Optimizing Micafungin Dosing in Patients with Critically Ill Candidemia and Trends of Candida Species Causing Bloodstream Infections in a Tertiary Hospital in Thailand: A Monte Carlo Simulation Approach

Introduction

Candida species are common components of the normal human microbiota but can act as opportunistic pathogens, especially in immunocompromised individuals. The five most common species causing invasive infections are C. albicans (38%), C. glabrata (Nakaseomyces glabrata) (29%), C. parapsilosis (17%), C. tropicalis (10%), and C. krusei (Pichia kudriavzevii) (1%).¹ A major concern with invasive Candida infections is candidemia, which carries significant morbidity and mortality, particularly in critically ill patients. In the United States, a 2020 report indicated that Candida accounted for up to 28% of central line–associated bloodstream infections in this population.^1,2 In Thailand, candidemia-related mortality is notably high, ranging from 50.8% to 71.2%, exceeding rates reported in China, South Korea, and Europe.^3–6

Despite its clinical significance, conventional diagnostic methods such as fungal cultures are often slow and insensitive, making timely diagnosis challenging.⁷ Therefore, empirical antifungal therapy is commonly used, guided by local epidemiological data, which can vary widely by region.⁸ The current guidelines for the treatment of Candida bloodstream infections from the Infectious Diseases Society of America (IDSA) 2016 and the global guideline for the diagnosis and management of candidiasis: an initiative of the European Confederation for Medical Mycology in cooperation with the International Society of Human and Animal Mycology and the American Society for Microbiology 2025^9,10 recommend echinocandins as the first-line therapy, due to the increasing resistance to fluconazole and its reduced efficacy against certain Candida species. Micafungin, an echinocandin, is commonly used, but current dosing recommendations are not adjusted for critically ill patients, potentially impacting treatment success.

Micafungin resistance in C. glabrata is an increasing concern in clinical practice. A national surveillance report from the United States, conducted between 2008 and 2014, documented a resistance rate of 4.8%.¹¹ In Thailand, C. glabrata generally remains susceptible to micafungin; however, recent data from university hospitals indicate a gradual decline in susceptibility.^3,12,13 Furthermore, C. auris has emerged as a significant fungal pathogen known for causing severe infections and exhibiting resistance to multiple antifungal agents. The Centers for Disease Control and Prevention (CDC) has highlighted the urgent threat posed by this organism. Despite global concern, reports of C. auris in Thailand are still relatively limited.^10,13,14

Considering these developments, this study aimed to evaluate the in vitro activity of micafungin against various Candida species and to use these susceptibility data in Monte Carlo simulations. The goal was to determine the optimal micafungin dosing strategy based on pharmacokinetic/pharmacodynamic (PK/PD) targets in critically ill patients with candidemia.

Materials and Methods

Sample Collection

Candida isolates were obtained from the blood of hospitalized patients aged ≥20 years at Phramongkutklao Hospital, Thammasat University Hospital, and Udonthani Hospital, Thailand, between September 2023 and December 2024. Duplicate isolates from the same patient were excluded from the analysis.

Fungal Strains and Antifungal Susceptibility Testing

Species identification was conducted using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility of Candida isolates was assessed using the Sensititre YeastOne system, a broth microdilution–based method, following the manufacturer’s instructions (Thermo Fisher Scientific, Cleveland, OH, USA). Isolates were first grown on blood agar at 35°C in a non-CO₂ incubator for 24–25 h, after which the inoculum was standardized to a 0.5 McFarland turbidity. A 20-µL aliquot of the suspension was added to the broth, mixed, and further diluted with Sensititre YeastOne broth. The plates were prepared with serial twofold dilutions of antifungal agents, including micafungin, ranging from 0.008 to 8 µg/mL. Minimum inhibitory concentrations (MICs) were determined after 24 h  of incubation, based on a color change from blue (no growth) to pink or purple (growth). Quality control was ensured using C. parapsilosis ATCC 22019 and C. krusei ATCC 6258, following the Clinical and Laboratory Standards Institute (CLSI) M27 guidelines.¹⁵ MICs were interpreted according to the breakpoints specified in CLSI M27M44S (3^rd edition). For antifungals lacking defined breakpoints, epidemiological cutoff values (ECVs) from CLSI M57S (4^th edition) were used.^16,17

