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. 2026 Jun 19;48(5):1787–1799. doi: 10.1007/s11096-026-02175-3

Research trends and emerging topics in antifungal therapeutic drug monitoring: a bibliometric analysis with implications for clinical pharmacy practice

Li-Chao-Yue Sun 1,#, Jian-Chun Li 1,#, Wen-Shu Li 2, Zhao Ren 1, Yi-Xin Yang 3, Wei Liu 4, Suo-Di Zhai 5, Shuo Liang 1, Zhi-Heng Yu 1,✉
PMCID: PMC13569520  PMID: 42319602

Abstract

Introduction

Therapeutic drug monitoring (TDM) plays an important role in optimizing antifungal pharmacotherapy because of the substantial pharmacokinetic variability and narrow therapeutic window of many antifungal agents. However, the global research landscape and emerging trends in antifungal TDM have not been systematically evaluated.

Aim

This study aimed to analyze global research trends, collaboration networks, and emerging research hotspots in antifungal TDM using bibliometric analyses.

Method

Relevant publications published between January 2014 and November 14, 2024, were retrieved from the Web of Science Core Collection. Bibliometric analyses were performed using CiteSpace and VOSviewer to evaluate publication trends, countries, institutions, authors, journals, and keyword co-occurrence.

Results

A total of 569 publications from 34 countries were included in this review. The United States, China, and Germany were the leading contributors, and the annual publication output increased steadily during the study period. The French National Institute of Health and Medical Research was the most productive institution. The most influential journals were Antimicrobial Agents and Chemotherapy and Clinical Microbiology and Infection. Keyword analysis identified voriconazole TDM, drug–drug interactions, caspofungin, invasive aspergillosis, extracorporeal membrane oxygenation, and immunocompromised pediatric populations as major research hotspots. Machine learning–assisted pharmacokinetic modeling has recently emerged as a research focus.

Conclusion

Although research on antifungal TDM is increasing globally, high-quality clinical evidence remains limited. Future research should prioritize multicenter clinical studies, optimization of TDM implementation in special populations, and integration of model-informed precision dosing approaches to support individualized antifungal therapy and clinical pharmacy practice.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s11096-026-02175-3.

Keywords: Antifungal agents, Therapeutic drug monitoring, Pharmacokinetics, Precision medicine, Clinical pharmacy, Bibliometrics

Impact statements

  • Therapeutic drug monitoring (TDM) is increasingly recognized as an important strategy for optimizing antifungal pharmacotherapy, particularly for agents with high pharmacokinetic variability, such as azoles.

  • The growing research focus on drug–drug interactions, special populations (e.g., critically ill and pediatric patients), and antifungal exposure variability highlights the need for pharmacist involvement in interpreting TDM results and individualizing dosing regimens.

  • Emerging approaches, such as population pharmacokinetic modeling and artificial intelligence–assisted prediction, may support more precise antifungal dosing and strengthen the role of clinical pharmacists in multidisciplinary antifungal stewardship.

Introduction

Invasive fungal diseases (IFDs) are an increasing global health challenge, particularly among immunocompromised populations [1]. Despite advances in antifungal therapy, the mortality associated with IFDs remains high, ranging from 30 to 50%. Current antifungal therapy mainly consists of triazoles, echinocandins, and polyenes, all of which exhibit substantial pharmacokinetic (PK) variability and exposure–response heterogeneity, often necessitating individualized therapeutic drug monitoring (TDM) strategies to optimize treatment outcomes [2].

Triazoles, the first-line therapy for invasive aspergillosis, demonstrate PK profiles that are strongly influenced by cytochrome P450 genetic polymorphisms, drug–drug interactions (DDIs), hepatic function, and formulation-related bioavailability differences [3]. Interindividual variability in voriconazole plasma concentrations can exceed ten-fold. Plasma concentrations below 1 mg/L are associated with increased treatment failure, whereas concentrations exceeding 5.5 mg/L markedly increase the risk of neurotoxicity [4]. Other antifungal agents also demonstrate clinically relevant PK variabilities. For example, echinocandins may exhibit an increased volume of distribution in critically ill patients, whereas hypoalbuminemia can alter free drug exposure [5]. Although liposomal amphotericin B reduces nephrotoxicity compared to conventional formulations, cumulative high-dose exposure remains associated with tubular injury [6]. In addition, the increasing global burden of antifungal resistance, including echinocandin-resistant Candida auris, further highlights the importance of precision dosing strategies in antifungal pharmacotherapy [7].

