INTRODUCTION — Fungal infections in neonates, other than those caused by Candida species, are uncommon. These are often overlooked because neonatal infections due to bacteria, viruses, and Candida are more prevalent [1]. Nonetheless, noncandidal fungal infections occur in neonates, resulting in significant mortality and morbidity. They include aspergillosis, cutaneous and intestinal zygomycosis, Malassezia sepsis, trichosporonosis, Pichia sepsis, cryptococcosis, coccidioidomycosis, blastomycosis, and dermatophytosis.
Similar to that of Candida infections, the incidence of noncandidal fungal infections in neonates appears to be increasing, particularly in preterm infants [2]. Preterm infants may be more vulnerable to fungal infections because of their immature immune systems and poorly developed epithelial skin and mucosal barriers as well as the high rate of invasive procedures, such as central venous catheters and intubation, that compromise host defenses (eg, skin integrity). (See "Epidemiology and risk factors for Candida infection in neonates".)
Noncandidal fungal infections in the neonate and their treatment will be reviewed here. The epidemiology, clinical manifestations, treatment, and prevention of neonatal Candida infection are reviewed separately. (See "Epidemiology and risk factors for Candida infection in neonates" and "Candida infections in children" and "Candidemia and invasive candidiasis in children: Management".)
NEONATAL FUNGAL INFECTIONS OTHER THAN CANDIDA
Aspergillus — Aspergillus species are ubiquitous molds commonly found in air, soil, decaying vegetation, and dust. Infections are most commonly caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and, rarely, Aspergillus tamarii [3]. Mortality is very high in infected neonates, even when treated with antifungal therapy. (See 'Treatment' below.)
Reports of neonatal Aspergillus infection appear to be increasing. In a review of the literature from 2002, 16 of the 17 cases of primary cutaneous aspergillosis were published after 1990 [2,4].
Risk factors for neonatal aspergillosis include gestational age below 32 weeks, birth weight (BW) below 1500 g, and new construction or hospital renovations [5]. In addition, hospital gauze, bedding, tape, and dressing are vehicles for transmission of Aspergillus spores [5,6]. The administration of broad-spectrum parenteral antibiotics and corticosteroids are also strongly associated with disseminated aspergillosis [2].
Clinical manifestations — In neonates, primary infection generally involves either the skin or respiratory tract. Rapid systemic dissemination may occur, resulting in significant mortality.
●Cutaneous – Preterm infants are at increased risk for primary cutaneous aspergillosis because their skin is thin and delicate. Typically, the skin lesion begins as an erythematous patch or a plaque that rapidly progresses to hemorrhagic bullae. Within 24 hours, the lesion subsequently develops into purpuric ulcerations and black eschar formation [2,7,8]. Lesions generally form on the back or other dependent areas.
●Respiratory – Respiratory involvement occurs with inhalation of Aspergillus spores, resulting in pneumonia.
●Disseminated disease – Respiratory failure, liver failure, seizures, and skin lesions are reported features of disseminated aspergillosis [2,9]. The organism also has a propensity to invade blood vessels, causing thrombosis, infarction, and necrosis. Hemorrhagic necrosis is frequently seen in the lung and gastrointestinal tract in autopsies of affected patients. Rare manifestations of disseminated disease include meningitis [10] and obstructive renal aspergilloma in a neonate with bladder exstrophy [11].
Diagnosis — The diagnosis of aspergillosis can be made by identifying Aspergillus by microscopic examination or culture of tissue obtained by biopsy or from body fluids. Polymerase chain reaction may be useful in detecting Aspergillus species in cerebrospinal fluid (CSF) or serum [12,13]. Galactomannan antigen testing is helpful for diagnosis of invasive aspergillosis in adult patients; however, it has not been evaluated in neonates. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)
Aspergillus must be distinguished from other fungi, including the following:
●Candida can be distinguished from Aspergillus because the hyphae of Candida are smaller and do not branch
●Zygomycetes can be distinguished from Aspergillus by their larger size, irregularity, and absence of septa
●Penicillium is the most difficult species to differentiate from Aspergillus, but its hyphae are generally broader and contain fewer septa than Aspergillus
Zygomycosis (mucormycosis) — There is some controversy over the terminology used to refer to infections due to this class of fungi. The older (and more common) term "mucormycosis" is familiar to most clinicians. However, zygomycosis has become the preferred term since other members of this class of fungi can cause infection, in addition to those in the order Mucorales.