Monte Carlo Simulation

The present analysis utilized micafungin PK parameters obtained from a study by Zhong et al¹⁸ involving critically ill patients are summarized in Supplementary Table 1. A two-compartment model was applied to describe the PK behavior of micafungin in relation to time and concentration, with the PK/PD target being the 24-h area under the concentration–time curve to the MIC (AUC_0-24/MIC). Although no specific PK/PD target has been universally established to define the safety of micafungin, its safety profile is well characterized and has been used at doses exceeding the standard recommended regimen. The model of the plasma concentration of micafungin, equations incorporating alanine aminotransferase (ALT) and the Sequential Organ Failure Assessment (SOFA) score as covariate factors were used.¹⁸ The target AUC_0-24/MIC values indicating the efficacy of micafungin were >3000 for all Candida species, >5000 for Candida species excluding C. parapsilosis, and >285 for C. parapsilosis.¹⁹

Micafungin regimens were administered intravenously at a loading dose ranging from 100 to 400 mg, followed by 100–400 mg every 24 h. The highest dose used in this study was determined according to doses administered in earlier clinical trials involving patients. The PK/PD of the micafungin regimens was evaluated using a 10,000-subject Monte Carlo simulation (Oracle Crystal Ball Classroom Faculty Edition-Oracle 1-Click Crystal Ball 201, Thailand). The predicted likelihood that each dosage regimen would reach the established PK/PD index and target at each MIC was defined as the probability of target attainment (PTA). Furthermore, the cumulative fraction of response (CFR) for each regimen calculated by multiplying the proportion of Candida isolates at each MIC by the corresponding PTA. Dosage regimens were considered appropriate if the CFR and PTA were at least 90% in empirical and documented therapy, respectively.

Results

Candida Isolates the Distribution

Over the course of the investigation, 128 clinical isolates of Candida were identified. In our study, the five most frequently isolated Candida species included C. tropicalis (32%), C. albicans (22.7%), C. parapsilosis (16.4%), C. glabrata (12.5%), and C. auris (9.4%). Other Candida species accounted for 8.1% of the isolates, including C. orthopsilosis (3.1%), C. guilliermondii (Meyerozyma guilliermondii) (1.6%), C. lusitaniae (0.8%), C. dubliniensis (0.8%), and C. krusei (0.8%).

In vitro Susceptibility of Micafungin

All C. albicans isolates exhibited 100% susceptibility to micafungin, with MIC50 and MIC90 values of 0.008 and 0.015 µg/mL, respectively. Among the non-albicans Candida species, susceptibility to micafungin remained generally high; however, an increasing trend in MIC values was observed. C. tropicalis exhibited MIC50 and MIC90 values of 0.03 and 0.06 µg/mL, respectively. For C. parapsilosis, the MIC50 and MIC90 values were 1 and 2 µg/mL, respectively; the MIC90 corresponds to the upper limit of the susceptibility breakpoint. C. glabrata exhibited MIC50 and MIC90 values of 0.015 and 0.03 µg/mL, respectively; however, an isolate with an MIC exceeding 8 µg/mL was also detected. Furthermore, C. auris exhibited relatively high MIC values, with MIC50 and MIC90 values at 0.12 and 0.25 µg/mL, respectively. Table 1 presents the MIC distribution, as well as the MIC50 and MIC90 values of micafungin for each Candida species. Additional susceptibility data for caspofungin and anidulafungin are presented in Supplementary Table 2.

Table 1 MIC Distribution of Micafungin Against Candida Species Isolates

Monte Carlo Dose Simulation

In critically ill patients with normal ALT levels (<40 U/L), micafungin therapy at a standard dose of 100 mg/day was sufficient to cover Candida isolates with MICs up to 0.015 µg/mL. For critically ill patients with ALT levels ≥40 U/L, the same regimen provided adequate coverage for isolates with MICs up to 0.03 µg/mL. Isolates with MICs as high as 0.25 µg/mL required increased micafungin doses to achieve PK/PD targets, defined as a PTA of ≥90%. PTA values for different micafungin dosing regimens against Candida species are summarized in Supplementary Table 3.

