The objective of our study was to explore the possibility of the antifungal efficacy of various micafungin dosage regimens against
Candida spp in HIV positive patients with EC. According to pharmacokinetic/pharmacodynamics parameters of micafungin in HIV positive patients and MICs distribution of micafungin against
Candida spp. in published studies, the dosage regimens of micafungin were 50, 100 and 150 mg QD iv. Monte Carlo Simulation analysed the probability of target attainment and cumulative fraction of response. The results showed that micafungin has good antifungal effect in treating HIV positive patients with EC when pathomycetes are
Candida albicans,
Candida glabrata or
Candida tropicalis, in dosage at 100 mg QD and 150 mg QD.
Monte Carlo Simulation Micafungin HIV Positive Patients Esophageal Candidiasis1. Introduction
In recent years, invasive fungal infections (IFIs) had been a significant factor in the morbidity and mortality of inpatients with invasive infections, especially in patients with immunodeficiency [1] [2]. The primary pathogenic fungi for IFIs are Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis and Candida tropicalis [1].
In patients with the human immunodeficiency virus (HIV) infection, esophagal candidiasis (EC) is a common and severe complication, the incidence is 15% - 20%, and micafungin has shown great efficacy and tolerability in treating EC in HIV positive patients [3]. Micafungin is an echinocandin antifungal agent, which plays an antifungal role in selective inhibiting the synthase of β-(1,3)-D-glucan in the fungal cell wall [4] [5]. Micafungin mainly binds to albumin in vivo, the protein binding rate in plasma is 99% [6]. In vivo, micafungin is metabolized by the liver and excreted through the biliary tract, and mainly excreted through faeces [7]. Studies showed that micafungin has antifungal activities against Candida spp. both in vitro and in vivo, even for fluconazole resistance fungus [8] [9] [10] [11].
Monte Carlo simulation (MCS) is a useful tool for clinical treatment of dose selection, which can be sufficient to evaluate the effect of antifungal drugs and minimise the possibility of antifungal drug resistance. MCS has been used to assess the dosing regimens of micafungin in morbidly obese patients [12], critically ill patients with invasive fungal infection [13], critically burned patients with abdominal disease [14] and children [15]. In this study, MCS was used to optimise the micafungin dosage regimen of EC in HIV positive patients, to provide a basis for clinical application.
2. Materials and Methods2.1. Pharmacokinetic Parameters
Pharmacokinetic parameters for micafungin in HIV positive patients with EC from the literature [3], PK data of intravenous micafungin in HIV-positive patients are shown in Table 1. Micafungin is a concentration-dependent antifungal drug with long-term aftereffects, and the antifungal effect is measured by fAUC24h/MIC, PD target of Candida spp. is fAUC24h/MIC = 10 [16], Free drug fraction f is 1%.
2.2. The Minimum Inhibitory Concentration (MIC) Data
The MICs distribution of Candida spp. is from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (http://www.eucast.org). The data has shown in Table 2.
2.3. Monte Carlo Simulation
The probability of target attainment (PTA) is the target value of Pharmacokinetic/pharmacodynamic (PK/PD); the calculation formula is
Pharmacokinetic parameters for micafungin in HIV positive patients
PK parameters
50 mg/day (n = 20)
100 mg/day (n = 20)
150 mg/day (n = 14)
CL (mL/h/kg)
19.3 ± 5.9
19.8 ± 5.4
20.4 ± 5.5
AUC0-24 (kg h/mL)
35.7 ± 8.9
74.5 ± 18.7
104.3 ± 26.3
Cmax (μg/mL)
4.1 ± 1.4
8.0 ± 2.4
11.6 ± 3.1
The MICs distribution of micafungin against Candida spp
Species
n
MIC (μg/ml)
0.002
0.004
0.008
0.016
0.032
0.064
0.125
0.25
0.5
1
2
4
8
Candida albicans
1569
4
286
360
763
146
7
1
0
0
2
0
0
0
Candida glabrata
692
0
90
182
273
135
3
5
0
1
1
2
0
0
Candida krusei
483
0
1
0
4
26
185
215
37
9
2
4
0
0
Candida parapsilosis
743
0
0
0
3
1
0
1
35
113
332
244
14
0
Candida tropicalis
732
0
48
51
247
298
59
15
2
1
6
5
0
0
f A U C 24 h / M I C = ( f × d o s e ) / ( C L × M I C ) MCS simulated ten thousand patients through Crystal Ball software (version 11.1.2.4.600, Oracle). CL follows a logarithmic normal distribution, dose (mg) and f follow a uniform distribution, and MICs follows the custom distribution.
