Abstract
Invasive fungal infections remain the leading causes of morbidity and mortality in neonates, especially preterm and very low birth weight infants. Most invasive fungal infections are due to Candida or Aspergillus species, and other fungi are increasingly reported and described. Appropriate identification and treatment are required to augment activity and reduce the toxicity of antifungal drugs. Successful use of antifungals in the vulnerable neonatal population is important for both prevention and treatment of infection. Strategies for prevention, including prophylactic antifungal therapy as well as reducing exposure to modifiable risk factors, like limiting antibiotic exposure, discontinuation of central catheters, and hand hygiene are key techniques to prevent and decrease rates of invasive fungal infections. In conclusion, this is a review of the most common causes, prevention strategies, prophylaxis, and treatment of invasive fungal infections in neonates.
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Introduction
Invasive fungal infections (IFI) are a leading cause of morbidity and mortality in neonates, especially preterm and very low birth weight (VLBW, <1500 g birth weight [BW]) infants in the neonatal intensive care unit (NICU).1 These infants are immunocompromised, exposed to broad-spectrum antibiotics, have immature epithelial barriers, and often undergo invasive procedures, putting them at increased risk for opportunistic fungal infections. The majority of IFI are due to Candida species; however, cases due to other fungi are increasingly reported. Having a high index of suspicion is crucial for early diagnosis and treatment. However, morbidity and mortality are high for some IFI, even with appropriate therapy. Strategies for prevention, including prophylactic antifungal therapy as well as reducing exposure to modifiable risk factors, like antibiotic exposure, have decreased rates of some infections. We will review the most common causes of IFI in neonates, treatment, and prophylaxis strategies.
Invasive candidiasis
Epidemiology
Candida species, commensal yeast, and common nosocomial pathogen are the most common fungal infection in neonates. They are colonizers of the skin as well as oral, gastrointestinal (GI), and vaginal mucosal surfaces, and infection occurs when this balance is disrupted. Invasive candidiasis (IC) is the third most common cause of late-onset sepsis in VLBW infants and a significant cause of morbidity and mortality in the NICU.1,2 The incidence of IC in the NICU range from 0.5 to 20% and vary significantly by center, patient population, and have an inverse correlation with BW, with the highest incidence among ELBW infants (5–20%).1,2,3,4,5,6,7 A recent study suggests that the incidence of IC in the NICU is decreasing, likely secondary to fluconazole prophylaxis, decreased use of broad-spectrum antibiotics, and improved care of central venous catheters.7,8 Candida albicans is the most frequently isolated species, accounting for 60–75% of infections, followed by C. parapsilosis (14–30%).3,9,10 Other species, including C. tropicalis, C. lusitaniae, C. glabrata, and C. krusei are a much less common cause of infection. IC is associated with significant morbidity and mortality (~30%), with one study reporting 73% death or neurodevelopmental impairment in ELBW infants with IC.1,2,11,12
Risk factors
Risk factors for IC encompass three main domains, (1) immunocompromised host, (2) disruption of epithelial barriers, and (3) level of colonization (Table 1).
