Feasibility of serum Cystatin C for predicting Vancomycin concentration in abdominal cancer patients with severe infectious disease

Background: This study was designed to investigate the population pharmacokinetics and impact indicator of vancomycin in abdominal cancer patients complicated with severe infectious disease. Methods: A total of 78 patients abdominal cancer patients complicated with severe infectious disease were included. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The patients were divided into early and delayed groups based on whether they achieve the target concentration. And clinical factors were compared between two groups. Results: The average initial therapeutic dose of vancomycin was 15.18±3.29 mg/kg (q12h). The research revealed that the abdominal cancer patients complicated with severe infectious disease had significantly lower initial vancomycin trough concentrations (median [IQR]: 6.90[5.28-11.20] mg/L). Multiple regression analysis revealed that Cys-C was the most important variable for vancomycin target trough achievement. The duration of mechanical ventilation in Early group was considerably shorter compared with group Delayed group (χ2=4.532; p < 0.05; Fig 1E). Propensity score weighting further confirmed that the duration of mechanical ventilation (χ2=6.607; p < 0.05; Fig 1F) and vasoactive agent (χ2=6.106; p < 0.05; Fig 1D) was considerably shorter compared with group Delayed group. Conclusions: The steady-state initial vancomycin trough concentration was significantly reduced in abdominal cancer patients complicated with severe infectious disease. The baseline Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether


Introduction
Vancomycin is a bactericidal glycopeptide antibiotic which inhibits bacterial growth by hindering the synthesis of cell wall in bacteria. It has strong antibiotic effect on Gram-positive bacteria. It includes methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus, or methicillin-resistant Staphylococcus epidermidis (MRSE) [1]. The pharmacokinetic-pharmacodynamic breakpoint of vancomycin is defined as the ratio of the area from 0 to 24 hours (area under the curve (AUC) 0-24) under the concentration-time curve to minimal inhibitory concentration (MIC), and is at least 400 h in adults with Staphylococcus aureus pneumonia [2]. Intravenous vancomycin mainly combined with albumin and IgA, protein-bound protein is 25% to 50%, almost completely eliminated by the renal pathway. Therefore, the most important factor in determining vancomycin dosage is renal function [3]. Therapeutic drug monitoring (TDM) as an optimizing vancomycin therapy is widely recommended for avoiding secondary clinical complications because of its narrow therapeutic window, such as vancomycin toxicity due to over-dosing or resistance due to under-dosing [3].
Patients with malignant tumors represent a critical population in whom empirical antibacterial therapy deficiency may significantly increase infection-related morbidity and mortality. In addition, previous studies have demonstrated that the pharmacokinetic parameters of cancer patients often exhibit different characteristics compared to non-cancer patients [4] [5], so optimizing drug dosing regimens is critical. Researches have shown that vancomycin has a significantly increased clearance rate in adults with hematologic malignancies compared to adults without malignant tumors, but there is insufficient pharmacokinetic data. [6] [7]. Therefore, we aimed to elucidate the possible effects of this pharmacokinetic difference on conventional vancomycin treatment and conducted a retrospective researcher to study the influencing factors of the trough concentrations for vancomycin dose adjustment in abdominal cancer patients complicated with severe infectious disease. Data collection: Demographic data obtained included age, gender, admission diagnosis, acute physiology and chronic health assessment II score (Apache II score) at admission to the ICU. For the treatment program, daily doses, interval time, and the occurrence of acute kidney injury (AKI) and renal replacement therapy (RRT) were recorded.
New-onset acute kidney injury was defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) stage II criteria after at least 24 hours and within 7 days of vancomycin administration initiation [10]. The duration of the vasoactive agent, the duration of mechanical ventilation, the duration of the antibiotic, and the 28-day all-cause mortality were also recorded. The definition of clinical outcomes after cessation of the study drug, including clinical success and clinical failure, are shown in Table 1. Finally, inverse probability of treatment weighting (IPTW) was used to measure participants based on the estimated exposure probability (the propensity score) for a given confounding factor to balance the observed confounding factors between the early and delayed groups.

Statistical analysis
Values for categorical variables are given as count (percentage), for continuous variables, as mean±standard deviation or as median [interquartile range]. Pearson 2 testwas used for categorical variables, and t test was used for continuous variables.
Univariate and multivariate analysis is used for covariates associated with target trough achievement. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using the SPSS statistical package (version 24.0, SPSS Inc., Chicago), P 0.05 was considered statistically significant.

