Fungal Infections in the Neonatal Intensive Care Unit Margaret K. Hostetter, MD The past 2 decades have witnessed a 4- to 6-fold increase in the incidence of fungal infections in the neonatal intensive care unit. Although symptoms are similar to those of the more commonly encountered bacterial infections ascribable to maternal genital flora, fungal infections derive from different predisposing factors and require a distinctly different approach to diagnosis and treatment. This article reviews the most common presentations of fungal infection in the nursery, the risk factors for susceptible infants, and the treatment strategies that generally are accepted. Copyright © 2001 by W.B. Saunders Company
ecause the factors that predispose the infant in the neonatal intensive care unit (NICU) to fungal infections are virtually identical to the ones that mandated the infant’s hospitalization, few are amenable to modification. The greater the degree of prematurity, the greater the risk of fungal infection. This correlation derives not only from the incremental handicaps of host defense that accrue with increasing prematurity but also from the length of time that immature infants must remain in the nursery. Because most fungal infections in the NICU are caused by Candida species, this section will focus on the epidemiology of candidemia. In infants weighing more than 2,500 g at birth, the incidence of candidemia is 0.6 percent, although the number of patients reviewed is small.1 In a prospective study conducted by the National Epidemiology of Mycosis Study Group, 2,847 infants in 6 geographically diverse nurseries had an overall incidence of 1.2 percent that rose to 5.5 percent for infants weighing less than 1,000 g.2 Even after adjustment for birth weight, gestational age of less than 32 weeks and 5-minute Apgar less than 5 (another indication of possible prematurity) are significant predictors of subsequent development of candidemia.2 Numerous studies have shown an association between the use of intravascular catheters and the subsequent onset of infections caused by bacteria and yeasts. Parenteral nutrition and the use of lipid preparations also are independently associated with development of candidemia.2 Al-
From the Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT. Supported in part by National Institutes of Health Grants AI25827 and AI45145. Address correspondence to Margaret K. Hostetter, MD, Yale Child Health Research Center, Yale University School of Medicine, 464 Congress Ave, New Haven, CT 06519; e-mail: [email protected]
Copyright © 2001 by W.B. Saunders Company 1045-1870/01/1204-0006$35.00/0 doi:10.1053/spid.2001.26637
though not all studies agree, the use of broad-spectrum antibiotics, postnatal steroids, and H2 blockers also are implicated.2,3 Topical petrolatum ointment also has been identified in a case-control study as a risk factor for candidemia.4 The mechanisms by which these risk factors increase susceptibility for fungal infections are incompletely understood. Degree of prematurity is well correlated with level and activity of complement proteins5 and with white blood cells, particularly neutrophils.6 Although no fungal infections have been definitively proven to be susceptible to antibody-mediated host defense, one must recall that transplacental antibody is not transferred in significant amounts until after the 30th to the 32nd week of gestation; therefore, most premature infants will be entirely lacking in maternal antibody and unable to synthesize their own. T lymphocytes, an important component of defense against fungal infections, are not quite so impaired as are neutrophils. In normal newborns, measurable levels of cytokines, such as tumor necrosis factor ␣ and interleukin (IL) 6, appear in cord blood, and cord blood mononuclear cells of full-term infants can respond to superantigens as well as can adult cells.7,8 Hyperalimentation solutions containing 20 percent glucose provide an appealing nutrient source for many fungi. For example, for most Candida species, glucose is a preferred carbohydrate source. Other components of parenteral nutrition, including individual amino acids and relative concentration of divalent cations such as zinc, may contribute to optimal nourishment of colonizing fungi as well as the host. For those fungi considered to be “lipophilic,” such as Malassezia furfur, the high concentration of lipids in fat emulsions provides an essential nutrient. A molecular explanation for this association, such as a lipid receptor on the surface of the fungus, has not been discovered. Broadspectrum antibiotics predispose to fungal disease by eradicating bacteria in the intestine that compete for nutrients. The possibility that gram-negative aerobes in the intestine also may synthesize factors that inhibit the growth of col-
Seminars in Pediatric Infectious Diseases, Vol 12, No 4 (October), 2001: pp 296-300
Fungi in the NICU onizing fungi has been entertained but not proven. Steroids inhibit the phagocytic function of neutrophils and several of the components of T-cell–mediated immunity and may interact with various fungi through corticosteroid-binding proteins on the organisms’ surface.9 The consequences of this putative interaction have not been determined. The occlusive effects of topical petrolatum ointment are thought to be responsible for its association with candidal infection,4 but a more definitive mechanism has not been identified. The most common causes of fungal infection in the NICU are Candida species. Candida albicans still holds a slight edge over Candida parapsilosis in many series, but species other than albicans, such as Candida tropicalis, Candida glabrata, Candida krusei, and Candida lusitaniae, have been encountered with increasing frequency. Aspergillus species typically appear as an invasive fungal dermatitis rather than as a primary pulmonary infection. M furfur and Malassezia pachydermatis cause transient fungemia in the context of lipid infusion.
