Study design and microbiological definitions
Between January 2008 and December 2017, patients with confirmed HCC presenting at the Department of Internal Medicine 1 of the Frankfurt University Hospital were included in this study. HCC was diagnosed according to current guidelines by dynamic imaging techniques with 4‐phase multidetector computed tomography (CT) scan or dynamic contrast‐enhanced magnetic resonance imaging (MRI) and the typical hallmark of HCC (hypervascularity in the arterial phase with washout in the portal venous or delayed phases) or by histopathological examination of biopsies taken from liver tumors or metastases (European Association for the Study of the Liver 2018).
BCLC stage, model of end‐stage liver disease (MELD) score, Child–Pugh score and Albumin–Bilirubin (ALBI) grade were assessed by clinical examination, laboratory parameters and the results of ultrasound, CT scans and MRI imaging (Llovet et al. 1999; Kamath et al. 2001; Pugh et al. 1973; Johnson et al. 2015). The BCLC stage determined HCC treatment (European Association 2012). Briefly, patients with early stage HCC within the Milan criteria were either listed at Eurotransplant for liver transplantation, received resection or local ablative therapy by radiofrequency ablation (RFA). HCC patients with intermediate or advanced disease received treatment of HCC with local ablative therapy including RFA, TACE or systemic treatment as recommended by the current guidelines. Patients with end‐stage HCC received best supportive care.
The study was performed in accordance with the Declaration of Helsinki. The study was approved by the institutional review board of the Frankfurt University Hospital.
Screening procedure and definitions
According to German infection law (Infektionsschutzgesetz, IfSG, initially decided in the year 2001) an infection control protocol to prevent the transmission of MDRO is required (Bundesministerium der Justiz und für Verbraucherschutz 2019). At the University hospital Frankfurt, this legal requirement by IfSG and the recommendations of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute, Berlin, Germany were updated regularly and entirely fulfilled (Robert Koch Institut 2012). Patients reporting defined risk factors, e.g., arriving from high-prevalence countries and patients, e.g., admitted to oncology wards are systematically screened for MDRO at the day of admittance by nasal, rectal and pharyngeal swabs (Reinheimer et al. 2016, 2017).
MDRO were defined as Enterococcus faecalis or Enterococcus faecium with vancomycin resistance (VRE), Methicillin-resistant Staphylococcus aureus (MRSA) and MDRGN. MDRGN were defined as Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Proteus mirabilis with extended spectrum beta-lactamase (ESBL)-like phenotype as well as Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa resistant against piperacillin, any 3rd/4th generation Cephalosporin, and fluoroquinolones ± carbapenems. MDRGN with resistance against carbapenems have been described as Carbapenem-resistant Enterobacteriaceae (CRE) (Temkin et al. 2014).
Patients with a detection of MDRO before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients. Patients in which never a MDRO was detected were defined as noncolonized HCC patients. Patients who acquired MDRO later than 90 days after HCC diagnosis and patients that never received MDRO screening were not further investigated.
Detection of MDRO
For MDRO, screening culture swabs were transferred from Amies collection and transport medium onto selective agar plates for the detection of VRE, MRSA and MDRGN. Species identification was performed by Matrix-assisted laser desorption ionization–time-of-flight analysis (VITEK MS, bioMérieux, Nürtingen, Germany; since the year 2011) or biochemical analysis. Antimicrobial susceptibility testing was performed according to guidelines set by Clinical and Laboratory Standards Institute (CLSI) and using VITEK 2 since the year 2010 (bioMérieux), antibiotic gradient tests or disc diffusion method.
This study was designed as a retrospective cohort study. All patients with diagnosed HCC were retrospectively collected from the patient’s documentation system. They were followed up until death or last contact. The primary end point was overall survival. Continuous variables are shown as means ± standard deviation and categorical variables are reported as frequencies and percentages. Differences between different patient cohorts were determined using the nonparametric Wilcoxon–Mann–Whitney and Kruskal–Wallis tests. For sub‐analysis of a statistically significant Kruskal–Wallis test, the Bonferroni correction was used. P values < 0.05 were considered to be significant. Predictors of survival were determined using a univariate Cox regression hazard model. Death was recorded as event. For assessment of independent predictors of survival, a multivariate Cox regression hazard model with forward stepwise (likelihood ratio) entry was used. Survival curves with the estimated hazards were calculated with the Cox regression model. Statistical analyses were performed with SPSS (Version 27.0, IBM, New York, USA) and GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA, USA).