- Case report
- Open access
- Published:
Case report: therapeutic monitoring of vancomycin in an acute liver failure patient with anuria under high-flow continuous hemodiafiltration
Journal of Pharmaceutical Health Care and Sciences volume 9, Article number: 15 (2023)
Abstract
Background
High-flow continuous hemodiafiltration (HF-CHDF) combines diffusive and convective solute removal and is employed for artificial liver adjuvant therapy. However, there is no report on dosage planning of vancomycin (VCM) in patients with acute liver failure under HF-CHDF.
Case presentation
A 20-year-old woman (154 cm tall, weighing 50 kg) was transferred to the intensive care unit (ICU) with acute liver failure associated with autoimmune liver disease. On the following day, HF-CHDF was started due to elevated plasma ammonia concentration. On ICU day 8, VCM was started for suspected pneumonia and meningitis (30 mg/kg loading dose, then 20 mg/kg every 12 hrs). However, on ICU day 10, VCM blood concentration was under the limit of detection (< 3.0 μg/mL) and the patient developed anuria. The VCM dose was increased to 20 mg/kg every 6 hrs. Calculation with a one-compartment model using the HF-CHDF blood flow rate as a surrogate for VCM clearance, together with hematocrit and protein binding ratio, predicted a trough VCM blood concentration of 15 μg/mL. The observed concentration was about 12 μg/mL. The difference may represent non-HF-CHDF clearance. Finally, living donor liver transplantation was performed.
Conclusion
We report an acute liver failure patient with anuria under HF-CHDF in whom VCM administration failed to produce an effective blood concentration, likely due to HF-CHDF-enhanced clearance. VCM dosage adjustment proved successful, and was confirmed by calculation using a one-compartment model.
Background
High-flow continuous hemodiafiltration (HF-CHDF) is used as artificial liver adjuvant therapy for blood purification in acute liver failure [1,2,3], since it efficiently removes small-molecular compounds such as ammonia (NH3) and pathogenic cytokines, and promotes emergence from hepatic coma [1, 3]. However, coadministered therapeutic drugs with low molecular weight and low protein binding rate are also easily removed [4, 5], so it is necessary to ensure an appropriate administration dosage and schedule for patients receiving drug treatments.
Vancomycin (VCM) is a glycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). To ensure efficacy and to avoid adverse effects of VCM, therapeutic drug monitoring is critically important [6]. Furthermore, since VCM is removed by hemodiafiltration [7], individual dosage design is essential [8,9,10].
CHDF, used for renal replacement therapy, is a continuous dialysis method that reduces the blood and diafiltrate flow rates (generally, blood flow rate: about 80 ~ 100 mL/min > dialysis flow rate + filtration flow rate: about 10 ~ 25 mL/min) compared with normal dialysis. However, we experienced a case of vancomycin administration under HF-CHDF, involving continuous high-flow on-line hemodiafiltration (on-line HDF) (blood flow rate: 200 mL/min < dialysis flow rate + filtration flow rate: 600 mL/min) for 24 hrs. Although VCM clearance during 4 hrs of on-line HDF has been examined [11], there is no report on the dosage design of VCM during HF-CHDF.
Here, we report a one-compartment model developed to aid dosage planning of VCM in an acute liver failure patient with anuria who was treated with VCM while receiving HF-CHDF. The results of VCM monitoring are also presented.
Case presentation
A 20-year-old woman (154 cm tall, weighing 50 kg), who had been under long-term prednisolone treatment for dermatomyositis and autoimmune hepatitis, was hospitalized with acute liver damage. On the 11th day of hospitalization, her prothrombin time (PT) activity was 25% and NH3 level was 113 μg/mL. She was diagnosed with acute liver failure and transferred to the intensive care unit (ICU). Plasma exchange (PE) was conducted and steroid pulse therapy was started. On the following day (ICU day 2), HF-CHDF (Fig. 1: The system employs on-line HDF in a predilution mode) was started because the NH3 plasma concentration was elevated and she was diagnosed with coma II hepatic encephalopathy. Thereafter, HF-CHDF was mainly used in combination with PE and continuous plasma filtration with dialysis (CPDF; a combination of slow, continuous PE and hemodiafiltration [12]) to replenish coagulation factors and to control the NH3 level.
