# Biliary diffusion and antifungal activity of caspofungin and fluconazole in liver transplant recipients: A pilot study

Cécile Garnaud, Thibaut Gelé, Elodie Gautier-Veyret, Agnès Bonadona, Thomas Lefebvre, Christelle Boglione-Kerrien, Françoise Stanke-Labesque, Jean-Pierre Gangneux, Françoise Botterel, Anne Hulin, et al.

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Cécile Garnaud, Thibaut Gelé, Elodie Gautier-Veyret, Agnès Bonadona, Thomas Lefebvre, et al. Biliary diffusion and antifungal activity of caspofungin and fluconazole in liver transplant recipients: A pilot study. Journal of Medical Mycology = Journal de Mycologie Médicale, 2025, 35 (1), pp.101531. 10.1016/j.mycmed.2024.101531. hal-04997699

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# Biliary diffusion and antifungal activity of caspofungin and fluconazole in liver transplant recipients: A pilot study

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Cécile Garnaud<sup>a</sup>, Thibaut Gelé<sup>b</sup>, Elodie Gautier-Veyret<sup>c</sup>, Agnès Bonadona<sup>d</sup>, Thomas Lefebvre<sup>d</sup>, Christelle Boglione-Kerrien<sup>e</sup>, Françoise Stanke-Labesque<sup>c</sup>, Jean-Pierre Gangneux<sup>f</sup>, Françoise Botterel<sup>g</sup>, Anne Hulin<sup>b</sup>, Muriel Cornet<sup>a,\*</sup>

## ARTICLE INFO

**Article History:**
Received 19 June 2024
Revised 17 December 2024
Accepted 31 December 2024
Available online 31 December 2024

**Keywords:**
Caspofungin
Fluconazole
Diffusion
Bile
Liver transplantation

## ABSTRACT

Invasive candidiasis, including intra-abdominal candidiasis (IAC), is a common complication after liver transplantation. Antifungal drugs such as echinocandins and fluconazole (FCZ) are frequently used to prevent or treat such fungal infections. The diffusion of these antifungals within abdominal body sites has been rarely reported, in particular, in liver transplant recipients. This study aimed to evaluate the biliary diffusion of caspofungin (CAS) and FCZ. CAS and FCZ concentrations were determined in plasma and bile using a validated liquid chromatography-mass spectrometry method. Biliary concentrations of CAS (n = 5) and FCZ (n = 12) ranged from 1.6 to 4.4 and 6.4 to 33.4 mg/L, respectively, with respective medians of 1.9 and 17.7 mg/L. These values are higher than the MICs for yeast species frequently involved in IAC, suggesting that such antifungal exposure is sufficient to prevent/cure these infections. However, yeast was found in bile collected during CAS treatment from 3/5 patients, raising questions about the effective antifungal activity of this echinocandin at this anatomical site. Our pilot study shows that CAS and FCZ diffuse to the bile of liver transplant recipients. However, whether the observed antifungal concentrations are sufficiently high to prevent/cure IAC remains an unanswered question

© 2024 The Author(s). Published by Elsevier Masson SAS on behalf of SFMM. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

## Introduction

Liver transplantation (LT) is among the most at-risk procedures for invasive fungal infections [1,2]. Invasive candidiasis, including intra-abdominal candidiasis (IAC), accounts for up to 75 % of such invasive fungal infections, partially due to the commensalism of the *Candida* spp. found in the gastrointestinal tract. Specific risk factors for IAC during LT are multiple and prolonged surgeries, choledochojejunostomy, and anastomotic leakage. In this setting, invasive candidiasis is associated with high global mortality (up to 70 %) [3,4]. Thus, LT recipients commonly receive antifungal prophylaxis with azoles (especially fluconazole (FCZ)) or echinocandins. The duration of such prophylaxis is not well defined, ranging in practice from one to 10 weeks post-

transplantation [5]. As the pharmacokinetics of FCZ and echinocandins are known to vary little, there have been few studies to explore the pharmacokinetics and/or pharmacokinetics-pharmacodynamics of these drugs, in particular, in LT patients [6]. In this context, the diffusion of antifungals to the targeted body sites (i.e., abdominal cavity) is largely unknown. Overall, data on the tissue penetration of antifungals in the abdominal cavity and organs are scarce and mostly focus on peritoneal fluid [6–10].

