Open access peer-reviewed chapter

Fungal Infections in Neonatal Intensive Care

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Rejane P. Neves, Ana Maria R. de Carvalho Parahym, Carolina M. da Silva, Danielle P.C. Macêdo, André F.G. Leal, Henrique J. Neves and Reginaldo G. Lima-Neto

Submitted: October 10th, 2016Reviewed: July 4th, 2017Published: December 20th, 2017

DOI: 10.5772/intechopen.70302

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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
  • neonates
  • sepsis

1. Introduction

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 Candida[3, 4].

In addition, species of the genus Candidahave the capacity to inhabit several niches, thus, as part of the skin, mucosa and gastrointestinal tract [5]. Therefore, is considered that there is an association between colonization and systemic candidiasis mainly in seriously ill patients [6].

Although Candida albicansare more frequent, species of Candidanon-albicansare also cause of diverse clinical pictures important in neonates, especially those that are in NICUs. The main Candida non-albicans species included are Candida parapsilosiscomplex, Candida glabrataand Candida krusei. However, uncommon species as Pichia fabianiiand Kodamaea ohmerimay occur [7, 8, 9, 10].

The newborns clinical course in the Intensive Care Units usually complicates after the onset of fungal infections [11]. In this hospital environment, adverse events may occur due to the complexity of the patients [12]. 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 [13].

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 [9].


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, Candidaand Malasseziaspecies are the most prevalent pathogen involved in fungal infections in NICU [18].

The incidence of bloodstream infections due to Candidaspecies in the overall population ranges from 1.7 to 10 episodes per 100,000 inhabitants. An estimated 33–55% of all episodes of candidemia occur in intensive care units and are associated with mortality rates ranging from 5 to 71% [16].

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) [19].

C. albicanshas been the most frequently isolated species; however, infections caused by others species have been diagnosed with increased frequency. In the NICU in the 1990s, the overall incidence of candidemia increased because of the increased survival and intensive care of extremely preterm infants. During that time period, the proportion of candidemia decreased because of C. albicans, whereas increased because of C. parapsilosis[20, 21].

Invasive infections associated with C. parapsilosiscause fewer acute lethal events in premature newborns than systemic infections with C. albicans; nevertheless, C. parapsilosisfungemia significantly increases the morbidity and mortality of severely ill infants who require care in a NICU [22].

Laboratory studies have documented that C. parapsilosisis less virulent than C. albicans. However, the capability to adhere tenaciously to prosthetic materials forming biofilm and to proliferate rapidly in high concentrations of glucose are factors that facilitate the infection in the hospital environment. This trait may contribute to its ability to adhere to plastic catheters and cause systemic infections in premature newborns receiving total parenteral nutrition, blood pressure transducers or other invasive devices. Such a route of transmission may account for the occurrence of epidemic outbreaks of C. parapsilosisbloodstream infections [21].

Other emerging Candidaspecies such as C. haemuloniii, C. pelliculosaand C. tropicalishave also been associated with infections in NICU. C. pelliculosaand C. haemuloniiicaused clonal infection in NICU [11]. An outbreak of C. tropicalisfungemia in a NICU was traced to receipt of total parenteral nutrition and antimicrobial agents [23].

Malasseziaspecies in immunocompromised patients may be associated with several skin conditions and systemic diseases, including folliculitis, seborrhoeic dermatitis, catheter-related fungemia and sepsis. However, this yeast may also cause invasive infections in critically ill low birth weight infants. Malasseziafungemia is predominantly caused by Malassezia furfurand Malassezia pachydermatis. M. furfurhas been described predominantly in conjunction with nosocomial outbreaks in NICU, particularly in neonates and infants receiving intravenous lipids solution. Additionally, M. pachydermatishas been associated with bloodstream infection in preterm with very low birth weight and the prolonged use of indwelling catheters and parenteral lipid formulations [18, 24].


3. Neonatal Candidainfections

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 [29].

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, Candidaspecies are common gastrointestinal flora that causes a wide range of severe manifestations when disseminated into the bloodstream. Thus, candidemia has been described as the most common manifestation of invasive candidiasis [32].

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. [33], 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 Candida albicans, disseminated disease, pneumonia and cardiovascular disease were significantly more common in EOD than in LOD. Also, neurodevelopmental impairment and mortality were also higher than controls.

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. [34] developed a retrospective observational study to investigate the risks for sepsis in neonates, including Candidainfections, and verified an association between healthcare-associated sepsis, antibiotic therapy in day 1, the duration of parenteral nutrition and the use of central vascular catheter. For each extra week on gestational age, the risks declined in 20%, and for each day of parenteral nutrition, the risk increased 22%.