Immunocompromised host
Neonates, particularly those that are preterm, have immature innate and adaptive immune systems that predispose them to infection.13,14,15,16 Neutropenia is associated with IC in neonates.17,18 In addition, several studies have shown an association between IC and lower gestational age (GA) and BW, with younger and smaller infants being at the highest risk.2,5,6,12,19 Mortality from IC is also inversely proportional to BW.12 Finally, the use of corticosteroids, an immunosuppressant, has been associated with an increased risk of IC in preterm infants.12,20,21
Disruption of epithelial barriers
Preterm infants have thin and incompletely developed epidermal and mucosal layers that allow pathogens to penetrate more easily, increasing the risk for IC.22,23 In addition, procedures and equipment used in the NICU disrupt epithelial barriers and are associated with IC, including endotracheal tubes and central venous catheters17,24,25. Delayed catheter removal (>1 day after antifungal initiation) is also associated with an increased risk of death or neurodevelopmental impairment.2 Disruption of the GI tract, allowing translocation of Candida out of the intestines, is also a frequent source of IC, including necrotizing enterocolitis (NEC), spontaneous intestinal perforation, GI anomalies, and other abdominal surgeries.12,17,26,27,28
Colonization
Several studies demonstrated a correlation in VLBW infants between IC and Candida colonization, with the risk increasing with number and type of site (high risk vs. low risk).18,29,30 In addition, numerous studies have shown an association between antibiotic use, which decreases commensal bacteria and can increase Candida colonization, and IC in VLBW infants, particularly the use of prolonged or broad-spectrum antibiotics (third-generation cephalosporins).2,4,6,17,19,24,31,32 Other factors that increase the risk of IC through overgrowth or increased colonization of Candida include use of postnatal steroids, histamine-2-receptor antagonists, and intravenous lipid emulsions.6,12,20,21,24
Clinical presentation
Infants with IC often present with a sepsis-like illness, including lethargy, apnea, respiratory distress, cardiovascular instability, and/or feeding intolerance that is similar to infants with other late-onset infections. Although nonspecific, persistent hyperglycemia and thrombocytopenia are associated with fungal infections and should prompt further evaluation.24,33,34,35,36 Candidemia, especially when present >5 days, can spread to multiple organ systems via hematogenously or via septic emboli leading to fungal masses and inflammation, most commonly in the kidneys (5–30%), heart (5–15%), central nervous system (CNS, 5–64%), eyes (chorioretinitis and endophthalmitis, 3–50%), bones/joints, skin, and lungs.37,38,39,40,41,42,43,44,45,46 Candida CNS disease usually presents as meningoencephalitis in the setting of candidemia, but can also present as brain abscesses, ventriculitis and vasculitis, and with a negative blood culture.2,47
Congenital cutaneous candidiasis (CCC) is an invasive infection of the dermis and epidermis acquired in utero or at the time of delivery. Infection can occur in term and preterm neonates, but the risk for systemic disease is greatest for extremely low birth weight (ELBW, <1000 g BW) infants. In an 11-year study of over 19,000 NICU admission (two units), Kaufman et al. reported a CCC incidence of 0.1%, with >90% of affected infants <37 weeks GA and the highest incident in ELBW infants (0.6%).48 Risk factors for CCC include prematurity, vaginal foreign bodies (intrauterine device, cerclage), ruptured membranes, chorioamnionitis, and history of vaginal candidiasis (Table 1).48,49,50 CCC typically presents with a rash in the first few days of life (71% on the first day, 0–6 days median)48. The rash can consist of one or more of the following: peeling, sloughing, or desquamation (62%); maculopapular rash (48%); pustule/papule (40%); diffuse erythema (33%); yellow plaques or secretions (19%); dry flaking, scaling, or cracking skin (19%).48 The majority of infants (57%) had two or more of these skin findings and 19% had funisitis. The most commonly involved surfaces include the back, extensor surfaces of extremities, skin folds, and, unlike other common neonatal rashes, the palms and soles.49 Preterm infants with CCC often present with respiratory distress, elevated white blood cell count, and hyperglycemia.49 CCC is associated with disseminated infection and high mortality (40% <1000 g, 14% 1000–2500 g, 4% >2500 g)49; however, early systemic therapy can significantly reduce morbidity and mortality (95% survival).48
Candida are also a common cause of urinary tract infections (UTIs) in the NICU.51,52 Symptoms are nonspecific and include apnea, bradycardia, and, if obstruction is present, decreased urine output. Infection can range from cystitis, especially in those with indwelling catheters, to renal parenchymal disease with mycetoma formation.53,54 Up to 30% of infants with candidemia have renal involvement, and a candidal UTI can progress to disseminated disease.40,51 Isolated IC of other organ systems (cardiac, CNS, ophthalmologic, musculoskeletal) can also occur, especially in the presence of indwelling devices.
Finally, IC can lead to peritonitis with spontaneous intestinal perforation or NEC-like presentation. It is unclear in these cases whether Candida causes the mucosal damage and/or perforation or if it invades after a primary insult.26,27,55
Diagnosis
Candidemia
Blood culture is the gold standard for diagnosis of IC. Candida can be detected the typical blood culture media used for bacteria. Historically, while the specificity was high (100%), sensitivity was low.56,57 However, newer blood culture techniques are available that are more accurate.58 For infants not on antifungal therapy, the median time to positivity was 36 h, with 97% of blood cultures positive by 72 h. This increased to a median of 42 h and 91% positive by 72 h for infants on antifungal therapy.59 In addition, the majority of infants with Candidemia have more than one positive culture (median 3–5 days).2,40
Infants with a high clinical suspicion for IFI should be started on empiric antifungal therapy until IC is ruled out and a positive culture for Candida should never be considered a contaminant.
