**5. Treatment of neonatal fungal infections**

Invasive fungal infections in NICUs show high mortality. The better prognosis of the patient with invasive candidiasis/or candidemia admitted in NICU is associated with the early diagnosis and fast treatment. Evidence suggests an estimated mortality rate of 40% if therapy is not initiated early. Therefore, it is not a good practice to wait for cultures to become positive. This need for early therapy must be balanced against the need to use antifungal agents to avoid selection of resistant strains. Early empiric therapy guided by stratification systems for

The score for exact risk measurement of invasive candidiasis has yet to be developed. The "Candida Score" presented by Spanish group in 2006 provides an easy-to-use tool to assist the health professionals with critically ill adults [42]. However, we believe that will should be adapted to pediatric patients, in the near future. In this stratification, the selected variables by logistic regression model with increasing weight are total parenteral nutrition, surgery,

Recent Infectious Disease Society American guidelines suggest that "empirical antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever." Risk factors for invasive candidiasis are well identified. When analyzing clinical data, surveillance culture and levels of anti-*Candida* antibodies plus β-D-glucan in the serum, the same Spanish researchers showed a positive correlation among increasing values of the "*Candida* score" and the rate of invasive *Candida* infections. Such a score was calculated by variables such as total parenteral nutrition, surgery, multifocal *Candida* colonization and severe sepsis. Thus, *Candida* score ≥3 suggest patients at high risk for invasive candidiasis and enable to differentiate patients who would benefit from early antifungal treatment from those for whom invasive candidiasis is highly improbable [43].

Despite *C. albicans* is known to be primarily responsible for most neonatal fungal diseases, the prevalence of infections caused by other fungi in neonates and young infants is not signifi-

Since 1980, this genus has been recognized in sepsis and systemic infections involving neonates receiving lipidic parenteral nutrition using a central venous catheter. It is believed that lipid supplementation facilitates the colonization of the catheter that used to infuse the nutrients. In newborns, colonization by *Malassezia* can progress to fungemia. The removal of the

The vast majority of cases of fungemia occur in children less than 12 months old. In this population, this *Malassezia* infection rarely remains asymptomatic. Interstitial pneumonia and thrombocytopenia are common clinical manifestations in this group of patients, and the most frequent symptoms in systemic infections are fever and respiratory dysfunction with or with-

cant, except for *Malassezia* species, which may occur in epidemic outbreaks [44–46].

infected catheter is sufficient to limit infection in most cases [46, 47].

high-risk patients should help address these cases [41].

114 Selected Topics in Neonatal Care

multifocal *Candida* species colonization and severe sepsis [42].

**4. Other neonatal fungal infections**

out apnea [46, 48].

The appropriate use of antifungals agents is of particular importance in the prevention and treatment of invasive fungal infection in neonates; however, guidelines to facilitate the optimal therapy choice do not exist. The current therapeutic options that are available to treat fungemia among newborns and children are based on clinical trials in adults, since there are few comparative studies of antifungal agents in infants. The optimal treatment of fungal infection in this special population requires detailed studies on pharmacokinetics, safety and efficacy of antifungal therapies [51–54].

Similar to neonatal invasive infections by species of *Candida*, the management of *Malassezia* sp. fungemia requires the removal of any catheter as soon as the first positive blood culture occurs and the temporary discontinuation of parenteral nutrition in combination with an intravenous antifungal therapy. The most commonly used agents for the treatment of invasive fungal infections in NICU are classified into four different classes: polyene, azoles, analogs of pyrimidines and echinocandins. Among many years, the drugs of choice in this group of patients were amphotericin B alone or in combination with fluocitosin, liposomal formulation of amphotericin B or fluconazole. However, the development of a new generation of azoles and echinocandins, such as micafungin, has increased the therapeutic options for the treatment [45, 54].

Amphotericin B deoxycholate and lipid preparations are traditional choices for invasive fungal infections being active against a majority of clinical important *Candida* species and with reported use for *Malassezia* [45, 55]. Amphotericin B deoxycholate is well tolerated by neonates who do not exhibit many of the toxicities seen in older children and adults. However, liposomal amphotericin B has been found to be safe and efficacious in newborns with renal impairment. Another polyene agent, nystatin suspension, is administered orally to infants with gestational age ≤ 27 weeks or birth weight less than 750 g until removal of central venous catheters; this is shown to reduce colonization of the gastrointestinal tract and the rate of invasive candidiasis [55].

**Author details**

Rejane P. Neves1

Recife, Brazil

**References**

Danielle P.C. Macêdo2

\*, Ana Maria R. de Carvalho Parahym2

, Henrique J. Neves1

1 Department of Mycology, Centre of Biosciences, Federal University of Pernambuco (UFPE),

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Among the azoles, fluconazole is more frequently used in NICUs for the treatment of oropharyngeal and systemic candidiasis, but has no inherent activity against the genus *Aspergillus*, which is rare pathogen in neonates. This antifungal agent is commonly recommended as prophylactic therapy in NICU with a high incidence in fungal infections. Fluconazole prophylaxis is effective in reducing the rate of colonization and progression to systemic infection in nursery; on the other hand, some studies have revealed that prophylactic or empiric therapy with antifungal agents may be associated with changes in *Candida* ecology and antifungal agent susceptibility. Actually, the fluconazole dose recommended for neonates is 6 mg/kg/ day, and maintenance doses currently used in NICUs in Europe is often higher, between 6 and 12 mg/kg [53, 56–58].

New azoles such as voriconazole, posaconazole and ravuconazole have limited utility in the nursery and are rarely used to treat neonatal infections. Voriconazole is a second-generation triazole that has excellent activity against *Candida* and *Aspergillus* spp.; however, data on its use in neonates are limited. Posaconazole and ravuconazole are the newest agents of the triazole family with added action against zygomycetes, however there are scarces of survey involving these antifungal agents in infants and the use of ravuconazole is not already approved by the Food and Drug Administration (FDA) [59, 60].

The echinocandins (micafungin, caspofungin and anidulafungin) are increasingly used for treatment of *Candida* sp. infections. Their role in the nursery is not so clear, although accruing evidence suggests they may be safe and effective, especially for the treatment of invasive infections caused by *Candida* spp. Some point have to be taken under consideration before the use of echinocandins in NICUs: first, limited clinical data also suggest that these agents may be effective for the treatment of central nervous system infections. Second, a high incidence of *C. parapsilosis* in NICUs is usually reported and this species is related to higher minimum inhibitory concentration (MIC) front of echinocandins [56, 57].

Among the three representatives of the group, micafungin is the most recommended and its use is approved for adults, children and newborns, being considered the one with better description for neonatal population. The use of caspofungin is approved by the FDA, but only for adults and children over 3 months of age. There were no relevant clinical trials that support the administration of anidulafungin among neonates and children [56, 57].

Invasive fungal infections are devastating pathologies that still result in death or serious longterm morbidity in neonates; however, the management of this mycosis has progressed greatly, with the azole agents playing a significant role. Effective prophylactic strategies have recently become available; therefore, the choice and use of appropriate antifungal drugs need careful assessment of neonatal characteristics, the epidemiology and drug pharmacokinetics [53].