Clinical Symptoms Nonspecific symptoms and signs such as apnea, bradycardia, feeding intolerance, abdominal distension, and, less frequently, fever suggest an underlying infection in the premature newborn. These findings also are seen with bacterial infections, and as yet no particular hallmark differentiates among these potential causes. Laboratory findings often include hyperglycemia that requires insulin infusion and a mild thrombocytopenia in the context of a positive skin or perianal culture for the infecting organism.
Candidal Disease in the NICU Four manifestations of candidal infection are reviewed in this section: (1) congenital candidiasis in the full term and the premature infant; (2) local disease such as cystitis, peritonitis, or wound infections; (3) line infections with or without atrial thrombi; and (4) disseminated candidiasis.
Congenital Candidiasis By definition, congenital candidiasis is seen within the first 24 hours of life, the infant having acquired the organism from the maternal genitourinary tract. The full-term infant may have no history of ruptured membranes, but in the premature infant, rupture of membranes for 12 hours or more and ascension of the organism from the vagina to cause an amnionitis are thought to be common predisposing factors. Two clinical pictures emerge. In the first, more common in full-term infants, a diffuse erythematous rash covers the entire body, often appearing somewhat more intense and confluent on the trunk as opposed to the extremities. Satellite lesions and pustules may be present; Gram’s stain of the latter may yield the characteristic germ tubes of C albicans or the yeast forms of species other than albicans. Within 3 to 5 days, a massive desquamation occurs; the
uppermost layers of the epidermis are sloughed, leaving the underlying skin fiery red. The accompanying leukocytosis frequently surpasses 40,000 to 50,000 white blood cells per microliter. In the full-term infant, the prognosis is excellent provided that the disorder is recognized quickly and that more invasive therapy, such as administration of broad-spectrum antibiotics, is withheld. Use of topical antifungal creams is the therapy of choice. Administration of systemic antifungal agents orally or parenterally is not required for resolution when the skin is the only site of involvement. A second syndrome, featuring a diffuse rash in the context of respiratory distress, is far more common in premature infants and portends a graver prognosis. Because congenital candidiasis in the premature infant typically is the residuum of an amnionitis, the infant often has aspirated the organism from amniotic fluid, and pneumonia will ensue. Parenteral antifungal therapy is the treatment of choice, but the disease typically takes a fatal course.10 Amphotericin B should be administered in a sufficiently rapid fashion so that a dose of 0.5 mg/kg is attained within 24 hours. Most infants are advanced to a total daily dose of 1.0 mg/kg/d and treated for at least 14 days, although pulmonary manifestations typically require a longer course. No prospective clinical studies have validated therapy with azoles, such as fluconazole, as an efficacious alternative. Unfortunately, despite rapid recognition and institution of therapy, the mortality rate in the premature infant with congenital candidiasis approaches 25 percent.