On ICU day 6, the patient developed fever at night, and piperacillin/tazobactam (PIPC/TAZ) treatment (4.5 g, every 6 hrs) was started for suspected ventilator-associated pneumonia (Culture result: Supplemental Table). On ICU day 7, cervical rigidity was observed, and PIPC/TAZ was changed to cefepime (CFPM) (2.0 g, every 12 hrs) for suspected meningitis. On ICU day 8, PE with HF-CHDF was changed to CPDF, and the antibiotic therapy was switched to VCM with meropenem (MEPM) (2.0 g, every 8 hrs) to achieve distribution to the cerebrospinal fluid (Fig. 2). At this time, accurate assessment of renal function was difficult because serum creatinine was removed by the dialysis, and the estimated glomerular filtration rate (eGFR) was more than 150 mL/min/1.73 m2. Since urine output was maintained (> 0.5 mL/kg/hr), and renal function before admittance to ICU was preserved (eGFR> 100 mL/min/1.73 m2), a loading dose of 30 mg/kg and maintenance dose of 20 mg/kg VCM every 12 hrs were adopted, according to the TDM Guidelines for Antibiotics 2016 [6] (Japan, The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring).
On ICU day 9, due to elevated NH3 and prolonged disturbance of consciousness, dialysis was switched from CPDF to HF-CHDF again (flow rate: see Table 1), and PE was performed simultaneously for approximately 2 hrs. Meningitis was ruled out by spinal fluid examination, but fever and high inflammatory response persisted. VCM administration was continued because we could not rule out ventilator-associated pneumonia or catheter-related bloodstream infection associated with gram-positive cocci. On ICU day 10, the initial TDM for VCM was performed, and the blood level was under the detection limit (< 3.0 μg/mL), presumably due to the effects of HF-CHDF and PE. At the same time, the onset of anuria due to hepatorenal syndrome was noted. It was decided that a living donor liver transplantation (LDLT) would be performed 2 days later (ICU day 12), and HF-CHDF would be continuously performed until the day of LDLT. To maintain the VCM concentration in the therapeutic range prior to LDLT, the VCM dose was increased to 20 mg/kg every 6 hrs from the evening of ICU day 10 (MEPM was changed to 1.5 g every 6 hrs). The trough blood concentrations before the 3rd, and 4th (ICU day 11), and 7th (ICU day 12) VCM administrations were 9.5, 12.6, and 11.1 μg/mL, respectively. On ICU day 12, after the 7th administration of VCM, LDLT was conducted as scheduled and VCM administration was discontinued after the LDLT. No infection was apparent during VCM administration.
Discussion
In this case, administration of VCM according to the TDM guideline resulted in VCM concentrations below the therapeutic range during HF-CHDF. There is no report on the dosage design of VCM under conditions of enhanced clearance, such as HF-CHDF. We therefore adjusted the maintenance dosing schedule of VCM, and subsequent calculation of VCM blood concentration using a one-compartment model with the parameters shown in Table 1 supported the appropriateness of the adjusted dosage.
Clearance calculation
The total body clearance (CLtot) under dialysis is expressed as follows,
CLR:renal clearance, CLNR:non-renal clearance, CLHDF:HF-CHDF clearance.
Since the patient was anuric on ICU day 10 and VCM is excreted almost exclusively from the kidneys, CLtot could be approximated by CLHDF (Eq. 2).
Clearance never exceeds the liquid inflow rate to dialyzer (QB in) or the dialysis outflow rate (QHDF = QF + QD), and the slower flow is rate-determining in blood purification therapy [4, 15,16,17]. If QB in < QD + QF and assuming complete removal of the drug from the blood, the maximum clearance is defined by QB in.
Although QB in appears to be the blood flow rate (QB) + substitute fluid flow rate (QS) in the pre-dilution mode, the drug concentration is decreased by dilution before dialysis. Therefore, corrected clearance should be considered, since dilution reduce the efficacy of solute removal. In a previous report, corrected clearance (CL’) was defined [18] as follows:
where QBI’ is the blood flow rate before dilution, i.e., QB, and QBI is blood flow rate after dilution, i.e., QB + QS. Substituting Eq. (3) into Eq. (4) gives the following result for CL’:
If the dialysis outflow rate (QHDF = QD + QF) is greater than the blood flow rate (QB), clearance is limited by QB. In this case, QHDF was greater than QB, so clearance is defined by QB. In fact, only unbound drug in plasma is eliminated, so actual CLHDF can be expressed as follows [4].