Although Zygomycetes fungi are uncommon causes of neonatal infections, there are several reports of infections in newborn infants [14-19]. Infections are due to organisms from the genera Rhizopus, Mucor, and Absidia.
Risk factors for neonatal zygomycosis include prematurity, low BW, use of broad-spectrum antibiotics and corticosteroids, and local skin trauma due to vascular catheters and adhesive dressings. Transmission of the fungi may be due to contact with contaminated surfaces such as adhesive tape or dressing [20,21]. In one report, four cases of Rhizopus microsporus in preterm infants were due to contaminated wooden tongue depressors used as splints to secure intravenous and arterial cannulation sites [22]. An outbreak of zygomycosis in a pediatric hospital due to contaminated hospital linens has been reported [23].
Clinical presentations of neonatal zygomycosis include primary cutaneous disease [16] or gastrointestinal involvement [14,15,17,18]. Gastrointestinal disease resembles necrotizing enterocolitis (but without the radiologic changes) and is associated with a high mortality rate [14,17,24]. Presentation with gastric perforation or with clinical signs and symptoms mimicking intestinal intussusception have also been reported [25,26]. Vascular invasion is the hallmark of zygomycosis and is often associated with vascular thrombosis and tissue necrosis [27]. A case of neonatal acute liver failure due to zygomycosis has been reported [28].
The diagnosis relies upon the identification of organisms in tissues by histopathology with culture confirmation. However, the organism often does not grow in culture and histopathologic identification of a Zygomycete may provide the only evidence of infection. (See "Mucormycosis (zygomycosis)".)
Therapy consists of local debridement or surgical resection as well as the administration of amphotericin B [15-17,29,30]. Maintaining skin integrity by avoiding trauma to the skin by insertion of catheters and dressings, as much as possible, is the best approach to prevent primary cutaneous infection. (See 'Amphotericin B' below.)
Malassezia — In 1981, the first case of a neonatal infection with a Malassezia species was reported in a preterm infant receiving intralipid emulsion [31]. Subsequently, several other cases of Malassezia infections were reported in preterm and low BW infants.
Malassezia mainly colonizes the skin and, occasionally, the respiratory tract [32-34]. Neonatal infections are caused by one of four species: Malassezia furfur, Malassezia pachydermatis, Malassezia globus, and Malassezia sympodialis [32]. All Malassezia species except M. pachydermatis require exogenous long-chain fatty acids for growth. This requirement may explain the associated risk of this infection in infants who receive intralipid emulsions [15].
Risk factors for Malassezia colonization and infection include prematurity, increased length of stay in a neonatal intensive care unit (NICU), administration of intralipid emulsions, central venous catheters, skin emollients, and the administration of broad-spectrum antibiotics [35,36]. A molecular investigation into an M. pachydermatis outbreak showed that multiple genotypes are present in a single patient and that the outbreak was related to a lipid-rich moisturizing cream used by health care staff [37].
The clinical manifestations of neonatal Malassezia fungemia are nonspecific and include apnea, bradycardia, fever, respiratory distress, and thrombocytopenia [38]. In addition, thrombus and thromboembolism are reported complications from catheter-related fungemia [39].
Malassezia infections, including the diagnosis, are discussed in greater detail separately. (See "Invasive Malassezia infections".)
Dermatophytes — Dermatophytes refer to the classes of fungi that cause the most common type of fungal skin and nail infections in healthy older patients, commonly referred to as "ringworm." Three types of superficial fungi/dermatophytes account for the majority of these infections: Epidermophyton, Trichophyton, and Microsporum.