Beta-d-glucan (BDG) is a cell wall component found in many fungi and may aide in the in diagnosis of IFI. BDG is frequently used to aide in the diagnosis of IC in adults, with sensitivity of up to 97% and specificity up to 93%.60 A study of 61 neonates in the NICU found that BDG levels were significantly higher in infants with IC, but a higher cutoff level of ≥125 pg/mL was needed (compared to >80 pg/mL recommended by the assay kit).61 Another study reported similar findings in neonates with invasive yeast infections, with a cutoff of 105 pg/mL, and a higher sensitivity/specificity if only looking at IC. For both studies, the change in BDG levels were useful for monitoring treatment efficacy over time. The authors hypothesized that the higher baseline BDG levels could be due to higher rates of Candida colonization or a false positive. BDG is not specific to Candida and previous studies have reported false positives secondary to antibiotic exposure, some bacterial infections, albumin, and transfusion of blood products.62,63,64,65,66,67,68 Currently, BDG is most useful in neonates for to aide in the decision to start empiric antifungal therapy and to monitor response to therapy.
Polymerase chain reaction (PCR)-based assays that detect the ribosomal subunit of fungi are being developed, but are not as sensitive (77–95%) or specific (70–95%) as culture.57 In addition, these assays cannot provide sensitivity data and there is concern about contamination and detecting colonization rather than infection.
Congenital cutaneous candidiasis
Diagnosis is made by identification of budding yeast and pseudohyphae on a Gram stain or potassium hydroxide (KOH) preparation of skin scrapings, vesicular contents, or skin biopsy. Evaluation for systemic infection should be done with cultures of blood, urine and cerebrospinal fluid, and can aid in the diagnosis.
Urinary tract infection
A diagnosis of candidal UTI is made based on a positive urine culture (>1000 colony-forming units per mL (CFU/mL) from suprapubic aspiration or >10,000 CFU/mL from catheterized specimen).69,70 Urine culture is a poor predictor of renal involvement and should not be used to rule out renal involvement.57
CNS infection
As with blood, diagnosis of Candida CNS disease is made by isolating the fungi from cerebrospinal fluid (CSF) culture. CSF of infants with Candida meningitis can have normal gram stain, cell count, and chemistries because of a low or delayed inflammatory response or localized CNS infection (abscess) and negative blood cultures.43,47 In a study of 20 infants with culture-positive Candida meningitis, 43% (3/7) had normal CSF parameters and 63% (11/19) had a negative blood culture.47
Multisystem or disseminated disease
As mentioned previously, IC is frequently a multisystem disease. Candida detected in one system should prompt evaluation of other systems for involvement, including blood culture, urine culture, lumbar puncture, echocardiogram, dilated eye exam, head ultrasound, and ultrasound of the liver, spleen, and kidneys to determine guide antifungal therapy and duration (Table 2).71
Aspergillosis
Epidemiology
Aspergillus species are ubiquitous molds found throughout the environment, including in air, soil, plants, and food. Aspergillus is a leading cause of IFI in immunocompromised adults and children, but is uncommon in neonates.1,72 There are over 200 known species, with at least 20 known to cause human disease. Aspergillis fumigatus is the most commonly isolated species, followed by Aspergillus flavus and A. niger.72,73,74,75 Aspergillus is associated with high morbidity and mortality and there are an increasing number of case reports in neonates.5,72,73
Risk factors
As with IC, risk factors for aspergillosis in neonates include factors that increase host susceptibility, disrupt epithelial barriers, and disrupt the normal flora, including prematurity, VLBW, exposure to broad-spectrum antibiotics, central venous catheters, and corticosteroids.72,73 However, there are also environmental factors that can increase the risk of Aspergillus infection in an at-risk host, including hospital construction or renovations, contaminated gauze, bedding, tape, and other dressings (Table 1).73,76,77
Clinical presentation
Aspergillosis typically begins as a pulmonary infection, but in neonates, other sites of entry include invasive catheters, the GI system, sites of skin breakdown from medical equipment (tape, arm boards), and wounds.78
Primary cutaneous aspergillosis (PCA)
