INTRODUCTION
Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer or diseases that require hematopoietic stem cell transplantation (HSCT) for their cure (1). IFIs in children and adolescents differ in multiple ways from those in adults in terms of epidemiology, diagnostic methods, drug doses, pharmacokinetics (PK), pharmacodynamics (PD) and the absence of clinical trials (2). The highest degree of evidence on IFIs in pediatrics is included in the guidelines of the Fourth European Conference on Infections in Leukemia (ECIL-4) (3).
The incidence of IFI one year after bone marrow transplantation reported in several retrospective series varies between 13 and 20%, with 50-83% mortality. Candida spp . and Aspergillus spp . are the most common agents causing IFI after HSCT. Candida spp . present increased risk during the neutropenia phase posttransplant, whileAspergillus spp . present a bimodal distribution, with a first peak at approximately 16 days and a second peak at 96 days after transplantation (4, 5). Recent studies in pediatric patients focus on myeloid and lymphoid leukemia, allogeneic HSCT and/or immunodeficiencies (1).
Our center, a national referral hospital for erythropathology, performs a significant percentage of HSCT in sickle cell disease (SCD) (6). Patients with SCD have vasculopathy, poor tolerance of immunosuppressants and high renal, arterial and neurological toxicity (6-8).
The incidence of IFIs in transplant patients with SCD is currently unknown. Isolated cases have been published in the literature (8-11). Mortality after HSCT is approximately 7%, and infections are the main cause (12). At present, transplantation guidelines recommend the use of antifungal prophylaxis in this population.
A retrospective review of IFI cases in the last 10 years in our center found a cumulative incidence of 15% in pediatric bone marrow transplant patients with different pathologies (13); IFI in other patients at risk was not included.
Voriconazole has been shown to be an effective and safe prophylaxis in the pediatric population and has the advantage of oral administration (3). However, voriconazole interacts with several immunosuppressants. Molina et al. (14) published a pediatric series in which 17.8% of patients experienced adverse effects associated with its use, leading to longer hospital stays and higher costs of care. Posaconazole has the advantage of oral administration and is the treatment of choice for graft-versus-host disease (GVHD). Its main limitations are its use in patients >13 years and the lack of pharmacokinetic data for pediatric patients, especially in children under 2 years of age (15, 16).
In our clinical experience, the transition to oral azoles after the administration of micafungin in the early phase of HSCT involves a high rate of side effects and the prolongation of hospital stays.
Among echinocandins, micafungin is known for its safety profile; it is a very well-tolerated drug with few side effects (17, 18). Its use for prophylaxis during the hospital phase of transplantation, at a dose of 1 mg/kg/day, has been shown to be at least as effective as fluconazole during the engraftment phase in large prospective studies. However, post- engraftment evidence is still limited, and daily intravenous use negatively affects the quality of life of patients at discharge.
Micafungin as a prophylaxis in HSCT has been shown to be effective in adults and children (5, 17, 19). Current data suggest differences in PK between adults and children. Safety and PK studies in infants, children and adolescents reinforce the use of micafungin for prophylaxis in HSCT in this population (20, 21).
The PK parameters of micafungin have been well-studied in children and depend on age and weight: in younger children, micafungin showed greater clearance, greater volume of distribution and a shorter half-life than in older children.
Some studies suggest the use of micafungin every 48 h as a safe alternative in pediatric patients to facilitate its administration (22-25); however, those series are small. Some PK studies show greater clearance of the drug and volume of distribution according to patient weight. The dose of 3 mg/kg/48 h seems to be the safest and most commonly used in pediatric patients with lower weight and younger age (23).
In adults, Neofytos et al. (26) studied the efficacy of intermittent doses (300 mg of micafungin 2-3 times weekly) in patients with acute leukemia and HSCT. This regimen was well tolerated, with a low incidence (6%) of breakthrough fungal infection.
OBJECTIVE:
To analyze whether the implementation of an antifungal prophylaxis protocol with alternate-day micafungin administration three times weekly (Monday, Wednesday and Friday) after bone marrow engraftment in pediatric transplant patients is a safe practice in terms of toxicity and breakthrough infections in our patients and setting.