TDM has become an important strategy for improving the efficacy and safety of antifungal therapy. Clinical guidelines from the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) recommend routine TDM for voriconazole and itraconazole [8], whereas TDM for echinocandins is generally reserved for selected clinical situations, such as critically ill patients with hepatic dysfunction or suspected drug resistance [9]. From an analytical perspective, liquid chromatography–tandem mass spectrometry (LC–MS/MS) has become the gold standard for triazole TDM because of its high sensitivity and specificity [10]. In addition, pharmacogenetic variability may substantially influence antifungal exposure. For example, the prevalence of the CYP2C19 poor metabolizer genotype is significantly higher in Asian populations than in Caucasian populations, suggesting that population-specific TDM targets and individualized dosing strategies may be necessary [11].

In clinical practice, antifungal TDM is increasingly integrated into multidisciplinary antifungal stewardship programs [12–14], in which clinical pharmacists play a central role in interpreting drug concentrations, identifying DDIs, and recommending individualized dose adjustments. However, several challenges remain. The consensus regarding the necessity of TDM for certain antifungal agents remains inconsistent, and the impact of TDM on clinical outcomes, safety, and cost-effectiveness requires further clarification [15]. In addition, optimal TDM strategies for special populations, including pediatric, obese, and critically ill patients, remain insufficiently defined [16]. Evidence supporting exposure–toxicity relationships for several antifungal agents remains limited [17]. These uncertainties highlight the need for a comprehensive overview of current research trends, emerging hotspots, and future directions in TDM.

Bibliometric analysis quantitatively evaluates publication trends, collaboration networks, and knowledge structures within a scientific field and has been widely applied to map research and development in clinical pharmacology and antimicrobial therapy [18]. To date, no comprehensive bibliometric study has specifically examined the global research landscape of antifungal TDM. A systematic mapping of this literature may provide important insights into evolving research priorities, emerging technologies, and implementation challenges relevant to precision antifungal pharmacotherapy and clinical pharmacy.

Aim

This study aimed to perform a bibliometric analysis of antifungal TDM research using the Web of Science Core Collection to characterize global publication trends, collaboration networks, influential contributors, and emerging research hotspots relevant to precision antifungal pharmacotherapy and clinical pharmacy practice.

Method

Data source and search strategy

The Web of Science Core Collection (WoSCC) was selected as the primary literature database because of its extensive coverage of high-quality scientific publications and widespread use in bibliometric research. Studies published between January 2014 and November 14, 2024, were retrieved from WoSCC, with November 14, 2024, defined as the final search date. This study focused on publications from the past decade to better capture recent advances and emerging research trends in antifungal TDM. In addition, relatively few studies in this field have been published before 2014. Only original research and review articles were included, whereas retracted publications, conference proceedings, book chapters, editorials, and other non-article formats were excluded. The search was restricted to English-language publications only.

A topic-based search (TS) strategy was applied using the following search formula: TS = ((antifungal OR antimycotic OR "antifungal agent*" OR azole* OR triazole* OR voriconazole OR itraconazole OR fluconazole OR posaconazole OR isavuconazole OR amphotericin OR caspofungin OR micafungin) AND ("therapeutic drug monitoring" OR TDM OR "drug monitoring" OR "plasma concentration*" OR "serum concentration*" OR "blood concentration*" OR pharmacokinetic* OR "population pharmacokinetic*" OR "model-informed precision dosing" OR "area under the curve" OR AUC OR "peak concentration" OR "trough concentration"))**

The search was limited to the title, abstract, and author-keyword fields. Studies included if they (1) addressed TDM related to antifungal agents, (2) were indexed in WoSCC as original articles or reviews, and (3) were published between January 2014 and November 2024. Records with incomplete bibliographic information, duplicate publications, and non-article formats were excluded from the study.