In neonates, tinea facei, tinea capitis, tinea corporis, and extensive skin lesions have been reported due to Microsporum infections as isolated case reports as well as in one reported outbreak in a newborn nursery due to transmitted infection by a health care worker [40-44]. Kerion celsi is an inflammatory response to dermatophyte infection and has been reported in three neonates [45]. Topical antifungal agents may be used in neonates with superficial infection. However, in cases with suspected disseminated disease, systemic antifungal therapy should be initiated.
Trichosporon — Trichosporon species are rare fungi that may cause superficial infections of hair shafts in the head, axilla, and genital area. Nodules of approximately 0.5 mm, referred to as white piedras, are attached to the hair shafts. In a review of the literature published in 2000, 12 cases of neonatal Trichosporon infections were identified [46]. Possible risk factors included prematurity, low BW (BW below 1500 g), and use of systemic antibiotics.
In immunocompromised hosts, including preterm infants, disseminated and often fatal infections usually occur. Although most neonates have disseminated disease (approximately 70 percent), there are reports of isolated urinary tract infection and colonization of a central venous catheter [2].
In a case report from one NICU in 1991, a cluster of four cases occurred over a two-month time period [47]. Three patients were very low BW infants with gestational age 23 to 25 weeks, two of whom died. The fourth was a full-term infant with respiratory distress and a femoral central venous catheter.
Trichosporon species have been identified in genital cultures in women, which makes vertical transmission a possibility [48,49]. The respiratory or gastrointestinal tract may act as portals of entry into the systemic circulation, resulting in disseminated disease.
Trichosporon infections, including the diagnosis, are discussed in greater detail separately. (See "Infections due to Trichosporon species and Blastoschizomyces capitatus (Saprochaete capitata)".)
Cryptococcal infection — Cryptococcal infection in neonates is rare, and only a few cases of meningitis and disseminated fungemia due to Cryptococcus neoformans and Crycptococcus laurentii have been reported [50-52]. Transplacental transmission of cryptococcal infection in conjunction with maternal HIV has been reported [53,54]. In infants, dissemination of the organism results in multisystem involvement of the brain, meninges, eyes, liver, and spleen. It is invariably a fatal infection without therapy. The diagnosis is made by visualization of the organism by India ink staining of affected body fluids or by detection of cryptococcal antigen in body fluids, such as CSF or respiratory secretions. Positive culture results from blood, CSF, sputum, or urine specimens confirm the diagnosis. (See "Cryptococcus neoformans infection outside the central nervous system" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)
Coccidioidomycosis — There are a few reported neonatal cases of coccidioidomycosis, which generally have presented with severe pulmonary disease with systemic dissemination, resulting in multisystem involvement including the brain and meninges [2]. Coccidioides immitis is the only species known to cause coccidioidomycosis and is thought to be transmitted to the infant during delivery with the neonatal aspiration of infectious vaginal secretion. There is, however, one case of an infant who developed neonatal coccidioidomycosis and was delivered by cesarean delivery, suggesting in utero transplacental vertical transmission [55].
The diagnosis can be made by identification of the organism by microscopic examination of respiratory secretions or tissues or by a positive culture of the CSF, urine, or sputum, or serologic testing. (See "Primary pulmonary coccidioidal infection".)
Blastomycosis — Rare fatal case reports of neonatal blastomycosis have been reported that presented with pulmonary disease [56]. Similar to other neonatal fungal infections, the mode of transmission of the infection is thought to be from an infected mother to her offspring [2,56]. Diagnosis is by direct microscopic visualization or a positive culture of the organism from respiratory secretions and tissues. The validity of serologic tests for diagnosis is not known in neonates. (See "Mycology, pathogenesis, and epidemiology of blastomycosis".)
Pichia infections — Pichia anomala (formerly known as Hansenula anomala) is a yeast of the class ascomycetes. It has been the cause of reported isolated cases and nosocomial outbreaks of infections in NICUs [57-61]. Risk factors associated with P. anomala infections include prematurity, low BW, central venous catheter, broad-spectrum antibiotics, and total parenteral nutrition with lipids [57-59]. Outbreaks of infections have been due to nosocomial transmission of the organism from carriers who were health care workers [58,59].
