Therapeutic Drug Monitoring and Impact Indicator of Vancomycin Pharmacokinetics in Abdominal Cancer Patients complicated with Severe Infectious Disease

doi:10.21203/rs.2.9533/v1

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Therapeutic Drug Monitoring and Impact Indicator of Vancomycin Pharmacokinetics in Abdominal Cancer Patients complicated with Severe Infectious Disease

https://doi.org/10.21203/rs.2.9533/v1

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Abstract Objective: This study was designed to investigate effectiveness of therapeutic drug monitoring (TDM) and impact indicator of vancomycin pharmacokinetics 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). Ultimately, we collected 78 patient‘s trough concentrations data. 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) compared with the recommended standard goal vancomycin trough concentration (10-15 or 15-20 mg/L). Multiple regression analysis revealed that Cys-C was the most important variable for vancomycin target trough achievement. We divided patients into early and delayed groups based on whether the initial trough concentration achieved standard goal trough concentration. Although the clinical outcomes were similar between two groups, 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. Higher initial dosage regimen is needed to ensure clinical effectiveness. The baseline Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Early attainment of target concentration significantly improved hemodynamic stability and reduced duration of mechanical ventilation.

Infectious Diseases

Vancomycin

Abdominal cancer

Trough concentration

Pharmacokinetics

Severe infectious

Vancomycin is a bactericidal glycopeptide antibiotic which inhibits bacterial growth by hindering the synthesis of cell wall in bacteria. It exerts strong antibiotic effect to 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 under the concentration-time curve from 0 to 24 hours (area under the curve (AUC) 0-24) 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 inadequate empirical antibacterial therapy may lead to increased infection-related morbidity and mortality. In addition, previous studies have confirmed that pharmacokinetic parameters often exhibit different characteristics than patients with non-cancer diseases [4] [5], making optimization of drug dosing regimen essential. Research confirms that vancomycin has an increased clearance rate in adults with malignant hematological disease compared with adults without malignant tumors, but the pharmacokinetic data are limited [6] [7].Therefore, we aimed to clarify the possible impact of this difference in pharmacokinetic on the routine vancomycin therapy and conducted a retrospective study on the factors influencing the trough concentrations for vancomycin dose adjustment in abdominal cancer patients complicated with severe infectious disease.

Subjects: Between February 2014 to June 2017, we retrospectively reviewed 78 patients of abdominal cancer aged more than 18 years who were complicated with severe infectious disease and who were treated in the intensive care unit of Tianjin Cancer Hospital (Tianjin, China). This clinical trial was agreed by the Ethics Committee and approval from the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital and complied with the Declaration of Helsinki. And their data were collected from the clinical charts. All patients received vancomycin therapy for more than five estimated terminal disposition half-lives, by which time serum vancomycin levels were supposed to have reached a steady state. Human subjects with poor kidney function (CLcr <50 mL/min), pregnant and lactating women, hemodialysis patients were excluded. Other anti-infective treatments were administered if patient condition needs.

Pharmacokinetic analysis and Vancomycin therapeutic drug monitoring (TDM):

The vancomycin dosage was administered over a 1-hour period. The steady state vancomycin trough concentration was measured prior to subsequent treatment to adjust dose and dose intervals [8] . The target serum vancomycin trough concentrations ranged from 10-15 or 15-20 mg/L[9].Serum vancomycin concentrations were measured by FPIA method using a Cobas 6000 c501 analyzer (Roche Diagnostics, China). Meanwhile, the laboratory staff records information about each specimen, including gender, age, body weight, serum creatinine concentration, daily dosage, dose interval, infusion time, sampling time since infusion end and measure concentration for pharmacokinetic analysis.

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 c² test was 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.

A total of 78 patients received recommended standard vancomycin dosage adjustment. Clinical characteristics, pharmacokinetic parameters and clinical outcomes are summarized in Table 2 and Table 3. Our research revealed that the abdominal cancer patients complicated with severe infectious disease have a significantly lower initial vancomycin trough concentration (median [IQR]: 6.90[5.28-11.20] 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 new-onset 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 (χ²=4.532; p < 0.05;Fig 1E). Propensity score weighting (IPTW) 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) in Early group were considerably shorter compared with Delayed group.

