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Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, GermanyCentre for Individualised Infection Medicine a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany
# CirPK – Study Group: Thorsten Book, Birgit Bremer, Benjamin Schulte, Michael P. Manns, Heiner Wedemeyer, Korbinian Brand † JJS and BM contributed equally. ☆ Guest Editor: Dominique Valla
Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital.
With great interest, we read the study of Wong et al. who investigated risk factors for an acute-on-chronic liver failure (ACLF) in patients with decompensated cirrhosis and bacterial infections. Spontaneous bacterial peritonitis (SBP) was the most frequent site of infection and an independent risk factor for ACLF development. Moreover, ACLF was more common in patients infected with multidrug resistant bacteria (MDRB) and those with an insufficient response to the initial antibiotic treatment.
Their study once more underlines the critical role of fast and adequate antibiotic treatment in patients with decompensated cirrhosis.
However, adequate anti-infective drug administration is challenging in these patients. Decompensated cirrhosis is often accompanied by impaired kidney function, which may cause drug accumulation and increased drug toxicity.
Inadequate anti-infective drug levels may lead to insufficient or delayed treatment responses, increasing the risk of MDRB or further complications such as ACLF.
Current EASL guidelines recommend using a carbapenem for treatment of nosocomial SBP (nSBP).
Of note, detailed data on pharmacokinetics of meropenem in patients with advanced liver disease, especially with regard to the ascites compartment, are lacking. Therefore, we decided to investigate the pharmacokinetics and pharmacodynamic target attainment in plasma and ascites of the current meropenem dosing practice in patients with decompensated cirrhosis and nSBP.
Patients with decompensated cirrhosis and nSBP were prospectively enrolled. Further inclusion criteria were initiation of meropenem therapy and paracenteses by transient peritoneal catheter. Exclusion criteria were age <18 years, chronic kidney failure (CKD >4), symptomatic anemia and/or a hemoglobin-level <7 g/dl, pregnancy/lactation period and missing ability to give consent. The meropenem dosing regimen was chosen by the treating physician independent of participation in the study. At day 1 and once between treatment day 3-5, plasma and ascites samples were collected 0, 15, 30, 45, 60, 120, 480, 510, 960 minutes after meropenem infusion. On the remaining treatment days 1 plasma and 1 ascites sample were collected before the first meropenem infusion. The minimal inhibitory concentration (MIC, 2 mg/L) was defined for meropenem susceptible Enterobacterales according to “EUCAST”.
All patients provided written informed consent. The study was approved by the local ethics committee (No.7912) and registered at clinicaltrials.gov (NCT03571711).
A total of 100 plasma and 110 ascites samples were collected from 7 patients. All but 1 patient received a short initial meropenem infusion (30 min), 1 patient was treated with an initial prolonged infusion (4 h). Prolonged infusion was used in 4 patients and short infusions in 3 patients during further treatment. SBP resolved in 6 patients, while a further increase of polymorphonuclear cells in the ascites was documented in 1 patient (Table 1). Trough concentration (Cmin) of meropenem was similar in plasma and ascites (12.4 vs. 12.2 mg/L, p = 0.565) (Fig. S1). However, peak concentrations (Cmax) differed significantly between plasma and ascites (44.7 vs. 26.0 mg/L, p = 0.008). Accordingly, the AUC0-8 was 178 mg∗h/L in plasma and 124 mg∗h/L in ascites. While median time to Cmax was 30 min in blood, it was 120 min in ascites (Fig. 1). However, the MIC was exceeded in ascites within 15 min after the first infusion in all patients and remained above the MIC in both compartments at all times. Furthermore, in all patients 4∗MIC was reached in plasma and ascites at least during 44% of treatment time. The median prescribed meropenem dose was 3 g/day. Acute kidney injury was present at the time of study inclusion in 5 patients. As recommended in severe infections, meropenem dosage was not strictly adjusted according to kidney function
Patient one was not taken into consideration for medium concentration as the application form differed (prolonged infusion over 4 h). Meropenem concentrations were measured using a certified HPLC method. HPLC, high-performance liquid chromatography; MIC, minimal inhibitory concentration. (This figure appears in color on the web.)
therefore, early adequate drug levels at the infection site (ascites fluid) are required. While exact pharmacodynamic targets in nSBP are still unclear, Cmin/MIC ratios of at least 4 are beneficial in severe respiratory infections.
With a median trough concentration of 12.4 mg/ml, the Tc was at least >4∗MIC for 44% of the treatment time and >1∗MIC for 100% of the treatment time. Although intraperitoneal application of meropenem is feasible in non-cirrhotic patients undergoing peritoneal dialysis, the fast attainment of drug concentrations above the MIC in ascites documented in our study does not implicate the need for a different route of drug administration in nSBP. Of note, only moderate dose adjustments in patients with acute kidney injury were applied in our study, as widely recommended for patients with severe illness/infections.
Despite the high trough concentration, no meropenem-associated side effects were reported. Retrospective studies associated trough concentrations of >64.2 mg/L and >44.45 mg/L with a 50% risk of developing neurotoxicity and nephrotoxicity events, respectively.
In summary, the current treatment practice of nSBP with meropenem provides early effective drug levels in plasma and ascites without reaching toxic concentrations.
Financial support
MS and this work were supported by the ‘KlinStrucMed Programm – Promotionskolleg’ funded by the Else Kröner-Fresenius-Stiftung. BM was supported by the “Clinician Scientist”-program (Junge Akademie) of Hannover Medical School.
Authors’ contributions
B.M. and J.J.S. designed the study. M.S., B.M., D.G. and J.J.S. collected the samples and analyzed the data. All authors substantially contributed to the interpretation of the data. B.M., J.J.S., M.C. and M.S. drafted the manuscript. All authors critically revised the manuscript. All authors approved the manuscript to be published and therefore are accountable for all aspects of the work. B.M. and J.J.S. supervised the work.
Data availability statement
To ensure the privacy of the participating patients further research data remains confidential and is not available.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Acknowledgement
We thank the patients participating in the study.
Supplementary data
The following are the supplementary data to this article:
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