PCA occurs most commonly in hospitalized, preterm infants.73 Lesions vary, but usually start as an erythematous patch or plaque that changes to a pustule, and then ulcerates to form a necrotic eschar.79 The mean age of appearance is 10 days (3–33 days range) and the lesions are usually found on the back or sites of trauma.72,73,80 If treatment is not started early, PCA can progress to a system infection.77,80
Invasive aspergillosis
Invasive aspergillosis most commonly presents as pulmonary or disseminated disease in neonates, but can also present in the CNS and GI tract.73,81,82 Like with PCA, localized invasive Aspergillus often progresses to disseminated disease, especially if treatment is not started early.83 Aspergillus can invade blood vessels, leading to thrombus formation or hemorrhage, or other tissues, including pulmonary, cardiac, muscles, and bone.82,83
Diagnosis
In adults and pediatric patients, imaging studies, particularly of the chest, are a mainstay of diagnosis. However, neonates do not usually present with these classic findings.72 Diagnosis of Aspergillus infection in neonates typically relies on culture or histopathological examination of body fluid or tissue sample. PCR assays for Aspergillus have been developed and may aide in the diagnosis, especially of CSF, but have low sensitivity and specificity (80% for both) and are not available at all centers.83 Galactomannan antigen testing is useful for diagnosis of Aspergillus in adults, but are not recommended for neonates because of the risk of false positives.72,84
Zygomycosis
Epidemiology
Zygomycetes are ubiquitous fungi found in soil and vegetation and encompass the orders Entomophthorales and Mucorales (Rhizopus, Rhizomucor, Mucor, Absidia).85 Zygomycosis is rare in neonates, but associated with high mortality and reported cases neonates as increased significantly since 1990.86 Rhizopus (44–72%) and Mucor (4–15%) are the most commonly isolated species in neonates.86,87
Risk factors
As with other invasive fungal infections, the greatest risk factor for zygomycosis is prematurity.86,87 Broad-spectrum antibiotics, corticosteroid therapy, invasive catheters, acidosis and hyperglycemia are also associated with zygomycosis in neonates.86,87,88 Finally, outbreaks of zygomycosis have been associated with contamination of wooden tongue depressor, adhesives and hospital linens (Table 1).89,90,91
Clinical presentation
Zygomycetes are invasive fungi and often lead to tissue necrosis, thrombosis, and disseminated disease.92 In neonates, zygomycosis typically presents as a cutaneous disease (36%) or GI disease (51%), and both often lead to disseminated disease (56%).87
Primary cutaneous disease
Cutaneous lesions can remain localized or extend to invasive or systemic diseases.86 Lesions often begin as erythema and induration, particularly around sites of trauma and skin breakdown, and then progress to deep necrotic eschars that can extend through multiple layers of skin.93,94
GI disease
The clinical presentation of GI disease is very similar to NEC, except that there is no pneumatosis intestinalis or other hallmark radiologic findings and, while NEC is generally limited to the small bowel, zygomycosis can extend from the esophagus to the large intestines.87,88,95 Skin lesions may or may not be present with GI disease and it is associated with a very high mortality (78%).87
Neonates treated with a combination of surgery/surgical debridement and antifungal therapy have the highest reported rates of survival (30% mortality), although studies are small (Table 2). Cutaneous disease also has a higher survival compared to GI disease—77% cutaneous vs. 39% GI survival for infants who had surgery and antifungal therapy (Table 2), likely due at least impart to delayed diagnosis.86 Interestingly, surgery did not seem to increase survival in GI zygomycosis. Early diagnosis and initiation of antifungal therapy is crucial to survival.
Diagnosis
Zygomycosis is difficult to diagnose in neonates. Diagnosis relies on histopathologic examination of a tissue sample with culture confirmation, if available. However, Zygomycetes are very difficult to grow in culture and many cases have been diagnosed on autopsy.86 PCR and other molecular assays are being developed, but are not readily available in most locations and have not been tested in neonates.96 Zygomycetes do not have the cell wall components detected by BDG and galactomannan assays.
Malassezia
Epidemiology
Malassezia are lipophilic yeasts and a part of the normal human skin flora.97 Infection in neonates is uncommon. The most commonly isolated species from neonatal infections are Malassezia furfur, M. pachydermatis, M. globus, and M. sympodialis.98 Malassezia cannot synthesize medium- and long-chain fatty acids and require an exogenous supply for growth.
