samples were immediately centrifuged at 3000 RCF and 4 °C for 10 minutes. Plasma and effluent samples were frozen in cryovials (Fisher Scientific, Pittsburgh, PA) at −20 °C for <24 h and stored at −80 °C until analysis. Physiologic pH of circuit blood was tested each hour with an i-STAT 1 Analyzer (Flextronics Manufacturing, Singapore) and EG6+ cartridge (Abbott, Abbott Park, IL) and adjusted with tromethamine or carbon dioxide.

Analysis

Plasma and effluent concentrations were measured at OpAns Laboratory (Durham, NC) using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The ceftazidime assay was validated in both plasma and effluent using standard curves achieving coefficients of determination (R²) >0.992 with coefficients of variation <9.6% for concentrations across the range of the standard curves (0.3–342.8 mg/L). The LLOQ for ceftazidime was 0.3 mg/L and the accuracy ranged from 95.4% to 104.2%. The clindamycin assay was validated in both plasma and effluent using standard curves achieving coefficients of determination (R²) >0.998 with coefficients of variation <3.4% across the range of the standard curves (0.05–25 mg/L). The LLOQ for clindamycin was <0.05 mg/L and the accuracy ranged from 94.2% to 104.0%. Internal standards ([²H₅]-Ceftazidime; [²H₃]-Clindamycin HCl) were purchased from Toronto Research Chemicals (Toronto, ON, Canada). Reference standards for ceftazidime and clindamycin were purchased from Toronto Research Chemicals and AK Scientific (Union City, CA), respectively. Additional assay details are included in the Supplementary Material.

Percent Recovery Calculation

Because initial concentrations differed slightly for each circuit, we normalized concentrations by calculating drug percent recovery. Drug percent recovery in circuit and control experiments was calculated for each sample using the following equation:

$$\mathit{\text{Recovery}}(\%)=\frac{C_t}{C_{ref}}\cdot 100$$ (1)

where C_t is the concentration at time t and C_ref is the reference concentration of drug in the circuit, which is the maximum or initial concentration after mixing of the drug. About 5 minutes are required for the drug to become evenly distributed throughout the ECMO circuit (Supplementary Figure 1). Therefore, the 5-min sample was the reference concentration for ceftazidime ECMO circuits. For the ceftazidime CRRT circuits and control experiments, the reference concentration was the plasma concentration measured at 1 min. For clindamycin ECMO, CRRT, and control experiments, the reference concentration was the maximum plasma concentration observed during the experiment.

For the CRRT experiments, the fraction of administered dose collected in effluent after 6 h was estimated from the effluent drug concentration and effluent flow rate as follows:

$$\mathit{\text{Fraction}}of\mathit{\text{dose}}in\mathit{\text{effluent}}=\left\{{\int }_{t=0h}^{t=6h}\left[C(t)\cdot \dot{v}(t)\right]dt\right\}/D$$ (2)

where C(t) is the mass concentration of drug in the effluent, v̇(t) is the effluent volumetric flow, and D is the dose administered to the circuit.

Saturation Coefficient

For the CRRT experiments, the saturation coefficient and transmembrane clearances were calculated using paired plasma and effluent samples with the following equations:

$$S_{a(HDF)}=\frac{C_{eff}}{C_p}$$ (3)

$$Q_{eff}=Q_{PBP}+Q_{REP}+Q_{PFR}+Q_{DIA}$$ (4)

$$C{L}_{\mathit{\text{CVVHDF}}}=Q_{eff}\cdot S_{a(HDF)}$$ (5)

Where C_eff and C_p are the effluent and plasma drug concentrations, respectively, S_a(HDF) is the saturation coefficient for hemodiafiltration, Q_eff, Q_PBP, Q_REP, Q_PFR, and Q_DIA are the effluent, pre-blood pump, replacement fluid, patient fluid removal, and dialysate volumetric flow rates, respectively, and CL_CVVHDF is the transmembrane clearance.

Statistics

A two-sample one-tailed t-test with significance as p < 0.05 was used to compare the drug percent recovery between circuit and control experiments after 6 h (ECMO & CRRT) and 24 h (ECMO). Analysis of covariance with simple linear regression, omitting the 1 min samples, was used to compare the ECMO percent recovery after multiple ceftazidime doses with the control experiment.