Of concern, there are increasing reports of invasive breakthrough candidiasis under targeted prophylaxis after LT [11]. In addition, it has been suggested that IAC could be a source for the selection of antifungal-resistant mutants due to prolonged subinhibitory concentrations *in situ* [12,13]. As colonization or infection of the biliary tree with *Candida* spp. is common in routine practice, knowledge of whether the diffusion of caspofungin (CAS) and FCZ is sufficient to eradicate *Candida* spp. and avoid the selection of resistance is critical. In this pilot study, we aimed to evaluate the biliary diffusion of CAS

<footnote><sup>a</sup> Univ. Grenoble Alpes, CNRS, UMR 5525, CHU Grenoble Alpes, VetAgroSup, Grenoble INP, TIMC, 38000, Grenoble, France</footnote>

<footnote><sup>b</sup> Laboratory of Biological Pharmacology, AP-HP, GHU H. Mondor, Paris-Est Créteil University, Créteil, France</footnote>

<footnote><sup>c</sup> Univ. Grenoble Alpes, Inserm, HP2, CHU Grenoble Alpes, 38000, Grenoble, France</footnote>

<footnote><sup>d</sup> Hepatology and Transplantation, CHU Grenoble Alpes, 38000, Grenoble, France</footnote>

<footnote><sup>e</sup> Department of Biological Pharmacology, Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>f</sup> Department of Parasitology-Mycology, Excellence Center in Medical Mycology (ECMM EC), Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>g</sup> Unit of Parasitology-Mycology, Henri Mondor Hospital, Dynamyc Team, Paris Est University, EnvA, USC ANSES, France</footnote>

<footnote>* Corresponding author.
E-mail address: mcornet@chu-grenoble.fr (M. Cornet).</footnote>
and FCZ and describe the evolution of yeast infection under CAS therapy in routine practice.

## Patients and methods

LT recipients treated with FCZ or CAS were included in the study. Patients were recruited in two university hospitals in France (UH1 and UH2) from two different regions. This non-interventional study involving data and samples from human participants was carried out according to current ethical and legal requirements of the French law (15 April 2019) and the Declaration of Helsinki. Subjects were all informed and did not oppose the study; written consent for participation was not required.

Patients in UH1 were treated with CAS at the standard dose (loading dose of 70 mg and then 50 mg daily). CAS was prescribed either before (prophylaxis) and/or after the detection of yeast in the bile fluid (curative treatment). Thus, the detection of yeast in the bile was considered to be a sign of infection. All the bile samples were obtained during endoscopic retrograde cholangiopancreatography (ERCP). ERCP was performed when infection, leakage, or other complications were suspected. A blood sample was collected the same day as the bile sample to measure the antifungal plasma trough concentration. For mycological testing, bile samples were cultured in BD BACTECTM Mycosis IC/F bottles (Becton Dickinson, Pont-de Claix, France) and on chromIDTM Candida Agar plates (BioMérieux, Marcy-l'Étoile, France). Then, yeast species were identified by MALDI-TOF MS (Microflex LT instrument from Bruker Daltonics GmbH, Bremen, Germany) and minimal inhibitory concentrations (MICs) for echinocandins determined using E-test strips (BioMérieux). Mycological testing of bile samples collected after the end of CAS treatment was also included in the study to assess the evolution of the species and antifungal susceptibility of the biliary yeasts.

