*Review* **Invasive** *Candida* **Infections in Neonates after Major Surgery: Current Evidence and New Directions**

**Domenico Umberto De Rose 1, Alessandra Santisi 1, Maria Paola Ronchetti 1, Ludovica Martini 1, Lisa Serafini 2, Pasqua Betta 3, Marzia Maino 4, Francesco Cavigioli 5, Ilaria Cocchi 5, Lorenza Pugni 6, Elvira Bonanno 7, Chryssoula Tzialla 8, Mario Giuffrè 9, Jenny Bua 10, Benedetta Della Torre 11, Giovanna Nardella 12, Danila Mazzeo 13, Paolo Manzoni 14, Andrea Dotta 1, Pietro Bagolan 15, Cinzia Auriti 1,\* and on behalf of Study Group of Neonatal Infectious Diseases †**


**Abstract:** Infections represent a serious health problem in neonates. Invasive *Candida* infections (ICIs) are still a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Infants hospitalized in NICUs are at high risk of ICIs, because of several risk factors: broad spectrum antibiotic treatments, central catheters and other invasive devices, fungal colonization, and impaired immune responses. In this review we summarize 19 published studies which provide the prevalence of previous surgery in neonates with invasive *Candida* infections. We also provide an overview of risk factors for ICIs after major surgery, fungal colonization, and innate defense mechanisms against fungi, as well as the roles of different *Candida* spp., the epidemiology and costs of ICIs, diagnosis of ICIs, and antifungal prophylaxis and treatment.

**Keywords:** invasive *Candida* infections; invasive fungal infections; antifungal prophylaxis; newborns; surgery; neonatal surgery

**Citation:** De Rose, D.U.; Santisi, A.; Ronchetti, M.P.; Martini, L.; Serafini, L.; Betta, P.; Maino, M.; Cavigioli, F.; Cocchi, I.; Pugni, L.; et al. Invasive *Candida* Infections in Neonates after Major Surgery: Current Evidence and New Directions. *Pathogens* **2021**, *10*, 319. https://doi.org/10.3390/ pathogens10030319

Academic Editor: Jonathan Richardson

Received: 30 January 2021 Accepted: 4 March 2021 Published: 9 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

### **1. Introduction**

Yeasts are commensal microorganisms that usually colonize mucosal surfaces and skin. In particular clinical conditions, such as immune suppression, prolonged use of broadspectrum antibiotics and/or steroids, the balance of the colonizing flora of the skin is altered and fungi express numerous factors that contribute to pathogenicity. Adherence is one of the most important factors that facilitate the colonization and dissemination of fungi, by the expression of adhesins, which facilitate binding to host substrates, including beta–integrins, on the endothelium and white blood cells. The yeast-to-hypha transition of *C. albicans* facilitates biofilm formation, tissue invasion, and dissemination of the infection [1,2]. Other virulence factors are membrane and cell wall barriers, dimorphism, biofilm formation, signal transduction pathway, proteins related to stress tolerance, hydrolytic enzymes (e.g., proteases, lipases, hemolysins), and toxin production) [3].

Therefore, fungi can lead to severe infections in the host. Invasive fungal infections (IFIs) in neonatal intensive care units (NICUs) are a substantial health problem, as they are the second most common cause of infection-related death among critically ill neonates. IFIs lead also to significant neurodevelopmental disability among survivors, representing a substantial health problem, especially among the neonates with lowest gestational age and lowest birthweight [4–6]. Critically ill patients in NICUs (and in particular preterm neonates) are at high risk of IFIs, especially if they need broad-spectrum antibiotic treatments, surgery that disrupts natural defense barriers, intravascular catheters for prolonged periods, or implantation of invasive devices to survive. Their immunological impairments are predisposed to fungal colonization and to subsequent systemic infection. Bloodstream infections due to the *Candida* species (*C.* spp.) are considered the most common IFIs in critically ill patients in NICUs.

In specific subgroups (e.g., abdominal surgical patients), IFIs are also frequent, but there are no epidemiological studies on the incidence of IFIs in neonates with major surgical diseases. Clinical and epidemiological studies are needed to identify preventive strategies in preterm and term infants, who undergo major surgery or specific subgroups of this category of patients.

This review aims to summarize scientific evidence about invasive *Candida* infections (ICIs) in neonates undergoing surgery.

### **2. Methods**

This paper provides a review of the literature on ICIs in neonates after major surgery. An extensive literature search in the MEDLINE database (via PubMed) has been performed from 2000 up to 9 January 2021. The following keywords "*Candida*" OR "fungal infection" AND "surgery" AND "neonates" OR "infants" were searched as entry terms. All retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. References in the relevant papers were also reviewed.

Papers written in languages other than English, or not providing data about the main focus of this research (the number of neonates with ICIs after undergoing major surgery, separate data for neonates and children, and case reports and reviews) were excluded.

Major surgery is considered to be any invasive operative procedure in which a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges).

An infant is considered colonized by *Candida* when a surveillance culture (such as pharyngeal or tracheal swab, urine, feces, skin swabs) develops colonies of *Candida* spp., without signs or symptoms suggestive of infection [7].

Infants with ICIs have specific or nonspecific signs or symptoms, and isolation of a *Candida* spp. is obtained from a sterile cultural site (blood, cerebrospinal fluid, peritoneal fluid) [8].

We also provided an overview of risk factors for ICIs after major surgery, the innate defense mechanisms against fungi, the role of different *Candida* spp., the epidemiology and costs of ICIs, and the antifungal prophylaxis.

### **3. Results**

A total of 253 records were identified through literature search (via PubMed) from 2000 onwards. Among them 155 were excluded based on the titles, the abstracts, and the type (case reports and review). The remaining 71 full-text articles were assessed for eligibility. We found no studies focused on the incidence of IFIs in neonates who previously underwent major surgery.

Conversely, we found 19 studies that provided how many neonates with IFIs underwent major surgery before the onset of the infection [9–27]. The selection process is shown in Figure 1.

**Figure 1.** Literature selection of recent studies reporting incidence of previous surgery in infants with invasive fungal infections.

Of the 19 studies included in the quantitative synthesis, 8 collected patients' data retrospectively, while 11 collected it prospectively (Table 1). A total of 1637 neonates with IFIs were reported. Of these, 550 (33.6%) underwent major surgery before the onset of the infection. Abdominal surgery was not always reported by the studies, with percentages ranging from 13 up to 80. Fungal-infection-related mortality is difficult to demonstrate, therefore in-hospital overall mortality is more often reported.

*Pathogens* **2021**, *10*, 319


*Pathogens* **2021**, *10*, 319


VLBW: very low birth weight.
