Neutropenia with fever is a special group of patients. Due to low immune function, inflammation-related clinical symptoms and signs are often not obvious, and pathogenic bacteria and infection focus are not clear. Fever may be the only sign of infection. If appropriate antimicrobial treatment is not given in time, infection-related mortality is high. In our study, we aimed to optimize the dosage regimen of Micafungin in children with febrile neutropenic against Candida spp. by Mote Carlo Simulation (MCS). Pharmacokinetic parameters and microbiological data of Micafungin were collected. Then we used MCS to calculate Probability of Target Attainment (PTA) and Cumulative Fraction of Response (CFR). With dosages of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, and 4 mg/kg in oral group and dosages of 100 mg, and 200 mg in intravenous administration, all have different degree of antifungal effect. But when the dosage regimen was 50 mg IV, the therapeutic effect of Micafungin against Candida spp. w as not good.
Neutropenia is the most common cause of death and morbidity in childhood cancer patients. Invasive fungal infections have significant morbidity and mortality in pediatric patients. It is found shortly after chemotherapy-induced neutropenia or hematopoietic Stem Cell Transplantation (HSCT). Among patients, about one-third of neutropenia episodes have a febrile reaction. When the absolute neutrophil count is less than 500 cells/L, the risk of serious bacterial or fungal infection increases [
Micafungin is an echinocandin antifungal drug that selectively inhibits the synthesis of 1,3-β-D-glucan in the cell wall of fungi [
Mote Carlo Simulation (MCS) is an effective tool for dose screening in clinical treatment. It can evaluate the efficacy of antibacterial drugs, maximize the possibility of obtaining clinical efficacy, and minimize the possibility of antimicrobial resistance sex. This method has been used to analyze the suitability of the dosing regimen of Micafungin in critically ill patients with invasive fungal infection [
Micafungin is a concentration-dependent antifungal drug, and its antibacterial effect is evaluated by the ratio AUC/MIC of Area under the concentration time curve (AUC) and Minimum inhibitory concentration (MIC) [
The pharmacokinetic parameters of Micafungin in children with febrile neutrophil deficiency are derived from the research literature of Seibel et al. [
MIC distributions of Micafungin against Candida spp.derived from EUCAST website (https://mic.eucast.org/search/, MIC distributions for Micafungin, 2021-10-20) (shown in
MCSs combine pharmacokinetic parameters and MIC distribution characteristics
| Daily dose (mg/kg) | No. of patients | Mean wt (kg) ± SD | AUC0–∞ (h·μg/ml) | t1/2 (h) | CL (ml/h/kg) |
|---|---|---|---|---|---|
| 0.5 | 15 | 38.6 ± 19.59 | 25.9 ± 2.8 | 12.6 ± 0.7 | 22.7 ± 2.6 |
| 1.0 | 16 | 45.9 ± 32.91 | 52.4 ± 4.7 | 12.5 ± 1.1 | 21.8 ± 2.4 |
| 1.5 | 13 | 36.7 ± 18.33 | 106.8 ± 16.7 | 12.8 ± 1.1 | 17.4 ± 3.2 |
| 2.0 | 11 | 29.5 ± 11.98 | 113.8 ± 16.0 | 13.2 ± 2.0 | 20.8 ± 2.9 |
| 3.0 | 9 | 30.9 ± 13.18 | 206.6 ± 23.0 | 11.7 ± 0.6 | 15.9 ± 1.6 |
| 4.0 | 7 | 28.0 ± 11.61 | 247.1 ± 23.8 | 11.6 ± 1.0 | 17.4 ± 2.5 |
| Species | Observations | 0.002 | 0.004 | 0.008 | 0.016 | 0.032 | 0.06 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| C. albicans | 940 | 0 | 290 | 360 | 243 | 39 | 5 | 1 | 0 | 0 | 2 | 0 | 0 |
| C. glabrata | 418 | 0 | 90 | 182 | 100 | 35 | 3 | 4 | 0 | 1 | 1 | 2 | 0 |
| C. guilliermondii | 22 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 5 | 7 | 8 | 1 | 0 |
| C. krusei | 481 | 0 | 1 | 0 | 4 | 26 | 185 | 215 | 37 | 9 | 0 | 4 | 0 |
| C. parapsilosis | 743 | 0 | 0 | 0 | 3 | 1 | 0 | 1 | 35 | 113 | 332 | 244 | 14 |
| C. tropicalis | 623 | 0 | 48 | 51 | 247 | 200 | 59 | 14 | 2 | 0 | 2 | 0 | 0 |
to evaluate the probability of AUC/MIC pharmacodynamic target values in plasma [
C F R = ∑ i = 1 n P T A ( M I C i ) ⋅ i ( M I C ) i
Crystal Ball (Version 11.1.2.4.600, Oracle) was used for Monte Carlo simulation of drug administration schemes.
