
==== Front
BMC Infect Dis
BMC Infect Dis
BMC Infectious Diseases
1471-2334
BioMed Central London

39256640
9862
10.1186/s12879-024-09862-4
Research
Association of procalcitonin with voriconazole concentrations: a retrospective cohort study
Zhou Ju-Xiang 1
Xiong Chun-Lin 1
Chang Zao-Shang 2
Yin You-Cong 1
Su Kai-Peng 2
Zhang Ji-Hong zhangjihong1125@126.com

1
Wu Ji-Chu wujichu80@163.com

3
Sun Bao scy_csu2016@csu.edu.cn

4
1 https://ror.org/03petxm16 grid.508189.d 0000 0004 1772 5403 Department of Pharmacy, The Central Hospital of Shaoyang, Shaoyang, 422000 Hunan China
2 https://ror.org/03fx09x73 grid.449642.9 0000 0004 1761 026X Department of Physiology, Pu Ai Medical School, Shaoyang University, Shaoyang, 422000 Hunan China
3 https://ror.org/03petxm16 grid.508189.d 0000 0004 1772 5403 Department of gerontology, Shaoyang Central Hospital, Shaoyang, 422000 Hunan China
4 grid.216417.7 0000 0001 0379 7164 Department of Pharmacy, The Second Xiangya Hospital, Central South University, No. 139, People’s Middle Street, Changsha, 410011 China
10 9 2024
10 9 2024
2024
24 95230 5 2024
2 9 2024
© The Author(s) 2024
2024
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Inflammation is a potential risk factor of voriconazole (VCZ) overdose, procalcitonin (PCT) is reported to act as a diagnostic marker for bacterial infections. However, the association of PCT with VCZ trough serum concentrations (VCZ-Cmin) is not fully clear. Our study aims to investigate the associations between PCT and VCZ-Cmin. In this retrospective cohort study, we collected the clinical data of 147 patients who received VCZ and monitored the VCZ concentration of them in our hospital from August 2017 to August 2021. All patients underwent routine clinical examinations on the day or the day before VCZ administration. General information and clinical symptoms of these patients were recorded. Multivariate liner analysis showed that PCT was significantly associated with VCZ-Cmin (p < 0.001). Overall, it was shown that VCZ-Cmin was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bi1irubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-Cmin was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT. In conclusion, this research reveals the correlation between PCT and VCZ-Cmin, indicating that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-024-09862-4.

Keywords

Voriconazole
Procalcitonin
Plasma concentration
Hypoalbuminemia
Infections
Natural Science Foundation of Hunan Province2023JJ50252 2024JJ4080 Shaoyang City Science and Technology Plan General Project2022GZ3039 The Key Scientific Research Project of Hunan Provincial Department of Education22A0528 Scientific Research Project of Hunan Provincial Health CommissionB202303017333 B202313016776 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Fungal infection accounts for a large proportion of infectious diseases, especially in patients with tumours, haematological malignancies, organ transplantation and AIDS, and can even cause fatal systemic fungal infection [1]. VCZ is the first-line drug for the prevention and treatment of invasive aspergillosis [2]. VCZ has nonlinear pharmacokinetic characteristics in vivo, and it has great differences among individuals. In addition, since the plasma concentration of VCZ is associated with its efficacy and safety, it is recommended to adjust the dose by therapeutic drug monitoring to optimize treatment. The optimal range of VCZ-Cmin is 0.5–5 µg/mL [3, 4], and VCZ-Cmin>5 µg/mL may increase the risk of adverse events such as visual abnormalities and liver damage [5]. Naturally, determining the factors responsible for the variation in VCZ concentration is crucial to individualized VCZ therapy.

Numerous studies [6–12] have shown that VCZ concentration is affected by a variety of physiological, genetic and environmental factors, such as age, body weight, concomitant drugs, liver function and metabolic enzyme polymorphisms. In recent years, inflammation has attracted particular attention as a factor affecting plasma concentrations of VCZ [13]. The markers of inflammation include CRP, PCT, IL-6, and IL-8 [14]. Wanrooy et al. [12] reported a positive correlation between CRP level and VCZ-Cmin, finding a 0.015 mg/L increase in VCZ-Cmin for each 1 mg/L increase in CRP concentration. Maeda et al. [15] revealed that CRP level was positively correlated with VCZ concentration and body weight. Various studies have highlighted PCT as a diagnostic marker for bacterial infections. It is generally more effective than other common clinical markers, such as CRP concentration, erythrocyte sedimentation rate, and white blood cell count, and may be more reliable than some experimental markers, such as IL-6 or IL-8 [16, 17]. However, the association of PCT with VCZ-Cmin remains unknown. Zeng [18]. et al. reported that patients with high PCT might be more likely to have VCZ-Cmin exceeding 5.5 µg/mL. Cheng et al. [19] found that PCT had a significant effect on VCZ-Cmin in elderly patients. It is recommended to closely monitor the VCZ concentration in patients with high PCT, which is crucial for ensuring clinical safety of VCZ in these patientsThe present study aims to compare the effects of PCT and other clinical experimental parameters on the interindividual variation in VCZ-Cmin.

