DISCUSSION
In children, primary antifungal prophylaxis is indicated in HSCT (4, 5, 18, 21). Echinocandins are among the drugs available for this indication. Micafungin has been the only echinocandin authorized for pediatric use since 2008 by the European Medicines Agency (EMA). Its main disadvantage is its exclusively intravenous use. Micafungin exhibits linear PK, and the steady state is typically reached in 4 or 5 days.
The usual practice at the center for patients undergoing allogenic HSCT consisted of initial prophylaxis with micafungin at a dose of 1 mg/kg/day during the conditioning phase and until bone marrow engraftment, followed by oral azoles at discharge. In recent years, after an increase in the number of transplants in patients with SCD (approximately 10-15 transplants/year), we observed an increase in drug toxicity derived from the interactions of azoles with immunosuppressants, which are poorly tolerated in this population, with prolongation of hospital stay, viral reactivations and undesirable GVHD in SCD. This has led many clinicians to seek alternatives and explore the use of prophylaxis on alternating days.
There are studies in adults and children on the PK and PD of micafungin that reinforce the safety of these regimens. Muilwijk et al. (32) published a randomized multicenter study of 20 adult patients in which they found, from the PK/PD standpoint, that administering micafungin 300 mg twice weekly is equivalent to the administration of micafungin 100 mg once a day. Neofytos et al. published a series of 75 adult patients undergoing allogeneic bone marrow transplantation or with leukemia who received 300 mg micafungin three times weekly without adverse effects at the hepatic or renal levels, with an incidence of breakthrough IFI of 6% (26).
The administration of micafungin 3-4 mg/kg/day every other day has been shown to be safe in some pediatric series (17). Although Metha et al. (25) found that the micafungin levels reached at 48 h were greater than 0.2 mcg/mL, they concluded that after adjustment for high protein binding, the free micafungin concentrations were only suitable for highly susceptible fungal species. Recent studies suggest that a regimen of 5 mg/kg every 72 h is adequate (33).
To our knowledge, this is the largest series on alternating prophylaxis in pediatric patients. It also shows the safety of the drug when administered at different doses according to weight and pharmaceutical presentation. Most of the patients were children weighing <33 kg, and 87.1% received doses of 3 mg/kg. To date, no serious adverse effects or hepatic toxicity has been observed. There have not been any breakthrough IFIs. In this sense, our work raises the question of whether the population with SCD, which comprised the majority of the series, presents the same risk of IFI during and after HSCT as pediatric patients with malignant hematological disease. Although the use of double immunosuppression to avoid graft failure suggests that the risk is similar, the data that currently exist do not resolve this issue, and randomized studies are needed. The incidence of IFI in this population is unknown, although there are some case reports on HSCT. Publications with large series of transplant patients with SCD do not make reference to this complication or did not have cases of IFI (8, 10).
The incidence of breakthrough IFI in pediatric patients was described recently in a retrospective study that identified 8 pediatric patients (2.4%) out of 319 cases treated with micafungin who had breakthrough IFI by Candida. In 7 of the cases, the species was C. parapsilosis. The minimum inhibitory concentration (MIC) was susceptible (≤ 0,01 mg/L) in all cases (34). Chan et al. (35) described a study that examined adult patients on prophylaxis with echinocandins with an incidence of breakthrough IFI by Candida spp. of 1.5%. Pfeifer et al. (36) reported an IFI incidence of 1.8% in 649 adult patients treated with micafungin 100 mg/day for different indications. The main pathogens were wild-type C. glabrata and C. parapsilosis. The prospective multicenter OLYMPE study (NCT02127788) found an IFI incidence of 13.1% in patients of all ages after HSCT (37).
Micafungin has been shown to be a suitable drug against the most common species of Candida, including Candida albicans ,Candida glabrata and Candida tropicalis , all of which have a MIC ≤ 0.06 mg/L. Higher values have been observed for Candida parapsilosis (0.25-2 mg/L) and Candida guilliermondii (0.5-2 mg/L), although the clinical impact of this observation is doubtful.
The MIC of micafungin in the 150 cases of pediatric IFI byCandida species in our hospital during the study period reveals a MIC50 of 0.015 mg/L and a MIC90 of 2 mg/L for micafungin, the most prevalent species being C. albicansand C. parapsilosis . No resistance was observed. In the case of Aspergillus , the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) report a lack of evidence to determine MIC cut-offs (37,38), but there are publications that set cut-offs at 0.0125 mg/L for the most common species (39).
In 14 of the 30 analyzed cases in which micafungin levels were determined, we found no difference in children when the levels were correlated with weight, age and albumin values. Despite the different doses administered and the heterogeneity of the analyzed group, in 100% of the cases in which serum levels could be determined, they were above 0.25 mg/L, and in 10/14 (73%), serum levels exceeded the 2 mg/L cutoff for C. parapsilosis suggested in the reference methods (EUCAST) (38).
At present, serum levels of micafungin are not monitored for clinical purposes of dose adjustment since there is no evidence of the relationship between micafungin levels and clinical response and/or toxicity, for which PK/PD studies would be necessary. Our study is not intended to be a PK study (41).
The poor interaction of micafungin with other drugs, its safety profile and the administration on alternating days suggest a decrease in toxicity and days of hospitalization, especially for patients with SCD, without an increase in breakthrough on alternating days in pediatric patients.