RESULTS

Ceftazidime and Clindamycin in ECMO Circuits

The mean percent recovery of ceftazidime was similar in both the ECMO and the control experiments (Figure 2A). ECMO circuit recovery after a single dose was not significantly different from the control after 6 h: 84.1% vs 84.0% (p = 0.484). Likewise, the percent recovery of ceftazidime vs. time in ECMO circuits after administration of the second and third doses did not differ from the percent recovery vs. time in the control (p = 0.653 and 0.541, respectively). Ceftazidime percent recovery for ECMO experiments from 0 to 40 h are presented in Supplementary Figure 2. We observed a minimal yet statistically significant difference in ceftazidime percent recovery between ECMO and control experiments after 24 h: 65.0% vs. 70.0% (p = 0.015). Ceftazidime plasma concentration measurements for ECMO and control experiments are reported in Supplementary Tables 21 and 22.

Figure 2.

Plasma percent recovery from control and ECMO experiments for A. ceftazidime and B. clindamycin. Error bars represent one standard deviation for n=2 (clindamycin) or 3 (ceftazidime) control experiments, n=7 ECMO ceftazidime experiments, and n=3 ECMO clindamycin experiments. The asterisk indicates statistical significance.

In contrast, the percent recovery of clindamycin in both ECMO and control experiments increased linearly throughout the experiment (Figure 2B). Plasma clindamycin concentrations at 1 min in control and ECMO experiments measured 2.3% and 2.4% of the expected concentration of ~14 μg/mL, respectively, and increased to ~23% of the expected concentration by 24 h. Recovery of clindamycin in ECMO circuits after 24 h was not statistically significantly different from the control experiment: 40.2% vs 39.8% (p = 0.436). Clindamycin plasma concentration measurements for ECMO and control experiments are reported as Supplementary Tables 23 and 24.

Ceftazidime and Clindamycin in CRRT Circuits

Ceftazidime was rapidly cleared from the CRRT circuit: plasma concentrations measured below the limit of quantitation by 2 h (Figure 3A). 100% of the ceftazidime dose administered to the circuit accumulated in the effluent after two hours. The saturation coefficient and transmembrane clearance with mean (SD) of 1.12 (0.18) and 38.12 (6.11) mL/min, respectively remained consistent over the course of the experiment (Figure 3C). Ceftazidime percent recovery between CRRT circuits and controls after 6 h was statistically significant: 0.0% vs 84.0% (p = 0.00007). Ceftazidime plasma and effluent concentration measurements for CRRT experiments are reported as Supplementary Tables 25 and 26.

Figure 3.

Plasma and effluent percent recovery from CRRT circuit experiments with A. ceftazidime and B. clindamycin. Saturation coefficients for C. ceftazidime and D. clindamycin. Error bars represent one standard deviation for n=3 experiments.

In contrast, clindamycin exhibited slower recovery kinetics in CRRT experiments (Figure 3B). About 20% of the administered dose was recovered in effluent after 6 h. The saturation coefficient of clindamycin increased over the course of the experiment to a final value of 0.36 with a mean (SD) over the entire experiment of 0.19 (0.11) (Figure 3D). Likewise, the transmembrane clearance for clindamycin increased during the experiment to a final value of 4.82 mL/min with a mean (SD) over the entire experiment of 2.53 (1.49) mL/min (Figure 3D). Clindamycin percent recovery between CRRT circuits and controls after 6 h was statistically significant: 21.5% vs 40.2% (p = 0.041). Clindamycin plasma and effluent concentration measurements for CRRT experiments are reported as Supplementary Tables 27 and 28.

DISCUSSION

We performed ECLS experiments for two commonly used antibiotics and assessed interactions with the circuits. In ECMO circuits, ceftazidime recovery kinetics were not significantly different from the control experiments (Figure 2A), suggesting minimal adsorption to ECMO circuit components. Although the ceftazidime ECMO experiments were assembled with multiple combinations of components and coatings (Table 1), the recovery was consistent among all runs, suggesting that ceftazidime does not interact appreciably with these components or coatings. In both control and ECMO experiments, the slow linear decrease in ceftazidime concentrations over time is similar to degradation of meropenem observed in a previous experiment and may reflect the instability of the beta lactam ring.(22)

In contrast to the ECMO experiments, the CRRT circuit experiments demonstrated rapid clearance of ceftazidime: An estimated 100% of the ceftazidime dose administered to the circuit accumulated in the effluent after two hours, suggesting minimal adsorption to circuit components. Such rapid clearance agrees with ceftazidime’s relatively low protein binding and lipophilicity and suggests that ceftazidime dosing should be adjusted in patients treated with CVVHDF CRRT.