Patients in UH2 received 400 mg of FCZ daily for six weeks as prophylaxis, from the day of the LT. All patients had undergone orthotopic LT with inferior vena cava preservation. Biliary anastomosis consisted of a duct-to-duct procedure with systematic insertion of a T-tube. The excreted bile was collected through the T-tube between day 4 and day 8 after FCZ initiation. Routine follow-up of patients receiving FCZ prophylaxis did not include plasma therapeutic drug

monitoring or mycological follow-up in the absence of signs of infection.

The CAS concentration was determined in the plasma and bile of UH1 patients and that of fluconazole in the bile of UH2 patients. Serum and biliary concentrations of the two antifungal drugs were measured only once. The two antifungals were quantified using a validated liquid chromatography-mass spectrometry method (Quantis, Thermofisher, Villebon sur Yvette, France). The calibration standards ranged from 0.63 to 12.6 mg/L for CAS and 0.7 to 21.0 mg/L for FCZ. Low-, medium-, and high-concentration controls were 0.9, 5.4, and 10.8 mg/L for CAS and 1.0, 5.0, and 15.0 mg/L for FCZ, respectively.

Quantitative and qualitative data are presented as medians [minimal-maximal values] or numbers (%). Pearson's correlation was established using GraphPad Prism 10.2.0

## Results

### Patients

Seventeen patients were included in this study. Five patients (3 women and 2 men, mean age: 56 [31–61] years, mean weight: 74 [52–105] kg) treated with CAS in UH1 and 12 (3 women and 9 men, mean age: 56 [36–66] years, mean weight: 79.5 [50–107] kg) receiving FCZ prophylaxis in UH2 were included in the study.

### Caspofungin and fluconazole therapeutic drug monitoring

Antifungal concentrations measured in the bile and plasma samples from the patients are presented in Table 1.

CAS was quantifiable in the bile, with a median concentration of 1.9 mg/L, except for P5, for whom CAS was introduced only one day before sampling. Plasma CAS concentrations ranged from 2.5 to 13.1 mg/L, the lowest CAS concentration being measured in P5. Interestingly, comparable bile CAS concentrations from 1.6 to 2 mg/L were measured for patients with comparable time intervals of 4 to 8 days between the initiation of CAS and bile/blood sampling (P2 to P4). In addition, the highest concentrations in both bile and plasma were observed for the patient with the longest exposure to CAS before sampling (P1: Table 1 and Fig. 1). As 24 h is not sufficient to reach the pharmacokinetic steady state of CAS, the median CAS concentrations

<table><caption>**Table 1**
Concentration of caspofungin and fluconazole in bile and plasma samples.</caption><thead><tr><th>Antifungal</th><th>Patient (P)</th><th>Time of sampling<sup>*</sup> (days)</th><th colspan="2">Concentration mg/L</th><th>Ratio Bile/Plasma (%)</th></tr><tr><th></th><th></th><th></th><th>Bile</th><th>Plasma</th><th></th></tr></thead><tbody><tr><td rowspan="6">Caspofungin</td><td>P1</td><td>90</td><td>4.4</td><td>13.1</td><td>33.6</td></tr><tr><td>P2</td><td>6</td><td>2.0</td><td>5.9</td><td>33.9</td></tr><tr><td>P3</td><td>4</td><td>1.9</td><td>3.1</td><td>61.3</td></tr><tr><td>P4</td><td>8</td><td>1.6</td><td>4.2</td><td>38.1</td></tr><tr><td>P5</td><td>1</td><td>&lt; 0.6</td><td>2.5</td><td>&lt; 24.0</td></tr><tr><td>Median</td><td></td><td>1.9</td><td>4.5</td><td>33.9</td></tr><tr><td>Median without P5</td><td></td><td>2.5</td><td>6.6</td><td>41.7</td></tr><tr><td rowspan="12">Fluconazole</td><td>P6</td><td>4–8</td><td>33.4</td><td>NA<sup>*</sup></td><td>NA</td></tr><tr><td>P7</td><td>4–8</td><td>12.3</td><td>NA</td><td>NA</td></tr><tr><td>P8</td><td>4–8</td><td>19.9</td><td>NA</td><td>NA</td></tr><tr><td>P9</td><td>4–8</td><td>25.6</td><td>NA</td><td>NA</td></tr><tr><td>P10</td><td>4–8</td><td>17.6</td><td>NA</td><td>NA</td></tr><tr><td>P11</td><td>4–8</td><td>18.4</td><td>NA</td><td>NA</td></tr><tr><td>P12</td><td>4–8</td><td>14.6</td><td>NA</td><td>NA</td></tr><tr><td>P13</td><td>4–8</td><td>6.4</td><td>NA</td><td>NA</td></tr><tr><td>P14</td><td>4–8</td><td>19.9</td><td>NA</td><td>NA</td></tr><tr><td>P15</td><td>4–8</td><td>17.2</td><td>NA</td><td>NA</td></tr><tr><td>P16</td><td>4–8</td><td>10.2</td><td>NA</td><td>NA</td></tr><tr><td>P17</td><td>4–8</td><td>17.8</td><td>NA</td><td>NA</td></tr><tr><td>Median</td><td></td><td>17.7</td><td>NA</td><td>NA</td></tr></tbody></table>