Substitution of QB = 200 mL/min under this condition, Ht = 25% in this patient and fu = 0.65 from the literature value of VCM (Table 1) gave a calculated CLHDF value of 5.9 L/hr. The rate of disappearance (ke) of VCM in this patient was calculated as 0.17 hr− 1 based on Vd = 0.70 L/kg from the literature (Table 1) according to the following equation.
The t1/2 was calculated as 4.1 hrs using the formula t1/2 = ln2/ke.
Calculation of blood concentration
Since VCM is homogeneously distributed under steady-state conditions, a one-compartment model was applied. The steady-state blood concentration of the drug during intermittent infusion was approximated as follows,
R0: dosing rate, D: dose, t0: infusion time, τ: dosing interval, Css,max: maximum blood concentration, Css,min: minimum blood concentration.
To achieve a sufficiently high trough concentration while avoiding adverse effects, it is necessary to increase the frequency of dosing rather than the dosage amount, considering the short half-life of VCM. When a dose of 20 mg/kg was administered every 6 hrs, the values of Css,max and Css,min were calculated as 41.6 μg/mL and 15.2 μg/mL, respectively, from eq. 9 and 10. These values are suitable for VCM treatment, and based on the half-life of 4.1 hr, a steady state would be reached after the 3rd to 4th administration.
Comparison of measured and calculated values
The measured blood concentration was around 12 μg/mL at the 4th (ICU day 11) and 7th (ICU day 12) VCM administrations after dose escalation to 20 mg/kg every 6 hrs at ICU day 10. This lies within the effective range for preventing infection before LDLT.
Nevertheless, this measured concentration (around 12 μg/mL) was 20% lower than the calculated steady-state concentration of around 15 μg/mL, presumably due to factors such as non-renal clearance and changes in protein binding rate.
The systemic clearance of VCM in healthy adults is about 100 mL/min, and the urinary excretion rate of unchanged drug is more than 90% [13]. However, VCM is slowly excreted via an unknown route in patients without renal function [19]. Indeed, non-renal clearance of vancomycin was suggested to amount to 1.05 L/hr/70 kg [20, 21]. Moreover, the protein binding rate influences VCM clearance [22]. We applied a protein binding rate of 0.35 based on literature values in our clearance calculation, but it remains possible that the protein binding fraction was different because of inadequate albumin synthesis due to liver failure [23], hyperbilirubinemia, and the effect of pre-dilution of blood flowing into the dialyzer [24], which may have increased the measured CLHDF. All these factors might have contributed to a blood concentration lower than the calculated value. Thus, there is scope to increase the accuracy of the calculation of blood concentration by taking account of these factors.
In recent years, several academic societies in America (e.g., the Infectious Diseases Society of America) have recommended the use of AUC/MIC as an important biomarker for efficacy and safety evaluation [25], not just the trough concentration of VCM. In 2022, the Japanese TDM guideline was similarly revised, so the calculation of AUC should be employed in future work.
Conclusion
We report an acute liver failure patient with anuria under HF-CHDF who was treated with VCM. Dosage adjustment was required, and success was confirmed by calculation of VCM blood concentration using a one-compartment model. This calculation employs the HF-CHDF flow rate as a surrogate for clearance. Nevertheless, the measured VCM concentration was 20% lower than the calculated value (15 μg/mL), suggesting that other factors, such as non-renal clearance and protein binding rate, will need to be taken into account to improve the prediction of VCM concentration in patients under HF-CHDF.
Availability of data and materials
Not applicable.