In one of the reported outbreaks, 52 infants (10 percent of the infants in the NICU) were colonized with the organism [57]. Eight preterm infants became infected, of which all but one were heavily colonized before infection. Seven of the infants had disseminated fungemia, and two had central nervous system involvement. One patient only had central nervous system infection without fungemia.
Neonatal infections due to other Pichia species (Pichia fabianii, Pichia ohmeri, Pichia kudriavzevii) have also been reported [62-68].
TREATMENT — Neonates with noncandidal invasive fungal infection have a high risk of mortality. As a result, systemic antifungal agents should be administered to any infant who is suspected of having a serious fungal infection. The mainstay of therapy for neonatal invasive fungal infection is amphotericin B. Other antifungal agents that have been used, primarily in infants with candidal infections, include triazoles (eg, fluconazole), adjunctive nucleoside analogues (eg, flucytosine), and echinocandins.
In case reports, combination antifungal therapy has been successful in the treatment of serious and often fatal unusual fungemia [69,70]. However, the clinician's choice of therapy is dictated by the available information regarding the extent and outcome of infection by the specific fungi as well as the clinical condition of the patient.
In our practice, amphotericin B is used as the initial therapy. Other agents (eg, flucytosine or fluconazole) are added if there is central nervous system involvement, if the response to initial therapy is slow (especially in a critically ill patient), or to reduce the dose of amphotericin B during ongoing treatment in a patient who has responded to initial therapy.
Amphotericin B — Activity of amphotericin B has been demonstrated in vitro against a wide variety of clinical fungal isolates, including Candida species, C. immitis, Aspergillus species, Histoplasma capsulatum, Blastomyces dermatitidis, C. neoformans, and Sporothrix schenckii. Amphotericin B exerts its antifungal effect by disruption of fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol. (See "Pharmacology of amphotericin B".)
There are no randomized controlled trials demonstrating the efficacy of this agent in treating neonates with invasive noncandidal fungal infections. However, several cases have been reported of survival in neonates treated with amphotericin B with infections that are usually considered to be fatal if left untreated [5,16,20,29,50,51,57]. Hence, amphotericin B remains the first choice of treatment in neonates suspected of having an invasive fungal infection.
Amphotericin B is only available in parenteral form. Pharmacokinetic data demonstrate achievement of therapeutic plasma levels with administered dosing regimens between 0.5 to 1 mg/kg/day, although there is patient variability [71,72]. Excellent blood and tissue levels of amphotericin are achieved with the above dosing regimen. However, the penetration into the cerebrospinal fluid (CSF) of neonates is variable, ranging from 40 to 90 percent of plasma levels [71]. As a result, most experts do not recommend amphotericin B as the sole drug to treat central nervous system neonatal fungal infections. In these patients, fluconazole or flucytosine should be added to amphotericin because both agents penetrate the CSF well and are synergistic to amphotericin B.
Similar to the treatment of invasive candidal infection, the duration of therapy is uncertain. Most neonatologists and pediatric infectious disease specialists treat for a minimum of 14 days after sterilization of the infected body fluid. (See "Treatment of Candida infection in neonates".)
Amphotericin B lipid formulations — Lipid-based amphotericin B formulations have the ability to deliver a higher dose of medication with lower levels of toxicity but are significantly more expensive than standard amphotericin B. Although case reports have shown that they are effective in treating coccidioidomycosis [73] and Trichosporon infections [74], they are typically reserved for neonates who develop intolerant infusion-related reactions or renal dysfunction during standard amphotericin B administration. (See "Treatment of Candida infection in neonates", section on 'Amphotericin B lipid formulations'.)
Side effects — Adverse effects of amphotericin appear to be less common in neonates than in older children and adults. Although there is a potential for nephrotoxicity, most infants display no or only mild nephrotoxicity, which resolves with decreasing the dose of the medication [75]. Other reported adverse effects include hypokalemia and hypomagnesemia caused by excessive renal losses, bone marrow suppression with anemia and thrombocytopenia, and an increase in hepatic enzymes. These abnormalities are infrequent and dose dependent and resolve with cessation of the drug.
Because of the potential adverse effects, infants should have serial monitoring of serum potassium, magnesium and creatinine, liver enzymes, and complete blood count while receiving amphotericin B.