Local Infections With Candida Species Several types of local infections are encountered frequently in the NICU. In infants with indwelling urinary catheters, Candida cystitis is diagnosed by a positive bladder tap, but great care must be taken to ascertain that the infection is confined to the lower urinary tract. Simply culturing Candida species from the urine does not preclude upper urinary tract disease. When Candida are isolated from a bladder tap or an elective catheterization, a blood culture should be obtained, and many experts also will perform an ultrasound of the renal system to discern the presence of intrarenal lesions or collections of mycelia (“fungus balls”) in the calyces. In the presence of any evidence of upper urinary tract disease or disseminated infection, systemic treatment with amphotericin B is preferred. However, if the infection is confined to the lower urinary tract, a single daily dose of oral fluconazole, 3 to 6 mg/kg/d, is an alternative to lowdose amphotericin B at a dosage of 0.3 to 0.5 mg/kg/d. Candida peritonitis supervenes in those infants requiring peritoneal dialysis or in infants in whom necrotizing entrocolitis or congenital anomalies have been associated with perforation of the intestine. Gram’s stain of peritoneal fluid will show yeasts together with infiltrating neutrophils. Treatment requires removal of the dialysis catheter and institution of parenteral amphotericin B at a dose of 0.3 to 0.5 mg/kg/d. Such reduced doses have been shown to be effective for candidal peritonitis in older children and adults, provided that bloodstream invasion has not occurred as a consequence of the underlying event.
Margaret K. Hostetter
Cultures of surgical wounds that grow Candida species must be interpreted with caution because most infants will acquire the organism as part of their cutaneous flora within a very few days of hospitalization. A Gram’s stain showing the presence of yeast forms within polymorphonuclear leukocytes is considered strong supporting evidence for the diagnosis of wound infection, as is the presence of Candida species in surgical fields that may have been contaminated by perforation of the intestine, as in necrotizing enterocolitis. Once again, isolation of Candida species from peripheral sites should prompt performing a blood culture to ensure that no dissemination has occurred, particularly in the extremely premature infant, in whom a fungal dermatitis can lead to invasive fungemia (see below). For treatment in the absence of findings suggestive of systemic or disseminated disease, fluconazole is an acceptable alternative to amphotericin B. The length of treatment is not rigidly prescribed but must be based on clinical course and susceptibility of the causative organism. Recent data from 35 isolates analyzed in the study from the National Epidemiology of Mycosis Study Group shows that all C albicans (n ⫽ 22) were susceptible to amphotericin, but some albicans and non-albicans isolates exhibited resistance to fluconazole.2
Line Infections The widespread use of intravascular catheters has been associated with a marked increase in the incidence of fungal infection. For example, in 1 NICU study spanning 15 years, the incidence of candidemia increased from 2.5 cases/ 1,000 admissions (1981 to 1985) to 28.5 cases/1,000 admissions (1991 to 1995).11 The pathogenesis of this process is thought to relate both to the ease with which infants become colonized with Candida species during hospitalization in a NICU and to the adhesive capacity of the genus, particularly C albicans.9 Scanning electron micrographs of intravascular catheters have shown that the tip of the catheter readily becomes endothelialized, perhaps exposing components of the extracellular matrix to adhesins on C albicans.9 The genes that contribute to infections with C parapsilosis have not been identified. Concentrations of glucose (at least 20% for most hyperalimentation solutions) may be significant in the right atrium, approaching concentrations that are used in most fungal growth media. Other constituents of hyperalimentation solutions, such as single amino acids, also may facilitate colonization and replication of Candida species.12 Clinical manifestations of candidal fungemia are not much different from those associated with bacterial sepsis. Infants may experience increased periods of apnea or bradycardia, feeding intolerance, or rarely fever. Among laboratory studies, a mild thrombocytopenia or persistent hyperglycemia requiring insulin supplementation may occur, but no pathognomonic finding has been identified. In an infant with an intravascular catheter, Candida species growing in a blood culture never should be considered a contaminant.