Kung et al. [35] affirm that infants in NICU have a higher incidence of Candidainfections than any other pediatric or adult population. The predisposing factors were evaluated in Taiwan using a retrospective matched case-control study conducted in the NICUs of a teaching hospital from July 2003 to June 2006. A total of 164 infants with culture-proven bloodstream infections were identified and the common etiologic pathogens included coagulase-negative staphylococci (28.7%), Staphylococcus aureus(16.5%), Klebsiella pneumoniae(14.6%) and Candidaspecies accounting for 11 (6.7%) episodes. According to these authors, parenteral nutrition was a significant and independent risk of late-onset neonatal sepsis, including those caused by Candidaspecies. This risk should be considered when implementing early parenteral nutrition in NICUs.

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 Candidainfections in neonates [35].

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 [36].

Frequently, C. albicansis the most fungal clinical isolate; however, the incidence of bloodstream infections caused by Candidanon-albicans, mainly C. parapsilosiscomplex and C. glabrata, has increased over the past 15 years. The current high rate of Candida parapsilosisinfections may be attributed the capacity of this isolate to form biofilms and contaminate solutions, as those used in parenteral nutrition [8].

In recent Italian study, C. albicanswas the most frequently identified strain, but nearly 20% of infections were due to Candidanon-albicans, mainly C. kruseiand C. glabrata[10]. Since both these strains can be resistant to fluconazole, that is the antifungal drug with the best urinary penetration [37], treatment of these patients could be challenging, despite a recent report that showed effective concentrations of micafungin in the urinary tract [38]. In these search, fungemia was the second most frequent diagnosis and was more frequent in children with malignancy/hematopoietic stem cell transplantation, those undergoing abdominal surgery and in low birth weight neonates, also in this case, confirming other recent pediatric data such as Ota et al. [39] and Steinbach et al. [40].

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 [41].

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, multifocal Candidaspecies colonization and severe sepsis [42].

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-Candidaantibodies plus β-D-glucan in the serum, the same Spanish researchers showed a positive correlation among increasing values of the “Candidascore” and the rate of invasive Candidainfections. Such a score was calculated by variables such as total parenteral nutrition, surgery, multifocal Candidacolonization and severe sepsis. Thus, Candidascore ≥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].


4. Other neonatal fungal infections

Despite C. albicansis 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 significant, except for Malasseziaspecies, which may occur in epidemic outbreaks [44, 45, 46].

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 Malasseziacan progress to fungemia. The removal of the infected catheter is sufficient to limit infection in most cases [46, 47].

The vast majority of cases of fungemia occur in children less than 12 months old. In this population, this Malasseziainfection 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 without apnea [46, 48].

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 Malasseziais made by isolating the microorganism from blood collected through the catheter or by culturing the catheter tip after its removal. In suspected sepsis by Malassezia, the tip of the catheter should be cultured in broth enriched with lipids [45, 46].

The standard therapeutic management for systemic infections by Malasseziais still not well defined, since the fungemia by this microorganism is relatively unusual. However, some authors recommend the use of amphotericin B to treat these infections [45, 46, 49]. Morrison and Weisdorf [50] found that all patients enrolled in their study were cured without the administration of systemic antifungal therapy.

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 Candida, the management of Malasseziasp. 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 Candidaspecies 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].

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 Candidaecology 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, 57, 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 Candidaand Aspergillusspp.; 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 Candidasp. 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 Candidaspp. 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. parapsilosisin 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 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 [53].


