**4. Risk Factors for Invasive** *Candida* **Infections after Major Surgery**

Infants in NICUs for surgical diseases are at high risk for IFIs, as a result of prematurity, the need for invasive procedures, the disruption of natural barriers due to surgery and other many risk factors (Figure 2) [28,29]. Bloodstream infection due to *Candida* spp. is considered the most common IFI in critically ill patients [30–33].

**Figure 2.** Risk factors for invasive *Candida* infections after major surgery.

Well-recognized risk factors associated with ICIs are:


(13%), after *Coagulase-Negative Staphylococci* (28%), and *Staphylococcus aureus* (19%) in a study in 304 NICUs [38]. The length of stay of indwelling catheters is a strong risk factor for CLABSI and CRBSI, while no differences have been reported between the CLABSI incidence in femoral vein catheters, peripherally inserted catheters, and umbilical venous catheters [38]. Catheter removal is recommended if a CRBSI caused by *coagulase-negative Staphylococci*, gram-negative bacilli (*Pseudomonas aeruginosa* and *Klebsiella pneumoniae*), and fungi occurs, due to the particular ability of these germs to form an intraluminal biofilm, resistant to antibiotics and/or antifungals. Biofilms on indwelling catheters may be composed of gram-positive or gram-negative bacteria or yeasts. It consists of microbial cells surrounded by a self-secreting polymer matrix, that is released into the extracellular space [39]. The matrix is composed of water, polysaccharides, proteins, lipids, and extracellular DNA. This matrix provides a protective barrier from the surrounding environment and is able to hinder the penetration of antimicrobial drugs, while also providing protection against the host's immune defense mechanisms. From this biofilm, germs are progressively released, causing the infection to persist and favoring the dissemination of microbes to additional sites in the body. The biofilm is very difficult to eradicate from the catheter, due to the difficult penetration of antimicrobial drugs into the matrix. Therefore, CVC removal is the gold standard approach in cases of CRBSI that do not respond to systemic treatment [37,40]. The best timing of central venous catheter removal in the presence of an associated and/or catheter-related *Candida* infection has been studied by many authors [40,41], which demonstrated that early catheter removal in candidemia is associated with better outcomes in terms of shorter duration of infection, reduced mortality, and reduced long-term neurologic disabilities. When catheter removal is not recommended for the patient's condition, the lock therapy with antimicrobials may be an option. This rescue therapy has shown promise as a strategy for the treatment of CRBSI due to several *Candida* species. The most promising strategies of antifungal lock therapy include the use of amphotericin B, ethanol, or echinocandins [42,43].


contribute to potentially important extrinsic mechanism of infection in NICU patients [11]. Patients with species other than *C. albicans* were more likely to have PN than those with *C. albicans* (96.3% versus 71.4%, *p* = 0.039) [48].