Data extraction and bibliometric analysis

All retrieved records were exported from the WoSCC in plain text format, including information on article titles, authors, publication year, countries or regions, institutions, keywords, abstracts, references, and citation counts. Two researchers (SLCY and LJC) independently screened the retrieved records by reviewing the titles and abstracts, with full texts assessed when necessary to confirm eligibility. Disagreements were resolved through discussions with a third researcher.

Bibliometric analysis and visualization were performed using CiteSpace (version 6.2 R3), VOSviewer (version 1.6.20), and GraphPad Prism (version 10). CiteSpace was used for keyword clustering, burst detection, and timeline visualization to identify emerging research trends and thematic evolution in the field. VOSviewer was used to construct collaboration networks among countries, institutions, and authors, as well as journal citation, co-citation, and keyword co-occurrence networks. GraphPad Prism was used to generate publication and citation trend figures.

Results

Publication trends

The literature screening process is illustrated in Supplementary Figure S1. From January 2014 to November 2024, 569 publications related to antifungal TDM were identified in the literature search. Figure 1 presents the annual publication and citation trends. Overall, the publication output and citation counts increased steadily throughout the study period. Research activity peaked in 2023, with 73 publications and 2,145 citations, reflecting the growing scientific interest and increasing academic influence in antifungal TDM research.

Fig. 1.

Fig. 1

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Annual publication and citation trends in antifungal therapeutic drug monitoring research (2014–November 2024)

Contributions of countries, institutions, authors, and journals

Antifungal TDM research was conducted in 34 countries (Fig. 2A). The top 10 most productive countries are listed in Supplementary Table S1. The United States ranked first with 142 publications and 4,699 citations, followed by China (69 publications) and Germany (50). The strong contributions from these countries may reflect increasing investments in precision pharmacotherapy, antimicrobial stewardship, and clinical pharmacology research. The United Kingdom (60.03), France (55.03), and Germany (52.18) demonstrated the greatest academic impact in terms of average citations per publication.

Fig. 2.

Fig. 2

Fig. 2

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Collaboration and journal distribution networks in antifungal TDM research. (A) Country collaboration network. (B) Institutional collaboration network. (C) Author collaboration network. (D) Journal distribution network. Each node represents a country, institution, author, or journal. The size of the node reflects the number of publications. Lines between nodes indicate collaborative relationships, with thicker lines representing stronger collaboration strength. Different colors represent clusters of closely related nodes within the network

A total of 275 institutions contributed to the antifungal TDM research. The top 20 institutions by publication output are listed in Supplementary Table S2. The French National Institute of Health and Medical Research (Inserm) ranked first with 23 publications and 509 citations, followed by the University of Cologne (18 publications) and the German Center for Infection Research (17 publications). Regarding total citations, Westmead Hospital (820 citations), the University of Queensland (810 citations), and the German Center for Infection Research (727 citations) ranked the highest. Central South University demonstrated the highest average citation rate (73.56%). The institutional collaboration network is illustrated in Fig. 2B.

Between 2014 and 2024, 326 authors contributed to the antifungal TDM research. The top 20 most productive authors are presented in Supplementary Table S3. Cornely Oliver A ranked first with 15 publications and 479 citations, followed by Hoenigl Martin with 13 publications and 523 citations. Alffenaar Jan-Willem C contributed 10 publications with 737 citations, indicating a substantial academic influence in this field.

Co-authorship network analysis using VOSviewer identified 24 authors meeting the visualization threshold (Fig. 2C), which were grouped into nine collaborative clusters, representing the major research teams and collaboration patterns in the antifungal TDM research.

Journal distribution analysis was performed using VOSviewer (Fig. 2D). The top 20 most productive journals are summarized in Supplementary Table S4, including impact factors (IF), Journal Citation Reports (JCR) quartiles, publication counts, and citation numbers. All IF values and JCR quartiles were obtained from the 2025 JCR Database. Antimicrobial Agents and Chemotherapy (IF = 4.1, Q1) ranked first, with 34 publications and 2,883 citations, indicating its central role in antifungal TDM research. Other highly productive journals included Therapeutic Drug Monitoring (IF = 2.8, Q2) and Journal of Antimicrobial Chemotherapy (IF = 3.9, Q1).

