A guide to dissecting, there is a way to go: talk about the management of invasive mycoses in pediatric patients (Part 2)

*For medical professionals only

Hi, we're meeting again! Last time we talked about the epidemiological characteristics of invasive fungal disease (IFD) in children in recent years and the drug concentration monitoring and dose adjustment should be paid attention to when applying antifungal drugs in children, which made me gain a lot, and today my curiosity is bursting again, and I can't wait to know more! Truth-seeking, in the last issue, you left a tail and did not give me an answer, it seems that there is an academic feast waiting for me today!

Ha ha! That's right!

Classic Question 3

How should we choose a treatment when considering a child to have invasive candidiasis (IC)?

Follow the guide and there is a way to go! The 2012 European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines for the Diagnosis and Management of Candidiasis in Children: Prevention and Management of Invasive Infections Caused by Candida in Newborns and Children (hereinafter referred to as the "2012 ESCMID Guidelines for Newborn/Pediatric Candidiasis") divides pediatric IC management into two categories

■ Newborns

The guidelines state that because deep neonatal culture specimens are usually negative, it is more difficult to confirm whether a newborn has an IC.

Clinical studies have confirmed that amphotericin B liposomes (L-AmB) are safe and effective in the treatment of neonatal ICs^[1]; Preclinical models confirm that L-AmB crosses the blood-brain barrier and has antifungal activity in the brain^[1].

Table 1 Treatment options for infants with IC and/or hematogenous Candida meningitis ^[1].

■ children

The 2012 ESCMID guidelines for candidiasis in newborns/children indicate that in children, antifungal therapy is generally recommended to be initiated as soon as possible and that treatment should be continued until 14 days after sterility of the blood culture (provided there is no unresolved deep infection or severe persistent underlying immunodeficiency)^[1].


Recommended A-I agents for pediatric patients include L-AmB, capofenlinen, and micarfenclean, and it is worth noting that L-AmB has a lower risk of nephrotoxicity in children than in adults, so the level of guidance recommendation is higher ^[1].


If the child is assessed to be at low risk of IA, fluconazole (B-II) may be used^[1].


The recommended levels of antifungal drugs are detailed in the table below
.

Table 2 IC treatment options for children^[1].

Classic Question 4

Oh ~ I understand the treatment of IC, so when considering the child is invasive aspergillosis (IA), how should we make treatment decisions?

Empiric therapy is a common treatment modality
for IA.

As a fever-driven treatment, it can be used
as early as possible before further clinical signs and symptoms of IA develop.

Results from several randomized controlled studies (RCTs) in pediatric hematological tumor patients have shown that: (1) capofennet is comparable to L-AmB in the use of IA empiric/preemptive treatment in pediatric hematological tumor patients^[2]; (2) L-AmB is more effective than AMB ^[1].


Therefore, the ESCMID-ECMM Guidelines: Guidelines for the Diagnosis and Management of IA in Newborns and Children (2019) jointly issued by ESCMID and the European Federation of Medical Mycology (ECMM) recommend that both L-AmB and capofenin can be used in the empiric treatment (A-I) of IA in children, as detailed in the table below^[2].

Table 3 Recommendations for IA empiric/preemptive treatment in pediatric hematological tumor patients^[2].

The ESCMID-ECMM guidelines state that fezols are recommended for empiric or preemptive treatment in children receiving azole prophylaxis, such as L-AmB as a first-line antifungal regimen (A-II) and capofennet as an alternative (C-II) ^[2].

Classic Question 5

In the case of IFD in children, IC and IA are relatively high, and for rare fungi, Qiushijun also says something?

No problem! Let me first talk about mucormyces, when considering the child is mucormycosis, how should we choose the treatment drug?

The general principles of treatment of mucormycosis are similar
to those of IA treatment.

The 8th European Conference on Leukemia Infection: Guidelines for the Diagnosis, Prevention and Treatment of Invasive Fungal Diseases in Children After Cancer or Hematopoietic Stem Cell Transplantation 2020 (hereinafter referred to as the "IFD Guidelines for Pediatric Patients After Cancer or HSCT") emphasizes that the prognosis of mucormycosis is not age-dependent, but depends on the timing of AMB treatment initiation and surgery, and recommends that the first-line treatment of mucormycosis can choose L-AmB (A-II), as detailed in the table below^[3].

。
Based on pharmacokinetic considerations, L-AmB is the preferred drug for the treatment of CNS infection; Also due to low nephrotoxicity, L-AmB is indicated in patients with renal failure^[3
].

Table 4 Treatment recommendations for mucormycosis in postoperative childhood patients with cancer or HSCT who have confirmed or clinically diagnosed IFD ^[3].

Truth-seeking, I have noticed that the treatment of mucormyces is to start steady, accurate and fierce! Can't wait, can't delay, grab time, early treatment, large doses, time is life!

Classic Question 6

You also said that children have seen Cryptococcal meningitis as well, tell me about it

Xiao Anjun understood the essence of mucormyces treatment
.

So how should we respond when considering a child with cryptococcosis?

In the diagnosis and treatment of cryptococcal disease, special attention needs to be paid to CNS and pulmonary involvement
.

At present, the commonly used drugs that can effectively fight cryptococcal infection are AMB, azole and flucytosine
.

Treatment options for cryptocococcosis include a 2-week induction treatment period, an 8-week consolidation treatment period, and a maintenance treatment period to prevent recurrence, and the clinical practice guidelines for the management of cryptocococcosis: 2010 American Society of Infectious Diseases Update The current mainstream induction regimen is AMB plus flucytosine, as detailed in the table below ^[4].

Table 5 Treatment recommendations for cryptococcal disease in children^[4].

After 12 years, the drug selection recommendations for cryptococcal infection in the Expert Consensus on Clinical Practice of Invasive Pulmonary Fungal Infection in Children (2022) are similar to previous guidelines: for children with mild cryptococcal disease, fluconazole is preferred; For severe or primary immunodeficiency diseases, AMB (containing liposomes) is preferred for intensive therapy; Fluconazole may be combined in patients with extrapulmonary complications such as meningitis, or flucytosine may be considered, fluconazole is preferred in the maintenance and consolidation phases, and voriconazole is switched to those with poor efficacy ^[5].

Qiushijun's interpretation of the relevant guidelines for the diagnosis and treatment of children's IFD today is really three points, which makes people addicted and able to learn! If AMB is the "gold standard" in antifungal therapy^[6], then the liposome structure of L-AmB reduces the side effects of AMB and further consolidates the status of "gold standard"! We are looking forward to it clinically!

The Ann family has something to say

Due to the differences in the physiological characteristics and drug metabolism of children and adults, and the lack of antifungal-related research data in pediatric patients, pediatricians often encounter obstacles in formulating IFD treatment plans, and it is recommended to use guidelines as a guide to develop more appropriate antifungal regimens
for pediatric patients.

L-AmB is highly recommended in the IFD diagnosis and treatment guidelines or consensus of children at home and abroad, and the risk of nephrotoxicity of L-AmB in children is small, and clinicians can regard L-AmB as an efficient and reliable treatment drug for children's IC, IA and cryptocococcosis, and it is a first-line solution for the treatment of mucormycosis ^[1,2-5].


In addition, L-AmB has a high sensitivity to rare fungi such as Marnifilia and Histoplasma ^[6
].