  1. 1.Montagna M, Lovero G, De Giglio O, Iatta R, Caggiano G, Montagna O, Laforgia N. Invasive fungal infections in Neonatal Intensive Care Units of Southern Italy: A multicentre regional active surveillance (AURORA Project). Journal of Preventive Medicine and Hygiene. 2010;51:125-130
  2. 2.Smith ER, Bergelson I, Constantian S, Valsangkar B, Chan GJ. Barriers and enablers of health system adoption of kangaroo mother care: A systematic review of caregiver perspectives. BMC Pediatrics. 2017;25;17(1):35. DOI: 10.1186/s12887-016-0769-5
  3. 3.Chitnis AS, Magill SS, Edwards JR, Chiller TM, Fridkin SK, Lessa FC. Trends inCandidacentral line-associated bloodstream infections among NICUs, 1999-2009. Pediatrics. 2012;130(1):46-52. DOI: 10.1542/peds.2011-3620
  4. 4.Kaufman DA. “Getting to Zero”: preventing invasiveCandidainfections and eliminating infection-related mortality and morbidity in extremely preterm infants. Early Human Development. 2012;88:45-49. DOI: 10.1016/S0378-3782(12)70014-2
  5. 5.Harriott MM, Noverr MC. Importance ofCandida-bacterial polymicrobial biofilms in disease. Trends in Microbiology. 2011;19(11): 557-563. DOI: 10.1016/j.tim.2011.07.004
  6. 6.Brissaud O, Guichoux J, Harambat J, Tandonnet O, Zaoutis T. Invasive fungal disease in PICU: Epidemiology and risk factors. Annals of Intensive Care. 2012;22(1):6. DOI: 10.1186/2110-5820-2-6
  7. 7.Wu Y, Wang J, Li W, Jia H, Che J, Lu J, Liu L, Cheng Y.Pichia fabianiiblood infection in a premature infant in China: Case report. BMC Research Notes. 2013;6:77
  8. 8.Goel S, Mittal S, Chaudhary U. Role of non-albicansCandidaspp. and biofilm in neonatal ICU. Infectious Disorders Drug Targets. 2016;16(3):192-198
  9. 9.Vivas R, Beltran C, Munera MI, Trujillo M, Restrepo A, Garcés C. Fungemia due toKodamaea ohmeriin a young infant and review of the literature. Medical Mycology Case Reports. 2016, 20;13:5-8. DOI: 10.1016/j.mmcr.2016.06.001
  10. 10.Mesini A, Bandettini R, Caviglia I, Fioredda F, Amoroso L, Faraci M, Mattioli G, Piaggio G, Risso FM, Moscatelli A, Loy A, Castagnola E.Candidainfections in paediatrics: Results from a prospective single-centre study in a tertiary care children’s hospital. Mycoses. 2017;60:118-123
  11. 11.Silva CM, Carvalho-Parahym AM, Macêdo DP, Lima-Neto RG, Francisco EC, Melo AS, da Conceição MSM, Jucá MB, Mello LR, Amorim RM, Neves RP. Neonatal candidemia caused byCandida haemulonii: Case report and review of literature. Mycopathologia. 2015;180(1-2):69-73. DOI: 10.1007/s11046-015-9872-7
  12. 12.Arriaga Redondo M, Sanz López E, Rodríguez Sánchez de la Blanca A, Marsinyach Ros I, Collados Gómez L, Díaz Redondo A, Sánchez Luna M. Improving patient safety: Usefulness of safety checklists in a neonatal unit. Anales Pediatr (Barc). 2017;S1695-4033(16)30309-5. DOI: 10.1016/j.anpedi.2016.11.005. [Epub ahead of print]
  13. 13.Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clinical Microbiology Reviews. 2014;27(1):21-47. DOI: 10.1128/CMR.00031-13
  14. 14.Benjamin D, Stoll B, Gants M, Walsh M, Sánchez P, Das A, Walsh T. Neonatal candidiasis: Epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126(4):e865-e873
  15. 15.Shane AL, Stoll BJ. Neonatal sepsis: Progress towards improved outcomes. The Journal of Infection. 2014;68(Suppl. 1):S24e32
  16. 16.Bougnoux M, Kac G, Aegerter P. et al. Candidemia and candiduria in critically ill patients admitted to intensive care units in France: Incidence, molecular diversity, management and outcome. Intensive Care Medicine. 2008;34:292-299
  17. 17.Brady MT. Healthcare-associated infections in the neonatal intensive care unit. American Journal of Infection Control. 2005;33(5):268-275
  18. 18.Devlin R. Invasive fungal infections caused byCandidaandMalasseziaspecies in the neonatal intensive care unit. Advances in Neonatal Care. 2006;6(2):68-77
  19. 19.Aliaga S, Clark RH, Laugh M. et al. Changes in the incidence of candidiasis in neonatal intensive care units. Pediatrics. 2014;133(2):236-242
  20. 20.Huang Y, Lin R, Chou Y, Kuo C, Yang P, Hsieh W. Candidaemia in special care nurseries: Comparison ofalbicansandparapsilosisinfection. The Journal of Infection. 2000;40:171