Patients and methods

A single-centre retrospective cohort study was conducted on November 30, 2023 in the Central Hospital of Shao Yang, Hunan, China. We collected and compiled the usage information of patients who received VCZ and reached steady-state between August 2017 and August 2021. This study protocol was granted approval by the Ethics Committee of Shaoyang Central Hospital on November 22, 2023 (Registration number :20231105), all procedures were in accordance with ethical standards, and informed consent was waived for this retrospective review. This study was performed in accordance with the Declaration of Helsinki of 1964 and its subsequent amendments. All data retrieved from clinics as part of the audit were anonymized, and no informed consent was required from the participants for study enrolment or publication purposes. All patients underwent routine clinical examinations on the day or the day before voriconazole administration. The flow chart displaying patient selection is presented in Fig. 1. Inclusion criteria: patients were administered VCZ and their plasma concentration was monitored to achieve steady-state levels. For VCZ plasma concentrations, steady-state was defined as ≥ 24 h into a consistent maintenance dose regimen after two loading doses, or ≥ 6 days if loading doses were not given. The loading dose is administered intravenously at a rate of 6 mg/kg (the first 24 h), followed by a maintenance dose of 4 mg/kg via intravenous administration or sequential oral intake of VCZ (200 mg, q12h). Exclusion criteria: age < 18 years; severe heart, lung, liver, kidney and other organ dysfunction; haemodialysis; pregnant women; inappropriate therapeutic drug monitoring data; and incomplete clinical data. Inappropriate plasma concentration monitoring included VCZ concentration sampling before steady-state plasma concentration and VCZ concentration < 0.5 µg/mL. The clinical information of patients receiving VCZ treatment was collected from the medical charts and other medical documentation.

Fig. 1 Flow chart of the study

Cockcroft–Gault formula: estimated CrCl.

CrCl can be estimated from the Scr (µmol/L) level. The Cockcroft–Gault formula is the most widely used clinical method for estimating CrCl (mL/min) to adjust drug dosages. The formulas are as follows:

CrCl(male)=(140-age)*weight(kg)/[0.818*Scr(µmol/L)]

CrCl(Female) = 0.85*(140-age)*weight(kg)/[0.818*Scr(µmol/L)]

Measurement of VCZ concentration.

Two millilitres of patient blood were collected in an EDTA anticoagulant tube and then centrifuged at 3000 rpm for 5 min to separate the plasma. After centrifugation, 200 µl of plasma was mixed with 400 µl of acetonitrile protein precipitation, vortexed for 3 min, and then centrifuged at 14,000 rpm for 5 min. The supernatant (200 µl) was used for analysis using high-performance liquid chromatography from Hunan Demeter Instruments Co., Ltd. The linear range for the assay was 0.17–8.43 µg/mL, and the limit of quantitation was 0.17 µg/mL.

Statistical analysis

The preliminary analyses were conducted using a scatter plot to determine the curvilinear shape of the relationship. Patient characteristics were analyzed according to PCT tertiles. Categorical variables are expressed in numbers and percentages. Continuous variables are expressed as mean and standard deviation (SD) for normal distributions or median and interquartile range (IQR) for skewed distributions. We used the chi-square test, one-way ANOVA, and Kruskal‒Wallis test for the comparison of categorical, normally distributed, and non-normally distributed continuous variables, respectively.

Univariate linear regression analyses and multivariable linearregression analyses were performed to assess the association between PCT and VCZ-Cmin. Potential confounding factors were adjusted if one of the following criteria was present: (1) literature-based confounders, (2) P < 0.1 in univariate analyses, and (3) effect value changes in covariate screenings > 10%. According to the recommendation of the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement, analyses were first performed without adjustment. Further analyses cumulatively included adjustment for sex, age, albumin, and direct bilirubin, WBC (Adjusted model 1), AST and ALT (Adjusted model 2). Linear regression models were used for the subgroup analyses and included terms for sex group, age group, albumin group, and the interaction of each subgroup.

