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/m2 daily), [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.


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