If the Candida species has been identified, critically ill patients receiving the standard micafungin dose with ALT levels <40 U/L, regardless of SOFA score, achieved the CFR target only for C. albicans. In contrast, patients with ALT ≥40 U/L, regardless of SOFA score, attained the CFR target for C. albicans and C. glabrata, but not for C. tropicalis or C. auris. Notably, in patients with SOFA scores ≥10 and ALT levels >120 U/L, the standard micafungin dose achieved the CFR target for C. albicans, C. glabrata, and C. tropicalis. However, achieving the CFR target for C. auris requires a higher dose (up to 400 mg/day). The results demonstrated that the CFR target was attained only when high-dose micafungin and elevated ALT levels were present. Simulated PK/PD target attainment differed across Candida species and depended on the micafungin dosing regimen, as presented in Table 2.

Table 2 PTA and CFR of Various Micafungin Dosage Regimens Was Evaluated in Critically Ill Patients at Steady State, Stratified by Sequential Organ Failure Assessment (SOFA) Score and Alanine Aminotransferase (ALT), Using a PK/PD Target of AUC0–24/MIC > 5000 Against Candida Species Not Included C. parapsilosis

In cases involving C. parapsilosis with unknown MIC values, high-dose micafungin therapy was associated with a CFR exceeding 90% among critically ill patients presenting with elevated SOFA scores and ALT levels. In contrast, the standard-dose regimen failed to achieve the CFR target in patients with normal ALT levels. A daily dose of 400 mg was necessary to reach CFR values of 92.14% and 93.27% in patients with SOFA scores <10 and ≥10, respectively. When the MIC was known, a standard dose of micafungin was sufficient to achieve PTA when the MIC was ≤0.25 µg/mL, regardless of the SOFA score or ALT level. In patients with ALT levels ≥40 U/L, micafungin doses of at least 200 mg/day were effective in achieving PTA against C. parapsilosis isolates with MICs up to 1 µg/mL. Notably, the MICs of C. parapsilosis isolates in this study ranged from 0.5 to 2 µg/mL. Moreover, a 400-mg/day regimen achieved CFR targets even for isolates with MICs as high as 4 µg/mL. Comprehensive results for each dosing regimen against C. parapsilosis are presented in Supplementary Table 4.

Discussion

In this study, C. tropicalis was the most isolated species (32%), followed by C. albicans (22.7%), C. parapsilosis (16.4%), and C. glabrata (12.5%). Notably, C. auris was also detected, accounting for 9.4% of the isolates. Other Candida species accounted for 8.1% of the isolates, including C. orthopsilosis (3.1%), C. guilliermondii (1.6%), C. lusitaniae (0.8%), C. dubliniensis (0.8%), and C. krusei (0.8%). Between 2009 and 2017, the distribution of Candida species in the United States was dominated by C. albicans (48%), followed by C. glabrata (24%), C. parapsilosis (11%), and C. tropicalis (6%). The analysis of Candida isolates revealed that 57% were obtained from patients diagnosed with candidemia.²⁰ In the Asia-Pacific region, a 2022 study conducted in China reported the distribution of Candida species across all clinical specimens. Only 6.1% of these isolates were derived from blood. The predominant species were C. albicans (49.4%), C. tropicalis (21.9%), C. parapsilosis (13.9%), and C. glabrata (11.4%). In contrast, C. auris accounted for a mere 0.2% of all clinical isolates and was absent from bloodstream infection isolates.²¹ In Japan, the distribution of Candida species isolated from blood between 2010 and 2019 was as follows: C. albicans, 43.6%; C. glabrata, 19.5%; C. parapsilosis, 18.8%; and C. tropicalis, 6.7%. Notably, no C. auris isolates were identified.²² Based on blood culture data from separate single-center studies conducted at different hospitals across Thailand, C. albicans (53%) was the most common Candida species from 2012 to 2013, followed by C. tropicalis (27.3%) and C. glabrata (15.2%).¹² Between 2013 and 2016, C. tropicalis became predominant (36.9%), followed by C. albicans (29.2%), C. glabrata (17.7%), and C. parapsilosis (6.9%).¹³ During the 2016–2017 period, the predominant Candida species were C. tropicalis (49.4%), followed by C. albicans (28.8%), C. glabrata (16.7%), and C. parapsilosis (5.1%).¹³ In the subsequent study period (2018–2019), C. tropicalis remained the most frequently isolated species (33%), followed closely by C. albicans (29.6%).²³ The distribution of Candida species in Thailand has shifted over time, with a marked increase in non-albicans Candida species. This trend is clearly reflected in our study, where non-albicans Candida species accounted for as much as 77.3% of all isolates, whereas C. albicans was identified in only 22.7%. Although our results differ from those of previous research in this area, our study collected clinical Candida isolates from blood from multiple tertiary hospital centers. This study provides a comprehensive overview of Candida species distribution in Thailand and highlights the current epidemiological landscape.