Fluconazole — Triazoles are antifungal agents that inhibit the 14-alpha-sterol demethylase of the cytochrome P450 system, which is necessary for the production of ergosterol, a major component of the fungal cell membrane. Fluconazole is the most commonly used triazole in neonatal practice.
Fluconazole is available in both intravenous and oral preparations. Both of these formulations result in wide tissue penetration including the CSF and ocular fluid. Fluconazole has been used alone or in conjunction with amphotericin B in the treatment of neonatal cryptococcosis, coccidioidomycosis, and candidiasis. It has also been used as an alternate therapy in the treatment of histoplasmosis, blastomycosis, and sporotrichosis.
Pharmacokinetic data indicate that a longer dosing interval is required for neonates because fluconazole is renally excreted and the neonate has a low glomerular filtration rate. The dosing interval decreases with increasing postnatal age as glomerular filtration rate rises [76,77].
●Less than two weeks of age – 6 to 12 mg/kg/dose given every 72 hours
●Two to four weeks of age – 6 to 12 mg/kg/dose given every 48 hours
Other triazoles include itraconazole and voriconazole, but their use has been limited in neonates [78].
Flucytosine — In neonates, the most commonly used nucleoside analogue is flucytosine, a fluorine analogue of cytosine. It inhibits thymidylate synthetase, thereby disrupting DNA synthesis. It has a narrow spectrum of activity and has been shown to be effective in the treatment of candidal and cryptococcal infection.
The use of flucytosine as a sole agent is limited because of the rapid development of resistance when used as monotherapy. It is mainly used in combination with amphotericin B in neonates with candidal and cryptococcal meningitis because flucytosine has excellent penetration into the CSF and is synergistic with amphotericin B.
Flucytosine is only available in enteral form, thus limiting its use in critically ill neonates. The oral dose is 50 to 150 mg/kg/day divided into four doses at six-hour intervals. Serum levels of flucytosine should be monitored to avoid reversible bone marrow suppression, which has been associated with serum levels >100 mcg/mL [79].
Echinocandins — The echinocandins prevent the formation of glucan polymers, a major component of the fungal cell wall, by inhibiting the 1,3-beta-D-glucan synthase enzyme complex. These agents appear to be well tolerated with minimal adverse effects because this enzymatic complex is not found in mammals. Resistance to this class of antifungal agents is uncommon.
Echinocandins include caspofungin, anidulafungin, and micafungin, which have all been shown to be effective and safe in adult patients. In neonates, data are limited primarily to treating patients with candidal infection. (See "Treatment of Candida infection in neonates", section on 'Echinocandins'.)
SUMMARY AND RECOMMENDATIONS
●Fungal infections, other than those caused by Candida species, are uncommon in neonates. However, when they occur, these infections result in significant neonatal mortality and morbidity. Noncandidal fungal infections include aspergillosis, cutaneous and intestinal zygomycosis, Malassezia sepsis, trichosporonosis, Pichia sepsis, cryptococcosis, coccidioidomycosis, blastomycosis, and dermatophytosis.
●The incidence of these infections is increasing, particularly in preterm infants. Other associated risk factors for fungemia in addition to prematurity include the administration of broad-spectrum antimicrobial agents, use of immunosuppressive therapy (eg, corticosteroids), invasive procedures (eg, central venous catheters), and, in some cases, new hospital construction or renovations. (See 'Neonatal fungal infections other than candida' above and "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)
●Infants with known or suspected fungemia or central nervous system infection require immediate systemic antifungal therapy. (See 'Neonatal fungal infections other than candida' above and "Treatment of Candida infection in neonates".)
●We suggest amphotericin B as the preferred initial therapy in neonates with fungemia or with suspected fungemia (Grade 2C). Alternate therapy includes fluconazole as monotherapy or in combination with amphotericin B. (See 'Treatment' above.)
●In patients with or suspected to have noncandidal central nervous system infections, we suggest treatment with a combination therapy of amphotericin B and flucytosine (Grade 2C). Alternate therapy includes combination therapy of amphotericin B and fluconazole. (See 'Treatment' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