Neonates represent a unique and highly vulnerable patient population. Advances in medical technology have improved the survival and quality of life of newborns, particularly those with extreme prematurity or with congenital defects. Furthermore, immunologic immaturity and altered cutaneous barriers play some role in the vulnerability of neonates to nosocomial infections. In this context, the incidence of invasive fungal infections has increased significantly worldwide, representing an important infective complication in patients hospitalized in intensive care units. Invasive fungal infections in Neonatal Intensive Care Unit (NICUs) show high mortality; being species of Candida, the most isolates etiologic agents. The better prognosis of the patient is associated with the early diagnosis and fast treatment. However, guidelines to facilitate the optimal therapy choice for the treatment of neonatal fungal disease do not exist. The current antifungal agents 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 most commonly used drugs for the treatment of invasive fungal infections in neonates are classified in four different classes: polyene, azoles, analogs of pyrimidines and echinocandins.
- antifungal therapy
- fungal infections
- intensive care
During the last two decades, invasive fungal infections in preterm infants have become an increasing problem, mainly when hospitalized in a Neonatal Intensive Care Unit (NICU). Thus, for the last years, 6.3 million children under the age of 5 died each year are estimated, and more than 40% of these deaths occur in the neonatal period [1, 2]. These data have several causes and particularly the neonates are at high risk due to fungal infections, mainly by yeasts of the genus
In addition, species of the genus
The newborns clinical course in the Intensive Care Units usually complicates after the onset of fungal infections . In this hospital environment, adverse events may occur due to the complexity of the patients . In this sense, the treatments and procedures instituted for primary disease may be an important factor for the onset of fungal infections; birth weight between 1000 and 1500 g is also a predictive factor and a way for the clinical worsening .
The predisposing factors to fungal infections include prolonged use of antibacterial and use of medical devices, among other conditions that lead to fungal disease. In addition, biofilms are frequent on the surface of medical devices, being consider a negative event, since it characterizes greater pathogenicity and antifungal resistance of fungi.
Commonly, amphotericin B, azoles and echinocandins are used for the treatment of various invasive fungal infections. However, antifungal therapeutic failures contribute to a higher mortality rate and may occur due to intrinsic resistance, so it is important to perform antifungal sensitivity tests. These tests can predict the ideal antifungal or contribute in the choice according to the use of other medicines and the condition of the neonate .
2. Epidemiology and incidence of neonatal invasive fungal infections
Neonates represent a unique and highly vulnerable patient population. Advances in medical technology have improved the survival and quality of life of newborns, particularly those with extreme prematurity or with congenital defects. Immunologic immaturity and altered cutaneous barriers play some role in increasing the vulnerability of neonates to infections. In this context, neonatal infection is a major cause of mortality and morbidity in newborns. Estimates suggest that >1.4 million neonatal deaths worldwide annually are due to invasive infections [14, 15].
The occurrence of invasive fungal infections has increased significantly worldwide, representing an important infective complication in patients hospitalized in intensive care units. Premature infants in NICUs are at particular risk of these invasive fungal infections, and unfortunately, the incidence of fungal septicemia appears to be increasing [16, 17]. In this context,
The incidence of bloodstream infections due to
Invasive candidiasis is an important cause of sepsis in the NICU. Candida infections in infants are associated with significant mortality and morbidity, including neurodevelopmental impairment. The incidence of invasive candidiasis in NICU ranges from 2.6 to 13.2% in very low birth weight infants (1500–1000 g) and from 6.6 to 26.0% in extremely low birth weight infants (<1000 g) .
Invasive infections associated with
Laboratory studies have documented that
Candida species are correlated to invasive fungal infections among at-risk groups as neonatal patients admitted NICU in and have been ranked third to seventh as a cause of nosocomial bloodstream infection, defined as candidemia, depending on geographical patterns [25, 26, 27, 28]. Studies on invasive candidiasis infections and candidemia are frequently focused on specific diagnoses and/or specific populations. In all published studies, ICU was the most frequent localization of the patients, even with different frequencies .
