Current Concepts for Management of Invasive Fungal Infections in Paediatric Patients

Type of infection	Treatment recommendation	Useful comments
Candidaemia and deeply invasive candidiasis	First-line options approved by the FDA and/or the EMA: Liposomal amphotericin B (3 mg/kg daily) [1] Fluconazole (12 mg/kg daily) [2] Caspofungin (day 1, 70 mg/m; 25 mg/m²daily), [3] [4] Micafungin (<40 kg, 2–4 mg/kg; ‡40 kg, 100–200 mg daily; in neonates recommend 10 mg/kg daily) [5] Second-line options: Amphotericin B lipid complex (5 mg/kg daily) [6] Voriconazole (9 mg/kg/dose IV load day 1, then 8 mg/kg/dose or 9 mg/kg/dose PO maintainance. If >12 years, then load 6 mg/kg/dose and the 4 mg/kg/dose or give 200-300 mg PO per dose). *¹ Treatment of other forms of invasive candidiasis (endocarditis, peritonitis and meningitis) is ill-defined and based on pharmacological considerations such as a cidal mode of action and water solubility, and always includes the evaluation of surgical interventions. The additional use of flucytosine has a role in these situations. [7] [8]	Patients who have received azole prophylaxis, are haemodynamically unstable or granulocytopenic, are colonized with Candida glabrata or Candida krusei or are admitted to institutions with a high frequency of these organisms should receive a polyene or echinocandin up front. Central venous catheters should be removed promptly if feasible Neutropenic patients should receive colony-stimulating factors, and in immunosuppressed patients, steroids should be reduced, discontinued or replaced. The recommended duration of therapy for uncomplicated candidaemia is 14 days after clearance from the bloodstream and resolution of all symptoms Following clearance from the bloodstream and clinical stabilization, oral consolidation with fluconazole is feasible for susceptible isolates Fundoscopy is mandatory prior to end of treatment, to rule out endophthalmitis
Invasive aspergillosis	First-line options approved by the FDA and/or the EMA: Voriconazole (9 mg/kg/dose IV load day 1, then 8 mg/kg/dose or 9 mg/kg/dose PO maintainance. If >12 years, then load 6 mg/kg/dose and the 4 mg/kg/dose or give 200-300 mg PO per dose). *¹ Second-line options: Amphotericin B lipid complex (5 mg/kg daily) [9] Caspofungin (50 mg/m2 daily; day 1, [10] Voriconazole is currently recommended for Aspergillus terreus infections and infections affecting the CNS [11] In settings with a high frequency of mucormycosis, voriconazole may not be a choice for pre-emptive therapyDose escalation of liposomal amphotericin B to 10 mg/kg daily for the initial 14 days of treatment was not beneficial in a randomized comparative trial Combination of standard doses of either voriconazole or liposomal amphotericin B with caspofungin is promising, but valid clinical data are currently lacking. [12]	Adjunctive surgical interventions need consideration in skin and soft tissue infections, sinus infections, impeding erosion of pulmonary arteries, and operable CNS and lung lesions .
Emerging fungal pathogens	Amphotericin B is used as primary therapy for mucormycosis; posaconazole has shown encouraging clinical activity in the second-line setting. Limited and uncontrolled data indicate an important role of both voriconazole and posaconazole for treatment of Scedosporium and Fusarium infections. [13][14]
Empirical antifungal therapy	Options approved by the FDA and/or the EMA in this indication: Liposomal amphotericin B (1–3 mg/kg daily) Caspofungin (50 mg/m2 daily; day 1, 70 mg/m2) [15]	Empirical antifungal therapy is an established standard of care in haemato-oncological patients with prolonged neutropenia (ANC <500 for ‡10 days) and refractory or new fever that provides targeted prevention in a high-risk setting
Antifungal prophylaxis	Prophylactic fluconazole (8–12 mg/kg daily) remains a standard for post-allogeneic haematopoietic stem cell transplantation; alternatives may include the use of voriconazole or micafungin (1 mg/kg daily) [16] In patients with GVHD and increased immunosuppression, posaconazole (200 mg three times daily) has been shown to prevent IFIs antinvasive aspergillosis. [17] In adults with AML/MDS, posaconazole (200 mg three times daily) had a significant impact on the frequency of IFIs and, in particular, invasive aspergillosis, coupled with an overall survival benefit. [18]	Posaconazole may be given to children >12 years with high-risk haematological malignancies, or used for augmented immunosuppression for GVHD and voriconazole in younger children. Alternatives include liposomal amphotericin B (1 mg/kg every other day) or micafungin (1 mg/kg daily)
Prophylaxis in very low birthweight preterm neonates	Four randomized controlled trials, including a multicentre study, consistently reported significant decreases in colonization and infection by Candida spp. in the treated infants. On pooling of the results, fluconazole reduced IFI risk by 75%, and all-cause mortality by 24%. [19] [20] [21] [22]	Fluconazole may be given as antifungal prophylaxis in institutions with a substantial incidence (>5% to 10%) of invasive candidiasis in very low birthweight infants or in outbreak situations
* Data taken from Groll & Trachianidis Clinical Microbiol Infect, 16, 1343-53, 2010 AML, acute myeloid leukaemia; ANC, absolute neutrophile count; CNS, central nervous system; EMA, European Medicines Agency; FDA, Food and Drug Administration; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; GVHD, graft-versus-host disease; IFI, invasive fungal infection; MDS, myelodysplastic syndrome. (Modified from Dornbusch et al. Pediatr Infect Dis J 28:734-7, 2009, and Groll & Tragiannidis CMI 16, 1343, 2010. For details on the selected treatment options, please consult original publication). ¹ W. Steinbach, personal communication.