Highly cited and co-cited articles

Citation analysis was performed using VOSviewer, and the top 10 most-cited publications are listed in Supplementary Table S5. The most cited article was “Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline” [8], published in Clinical Microbiology and Infection in 2018, with 832 citations. The second most cited publication was “The global problem of antifungal resistance: prevalence, mechanisms, and management” [19], published in The Lancet Infectious Diseases in 2017, with 679 citations.

Co-citation burst analysis identified the top 25 publications with the strongest citation bursts (Supplementary Table S5), with burst periods ranging from 2017–2024. The publication demonstrating the strongest citation burst was “The Effect of Therapeutic Drug Monitoring on Safety and Efficacy of Voriconazole in Invasive Fungal Infections: A Randomized Controlled Trial” [4], with a burst strength of 20.54. This finding suggests the need for increased research attention on the clinical efficacy and safety of TDM-guided antifungal therapy.

A dual-map overlay of journals was generated to illustrate the citation relationships between the citing and cited journals (Fig. 3). Publications in medicine, medical, and clinical journals primarily cited studies from journals related to molecular biology, genetics, and health/nursing/medicine, highlighting the interdisciplinary nature of antifungal TDM research.

Fig. 3.

Fig. 3

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Dual-map overlay of journals in antifungal therapeutic drug monitoring research. The dual-map overlay illustrates the citation relationships between the citing journals (left) and the cited journals (right). Each ellipse represents a disciplinary journal cluster, and the curved lines indicate the citation pathways linking the two domains. The colored paths highlight the primary knowledge flows, showing that studies published in journals related to medicine and clinical sciences predominantly cite journals in molecular biology, genetics, and health sciences

Keyword co-occurrence and research hotspots

Keyword burst analysis using CiteSpace identified several emerging research hotspots in antifungal TDM (Fig. 4A), including DDIs, caspofungin, immunocompromised children, invasive aspergillosis, and extracorporeal membrane oxygenation (ECMO). Machine learning has also emerged as a recent research focus, suggesting a growing interest in model-informed precision dosing and exposure prediction.

Fig. 4.

Fig. 4

Fig. 4

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Keyword analysis in antifungal TDM research. (A) Top 25 keywords with the strongest citation bursts identified using CiteSpace, indicating emerging research trends. (B) Keyword co-occurrence network generated by VOSviewer, where each node represents a keyword, node size reflects keyword frequency, and links represent co-occurrence relationships between keywords. Different colors indicate clusters of related research topics. (C) Keyword cluster analysis illustrating major thematic groups within antifungal TDM research. (D) Timeline visualization of keyword clusters showing the temporal evolution of major research topics

Keyword co-occurrence analysis using VOSviewer (Fig. 4B) showed that “pharmacokinetics” was the most frequently occurring keyword (201 occurrences), followed by “voriconazole” (200 occurrences), “therapeutic drug monitoring” (190 occurrences), and “safety” (104 occurrences). These findings indicate that PK variability, individualized drug monitoring, and safety optimization remain the core themes in antifungal TDM research.

Keyword clustering analysis using CiteSpace identified ten major thematic clusters (Fig. 4C). The five largest clusters were #0 “prophylaxis” (31 keywords), #1 “management” (26 keywords), #2 “therapeutic drug monitoring” (26 keywords), #3 “metabolism” (25 keywords), and #4 “septic arthritis” (23 keywords).

The temporal evolution of these clusters is illustrated in the keyword timeline visualization (Fig. 4D), demonstrating the progressive evolution of research themes over time.

Discussion

Overview of research landscape

Bibliometric analysis enables the quantitative evaluation of publication trends, collaboration networks, and evolving research themes. Previous reviews of antifungal TDM have mainly focused on analytical techniques, antifungal agents, or plasma drug concentrations, whereas the broader evolution of this field has been limited. In this study, bibliometric methods were used to characterize the global research output, identify influential contributors, and map emerging themes in antifungal TDM research.