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. 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 [12], 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[13]. 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 [14]. 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 [15] [16].

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 [17].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 [18], 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 [19]. 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 [20]. 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 [19]. 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 [21]. 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 [22]. Human Cys-C is a housekeeping gene, and serum Cys-C is stably produced by all human nucleated cells [22]. In earlier studies, Cys-C was assessed to be independent of age, muscle mass or body mass index in healthy individuals [23]. Although previous studies have shown a significant correlation between serum Cys-C levels and malignant progression of colorectal cancer, melanoma and ovarian cancer [24], recent studies confirmed that Cys-C can be very effective in predicting renal function in cancer patients [25] [26]. 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 [27].

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.

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 conclusion still requires larger studies to confirm these observations, which will assist in establishing guidance of vancomycin dosing algorithm.

APACHE II, acute physiology and chronic health evaluation II;

AKI, acute kidney injury;

Cys-C, Cystatin C;

RRT, renal replacement therapy;

SOFA, Sequential Organ Failure Assessment;

VCM, Vancomycin.

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

The authors declare that they have 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. Yang Lyu was involved in the statistical analyses and the writing of the manuscript.

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Table 1．Clinical outcome definitions after study drug cessation

Clinical response	Definition
Clinical success	1. Cure or improvement of all signs and symptoms caused by the infection
	2. No additional antibiotic therapy required
Clinical failure	1. Persistent or worsening of any one of the clinical symptoms
	2. New clinical signs and symptoms of infection
	3. Other systemic antimicrobial therapy required

Table 2. Vancomycin Levels Achieved and Clinical Outcomes (n=78)

Characteristics
Sex (male/female)	17/61
Age (years)	65.04±12.72
	65[57-63]
Body weight(kg)	24.74±3.68
	79[71.5-86]
Apache II score	20.05±2.92
	19[18-22]
SOFA score	13.15±2.25
	13[12-15]
Albumin (g/L)	27.89±6.14
	28.20[24.85-32.30]
Serum creatinine (μmol/L)	68.74±22.97
	56.0[46.0-84.5]
Cys-C(mg/L)	1.237±0.560
	1.105[0.770-1.418]

Cancer type, n(%)
Hepatocellular carcinoma	16(20.5)
Pancreatic cancer	6(7.7)
Colorectal cancer	22(28.2)
Gastric cancer	32(41.0)
Gallbladder cancer	2(2.6%)

Suspected source of infection
Pulmonary	39(50)
Intra-abdominal	28(35.9)
Surgical incision	3(3.8)
Other/unknown	8(10.3)

Identified pathogens, n (%)
methicillin-resistant Staphylococcus aureus	21(26.9)
methicillin-resistant Staphylococcus epidermidis	12(15.4)
Enterococcus	35(44.9)
Other Gram-positive coccus	10(12.8)

Abbreviations: APACHE II, acute physiology and chronic health evaluation II; SOFA, Sequential Organ Failure Assessment; Cys-C, Cystatin C.

Table 3. Vancomycin Levels Achieved and Clinical Outcomes (n=78)

Characteristic
Initial dose (daily), n (%)
1000–2000 mg	4(5.1）
2001–3000 mg	50 (64.1）
＞3000 mg	24 (30.8）
Average daily dosage (mg/kg, q12h)	15.18±3.29
	15.38[14.29-19.27]
Vancomycin trough concentration, n (%)
＜10mg/L	55 (70.5)
10-15 mg/L	15 (19.3)
15-20 mg/L	8 (10.3)
Average trough concentration (mg/L)	8.26±5.01
	6.90[5.28-11.20]
Duration of vasoactive agent(day)	4[2-5]
Duration of ventilation(day)	4[3-5]
Duration of antibiotics(day)	5[5-7]
Composite outcome of new-onset AKI or RRT	7 (9.0)
Clinical success rate, n (%)	58(74.4)
28-day all-cause mortality	4 (5.1)

Abbreviations: AKI, acute kidney injury; RRT, renal replacement therapy.