Abbreviations
- CFPM:
-
Cefepime
- CL’:
-
Corrected clearance
- CLtot :
-
Total body clearance
- CLNR :
-
Non-renal clearance
- CLR :
-
Renal clearance
- CPDF:
-
Continuous plasma filtration with dialysis
- CRP:
-
C-reactive protein
- Css,max :
-
Maximum blood concentration
- Css,min :
-
Minimum blood concentration
- D:
-
Dose
- eGFR:
-
Estimated glomerular filtration rate
- fp:
-
Protein binding rate
- fu:
-
Protein unbound form
- HF-CHDF:
-
High-flow continuous hemodiafiltration
- Ht:
-
Hematocrit
- ICU:
-
Intensive care unit
- ke :
-
Rate of disappearance
- LDLT:
-
Living donor liver transplantation
- MEPM:
-
Meropenem
- MRSA :
-
Methicillin-resistant Staphylococcus aureus
- NH3 :
-
Ammonia
- on-line HDF:
-
On-line hemodiafiltration
- PE:
-
Plasma exchange
- PIPC/TAZ:
-
Piperacillin/tazobactam
- PT:
-
prothrombin time
- QB :
-
Blood flow rate
- QBI :
-
Blood flow rate after dilution
- QBI’:
-
Blood flow rate before dilution
- QB in :
-
Liquid inflow rate to dialyzer
- QD :
-
Dialysis flow rate
- QF :
-
Filtration flow rate
- QHDF :
-
Dialysis outflow rate
- QS :
-
Substitute fluid flow rate
- R0 :
-
Dosing rate
- t0 :
-
Infusion time
- τ:
-
Dosing interval
- T-Bil:
-
Total bilirubin
- VCM:
-
Vancomycin
- Vd:
-
Volume of distribution
References
Shinozaki H, Oda S, Abe R, et al. Blood purification in fulminant hepatic failure. Contrib Nephrol. 2010;166:64–72. https://doi.org/10.1159/000314854. Epub 2010 May 7
Yoshiba M, Inoue K, Sekiyama K, et al. Favorable effect of new lover support on survival of patients with fulminant hepatic failure. Artif Organs. 1996;20(11):1169–72. https://doi.org/10.1111/j.1525-1594.1996.tb00657.x.
Arata S, Tanaka K, Takayama K, et al. Treatment of hepatic encephalopathy by on-line hemodiafiltration: a case series study. BMC Emerg Med. 2010;10:10. https://doi.org/10.1186/1471-227X-10-10.
Pistolesi V, Morabito S, Mario F, et al. A guide to understanding antimicrobial drug dosing in critically ill patients on renal replacement therapy. Antimicrob Agents Chemother. 2019;63(8):e00583–19. https://doi.org/10.1128/AAC.00583-19. Print 2019 Aug
Urata M, Narita Y, Fukunaga M, et al. Simple formula for predicting drug removal rates during hemodialysis. Ther Apher Dial. 2018;22(5):485–93. https://doi.org/10.1111/1744-9987.12675. Epub 2018 Jul 10
Takesue Y, Omagari T, Okada K, et al. Vancomycin: TDM Guideline for Antibiotics, the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. Revised version. Tokyo: KYORINSHA; 2016. p. 35–58.
Petejova N, Martinek A, Zahalkova J, et al. Vancomycin removal during low-flux and high-flux extended daily hemodialysis in critically ill septic patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012;156(4):342–7. https://doi.org/10.5507/bp.2012.002. Epub 2012 Jan 30
Zelenitsky SA, Ariano RE, McCrae ML, et al. Initial vancomycin dosing protocol to achieve therapeutic serum concentrations in patients undergoing hemodialysis. Clin Infect Dis. 2012;55(4):527–33. https://doi.org/10.1093/cid/cis458. Epub 2012 May 9
Frazee EN, Kuper PJ, Schramm GE, Larson SL, Kashani KB, Osmon DR, et al. Effect of continuous venovenous hemofiltration dose on achievement of adequate vancomycin trough concentrations. Antimicrob Agents Chemother. 2012;56(12):6181–5. https://doi.org/10.1128/AAC.00459-12. Epub 2012 Sep 17
Tsuruyama M, Yamashina T, Tsuruta M, et al. Vancomycin pharmacokinetics in critically ill patients receiving continuous haemodiafiltration with a polyethyleneimine-coated polyacrylonitrile membrane. J Clin Pharm Ther. 2020;45(5):1143–8. https://doi.org/10.1111/jcpt.13197. Epub 2020 Jun 4
Sombolos KI, Fragidis SK, Bamichas GI, et al. Subtherapeutic serum vancomycin concentration during on-line hemodiafiltration. ASAIO J. 2011;57(6):507–10. https://doi.org/10.1097/MAT.0b013e3182306196.