PTA values of Micafungin under MIC distribution of the different Candida spp. infection in Febrile Neutropenic Pediatric Patients were shown in
Candida albicans, PTA was up to the standard for MIC ≤ 0.008 μg/mL, ≤0.016 μg/mL, ≤0.064 μg/ml, ≤0.032 μg/mL, ≤0.125 μg/mL and ≤0.125 μg/mL of dosage regimen included 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg and 4 mg/kg respectively. In Candida glabrata, PTA was reached the standard for MIC ≤ 0.004 μg/ml, ≤0.016 μg/ml, ≤0.016 μg/ml, ≤0.032 μg/ml, ≤0.064 μg/ml and ≤0.125 μg/ml of dosage regimen included 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg and 4 mg/kg respectively. In Candida guilliermondii, PTA of all MIC values did not meet the standards. When the administration scheme of C. krusei was 0.5 mg/kg, PTA of all MIC values did not meet the standards, and the rest reached the standards: 1 mg/kg, 1.5 mg/kg, 2 mg/kg with MIC ≤ 0.016 μg/ml; 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤0.064 μg/ml respectively. In C. parapsilosis, the PTA < 90% of all MIC values was dosage regimen of 0.5 mg/kg. And the rest reached the standards: 1 mg/kg, 1.5 mg/kg with MIC ≤ 0.016 μg/ml; 2 mg/kg, 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤ 0.064 μg/ml respectively. In C. tropicalis, the PTA < 90% of all MIC values was dosage regimen of 0.5 mg/kg and 1 mg/kg. And the rest reached the standards: 1.5 mg/kg, 2 mg/kg with MIC ≤ 0.016 μg/ml; 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤0.064 μg/ml respectively.
According to MCS analysis results, the CFR values of children who were neutropenia with fever treated with Micafungin under different administration regimens were obtained (shown in
Invasive fungal infections are the leading cause of death in children with neutropenia, with a high mortality rate for severe infections despite the introduction of antifungal agents in treatment [
Micafengin was initially administered at different doses for different Candida species, with a recommended dose of 0.5 - 4 mg/kg for children with neutropenia.
| Species | dosage regimen (mg/kg) | |||||
|---|---|---|---|---|---|---|
| 0.5 | 1 | 1.5 | 2 | 3 | 4 | |
| C. albicans | 89.91 | 95.56 | 98.82 | 98.51 | 99.71 | 99.85 |
| C. glabrata | 83.10 | 90.74 | 92.91 | 96.08 | 97.19 | 98.88 |
| C. guilliermondii | 5.17 | 10.83 | 34.71 | 37.59 | 50.67 | 62.12 |
| C. krusei | 34.24 | 43.07 | 68.34 | 73.30 | 83.25 | 89.57 |
| C. parapsilosis | 1.28 | 2.79 | 19.05 | 21.77 | 42.95 | 47.35 |
| C. tropicalis | 64.64 | 77.63 | 88.73 | 89.80 | 92.88 | 96.73 |
Our study showed that when micafengin administration regimen was 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, The infection caused by C. guilliermondii, C. krusei, C. Parapsilosis is not effective, The optimal dosing regimen for C. albicans and C. glabrata and C. tropicalis is 1 mg/kg, 1 mg/kg, and 3 mg/kg, respectively, and the results were similar to the recommended dosing regimen for micafennet for invasive Candida infection in children that has been reported [
Considering the imperfection of immune function in children and the immature development of liver and kidney organs, the drug should not be used empirically according to the adult dose. MCSs is a random sampling analysis method, which simulates tens of thousands of times according to the pharmacological process of drugs in different patients and fully considers the difference in drug sensitivity of different strains of the same pathogen, so as to calculate PTA and CFR values and evaluate the rationality of drug administration plan. However, this study still has some limitations. Due to the lack of grouping studies of children in different age groups, relevant PK data cannot be obtained, so patients cannot be evaluated according to specific age. In summary, micafennet has been recognized for the prevention and treatment of invasive Candida infections in infants and children. In the treatment of invasive fungal infection in children with neutropenia, micafennet should be fully considered to adjust the administration regimen. The results of this study showed that, for infection caused by C. albicans, C. glabrata and C. tropicalis, the optimal administration regimen was 1 mg/kg, 1 mg/kg, and 3 mg/kg, respectively. For C. guilliermondii, C. krusei, C. parapsilosis infection when the antifungal effect is not good, it is recommended to adjust other drugs or combined drugs.
In conclusion, the results of PK/PD modelling and Monte Carlo simulations suggest that Micafungin has significant effects on C. albicans and C. glabrata, C. tropicalis in children with febrile neutropenic. The optimal administration regimen was 1 mg/kg, 1mg/kg and 3 mg/kg. In the case of infection caused by C. guilliermondii, C. krusei and C. parapsilosis, Micafungin has a poor antifungal effect, and then it is suggested to adjust other drugs or combine with other antifungal drugs.
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 202006A072) and the Hospital Pharmacy scientific research project of the Hebei Pharmaceutical Society (No. 2020-Hbsyxhqn0030).
The authors declare no conflicts of interest regarding the publication of this paper.
Hu, J.L., Wang, Y., Hu, J.H., Yu, X.L. and Zhu, X.Q. (2022) Based on PK/PD and Monte Carlo Simulation Analysis of the Dosing Regimens of Micafungin in Children with Febrile Neutropenic. Open Journal of Pediatrics, 12, 711-717. https://doi.org/10.4236/ojped.2022.124072