**5.** *Candida* **Colonization**

The percentage of colonized preterm infants who develop invasive infections ranges from 5% to 30% [55], due to immunological immaturity, the immaturity of the skin and of mucous membranes, and to the need for invasive therapeutic supports. In general, all patients admitted to intensive care are exposed to fungal infections, some of them are effectively colonized, and only a minority develop systemic infections that originate from peripheral colonization. In intensive care units other than neonatal intensive care units (e.g., surgical intensive care units) the risk of colonization is greater in the presence of central venous catheters, bladder catheters, mechanical ventilation, and lack of enteral nutrition. Skin and the gastrointestinal tract are the most common sites for *Candida* colonization in preterm and term infants [35,56]. Colonization can take place either vertically, from the maternal genital tract, or horizontally, by transmission of the germ through the hands of health caregivers. The use of broad-spectrum antibiotic therapy favors *Candida* spp. colonization, even if it does not seem to condition the transition from colonization to systemic infection. Some researchers have shown that the addition of steroids to antibiotic therapy in animal models increases the intestinal colonization, with an increase in the incidence of invasive infections [44].

The frequency of colonization is inversely proportional to the neonate's gestational age and birth weight. Severely preterm infants are the most affected, experiencing invasive infections following colonization. Furthermore, the risk of invasive infections is proportional to the number of colonized body sites and their localization. More noncontiguous colonization sites are associated with a greater probability of progression to invasive infection. Therefore, preterm and full-term infants colonized in more than one body site are more likely to develop invasive *Candida* spp. infection the less contiguous the colonization sites are [57]. Colonization at two or more sites occurs similarly with *Candida albicans* and *Candida parapsilosis*, while *Candida albicans* is most frequently responsible when more than two sites are involved [58].

Isolation of *Candida* spp. from the urine of neonates can be indicative of contamination or of urinary tract infection (UTI), although any positive culture from normally sterile body fluids such as urine, peritoneal fluid, or cerebrospinal fluid is often considered as an invasive candidiasis that needs to be treated as well as candidemia [5]. To date, it is still not clear how often *Candida* UTI (defined as growth of *Candida* from urine at >10<sup>6</sup> CFU/L from a suprapubic aspirate or >107 CFU/L from a bladder catheter specimen) is a precursor of candidemia or of *Candida* infection at other sites [59]. Among 30 infants with candiduria, an active surveillance (PICNIC study) detected 4 infants who developed

extra-renal dissemination of *Candida* infection. In this study, the extra-renal site was blood in 3/4 cases and the central nervous system in 1/4; involved species were *Candida albicans* (75%) and *Candida parapsilosis* (25%) [59]. Three of these infants had a congenital heart disease and were treated between candiduria and positive culture at the extra-renal site with amphotericin B, fluconazole, or both; one was a 26-weeks preterm infant. Days between positive urine culture and positive culture at the extra-renal site ranged from 2 to 41 [59].