Risk factors
Risk factors associated with Malassezia in neonates include prematurity, intralipid emulsions, invasive catheters, skin emollients, prolonged NICU stay, and broad-spectrum antibiotics (Table 1).99,100,101
Clinical presentation
In healthy children and adults, Malessezia generally cause superficial skin infections like pityriasis versicolor, seborrheic dermatitis, and folliculitis. Neonates, especially preterm infants in the NICU, can present with systemic disease. Symptoms are nonspecific and similar to other etiologies of late-onset sepsis, including apnea, bradycardia, respiratory distress, and thrombocytopenia.102,103 Skin findings are uncommon with systemic disease. Like other fungi, Malassezia are also associated with thrombus formation.103,104
Diagnosis
As with other fungal pathogens, diagnosis of Malessezia in neonates is difficult and clinicians must have a high index of suspicion. Diagnosis is made by histologic identification or positive culture from a normally sterile tissue or body fluid. Malassezia do not grow in typical culture media because they require fatty acids for growth and can take up to 2 weeks to grow. Histopathologic identification can be confirmed with culture using specialized media. The BDG assay does not detect Malassezia.105 Newer molecular methods of diagnosis (PCR, mass spectrometry) are becoming more common, but have not been widely tested in neonates.101,106,107
Uncommon fungal pathogens
Blastomycosis
Blastomyces are dimorphic fungi found in soil and near water, particularly along St. Lawrence and Mississippi rivers in North America. Blastomycosis, most commonly caused by Blastomyces dermatitidis, occurs in both immunocompetent and immunocompromised hosts, usually from inhalation of spores. A handful of cases have been reported in neonates and were thought to be secondary to in utero or perinatal transmission.108,109 Reported neonatal cases presented as invasive pulmonary and disseminated diseases and were universally fatal. Diagnosis of blastomyces is typically by histopathologic examination or culture of infected respiratory secretions and/or tissue.
Coccidiodomycosis
Coccidioides immitis is a dimorphic fungi endemic in the Southwestern United States and is the causative agent of coccidiodomycosis. Infection occurs in immunocompetent and immunocompromised hosts, usually via inhalation of athroconidia. As with blastomycosis, a handful of cases have been reported in neonates, the majority of which were thought to occur secondary to maternal transmission; however, environmental acquisition has been reported.110,111,112,113 Coccidiodomycosis in infants often presents as disseminated and fatal disease. Serologic testing is frequently used for diagnosis in adults and children. However, for early and severe disease, as in neonates, diagnosis via histopathologic examination or culture of infected secretions or tissue is required because there has not been enough time for sufficient antibody production.
Cryptococcus
Cryptococci are encapsulated fungi found in soil throughout the world, particularly in areas contaminated by pigeon feces. Cryptococcal infection most commonly occurs in immunocompromised hosts, particularly those with AIDS, and Cryptococcus neoformans is the most commonly isolated species. Infection in the neonate is rare, but when it occurs, it results in multisystem dissemination, including to the brain, meninges, liver, spleen, and eyes.114,115 Most reported infants survive with appropriate therapy. There is little data, but risk factors for neonatal cryptococcus are thought to be similar to those for other invasive fungal infections.114 Transplacental transmission has been reported in the setting of maternal human immunodeficiency virus.116,117 Diagnosis is made by India ink staining or cryptococcal antigen testing of infected fluids. Culture can be used to confirm the diagnosis.
Trichosporon
Trichosporon are ubiquitous fungi commonly found in soil that can colonize human skin, respiratory, and GI tracts. They generally cause superficial infection of hair shafts (white piedra), but rarely can cause invasive disease in susceptible hosts. A handful of cases in the NICU have been reported.118 Risk factors for neonatal infection include prematurity, VLBW, and broad-spectrum antibiotics.118 Cutaneous infections generally present as 0.5 mm painless white nodules along the hair shaft. Reported systemic disease in infants includes UTI, catheter-associated infection, and disseminated disease (pulmonary, GI, renal).118 Trichosporon can also cause invasive skin lesions with central necrosis and ulceration.119,120 Diagnosis is made by KOH preparation of affected hair shaft, or culture and/or histopathology of blood or affected tissue.