Komura T, Taniguchi T, Sakai Y, et al. Efficacy of continuous plasma diafiltration therapy in critical patients with acute liver failure. J Gastroenterol Hepatol. 2014;29(4):782–6. https://doi.org/10.1111/jgh.12440.
Nakashima M, Katagiri K, Oguma T. Phase I studies on vancomycin hydrochloride for injection. Chemotherapy. 1992;40:210–24.
Lewis P. Vancomycin area under the curve simplified. Ther Drug Monit. 2018;40(3):377–80. https://doi.org/10.1097/FTD.0000000000000500.
Yamamoto T, Yasuno N, Katada S, et al. Proposal of pharmacokinetically optimized dosage regimen of antibiotics in patients receiving continuous hemodiafiltration. Antimicrob Agents Chemother. 2011;55(12):5804–12. https://doi.org/10.1128/AAC.01758-10. Epub 2011 Sep 12
Yamamoto T, Hisaka A, Suzuki H. Principle of dosage adjustment for patients receiving continuous renal replacement therapy (CRRT) based on the quantitative estimation of clearance by CRRT. Jpn J Nephrol Pharmacother. 2014;3(1):3–19.
Akashita G, Hosaka Y, Noda T, et al. PK/PD analysis of biapenem in patients undergoing continuous hemodiafiltration. J Pharm Health Care Sci. 2015;1:31. https://doi.org/10.1186/s40780-015-0031-6. eCollection 2015
Mineshima M, Hoshino T, Teraoka S, et al. Effect of dilution modality and filtration flow rate on solute removal characteristics in HF and HDF with high ultrafiltration. Jpn J Artif Organs. 1995;24(3):670–5.
Thomson Micromedex. United States Pharmacopeial Convention: Drug Information for the Health Care Professional 27th edition, vol. I; 2007. p. 2868.
Rotschafer JC, Crossley K, Zaske DE, et al. Pharmacokinetics of vancomycin: observation in 28 patients and dosage recommendations. Antimicrob Agents Chemother. 1982;22(3):391–4. https://doi.org/10.1128/AAC.22.3.391.
Emoto C, Johnson TN, McPhail BM, et al. Using a vancomycin PBPK model in special populations to elucidate case-based clinical PK observations. CPT Pharmacometrics Syst Pharmacol. 2018;7(4):237–50. https://doi.org/10.1002/psp4.12279. Epub 2018 Feb 15
Harada H, Miyagawa S, Kawasaki S, et al. Study of the pharmacokinetics of vancomycin in patients with impaired liver function. J Infect Chemother. 1999;5(2):104–7. https://doi.org/10.1007/s101560050018.
Oettl K, Stauber RE. Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties. Br J Pharmacol. 2007;151(5):580–90. https://doi.org/10.1038/sj.bjp.0707251. Epub 2007 Apr 30
Maheshwari V, Thijssen S, Tao X, et al. In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition. Sci Rep. 2019;9(1):909. https://doi.org/10.1038/s41598-018-37195-1.
Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2020;77(11):835–64. https://doi.org/10.1093/ajhp/zxaa036.
Acknowledgements
Not applicable.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
YI designed the study, collected and analyzed data, and wrote the first draft of the manuscript. JN, AS, RG, MO, SN, AF, TY, SY and TT designed the study, collected and analyzed data, and contributed to the writing of the manuscript. TS and YS supervised the project and contributed to the writing of the manuscript. All authors reviewed the results and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Since this is a case report, ethical approval was deemed unnecessary by the Medical Ethics Committee of Kanazawa University. Verbal consent was obtained from the patient.
Consent for publication
Not applicable.
Competing interests
The authors have no conflicts of interest to declare.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Ito, Y., Nakade, J., Seki, A. et al. Case report: therapeutic monitoring of vancomycin in an acute liver failure patient with anuria under high-flow continuous hemodiafiltration. J Pharm Health Care Sci 9, 15 (2023). https://doi.org/10.1186/s40780-023-00283-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s40780-023-00283-0