Cumulative fraction of response (CFR) describe the expected probability of the target value of the corresponding strain population, the calculation formula
is C F R = ∑ i = 1 n P T A i × F i . PTAi is probability of target for the specific MIC; Fi is
the probability of every MIC distribution for an individual fungal sample, to achieve an excellent antifungal effect, PTA > 90% and CFR > 90% [12] [13] [14] [15].
3. Results3.1. PTA Values
PTA values of micafungin against Candida spp. in HIV positive patients under different MICs distribution shown in Figure 1. The results showed that in dosage at 50 mg, the 5 Candida spp can reach the target when MIC is less than 0.032 μg/mL. In dosage at 100 mg and 150 mg, the 5 Candida spp can attain the goal when MIC is less than 0.064 μg/mL.
3.2. CFR
As the results are shown in Table 3, the effects of micafungin against Candida krusei and Candida parapsilosis are not sound, all CFR values cannot reach 90% in every dosage. The results also showed a good effect in micafungin against Candida albicans and Candida glabrata, all CFR values are higher than 90%. For Candida tropicalis, when the dosage of micafungin at 50 mg, CFR values below 90%, when the dosage of micafungin at 150 mg and 100 mg, the antifungal effect is proper, CRF values are higher than 90%.
4. Discussion
Micafungin is one of three currently available echinocandins in the treatment of Candidiasis, and the FDA recommends a dose of 100 mg QD for adult Candidiasis [17]. In HIV positive patients confirmed EC, no effect of race or gender
CFR (%) of micafungin against Candida spp in HIV positive patients with EC
Species
CFR%
50 mg/day
100 mg/day
150 mg/day
Candida albicans
97.75
99.79
99.85
Candida glabrata
96.99
98.80
99.15
Candida krusei
15.01
50.23
74.84
Candida parapsilosis
0.53
0.57
0.71
Candida tropicalis
86.75
95.89
97.40
on the pharmacokinetics of micafungin [3].
Pharmacokinetics of micafungin in treating patients with EC was linear, predictable, which is similar to the published studies in healthy adults [3].
In our study, the antifungal effect of micafungin against different Candida spp in HIV positive patients with EC was quite different. For Candida krusei and Candida parapsilosis, micafungin has no antifungal impact, which is similar to the published studies in intensive care unit patients [18]. Our study also showed that micafungin against Candida albicans, Candida glabrata and Candida tropicalis has good antifungal effect in dosage greater than or equal to 100 mg, which is similar to FDA recommendation [17].
In this study, MCS used to carry out hypothesis analysis based on certain PK and strain data, which was beneficial to optimise the type and dosage of micafungin against Candida spp in HIV positive patients with EC. However, the research results of this paper also have some limitations, such as the MIC distribution of micafungin from some regions but not world-wide, so it can not reflect the development trend and change of the fungus in the future.
5. Conclusion
In summary, MCS is a simple, safe method to optimise dosage regimen according to the characteristics of fungi and PK/PD parameters. When pathomycetes are Candida albicans, Candida glabrata or Candida tropicalis, micafungin has good antifungal effect in HIV positive patients with EC, when pathomycetes are Candida krusei or Candida parapsilosis, other antifungal treatments are needed.
Funding
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 201701A086).