Pichia
Pichia are ubiquitous yeast and opportunistic pathogens found in the environment (soil, water, plants, fruits, insects) and may be contaminants in foods and drinks—some species are used in cheese and wine making. Isolated neonatal infections, as well as outbreaks in NICUs, have been reported. Pichia anomala is the most commonly isolated species, followed by P. fabianii, P. ohmeri, and P. kudriavzevii.121,122,123,124,125 Identified risk factors include prematurity, VLBW, invasive catheters, previous antibiotic use, total parenteral nutrition with lipid emulsion, and invasive procedures.121,122,126 Some outbreaks were linked to carriage by healthcare providers.122,126 Pichia can lead to fungemia and ventriculitis and symptoms are similar to other late-onset illnesses, including respiratory failure, apnea, and bradycardia.121 As with other opportunistic fungi, colonization can occur without infection. Diagnosis is by a culture of infected bodily fluid. However, PCR or other molecular assays may be needed for appropriate identification.122,126,127
Antifungal prophylaxis for prevention of invasive infections
As discussed above, extremely premature infants are at high risk for developing IFI, which are associated with significant mortality, devastating morbidities, and long-term neurodevelopmental impairment in survivors. For this reason, fluconazole prophylaxis should be considered in high-risk infants, and especially those admitted to NICUs with high rates of IC.
Multiple trials have demonstrated the dosing, safety, and efficacy of using fluconazole prophylaxis against IC.128,129,130,131,132 In a patient-level data meta-analysis of four randomized, placebo-controlled trials including preterm infants from the United States, fluconazole prophylaxis decreased the odds of IC [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.08–0.51], as well as the composite outcome of death or IC (OR 0.48, 95% CI 0.30–0.78).133 In addition, fluconazole prophylaxis reduced the odds of Candida spp. colonization (OR 0.28, 95% CI 0.18–0.41).133
The Infectious Diseases Society of America (IDSA) currently recommends the use of intravenous or oral fluconazole prophylaxis at a dose of 3–6 mg/kg twice weekly for 6 weeks in infants with birthweights <1000 g who are admitted to NICUs with high rates (>10%) of IC.134 However, even in centers with low rates of IC, fluconazole prophylaxis should be considered in high-risk ELBW infants, particularly those with central line catheters, and those receiving broad-spectrum antibiotics.135
Treatment of systemic infections
Appropriate use of antifungals in the neonatal population is important for both prevention and treatment of infection with IFI. Empiric antifungal therapy is often instituted in infants given the poor performance of laboratory assays, the long turnaround time for culture results, and inaccuracy in clinician diagnosis.24,56 Empiric antifungal therapy in infants with birthweight <1000 g has been shown to increase survival without neurodevelopmental impairment.136 In order to maximize the activity of antifungals and minimize toxicity in this vulnerable population, isolation, and identification of a specific fungus should then guide further treatment (Table 2).
There are currently four main classes of antifungals that are used in infants, including polyenes, pyrimidine analogs, azoles, and echinocandins (Table 2).137 The most commonly used antifungals in the NICU are fluconazole and amphotericin B deoxycholate.138 Tables 2 and 3 below list recommendations for treatment of IFIs along with monitoring parameters. In addition to pharmacologic treatment, consideration should be given to the removal of indwelling catheters, due to biofilm formation, surgical debridement (Zygomycetes spp.), and cessation of intralipid emulsions as able (Malassezia spp.).86,139,140 Because of the limited data, variation in choosing a first-line agent in the NICU still exists, and future pharmacokinetic studies will inform neonatal practice better.141
Conclusion
In summary, in this era of improved survival of extremely premature ELBW infants, the risk of IFIs is extremely high. These infants have immature skin integrity, and coupled with their innate immunosuppression and other life-supporting therapies, they are at high risk of lethal IFIs. While Candida spp. are the most common causative organisms, others have been reported in the literature. Attempting to modify risk factors through care bundles, antibiotic stewardship programs, discontinuation of central catheters, and hand hygiene are key techniques to prevent IFIs. Maintaining a high index of suspicion for fungal infections to appropriately identify and promptly treat is critical. Consideration to fluconazole prophylaxis in high-risk infants should be given to reduce infection rates of IFIs. Further studies evaluating the safety, efficacy, and drug pharmacokinetics will allow targeted therapies in this vulnerable population.
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Weimer, K.E.D., Smith, P.B., Puia-Dumitrescu, M. et al. Invasive fungal infections in neonates: a review. Pediatr Res 91, 404–412 (2022). https://doi.org/10.1038/s41390-021-01842-7
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DOI: https://doi.org/10.1038/s41390-021-01842-7
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