The results demonstrated a continuous increase in publication output over the past decade, reflecting the growing scientific interest in antifungal TDM. The United States, China, and Germany contributed nearly half of all publications, which may reflect the increasing investment in precision pharmacotherapy, antimicrobial stewardship, and clinical pharmacology research [20]. Although several leading institutions were identified, the most highly cited contributors were academic centers rather than hospitals, suggesting that antifungal TDM research remains primarily driven by academia and that further clinical implementation research is still needed.

Keyword analysis identified several major research themes, including PK-guided dosing, antifungal drug monitoring, TDM in special populations, and emerging artificial intelligence (AI) approaches. These findings suggest that antifungal TDM research is increasingly evolving toward precision pharmacotherapy and individualized dosing strategies in the future.

Advances in TDM methodologies

Research related to antifungal TDM methodologies has primarily focused on PK modeling and drug concentration detection technologies. Frequently occurring keywords, such as “pharmacokinetics,” “population pharmacokinetics,” and “therapeutic drug monitoring” highlight the growing importance of model-informed precision dosing in antifungal therapy. Traditional TDM, based on isolated plasma concentrations, may inadequately capture complex PK variability. Population pharmacokinetic (PopPK) models allow the integration of physiological, pathological, and genetic covariates to improve individualized dosing strategies [21]. For example, CYP2C19 polymorphisms substantially influence voriconazole clearance, and the incorporation of genotype information may improve dose prediction [22]. However, PopPK models remain limited by reduced extrapolatability, particularly in critically ill patients, and often require interpretation by clinicians or pharmacists with specialized PK expertise.

Critically ill patients represent a particularly challenging population for antifungal therapy. Clinical interventions such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy may substantially alter drug distribution and clearance [23, 24]. Recent studies have demonstrated clinically relevant PK variability, even for antifungal agents previously considered relatively predictable, such as isavuconazole, supporting the value of TDM in critically ill patients [25].

Analytical technologies remain central to antifungal TDM. LC–MS/MS has become the standard analytical method because of its high sensitivity and specificity. Recent advances in ultra-high-performance liquid chromatography and automated sample preparation techniques may further improve the efficiency and accessibility of antifungal TDM in clinical laboratories [26–28].

Clinical pharmacotherapy and clinical pharmacy implications

Research hotspots in antifungal TDM were strongly associated with azole antifungal agents, DDIs, and individualized dosing strategies. Voriconazole remains the dominant antifungal agent in TDM research because of its substantial PK variability, clinically important CYP2C19 polymorphisms, and frequent DDIs [31, 32]. Clinically important interactions involving immunosuppressants, such as tacrolimus, further support the role of TDM in optimizing antifungal therapy and minimizing adverse drug reactions [33].

Current clinical guidelines support routine TDM for several triazole antifungal agents to improve treatment efficacy and safety [8]. However, the role of TDM in echinocandins and polyenes remains unclear [29, 30]. From a clinical pharmacy perspective, pharmacists play an important role in interpreting antifungal drug concentrations, identifying DDIs, evaluating patient-specific PK factors, and recommending individualized dosage adjustments. The increasing emergence of antifungal stewardship programs highlights the importance of multidisciplinary collaboration in optimizing antifungal therapy.

Evidence gaps and implementation challenges

Although antifungal TDM has attracted increasing research attention, high-quality clinical evidence is limited. Most publications consisted of PK analyses, methodological studies, or reviews, whereas large randomized controlled trials (RCTs) are relatively scarce. Several studies have demonstrated the potential benefits of TDM-guided antifungal therapy. For example, routine voriconazole TDM is associated with improved treatment response and reduced adverse events in patients with invasive fungal infections [4]. Other multicenter studies have also reported improved therapeutic drug concentration attainment and reduced toxicity with TDM-guided dosing [35, 36]. However, evidence regarding the clinical outcomes, long-term safety, and cost-effectiveness of this approach remains insufficient.

Several practical barriers continue to limit the large-scale implementation of antifungal TDM. However, limited access to LC–MS/MS platforms, delayed assay turnaround times, inadequate clinician familiarity with TDM interpretation, and poor integration into clinical workflows remain major challenges. In addition, limited health economic evidence may restrict policy support and reimbursement for routine TDM implementation.