<footnote>* post-antifungal treatment initiation</footnote>

<footnote>**NA: Not available.</footnote>
<figure><img src="image_8.png" /><figcaption>**Fig. 1.** Mycological testing results of bile sampled during and after CAS treatment of liver transplant patients included in the study. The dark blue arrows represent the time after the initiation of CAS treatment. The light blue arrows represent the duration of CAS treatment. The biliary CAS concentration was determined for one sample per patient. Day 0: initiation of CAS treatment, CAS MIC: caspofungin MIC of the yeast species determined by the E-test®, Ca: Candida albicans, Ng: Nakaseomyces glabratus, YI: Yarrowia lipolytica, Cd: Candida dubliniensis, Km: Kluyveromyces marxianus, Cp: Candida parapsilosis, Sc: Saccharomyces cerevisiae.</figcaption></figure>

and bile/plasma ratios were recalculated after the exclusion of P5 (Table 1). Thus, the median CAS concentrations were 2.5 mg/L in bile and 6.6 mg/L in plasma, leading to a median bile/plasma ratio of 41.7%.

In addition, the bile and plasma concentrations strongly correlated with each other (Pearson's r coefficient=0.923, *p* = 0.02 considering all patients, rho=0.97, *p* = 0.03 after the exclusion of P5). The median bile CAS concentration was two-fold higher than the MIC values for the yeast species isolated from these patients [14,15], as well as higher than the proposed efficacy threshold of 1 mg/L for the plasma CAS trough concentration [16].

FCZ was quantifiable for all UH2 bile samples, with a median concentration of 17.7 mg/L. Biliary FCZ concentrations ranged from 6.4 mg/L to 33.4 mg/L, with a coefficient of variation of almost 40%, suggesting some pharmacokinetic variability in this biological matrix. As all biliary fluid samples were taken between 4 and 8 days after FCZ initiation, we could not assess the association between the 'biliary concentration' and the 'time interval between sampling and treatment initiation'. All individual biliary FCZ concentrations, except for that of P8, were above the efficacy threshold of 10 mg/L proposed for the plasma FCZ trough concentration for a curative treatment [16,17]. No yeast infections occurred in these patients.

Mycological testing and follow-up of patients treated with caspofungin

The timelines of the evolution of biliary tract yeast infection of patients treated with CAS are shown in Fig. 1. Yeast species identified in the bile were highly diverse, including some species that are found frequently in abdominal samples following hepatic transplantation, such as *Candida albicans*, *Nakaseomyces glabratus* (=*Candida glabrata*), *Kluyveromyces marxianus* (=*Candida kefyr*), and other less frequently found species, such as *C. dubliniensis*, *Yarrowia lipolytica*, and *C. parapsilosis*. These yeast species are commensal to the digestive tract or of dietary origin.