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
Cite this paper
Wang, Y., Zhao, J.Y., Jiang, S., Yao, Y.H. and Wen, H.N. (2020) Optimizing the Dosage Regimen of Micafungin against Candida spp in HIV Positive Patients with EC Based on Mote Carlo Simulation. Open Journal of Preventive Medicine, 10, 120-125. https://doi.org/10.4236/ojpm.2020.106009
ReferencesKyriakidis, I., Tragiannidis, A., Munchen, S., et al. (2017) Clinical Hepatotoxicity Associated with Antifungal Agents. Expert Opinion on Drug Safety, 16, 149-165.Enoch, D.A., Yang, H.N., Aliyu, S.H., et al. (2017) The Changing Epidemiology of Invasive Fungal Infections. Methods in Molecular Biology, 1508, 17-65. https://doi.org/10.1007/978-1-4939-6515-1_2Under, N., Stevenson, P. and Baraldi, E. (2012) Pharmacokinetics of Micafungin in HIV Positive Patients with Confirmed Esophageal Candidiasis. European Journal of Drug Metabolism and Pharmacokinetics, 37, 31-38. https://doi.org/10.1007/s13318-011-0063-8Chen, S.C., Slavin, M.A. and Sorrell, T.C. (2011) Echinocandin Antifungal Drugs in Fungal Infections: A Comparison. Drugs, 71, 11-41. https://doi.org/10.2165/11585270-000000000-00000Carver, P.L. (2004) Micafungin. The Annals of Pharmacotherapy, 38, 1707-1721. https://doi.org/10.1345/aph.1D301Muilwijk, E.W., Lempers, V.J.C., Burger, D.M., et al. (2015) Impact of Special Patient Populations on the Pharmacokinetics of Echinocandins. Expert Review of Anti-Infective Therapy, 13, 799-815. https://doi.org/10.1586/14787210.2015.1028366Wasmann, R.E., Muilwijk, E.W., Burger, D.M., et al. (2018) Clinical Pharmacokinetics and Pharmacodynamics of Micafungin. Clinical Pharmacokinetics, 57, 267-286. https://doi.org/10.1007/s40262-017-0578-5Maesaki, S., Hossain, M.A., Miyazaki, Y., et al. (2000) Efficacy of FK463, a (1,3)-beta-D-glucan Synthase Inhibitor, in Disseminated Azole-Resistant Candida Albicans Infection in Mice. Antimicrobial Agents and Chemotherapy, 44, 1728-1730. https://doi.org/10.1128/AAC.44.6.1728-1730.2000Messer, S.A., Diekema, D.J., Boyken, L., et al. (2006) Activities of Micafungin against 315 Invasive Clinical Isolates of Fluconazole-Resistant Candida spp. Journal of Clinical Microbiology, 44, 324-326. https://doi.org/10.1128/JCM.44.2.324-326.2006Pfaller, M.A., Boyken, L., Hollis, R.J., et al. (2008) In Vitro Susceptibility of Invasive Isolates of Candida spp. to Anidulafungin, Caspofungin, and Micafungin: Six Years of Global Surveillance. Journal of Clinical Microbiology, 46, 150-156. https://doi.org/10.1128/JCM.01901-07Warn, P.A., Sharp, A., Morrissey, G., et al. (2002) In Vivo Activity of Micafungin in a Persistently Neutropenic Murine Model of Disseminated Infection Caused by Candida tropicalis. Journal of Antimicrobial Chemotherapy, 50, 1071-1074. https://doi.org/10.1093/jac/dkf247Wasmann, R.E., Smit, C., Heine, R., et al. (2019) Pharmacokinetics and Probability of Target Attainment for Micafungin in Normal-Weight and Morbidly Obese Adults. Journal of Antimicrobial Chemotherapy, 74, 978-985. https://doi.org/10.1093/jac/dky554Boonstra, J.M., van der Elst, K.C., Veringa, A., et al. (2017) Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis. Antimicrobial Agents and Chemotherapy, 61, pii: e01398-17. https://doi.org/10.1128/AAC.01398-17García-de-Lorenzo, A., Luque, S., Grau, S., et al. (2016) Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection. Antimicrobial Agents and Chemotherapy, 60, 5914-5921. https://doi.org/10.1128/AAC.00727-16Xu, G.Q., Zhu, L.Q., Ge, T.Y., et al. (2016) Optimal Micafungin Dosage Regimens in Pediatric Patients with Invasive Candida Infection. Chinese Journal of New Drugs and Clinical Remedies, 35, 482-486.Lepak, A.J. and Andes, D.R. (2015) Antifungal Pharmacokinetics and Pharmacodynamics. Cold Spring Harbor Perspectives in Medicine, 5, a019653. https://doi.org/10.1101/cshperspect.a019653Wasmann, R.E., Muilwijk, E.W., Burger, D.M., et al. (2018) Clinical Pharmacokinetics and Pharmacodynamics of Micafungin. Clinical Pharmacokinetics, 57, 267-286. https://doi.org/10.1007/s40262-017-0578-5Yang, Q.T., Wang, T.T., Xie, J., et al. (2016) Pharmacokinetic/Pharmacodynamic Adequacy of Echinocandins against Candida spp. in Intensive Care Unit Patients and General Patient Populations. International Journal of Antimicrobial Agents, 47, 397-402. https://doi.org/10.1016/j.ijantimicag.2016.02.004