These findings highlight the need for additional multicenter studies to evaluate the clinical effectiveness, safety, and cost-effectiveness of antifungal TDM. Future research should also focus on implementation strategies, clinician education, and the integration of TDM into antimicrobial stewardship programs and clinical decision-support systems.

TDM in special populations

Special populations, particularly critically ill and immunocompromised patients, remain a major focus of antifungal TDM studies. Altered physiology, organ dysfunction, extracorporeal support, and DDIs may substantially affect the antifungal PK profiles in these patients [40–42]. The emergence of ECMO-related keywords likely reflects the growing recognition that extracorporeal circuits can significantly alter antifungal exposure.

Pediatric patients also represent an important population for TDM of antifungals. Previous studies have demonstrated that only approximately half of pediatric patients receiving voriconazole achieve therapeutic plasma concentrations, supporting the importance of routine TDM in pediatric antifungal therapy [43]. However, evidence supporting TDM for several antifungal agents, including liposomal amphotericin B, is limited [44].

Emerging role of artificial intelligence

Consistent with the keyword burst analysis, machine learning has emerged as a recent research direction in antifungal TDM. Current studies have mainly focused on predicting voriconazole exposure and optimizing individualized dosing strategies [45–47]. Compared with conventional PK models, machine learning approaches may better handle nonlinear relationships and large datasets [48]. Nevertheless, most current studies are limited by relatively small sample sizes, incomplete PK sampling, and insufficient external validation. Therefore, further multicenter studies are required before widespread clinical implementation.

Strengths and limitations

This study presents the first comprehensive bibliometric analysis of the global research landscape of TDM. Using CiteSpace and VOSviewer, this study systematically evaluated publication trends, collaboration networks, influential publications, and emerging research hotspots. The findings identified several rapidly evolving areas, including AI-assisted PK modeling, ECMO-related PK variability, and TDM in special populations. Importantly, this study also highlights major evidence gaps, including the limited number of high-quality RCTs and the lack of standardized TDM strategies for specific patient populations.

This study has several limitations. First, only English-language publications were included, potentially resulting in language bias and the underrepresentation of non-English-speaking countries. Second, the analysis was limited to the WoSCC database; therefore, relevant studies indexed elsewhere may have been overlooked. Third, despite efforts to optimize the search strategy, some relevant studies may not have been captured. Fourth, bibliometric findings may vary slightly depending on the analytical algorithms used by CiteSpace and VOSviewer. Finally, bibliometric analysis evaluates publication characteristics rather than the methodological quality of the included studies. Therefore, the identified trends may not fully reflect the overall quality of the evidence in antifungal TDM research.

Conclusion

This bibliometric analysis provides a comprehensive overview of global research trends and emerging hotspots in antifungal TDM. Current research is increasingly focused on individualized dosing strategies, pharmacokinetic variability in special populations, and the integration of model-informed precision-dosing approaches. However, high-quality multicenter clinical trials and standardized implementation strategies are limited. Emerging research areas include advances in TDM analytical technologies, optimization of antifungal dosing, and TDM applications in critically ill and pediatric patients. Additionally, artificial intelligence–assisted pharmacokinetic modeling may further support exposure prediction and individualized antifungal therapy. Overall, these findings highlight the growing role of antifungal TDM in precision pharmacotherapy and the expanding contribution of clinical pharmacy practice to antifungal stewardship and individualized patient care.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 69 KB) (69.1KB, docx)

Acknowledgements

None.

Author contributions

Conceptualization: S. LCY and L. JC; methodology: S. LCY; software: S. LCY and L. JC; validation: L. JC; formal analysis: S. LCY; data curation: Y. ZH; writing—original draft preparation: S. LCY and LW; writing—review and editing: S. LCY, L. WS, R. Z, and Y. ZH; supervision: L. JC and LW. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Scientific Research Fund of Aerospace Center Hospital (Grant Number YN202527).

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

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

Li-Chao-Yue Sun and Jian-Chun Li are co-first authors who contribute equally to the manuscript. Zhi-Heng Yu and Shuo Liang are co-corresponding authors and contributed equally to this work. Correspondence may also be addressed to: Shuo Liang, Email:1280679306@qq.com.

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