All analyses were performed with the statistical software packages R (http://www.R-project.org, The R Foundation) and Free Statistics software version 1.9. P < 0.05 was statistically significant.

Results

Basic characteristics of the patients

Baseline characteristics of the 147 enrolled participants (91 men and 56 women) stratified by log2PCT level are shown in Table 1.Patients were grouped by the tertiles of PCT levels as follows: Log2PCT.T1 group,≥-0.342 to ≤-3.184, Log2PCT.T2 group,≥-2.943 to ≤-0.786, Log2PCT.T3 group,≥-0.713 to ≤ 6.644. Some differences existed between the Log2PCT level groups with respect to various covariates (sex, VCZ-Cmin, albumin, ALT, direct bilirubin, Scr). The number of patients in the three groups was 46, 52, and 49, respectively.

Table 1 Participants’ baseline characteristics of patients

Variables	Total
(n = 147)	Log2PCT.T1
(n = 46)	Log2PCT.T2
(n = 52)	Log2PCT.T3
(n = 49)	P	
Sex, n (%)					0.049	
male	91 (61.9)	22 (47.8)	34 (65.4)	35 (71.4)		
female	56 (38.1)	24 (52.2)	18 (34.6)	14 (28.6)		
Age (y)					0.964	
< 60 y	53 (36.1)	17 (37)	18 (34.6)	18 (36.7)		
≥ 60 y	94 (63.9)	29 (63)	34 (65.4)	31 (63.3)		
VCZ-Cmin (µg/mL)	3.9 ± 2.2	3.2 ± 1.5	3.5 ± 1.6	4.9 ± 2.7	< 0.001	
Albumin (g/L)	33.0 ± 5.4	34.9 ± 5.2	32.9 ± 4.3	31.3 ± 6.2	0.005	
AST(U/L)	29.7 ± 18.5	26.0 ± 13.2	31.2 ± 20.8	31.6 ± 19.9	0.254	
ALT(U/L)	28.9 ± 29.1	22.2 ± 15.6	36.6 ± 40.0	26.9 ± 23.1	0.041	
Total bi1irubin (µmol/L)	11.6 ± 7.7	10.9 ± 5.7	11.4 ± 7.5	12.6 ± 9.5	0.547	
Direct bi1irubin (µmol/L)	4.3 ± 4.7	3.3 ± 2.5	4.0 ± 3.5	5.6 ± 6.7	0.05	
CrCl (ml/min)	93.8 ± 217.7	75.2 ± 29.3	132.5 ± 361.7	70.3 ± 42.5	0.28	
Scr (µmol/L)	81.1 ± 65.2	72.3 ± 41.4	65.2 ± 21.3	106.1 ± 99.3	0.003	
Weight (kg)	55.3 ± 9.4	53.3 ± 10.1	55.9 ± 8.9	56.4 ± 9.3	0.244	
WBC (109/L)	9.9 ± 12.0	6.8 ± 4.6	11.7 ± 13.8	10.9 ± 14.1	0.095	
Log2NUE% (%)	5.8 ± 1.0	5.6 ± 1.1	5.7 ± 1.1	5.9 ± 0.9	0.336	
Loading dose (mg/kg)	4.4 ± 1.6	4.6 ± 1.2	4.2 ± 1.5	4.6 ± 2.0	0.32	
PPI, n (%)					0.621	
Not used	78 (53.1)	22 (47.8)	30 (57.7)	26 (53.1)		
Used	69 (46.9)	24 (52.2)	22 (42.3)	23 (46.9)		
Abbreviations: VCZ-Cmin:VCZ trough serum concentrations; AST: glutamic oxaloacetic transaminase; ALT: glutamic pyruvic transaminase; CrCl: creatinine clearance; WBC: white blood count; NUE: neutrophil; PPI: proton pump inhibitor.

