Therapeutic drug monitoring of vancomycin is widely recommended for clinical treatment . 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. This study clearly demonstrated the changes in the pharmacokinetic profile of vancomycin in abdominal cancer patients complicated with severe infectious disease for the first time. 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 useful guidelines for vancomycin dosage individualization in abdominal cancer patients complicated with severe infectious disease.
Previous studies have shown that malignant tumors themselves may have an impact on VCM PKs , in addition to changes in volume of distribution due to edema, peritoneum or pleural effusion. Chang et al. reported an increase in VCM clearance(CL) in pediatric cancer patients using the 2-compartment Bayesian PK approach and this was also confirmed in adult hematological malignancies. On the other hand, there are also different viewpoint, Omote et al. showed no significant differences in estimated VCM clearance between cancer patients and non-cancer patients, suggesting dosage adjustment by routine TDM only . Nevertheless, Shimada et al. proposed a direct activation of the renal organic anion/cation transporters (OCT1/2, OATs) by cytokines such as TNF-α, which indeed increased in the context of cancer in vivo experiments  .
Severe infectious disease was frequently combined with the development of systemic inflammatory response syndrome (SIRS). This inflammatory response leads to vasodilatation, capillary leakage and the development of hyperdynamic cardiovascular state characterized by third-space, high cardiac output and increased blood flow to the major tissue and organ .As water soluble, vancomycin is primarily cleared by the kidneys. Increased CL is very likely due to increase in renal blood flow, which enhances the elimination of vancomycin by urine and leads to a decrease in plasma vancomycin concentration. And increased volume of distribution (Vd) is usually attributed to the third space induced by SIRS , which results in significant overhydration. However, the underlying mechanism for increasing vancomycin CL and Vd still need further studied.
Recently, augmented renal clearance (ARC) has been proposed to describe the enhancement of renal elimination of circulating solutes observed in critically ill patients . Most studies have shown that hyperdynamic circulation is characterized by increased renal blood flow with an increase in glomerular filtration rate as a potential mechanism . Nevertheless, no information was given concerning the number of oncological patients in these studies. Previous study found that the risk factors for ARC are age, sepsis, and SIRS . Thus, the increased vancomycin CL observed in this study was very likely associated with ARC but not oncological status. However，Curth et al. had different opinions . They believed that oncological status can also cause occurrence of ARC. Considering that the study is only a case report, this opinion should be treated with caution. In practice, there is no guidance for this treatment and ARC has not been taken seriously in clinical work in China. Clinicians usually do not seriously consider increasing the dose even though dose adjustment is allowed at their discretion and the actual therapeutic drug monitoring results showed very low concentrations.
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. And our research strongly recommends that abdominal cancer patients require higher dose regimens.
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 non-glycosylated, low molecular weight basic protein containing 120 amino acids . Human Cys-C is a housekeeping gene, and serum Cys-C is stably produced by all human nucleated cells . In earlier studies, Cys-C was assessed to be independent of age, muscle mass or body mass index in healthy individuals . Although previous studies have shown a significant correlation between serum Cys-C levels and malignant progression of colorectal cancer, melanoma and ovarian cancer , recent studies confirmed that Cys-C can be very effective in predicting renal function in cancer patients  . These features partially explain the relationship between Cys-C and vancomycin trough concentrations.
This observational study was done on a real-time clinical practice. Since the serum Cys-C is readily available in clinical practice, these parameters may allow physicians and/or pharmacists to predict vancomycin dose requirements in a short period of time. Earlier identification of insufficient vancomycin trough concentrations could be used to optimize antimicrobial adequacy. Earlier initial goal vancomycin trough concentration achievement means shorter duration of mechanical ventilation, and shorter duration of vasoactive agent, which means earlier hemodynamic stability. With this conclusion, clinicians should be able to adjust the dose of vancomycin confidently. For specific dose adjustment algorithm, we need further research. Recently, Erin Frazee et al have confirmed that vancomycin dosing algorithm based on estimated glomerular filtration rate from creatinine and Cys-C levels significantly improved goal trough achievement compared to Cockcroft-Gault creatinine clearance among ICU patients with stable kidney function .
There are several potential limitations in research. First, the samples collected in this study were too limited to accurately assess the pharmacokinetics of vancomycin. Second, this is single-center and observational study with bias in case selection. Third, Inappropriately timed vancomycin trough concentration determination is a general challenge for therapeutic drug monitoring and is present regardless of the vancomycin administration algorithm used.