C. auris is an emerging fungal pathogen of major clinical concern due to its capacity to cause severe infections that are often resistant to multiple classes of antifungal drugs. This study presents the first report of the highest prevalence of C. auris in Thailand. Historically, C. auris was rarely detected in global surveillance, with only six cases of bloodstream infection reported across 135 medical centers in 39 countries from 2009 to 2016.²⁴ Recent data reveal a notable epidemiological shift: by 2023, the United States reported 4514 new C. auris cases, prompting the CDC to classify it as an urgent public health threat due to multidrug resistance. In this study, micafungin MICs for C. auris isolates ranged from 0.12 to 0.25 µg/mL, with 0.5 µg/mL representing the established ECV.¹⁷ The proximity of MIC values to the ECV indicates a potential trend toward reduced susceptibility, which is significant compared to United States data showing that fewer than 2% of C. auris isolates exhibit resistance to echinocandin-class antifungals.¹⁴ These findings highlight the importance of ongoing surveillance and the need for adaptable antifungal treatment strategies, especially in areas where multidrug-resistant strains are emerging.

Therefore, this study also evaluated the susceptibility of Candida isolates to micafungin to support clinical decision-making and monitor emerging resistance trends. Notably, susceptibility testing in this study used a standardized MIC method, recognized for its accuracy and reliability in clinical practice. Micafungin was chosen as the primary antifungal due to its wider availability in resource-limited settings like Thailand, where it is listed on the National List of Essential Medicines. Conversely, caspofungin is unavailable in Thailand, and anidulafungin is rarely used because of its high cost and exclusion from the essential medicines list. Although these agents were not included in the main analysis, their MIC data are provided in Supplementary Table 2 to support reference and future investigations. Previous research conducted between 2012 and 2013 reported that micafungin had a 90% susceptibility rate against C. glabrata, with MIC values of 0.015–0.25 µg/mL.¹² Further research from 2013 to 2016 demonstrated that C. albicans (MIC range: 0.008–0.015 µg/mL), C. tropicalis (MIC range: 0.015–0.06 µg/mL), and C. glabrata (MIC range: 0.008–0.015 µg/mL) all exhibited 100% susceptibility to micafungin.²⁵ The findings revealed that C. glabrata isolates from bloodstream infections were resistant to echinocandins, which are currently recommended as the first-line therapy for candidemia, particularly in critically ill patients. In particular, one sixteenth of C. glabrata isolates exhibited resistance to micafungin (MIC range from 0.015 to >8 µg/mL). Because MIC values were progressively higher, pan-resistant strains were also detected, raising serious concerns regarding the efficacy of current antifungal treatments. Compared with other reports, the resistance rate of C. glabrata to micafungin was previously reported as 0.4%, 0.6%, 0%, and 2.8% in the Asia-Pacific region, Europe, Latin America, and North America, respectively, between 2006 and 2016.²⁴

In this study, C. parapsilosis remained susceptible to echinocandins, though MIC values showed an upward trend compared to earlier reports. Specifically, micafungin MICs for C. parapsilosis ranged from 0.5 to 2 µg/mL, with MIC50 and MIC90 values of 1 and 2 µg/mL, respectively both higher than previously documented.^12,23 Notably, some micafungin dosing regimens did not achieve the established PK/PD target. In contrast, C. albicans remained uniformly susceptible to echinocandins, with micafungin MICs ranging from 0.008 to 0.015 µg/mL, an MIC50 of 0.008 µg/mL, and an MIC90 of 0.015 µg/mL (susceptibility breakpoint: ≤0.25 µg/mL).¹⁶ All regimens of micafungin successfully met the CFR target for C. albicans.