Associations between PCT and VCZ-Cmin

A scatter plot illustrating the relationship between log2PCT and VCZ-Cmin is presented in Fig. 2. The scatterplots show that there is a linear relationship between PCT and VCZ-Cmin. In univariate linear regression analysis, sex, age, albumin, AST, WBC and log2PCT were significantly associated with VCZ-Cmin (P < 0.001) (Supplementary Table 1). The β and corresponding 95% CIs for VCZ-Cmin are summarized in Table 2. Overall, in the crude model and all adjusted models (Models 1–2), it was shown that there was a correlation between PCT and VCZ concentrations. VCZ-Cmin was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bilirubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-Cmin was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT.

Fig. 2 Scatter plot of PCT and VCZ-Cmin. Abbreviations: PCT, procalcitonin; VCZ-Cmin: VCZ trough serum concentrations

Table 2 Multivariate linear regression analysis for PCT and VCZ-Cmin

Variable	N	Crude model	Adjusted model 1	Adjusted model 2	
Crude β(95%CI)	P	β(95%CI)	P	β(95%CI)	P	
Log2PCT	147	0.32 (0.18 ~ 0.45)	< 0.001	0.23 (0.09 ~ 0.37)	0.001	0.21 (0.08 ~ 0.35)	0.003	
Log2PCT.T1	46	0(Ref)		0(Ref)		0(Ref)		
Log2PCT.T2	52	0.28 (-0.53 ~ 1.09)	0.5	-0.19 (-0.98 ~ 0.59)	0.627	-0.1 (-0.88 ~ 0.67)	0.792	
Log2PCT.T3	49	1.73 (0.91 ~ 2.55)	< 0.001	1.03 (0.2 ~ 1.85)	0.016	0.99 (0.18 ~ 1.8)	0.018	
Trend.test			< 0.001		0.014		0.017	
Crude model: No adjusted;

Adjusted model 1: Adjusted for sex, age, albumin, direct bi1irubin and WBC;

Adjusted model 2: Adjusted for sex, age, albumin, direct bi1irubin, WBC, AST and ALT;

Abbreviations: PCT, procalcitonin; WBC, white blood count; AST: glutamic oxaloacetic transaminase; ALT: glutamic pyruvic transaminase.

Subgroup analysis between PCT and VCZ-Cmin

The stratified analyses were performed to examine whether the association between PCT and VCZ-Cmin was stable among different subgroups. Results were shown in Fig. 3. We found that sex (female and male) and age (< 60 years and ≥ 60 years) did not affect the interaction between PCT and VCZ-Cmin (P for interaction > 0.05). However, the albumin could affect the interaction between PCT and VCZ-Cmin (P = 0.013). For patients with albumin levels below 30 g/L, VCZ-Cmin levels could significantly increase the elevation of PCT.

Fig. 3 Subgroup analysis between PCT and VCZ-Cmin., Adjusted for sex, age, albumin, direct bi1irubin, WBC, AST and ALT. Abbreviations: WBC, white blood count; AST: glutamic oxaloacetic transaminase; ALT: glutamic pyruvic transaminase

Discussion

VCZ has a dose-exposure relationship, and its concentration correlates with therapeutic efficacy and toxicity, supporting close monitoring during treatment [4, 20]. Recent findings suggest that VCZ-Cmin in adults is significantly associated with level of inflammation in vivo [21]. In this retrospective case‒control study, we observed the correlation between PCT, a clinically specific indicator of inflammation, and VCZ-Cmin.This association was robust and independent of the underlying covariates and confounders. Linear subgroup analysis revealed that albumin affected the correlation between PCT and VCZ-Cmin. PCT has been widely used as an important reference index for the diagnosis and treatment of bacterial infectious diseases. Kinetics data has shown that bacterial infection can rapidly induce PCT production, which began to increase at 2–6 h and peaked at 12 h [22]. A retrospective clinical study showed that severe inflammation as assessed by PCT level had a significant effect on VCZ-Cmin in elderly patients (≥ 60 years), but this phenomenon was not observed in adult patients(< 60 years) [19]. The VCZ-Cmin in the elderly patients were significantly higher than those in the adult patients who received VCZ therapy. However, a single-centre retrospective study found that a significantly higher VCZ-Cmin was observed in adult patients with severe inflammation than those patients with moderate inflammation and no to mild inflammation(as reflected by PCT levels) and there was no significant difference between different degrees of inflammation in elderly patients. Therefore, inflammation may affect the metabolism of VCZ to VCZ-N-oxide both in adult and elderly patients [23]. The results of our study showed that PCT was associated with VCZ-Cmin regardless of age < 60 years or age ≥ 60 years. Furthermore, through the subgroup analysis, we also discovered that patients with hypoalbuminemia experienced a significant increase in VCZ-Cmin levels as PCT levels rose. A recent study [24] indicated a new steady state with hypoalbuminemic status, the same unbound/free drug concentration with lower bound and total drug concentrations. Kim Vanstraelen et al. reported that increased unbound VCZ plasma concentrations in patients with profound hypoalbuminaemia can cause adverse events, even when total VCZ plasma concentrations are within the reference range [25]. Buddharat Khan-asa et al. reported that patients with a lower albumin level should receive a lower dose of VCZ than patients with a normal albumin level [26]. In addition, Satoshi Dote et al. found that decreased albumin levels were significant predictors of the toxic trough concentration of VCZ [27]. Prawat Chantharit et al. discovered levels of ≤ 30 g/L required a lower daily maintenance dose to attain the therapeutic trough level [28].All these results are consistent with our study, suggesting that hypoalbuminaemia is associated with VCZ-Cmin.