Table 4. Univariate and Multivariate Analysis of Covariates Associated With Target Trough Achievement

	Univariate Analysis			Multivariate Analysis
Variants	OR	95% CI	p	OR	95% CI	p
Sex	1.470	0.423-5.105	0.544
Age (years)	1.057	1.003-1.114	0.039*	1.152	0.997-1.331	0.054
Body weight(kg)	1.057	1.002-1.116	0.043*	0.929	0.804-1.073	0.315
Apache II score	1.016	0.863-1.198	0.846
SOFA score	1.006	0.809-1.250	0.959
Albumin (g/L)	1.007	0.925-1.097	0.864
Serum creatinine (μmol/L)	1.018	1.002-1.035	0.032*	1.018	0.993-1.045	0.158
Cys-C(mg/L)	5.249	1.972-13.972	0.001*	5.274	1.780-15.627	0.003*

*p＜0.05

Abbreviations: APACHE II, acute physiology and chronic health evaluation II; SOFA, Sequential Organ Failure Assessment; Cys-C, Cystatin C.

Table 5． Patients’ Baseline Data Before and After Propensity Score Weighting (n=78)

	Entire Cohort				Propensity Score Weighting
Characteristics	Delayed group	Early group	c²	P	Delayed group	Early group	c²	P
	(n=55)	(n=23)			(n=23)	(n=23)
Age,years
Mean±S.D.	62.65±11.87	68.78±10.45		0.035*	65.22±10.76	68.78±10.45		0.260
Median(range)	65(56-70)	68(61-76)			67(60-74)	68(61-76)
Sex,n(%)				0.542				0.381
Male	42（76.4%）	19（82.6%）			21（91.3%)	19（82.6%）
Female	13（23.6%）	4（17.4）			2(8.7%)	4（17.4）
Body weight,kg
Mean±S.D.	75.53±12.38	81.61±9.302		0.038*	78.52±11.63	81.61±9.30		0.326
Median(range)	77(69-83)	84(75-88)			80(72-87)	84(75-88)
Apache II score on ICU
Mean±S.D.	19.51±2.73	19.65±3.60		0.849	20.00±2.73	19.65±3.60		0.714
Median(range)	19(18-22)	20(17-22)			20(17-22)	20(17-22)
SOFA score
Mean±S.D.	13.15±2.41	13.17±1.87		0.974	13.70±2.55	13.17±1.87		0.307
Median(range)	13[11-15]	13[12-14]			13[12-15]	13[12-14]
Albumin (g/L)
Mean±S.D.	27.86±5.50	28.10±6.53		0.867	27.24±3.70	28.10±6.53		0.587
Median(range)	28.0(25.7-32.3)	29.4(23.7-33.5)			27.7(25.7-29.4)	29.4(23.7-33.5)
Serum creatinine (μmol/L)
Mean±S.D.	62.73±29.81	79.00±26.24		0.026*	81.09±32.46	79.00±26.24		0.812
Median(range)	50(42-77)	76(63-89)			74(53-105)	76（63-89）
Clinical Outcomes
Composite outcome of new-onset AKI or RRT	4(7.3)	3(13.0)	0.143	0.705	4(17.4)	3(13.0)	0.000	1.000
Clinical success rate, n (%)	39(70.9)	19(82.6)	1.164	0.281	16(69.6)	19(82.6)	1.075	0.300
28-day all-cause mortality	4	0	0.585	0.444	3(13.0)	1(4.3)	0.274	0.601

*p＜0.05

Abbreviations: APACHE II, acute physiology and chronic health evaluation II; SOFA, Sequential Organ Failure Assessment，AKI, acute kidney injury; RRT, renal replacement therapy。

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Therapeutic Drug Monitoring and Impact Indicator of Vancomycin Pharmacokinetics in Abdominal Cancer Patients complicated with Severe Infectious Disease

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Abstract

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Background

Methods

Results

Discussion

Conclusions

Abbreviations

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References

Tables

Table 1．Clinical outcome definitions after study drug cessation

Table 2. Vancomycin Levels Achieved and Clinical Outcomes (n=78)

Table 3. Vancomycin Levels Achieved and Clinical Outcomes (n=78)

Table 4. Univariate and Multivariate Analysis of Covariates Associated With Target Trough Achievement

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