Results
A total of 78 patients were enrolled, all of whom received recommended standard vancomycin dosage adjustment. Clinical characteristics, pharmacokinetic parameters and clinical outcomes of the included patients were summarized in  28-11.20] mg/L) than the recommended standard vancomycin trough concentrations (10-15 or 15-20 mg/L).
The overall relationship between trough concentrations and potential covariates was screened by Univariate and multivariate analysis to explore potential information covariates. There was a strong correlation between vancomycin trough concentration and age, body weight, serum creatinine and serum Cystatin C level (Cys-C) ( Table 4). Multivariate regression analysis revealed that the Cys-C was the most important variable for vancomycin target trough achievement (odds ratio, 5.274; 95% CI, 1.780 to 15.627; p = 0.003) ( Table 4).
We divided patients into Early group and Delayed group based on whether the initial trough concentration achieved the target concentration. Although the Clinical outcomes were similar between two groups in Table 5 (e. g., the incidence of newonset AKI or RRT, clinical success rate, 28-day all-cause mortality), the duration of mechanical ventilation in Early group was considerably shorter compared with Delayed group (χ 2 = 4.532; p < 0.05; Fig 1E). Compared with Delayed group, propensity score weighting (IPTW) further confirmed that the duration of mechanical ventilation (χ 2 = 6.607; p < 0.05; Fig 1F) and vasoactive agent (χ 2 = 6.106; p < 0.05; Fig 1D) in Early group were considerably decreased.

Discussion
Of these 78 patients, small number of patients achieved the target level. The standard vancomycin dose recommended in the package instructions approved by the Chinese authorities appears to be too low to achieve the target trough concentrations in clinical practice. The reason for this result may be because the standard vancomycin administration algorithm was developed based on data from relatively healthy patients. Therapeutic drug monitoring of vancomycin is widely recommended for clinical treatment[11] [9]. However, few studies have been available to evaluate vancomycin (VCM) pharmacokinetics in abdominal cancer patients complicated with severe infectious disease. The aim of this study was to address the above issues and sought to find clinically useful information to predict and estimate the appropriate dosage of vancomycin. The conclusion is that initial vancomycin trough concentrations are significantly reduced in these patients. We also found that Cys-C was associated with target trough achievement. Accordingly, the traditional standard dose of vancomycin may result in a high risk of failing to achieve the recommended standard vancomycin trough concentrations. This finding confirms the need to design more effective guidelines for individualized vancomycin In this research, we observed a strong correlation between vancomycin trough concentrations and age, body weight, serum creatinine and especially the Cys-C.
This research confirmed the relationship between Cys-C and vancomycin trough concentrations for the first time in abdominal cancer patients. Cys-C is a nonglycosylated, low molecular weight basic protein composed of 120 amino acids [22].
Human Cys-C is a housekeeping gene and is stably produced by all human nucleated cells [22]. In earlier studies, Cys-C was considered to be independent of age, muscle There are several potential limitations in research. Firstly, the samples collected in this study were too limited to accurately assess the pharmacokinetics of vancomycin. Secondly, this is single-center and observational study with bias in case selection. Thirdly, inappropriately timed vancomycin trough concentration determination is a general challenge for therapeutic drug monitoring and is present regardless of the vancomycin administration algorithm used.

Conclusion
The serum initial trough concentration of vancomycin was significantly reduced in abdominal cancer patients complicated with severe infectious disease. Clinicians should pay special attention to changes in vancomycin pharmacokinetic, and higher dosage regimens are needed to ensure clinical effectiveness. The Cys-C level measured prior to vancomycin was administered is considered to be a potentially valuable parameter for predicting whether the vancomycin trough concentration is up to standard. Further, this study is promising, prospective validation of this or a similar Cystatin C-inclusive dosing model is warranted.

Acknowledgment
We thank the health professional staff from Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital.

Ethics approval and consent to participate
This retrospective cohort study was agreed by the Ethics Committee and approval from the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital and waived the requirement to obtain informed consent

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interest
All authors reported no competing interests.

Funding
The study was supported by a grant from the Oncology and Translational Medicine of Tianjin Medical University Cancer Institute and Hospital, China (No. 1611). The funders had no role in study design, data collection, data analysis, and data interpretation or writing of the manuscript.

Authors' Contributions
Xiaowu Zhang Donghao Wang were involved in the concept, interpretation of the data and writing of the manuscript. Xiaowu Zhang was involved in the statistical analyses and the writing of the manuscript.    Figure 1 Kaplan-Meier curves for (A) Duration of Antibiotics between the two groups before weighting