  21. 21.Lupetti A, Tavanti A, Davini P, Ghelardi E, Corsini V, Merusi I, Boldrini A, Campa M, Senesi S. Horizontal transmission ofCandida parapsilosiscandidemia in a neonatal intensive care unit. Journal of Clinical Microbiology. 2002;40(7):2363-2369
  22. 22.Fridkin S, Kaufman D, Edwards JR. et al. Changing incidence ofCandidabloodstream infections among NICU patients in the United States: 1995-2004. Pediatrics. 2006;117(5):1680-1687
  23. 23.Finkelstein R, Reinhertz G, Hashman N, Merzbach D. Outbreak ofCandida tropicalisfungemia in a neonatal intensive care unit. Infection Control and Hospital Epidemiology. 1993;14:587-590
  24. 24.Chryssanthou E, Broberger U, Petrini B.Malassezia pachydermatisfungaemia in a neonatal intensive care unit. Acta Paediatrica. 2001;90(3):323-327
  25. 25.Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Emerging infections program healthcare-associated infections and antimicrobial use prevalence survey team. Multistate point-prevalence survey of healthcare-associated infections. The New England Journal of Medicine. 2014;370:1198-1208
  26. 26.Yapar N. Epidemiology and risk factors for invasive candidiasis. Therapeutics and Clinical Risk Management. 2014;10:95-105
  27. 27.Lovero G, De Giglio O, Montagna O, Diella G, Divenuto F, Lopuzzo M, Rutigliano S, Laforgia N, Caggiano G, Montagna MT. Epidemiology of candidemia in neonatal intensive care units: A persistent public health problem. Annali di Igiene. 2016;28:282-287
  28. 28.Doi AM, Pignatari AC, Edmond MB, Marra AR, Camargo LF, Siqueira RA, et al. Epidemiology and microbiologic characterization of nosocomial candidemia from a Brazilian national surveillance program. PLoS One. 2016;11:e0146909
  29. 29.Sobel JD, Fisher JF, Kauffman CA, Newman CA.Candidaurinary tract infections epidemiology. Clinical Infectious Diseases. 2011;52(Suppl 6):S433-S436
  30. 30.Wisplinghoff H, Ebbers J, Geurtz L, Stefanik D, Major Y, Edmond MB, et al. Nosocomial bloodstream infections due toCandidaspp. in the USA: Species distribution, clinical features and antifungal susceptibilities. International Journal of Antimicrobial Agents. 2014;43:78-81
  31. 31.Diekema D, Arbefeville S, Boyken L, Kroeger J, Pfaller M. The changing epidemiology of healthcare-associated candidemia over three decades. Diagnostic Microbiology and Infectious Disease. 2012;73:45-48
  32. 32.Pfaller MA, Andes DR, Diekema DJ, Horn DL, Reboli AC, Rotstein C, et al. Epidemiology and outcomes of invasive candidiasis due to non-albicansspecies ofCandidain 2496 patients: Data from the Prospective Antifungal Therapy (PATH) registry 2004-2008. PLoS One. 2014;9:e101510
  33. 33.Barton M, et al. Early onset invasive candidiasis in extremely low birth weight infants: Perinatal acquisition predicts poor outcome. Clinical Infectious Diseases. 2017;64:cix001
  34. 34.Pereira H, et al. Risk factors for healthcare associated sepsis in very low birth weight infants. Acta Médica Portuguesa. 2016;29(4):261-267
  35. 35.Kung YH, et al. Risk factors of late-onset neonatal sepsis in Taiwan: A matched case-control study. Journal of Microbiology, Immunology and Infection. 2016;49:430-435
  36. 36.Cahan H, Deville JG. Outcomes of neonatal candidiasis: The impact of delayed initiation of antifungal therapy. International Journal of Pediatrics. 2011;2011:Article ID 813871
  37. 37.Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clinical Microbiology Reviews. 2014;27:68-88
  38. 38.Grau S, Luque S, Echeverría-Esnal D, et al. Urinary micafungin levels are sufficient to treat urinary tract infections caused byCandidaspp. International Journal of Antimicrobial Agents. 2016;48:212-214
  39. 39.Ota KV, McGowan KL. Declining incidence of candidemia in a tertiary inpatient pediatric population. Journal of Clinical Microbiology. 2012;50:1048-1050
  40. 40.Steinbach WJ, Roilides E, Berman D, et al. Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates. The Pediatric Infectious Disease Journal. 2012;31:1252-1257
  41. 41.Leroy G, Lambiotte F, Thévenin D, Lemaire C, Parmentier E, Devos P and Leroy O. Evaluation of “Candidascore” in critically ill patients: A prospective, multicenter, observational, cohort study. Annals of Intensive Care. 2011;1:50