In contrast to ceftazidime, clindamycin demonstrated unusual recovery kinetics in both ECMO and control experiments (Figure 2B). Importantly, these kinetics were not significantly different between ECMO and control experiments, suggesting minimal extraction of clindamycin by ECMO circuits. Nevertheless, alternative conclusions merit careful consideration. Clindamycin could rapidly adsorb to the surfaces of both the control tube and the ECMO circuit components and then desorb over time. However, this is less likely because the circuit offers a much larger surface area and more diverse surface types for adsorption than the control tube (Table 1). Additionally, clindamycin could immediately precipitate and then dissolve over time. However, reasons for this cannot include pH fluctuations because the pH was rigorously maintained near 7.2. Lastly, clindamycin could rapidly and extensively partition to blood components and thereafter release slowly over time. Clindamycin is known to concentrate within phagocytes(23) and exhibits a very high clinical volume of distribution.(19) Furthermore, the blood to plasma ratio of clindamycin in rat blood was measured at 7.59.(24) If clindamycin achieved similar blood to plasma ratios in these ECMO circuit experiments, an estimated 3% of the administered dose would be observable in plasma – corresponding to the initial observed fraction of dose in ECMO and control experiments of ~2%. Although total hemoglobin of circuit blood was measured throughout the experiment, the plasma free hemoglobin was not measured, and hemolysis by the ECMO circuit is well-documented.(25,26) Thus, rapid and substantial partitioning of clindamycin to erythrocytes and subsequent hemolysis could explain the rising plasma concentrations over time. In this case, significant interaction between clindamycin and ECMO circuit remains unlikely.

In contrast, CRRT circuits cleared clindamycin – albeit with slower recovery kinetics than ceftazidime. Plasma and effluent clindamycin concentrations peaked about 30 min and 120 min after administration to the circuit, respectively (Figure 3B), and the clindamycin saturation coefficient increased over 6 h (Figure 3D). About 80% of the clindamycin dose was retained by the CRRT circuit and/or the blood mixture even after 6 h. These results suggest more conservative, if any, clindamycin dosing adjustments for patients on CRRT. Notably, clindamycin is primarily hepatically cleared, and dosing adjustments are currently recommended in neither the context of renal impairment nor CRRT. (27,28) Clinical studies are needed to investigate the appropriateness of current dosing practices in the context of ECLS and to confirm the clinical consequence of the findings in this work.

This work is not without limitations. First, while ceftazidime ECMO circuit components and surface coatings represent several combinations, no single combination was tested against any other for drug extraction. Rather, the average percent recovery of these circuits was tested for significant differences with the control experiments. The remarkably similar recovery kinetics among all configurations tested suggests that none of these components or coatings appreciably interacts with ceftazidime. Next, faster CVVHDF flow rates were tested in the ceftazidime CRRT experiments than in those for clindamycin. While faster fluid flow rates are expected to increase drug clearance by CRRT, it is unlikely that this explains the observed difference in CRRT clearance pattern between ceftazidime and clindamycin.(20) Importantly, only one hemofilter model was tested, and the generalizability of these results should be confirmed. Finally, while the recovery kinetics for clindamycin in ECMO experiments were unexpected, they were nonetheless statistically indistinguishable from those of the control reaction, suggesting minimal interaction with circuit components. Interestingly, a previous report of clindamycin recovery in ex vivo cardiopulmonary bypass circuits also observed clindamycin plasma concentrations much lower than expected, with an increase over the course of the 5 h experiment.(29)

Physiologically based pharmacokinetic models are increasingly used to predict optimal drug dosing.(30–34) In the future, PBPK models accounting for patient pathophysiology(34) could incorporate ECMO and CRRT compartments using the data provided in this report to recommend optimal ceftazidime and clindamycin dosing for patients requiring ECLS. Importantly, impaired renal and hepatic function should be considered when dosing ceftazidime and clindamycin, respectively, in combination with clearance by ECLS.

In conclusion, neither ceftazidime nor clindamycin measurably adsorbed to the components of the ECMO circuit. Therefore, ceftazidime and clindamycin dosing adjustments for patients on ECMO should be informed by changes in volume of distribution due to exogenous fluids and patient pathophysiology (i.e., inflammation, edema, kidney/liver function, age, and body size) and not on the effect of drug adsorption to the ECMO circuit. In contrast, CRRT circuits rapidly cleared ceftazidime, and, to a lesser extent, clindamycin. These results reveal the need for future clinical investigation incorporating patient pathophysiology to support dosing adjustments for ceftazidime and clindamycin for patients requiring CVVHDF CRRT. This insight will help improve the safety and efficacy of ceftazidime and clindamycin in critically ill patients supported by ECMO and CRRT.

DATA AVAILABILITY STATEMENT

The datasets generated and analyzed for this study can be found in the Supplementary Material.