Since CYP2C19 is the primary enzyme responsible for the metabolism of VCZ, almost all pharmacogenetic studies on the drug have focused on the contribution of CYP2C19 genotypes or resulting metabolic phenotypes [29]. The CYP2C19 gene is highly polymorphic, with over 30 known variant alleles.Typically, the majority of individuals carry the *1, *2, *3 or *17 alleles. The *2 allele varies in frequency among populations, with frequencies of approximately 15% in Caucasians, 18% in African Americans and 29–34% in Asians [30]. Numbers of studies identified that the pharmacokinetic variability of VCZ was mainly influenced by the liver through CYP2C19 [31, 32]. Unfortunately, due to the limitation of economic and geographical conditions, our centre does not carry out VCZ genotype monitoring, so these are limitations of our study. In this study, the high variability of VCZ-Cmin may be partially explained by the loading dose and liver function [18]. For this study, VCZ was administered at a fixed dose: 400 mg loading dose and 200 mg maintenance dose every 12 h. In our study, patients were administered doses based on their body weight, as per the labelling instructions. This entailed approximating an initial dosage of 6 mg/kg, followed by a maintenance dosage of 4 mg/kg, both administered at 12-hour intervals. The label of VCZ clearly states that its metabolism is mainly through the liver, and only 2% of the drug is excreted in the urine. Therefore, we excluded patients with abnormal liver function, thus we did not find that liver function had an impact on VCZ-Cmin in our study. Qi Huang et al. [33] reported that lansoprazole and omeprazole interacted with VCZ via CYP2C19 and CYP3A4, which increased VCZ plasma concentrations in Chinese patients with malignant haematological diseases. Our study found no effect of proton pump inhibitors on VCZ-Cmin, which might be related to the types of PPI used.

Inevitably, our study has several limitations: (1) it was a retrospective single-centre study with a limited number of patients and clinical data; (2) we did not collect the CYP2C19 genotypes of patients and could not analyse the effect of such genotypes and drug interactions. Larger prospective multi-centre studies with the exam of CYP2C19 phenotype are needed in the future.

In conclusion, our study suggests that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

We sincerely thank the management and ethics committees of all participating hospitals for granting us data access for this study.

Author contributions

Ju-Xiang Zhou. Ji-Chu WU and ji-hong Zhang designed this study. You-Cong Yin and Kai-Peng Su collected the clinical data, Chun-Lin Xiong analyzed the data，and Ju-Xiang Zhou . Bao Sun and chang-zao Shang wrote the report. All authors contributed to the article and approved the submitted version. All authors reviewed the manuscript.

Funding

This work was supported by the Fund for Natural Science Foundation of Hunan Province, China (2023JJ50252, 2024JJ4080), Shaoyang City Science and Technology Plan General Project(2022GZ3039), The Key Scientific Research Project of Hunan Provincial Department of Education (22A0528), Scientific Research Project of Hunan Provincial Health Commission (B202313016776, B202303017333).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval and consent to participate

This study is a retrospective cohort study, but not a clinical trial, thus the clinical trial number is not applicable. Ethical approval was obtained from the Ethics Committee of Shaoyang Central Hospital on November 22, 2023 (Granted number: 20231105), all procedures were in accordance with ethical standards, and informed consent was waived for this retrospective review. All data retrieved from clinics as part of the audit were anonymized, and no informed consent was required from the participants for study enrolment or publication purposes.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ju-Xiang Zhou, Chun-Lin Xiong and Zao-Shang Chang contributed equally to this work.
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