Based on Monte Carlo simulations using population PK parameters from Zhong et al,¹⁸ high-dose micafungin regimens tailored to specific Candida species were essential to achieve PTA and CFR targets. The relatively high simulated doses in this study likely reflect reliance on PK/PD targets from prior literature, which do not fully account for all relevant pathogens, notably C. auris. Future research establishing species-specific PK/PD targets would enable more precise and clinically relevant dose optimization. Safety concerns are limited, as multiple real-world studies have demonstrated that high-dose micafungin is well tolerated. Repeated dosing up to 8 mg/kg/day (maximum 896 mg/day) for 1–4 weeks showed no dose-limiting toxicities in adults.²⁶ Similarly, doses exceeding 200 mg/day (median 300 mg; IQR 275–400) for at least three consecutive days were well tolerated, with no severe hepatic or hematologic adverse events observed.²⁷ Clinical evidence also suggests that higher-than-standard doses can shorten treatment duration and improve success rates compared with standard regimens.²⁸ Despite this, careful monitoring for adverse reactions remains essential. The high simulated doses also highlight the potential benefit of exploring combination therapy with other antifungals for synergistic effects and underscore the importance of defining species-specific targets, which could guide more effective and personalized treatment strategies in future studies.

Our study suggests that a standard daily dose of micafungin (100 mg/day) is appropriate for Candida species, excluding C. parapsilosis, when the MIC is ≤0.015 µg/mL, regardless of SOFA score or ALT level. A minimum micafungin dose of 200 mg/day is required to achieve the PTA target at an MIC of 0.06 µg/mL in patients with SOFA scores ≥10 and ALT levels ≥40 U/L. For C. parapsilosis, the standard micafungin dose is sufficient to achieve the PTA target when the MIC is up to 0.25 µg/mL, regardless of the SOFA score or ALT level. However, in patients with ALT ≥40 U/L, target attainment can be achieved for isolates with MICs up to 0.5 µg/mL. Micafungin clearance in adult ICU patients was 30–51% higher than that in non-ICU adult patients. The AUC_0-24 at steady state was 96.8 mg·h/L (72.0–132.3 mg·h/L) in ICU patients with SOFA scores ≥10 and 89.7 mg·h/L (70.7–131.7 mg·h/L) in those with SOFA scores <10. In contrast, non-ICU adult patients had a higher AUC_0-24 of 125.6 mg·h/L (95.3–149.4 mg·h/L). A dose adjustment may be necessary when treating infections caused by resistant Candida strains. Although previous studies have recommended 250-mg/day micafungin for treating C. glabrata-associated infections,²⁹ our findings demonstrated that a dose of 150 mg/day may be sufficient to achieve the CFR target in certain scenarios. However, even with simulated doses as high as 400 mg/day, effective coverage was only achievable for isolates with MICs ≤0.12 µg/mL. Notably, our study also identified isolates with MICs exceeding 8 µg/mL for which alternative antifungal agents outside the echinocandin class should be considered.

This study has several limitations that should be acknowledged. First, the dosing regimens used in our simulations were optimized to achieve established PK/PD targets; however, they have not yet been validated in real-world clinical settings. Second, this study did not collect isolates for investigating gene mutations. Finally, one limitation of this simulation study was the lack of measured PK data from the study participants. However, the population PK model of micafungin adequately describes the variability in PK parameters among critically ill patients.

Conclusion

Micafungin is one of the first-line treatment in critically ill patients with Candida bloodstream infections. Optimizing treatment outcomes requires appropriate dosing that takes local MIC values into account. C. auris should be acknowledged as an emerging and clinically significant pathogen in Thailand. Although administering doses higher than standard recommendations may enhance the likelihood of achieving PK/PD targets, particularly in cases of C. auris septicemia accompanied by high SOFA scores and elevated ALT levels, the safety of such regimens must be thoroughly assessed. Future studies evaluating clinical outcomes are necessary to determine the most effective micafungin dosing strategies for candidemia management.