  42. 42.León C, Ruiz-Santana S, Saavedra P, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients withCandidacolonization. Critical Care Medicine. Mar 2006;34(3):730-737
  43. 43.León C, Ruiz-Santana S, Saavedra P, Galván B, Blanco A, Castro C, Balasini C, Utande-Vázquez A, González de Molina FJ, Blasco-Navalproto MA, López MJ, Charles PE, Martín E, Hernández-Viera MA, Cava Study Group. Usefulness of the “Candidascore” for discriminating betweenCandidacolonization and invasive candidiasis in non-neutropenic critically ill patients: A prospective multicenter study. Critical Care Medicine. 2009;37:1624-1633
  44. 44.Kaufman D, Fairchild KD. Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants. Clinical Microbiology Reviews. 2004;17(3):638-680
  45. 45.Latta R, Cafarchia C, Cuna T, Montagna O, Laforgia N, Gentile O, Rizzo A, Boekhout T, Otranto D, Montagna MT. Bloodstream infections byMalasseziaandCandidaspecies in critical care patients. Medical Mycology. 2014;52:264-269
  46. 46.Maraschin MM, Spader T, Mario DAN, Rossato L, Lopes PGM. Infections byMalassezia: New approaches. Saúde. 2008;34(1):4-8
  47. 47.Marcon MJ, Powell DA. Human infection due toMalasseziaspp. Clinical Microbiology Reviews. 1992;5(2):101-119
  48. 48.Barder GR, Brown AE, Kiehn TE, Edwards FF, Armstrong D. Catheter-relatedMalassezia furfurfungemia in immunocompromised patients. The American Journal of Medicine. 1993;95(4):365-370
  49. 49.Strippoli V, Piacentini A, D’Auria FD, Simonetti N. Antifungal activity of ketoconazole and azole againstMalassezia furfur in vitroandin vivo. Infection 1997;25:303-306
  50. 50.Morrison VA, Weisdorf DJ. The spectrum ofMalasseziainfections in the bone marrow transplant population. Bone Marrow Transplantation. 2000;26(6):645-648
  51. 51.Blyth C, Chen S, Slavin M., Serena C, Nguyen Q, Marriott D, Ellis D, Meyer W, Sorrel T. Australian Candidemia Study. Not just little adults: Candidemia epidemiology, molecular characterization, and antifungal susceptibility in neonatal and pediatric patients. Pediatrics. 2009;123:1360-1368
  52. 52.Ericson J, Manzoni P, Benjamin D. Old and new: Appropriate dosing for neonatal antifungal drugs in the nursery. Early Human Development. 2013;89:S25-S27
  53. 53.Hassan M, Yasmeen B, Begum N. Fungal sepsis and Indications of antifungal prophylaxis and treatment in neonatal intensive care units: A review. Northern International Medical College Journal. 2015;6:6-8
  54. 54.Pana Z, Kougia V, Roilides E. Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients: An update. Expert Opinion on Pharmacotherapy. 2015;16:693-710
  55. 55.Lsetner J, et al. Systemic antifungal prescribing in neonates and children: Outcomes from the antibiotic resistance and prescribing in European children (ARPEC) study. Antimicrobial Agents and Chemotherapy. 2015;59:782-789
  56. 56.Hope W, et al. ESCMID* guideline for the diagnosis and management ofCandidadiseases 2012: Prevention and management of invasive infections in neonates and children caused by Candida spp. Clinical Microbiology and Infection. 2012;18:38-52
  57. 57.Leroux S, et al. Randomized Pharmacokinetic Study of fluconazole and micafungin in preterm neonates with suspected or proven fungal infection. American Journal of Perinatology. 2016;33, n. S 01, p A006
  58. 58.Manzoni P, Mostert M, Castagnola E. Update on the management ofCandidainfections in preterm neonates. Archives of Disease in Childhood‐Fetal and Neonatal Edition 2015;100:F454-F459
  59. 59.Shane A, Stoll B. Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis. American Journal of Perinatology. 2013;30:131-142
  60. 60.Watt K, et al. Triazole use in the nursery: Fluconazole, voriconazole, posaconazole, and ravuconazole. Current Drug Metabolismo. 2013;14(2):193-202

Written By

Rejane P. Neves, Ana Maria R. de Carvalho Parahym, Carolina M. da Silva, Danielle P.C. Macêdo, André F.G. Leal, Henrique J. Neves and Reginaldo G. Lima-Neto

Submitted: October 10th, 2016Reviewed: July 4th, 2017Published: December 20th, 2017