Discussion

With the development and validation of an analytical method to quantify CAS and FCZ in bile samples, our pilot study demonstrates that CAS and FCZ diffuse into the bile at theoretically efficient concentrations.

The biliary concentrations of CAS and FCZ measured in our case series are in accordance with those found in the few published case reports [18–20]. In addition, these bile antifungal concentrations were almost all higher than the MIC of yeast species usually isolated from liver transplant patients [14,15] and were also above the efficacy thresholds proposed for plasma trough concentrations of both CAS and FCZ [16,17]. However, such *in situ* CAS exposure appears to be insufficient to prevent or eradicate the yeast infection, as several yeast species were isolated and persisted in liver transplant patients treated with CAS. Indeed, yeast persisted even for the patient with the highest measured biliary CAS concentration (P1) of 4.4 mg/L, which is 6- to 100-fold higher than the MIC values of the strains isolated in the bile fluid (Fig. 1). P1 had favorable outcome after the end of CAS therapy despite persistent yeast colonization of the bile with the same species. P2 died one month after the second biliary sampling. She developed multiple liver abscesses and pancreatic necrosis despite CAS therapy which was maintained. P3, P4 and P5 had favorable outcome after the end of CAS therapy without persistent yeast colonization. "We observed no acquired resistance in our patient isolates. However, the CAS low-susceptibility species *Y. lipolytica* and *C. parapsilosis* were isolated from P1 and P3, respectively, after the initiation of CAS. Acquired resistance has previously been described in LT recipients after at least one month of CAS treatment [21].

Although only five patients treated with CAS were included in the study, it appears that both biliary and plasma CAS concentrations are influenced by the time interval between treatment initiation and sampling. Indeed, for P5, for whom blood and bile samples were collected one day after CAS initiation, CAS was undetectable in the bile
and present at the lowest measured concentration in the plasma. Conversely, the highest CAS concentrations were observed in the bile and plasma sampled three months after CAS initiation (P1), suggesting the accumulation of CAS over time. Concomitant blood and bile sampling allowed us to determine a median bile/plasma ratio of 41.7 %, which is near the previously reported ratios for CAS [19] and micafungin [10]. Overall, these findings are in accordance with those of studies reporting a long time to achieve the pharmacokinetic steady state of CAS [22]. In addition, we observed a high correlation between plasma and bile concentrations, suggesting that therapeutic drug monitoring performed in plasma could be sufficient to assess CAS concentrations in the bile in the context of the curative treatment of IAC.

The biliary concentrations for patients receiving FCZ were surprisingly variable, with concentrations ranging from 6.4 mg/L to 33.4 mg/L, even though all bile samples were collected between 4 and 8 days after FCZ initiation. The plasma FCZ concentrations were not determined in routine care for these patients. However, previous studies have reported that bile concentrations of FCZ appear to be similar to plasma concentrations [18,20]. We, therefore, hypothesize that such variability in bile FCZ exposure was related to varying plasma exposure, probably linked to differences in renal function between patients.

Our study had several limitations, the most important being the small number of patients included (especially for CAS) and the lack of plasma concentration determination and mycological follow-up for the patients receiving FCZ prophylaxis.

## Conclusion

Our pilot study demonstrates that CAS and FCZ diffuse to the bile at concentrations that appear to be sufficient regarding the susceptibility of the yeast species involved in IAC. However, the persistence of yeast in the bile of patients treated with CAS raises questions about the effective antifungal activity of antifungals at this anatomical site.

## Funding

This study was supported by the French Society of Medical Mycology and the French Society of Pharmacology and Therapeutics.

## Declaration of competing interest

The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for *Journal name* and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MC received consulting fees from Mundipharma and support to travel to and attend conferences from Gilead Sciences and Pfizer. JPG received consulting fees and support to travel to and attend conferences from Gilead Sciences, Mundipharma, Pfizer, and Shionogi. FB received support to travel from Gilead Sciences, Pfizer and Mundiparma.

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