Candidemia is associated with high rates of illness and death and has an attributable mortality rate that varies widely in the literature, ranging from 29 to 76%, both in adult and pediatric patients [30, 31]. Furthermore,
These yeasts are less frequent than those infections caused by Gram-positive or Gram-negative bacteria; nonetheless, they are higher rates of morbidity and mortality. Particularly, among newborn with extremely low weight, 10% may to develop candidemia that has until 30% mortality in this patient group. Among infants who survive these infections, several long-term neurological impairments such as cerebral palsy, blindness, hearing and cognitive deficits and periventricular leukomalacia may occur [9, 27].
Neonatal candidemia during the first week of life is less common and less well described than the later onset of this group of infections. According to Barton et al. , risk factors for candidemia among neonates had not been studied before their research, in early onset disease (EOD, ≤7 days) or compared to late onset disease (LOD, >7 days). After a 2-year study, the authors concluded that risk factors such as birthweight <750 g, gestation <25 weeks, chorioamnionitis and vaginal delivery were strongly associated with EOD. Infection with
Extremely low birth weight is considered a risk factor related to a poor prognosis in EOD. Also, the role of perinatal transmission is supported by its association with chorioamnionitis, vaginal delivery and pneumonia. Dissemination and cardiovascular involvement are common, and affected infants often die. Empiric treatment should be considered in these risk situations [33, 34].
Pereira et al.  developed a retrospective observational study to investigate the risks for sepsis in neonates, including
Kung et al.  affirm that infants in NICU have a higher incidence of
The collected potential risk factors consisted of: (1) prenatal and maternal history such as toxemia, multiple gestation, intra-uterine growth retardation and perinatal infections; (2) perinatal history such as premature rupture of membrane greater than 18 hours and delay in initial crying; (3) invasive procedures such as instrument insertion and its duration (e.g., placement of nasogastric tubes, endotracheal tubes, mechanical ventilation, peripherally inserted central catheters, chest tubes, blood transfusion or exchanged blood transfusion and lumbar puncture); (4) the concomitant use of medications such as parenteral nutrition and intravenous lipid, antibiotics and steroids and (5) comorbidities such as meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), inborn error of metabolism and cardiac anomalies (except for patent ductus arteriosus and secundum type of atrial septal defect). However, transfusion, antimicrobial treatment, use of steroids and the presence of other comorbidities were not associated with
Invasive neonatal candidiasis presented an overall mortality rate of 35% during a study in Los Angeles (USA) in a neonatal intensive care unit. In general, every infant used a central venous catheter (CVC), required mechanical ventilation and previous administration of antibacterial agents. According to the authors, delayed institution of antifungal therapy was associated with increased mortality as well as length of hospitalization and the duration of prior antibacterial therapy .
In recent Italian study,
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 high-risk patients should help address these cases .
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 . 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, multifocal
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-
4. Other neonatal fungal infections
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
The vast majority of cases of fungemia occur in children less than 12 months old. In this population, this
Other less common symptoms include lethargy, malnutrition, bradycardia and hepatosplenomegaly. However, no signs of erythema, swelling or purulence appear at the catheter entry site. Signs of skin rash are also not evident in children with systemic infections. Interstitial bronchopneumonia can be found in 40% of children [44, 45, 46].
The diagnosis of fungal infection by
The standard therapeutic management for systemic infections by
Studies have indicated that the most important factor for therapeutic success against systemic infection is the removal of the infected catheter and the interruption of lipid infusion, with or without antifungals [18, 45, 46].
5. Treatment of neonatal fungal infections
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, 52, 53, 54].
Similar to neonatal invasive infections by species of
Amphotericin B deoxycholate and lipid preparations are traditional choices for invasive fungal infections being active against a majority of clinical important
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
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
The echinocandins (micafungin, caspofungin and anidulafungin) are increasingly used for treatment of
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 long-term 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 .