However, because of the proclivity of Candida species to invade to deeper tissues, the isolation of this organism from the blood should prompt an evaluation for disseminated candidiasis. In this regard, most experts will evaluate the central nervous system with a lumbar puncture, the eyes with retinoscopy, and the liver, spleen, and kidneys with ultrasound. Approximately 50 percent of infants with fungemia have a concomitant meningitis.13 If a work-up for evidence of disseminated disease is negative, amphotericin B is the treatment of choice. Dosage should attain 0.5 mg/kg on the first day and increase to a daily dose of 1.0 mg/kg/d within 24 hours for the remainder of therapy. Removal of the intravascular catheter is the mainstay of therapy. Data from premature newborns and from older children have emphasized that failure to remove the intravascular catheter is associated with prolonged morbidity and increased mortality.14,15 For example, no deaths occurred among 50 infants whose intravascular catheters were removed within 3 days after the first positive blood culture for Candida species was obtained, but the mortality rate was 39 percent among 54 control infants whose catheters remained in place for more than 3 days.14 Replacement of the catheter over a guidewire is insufficient. In some nurseries, fluconazole is administered as an alternative, but to date no randomized, well-controlled studies have compared the efficacy of both drugs in fungemia or disseminated candidiasis in NICU infants. One consideration that militates against the use of fluconazole as a first-line agent in fungemia ascribable to intravascular catheters is the fungistatic nature of this drug. Fungistatic agents certainly are acceptable if host defenses can be counted on to potentiate the effects of the drug, but in the premature newborn, all anti-Candida defenses (complement, neutrophils, and T lymphocytes) are impaired to a greater or lesser extent. Attention to remediable causes of amphotericin B treatment failure (Table 1) often leads to the resolution of fungemia without changing antifungal agents.
Disseminated Candidiasis Invasion of blood-borne Candida species into tissues such as the liver, spleen, or renal cortex is a dreaded consequence of fungemia. The growth of Candida species from normally sterile body fluids such as cerebrospinal fluid or urine; the
Table 1. Common Reasons for Amphotericin B Treatment Failure Failure to remove the line Failure to recognize an intravascular focus Fungus ball in atrium Infected cardiac graft or patch Lesion requires surgical approach Dose too low (⬍0.5 mg/kg/d) Too short a course (eg, ⬍7 days for line infection because of rising creatinine) Resistant organism
Fungi in the NICU radiographic detection of mycelia or abscesses in the right atrium, the liver, the spleen, the kidneys, or the bone by radiographic techniques; or the finding of Candida endophthalmitis herald a disease in which mortality rate for the NICU patient exceeds 30 percent. The presence of thrombi in the right atrium can be treated with systemic amphotericin B at daily doses of 1.0 mg/kg, but even partial resolution typically requires 6 to 10 weeks of therapy. This complication may be handled best by atriectomy.16 Disseminated candidiasis must be treated aggressively and for long duration. In the author’s experience, C albicans was isolated from an infant’s spinal fluid in conjunction with a persistent pleocytosis more than 7 months after an episode of neonatal Candidemia that received only 10 days of therapy. Thus, an exhaustive effort to identify all potential sites of seeding should be undertaken. The treatment of choice for disseminated candidiasis is amphotericin B at a maintenance dose of 1.0 mg/kg/d. Monitoring for toxicity should include blood urea nitrogen, creatinine, potassium, and magnesium 2 to 3 times per week, a complete blood count with differential count and platelets approximately once a week, and hepatic transaminases approximately once a week. At least 80 percent of patients treated with amphotericin B experience a rise in creatinine. A doubling or trebling of serum creatinine may prompt a change to liposomal amphotericin B, but 2 caveats exist. First, the dose of liposomal amphotericin B should be increased to 4 to 6 mg/kg/d. Second, the larger particles associated with at least 1 liposomal preparation have failed to eradicate renal candidiasis in 3 patients.17 Those infants with persistently positive cultures more than 24 hours after beginning appropriate antifungal therapy stand at increased risk for the development of uropathy, renal infiltration, or death from invasive disease. Other focal complications such as endocardiditis, abscess, ventriculitis, and invasive dermatitis also were more frequent occurrences in the persistently fungemic group.18 The likelihood of focal complications increase as duration of fungemia increases. The responsible Candida species also predicts outcome. In at least 2 retrospective series comparing fungemia caused by C albicans versus C parapsilosis, mortality was significantly higher with the former.10,13 In addition to the prompt institution of amphotericin B at a treatment dose of 1 mg/kg/d, 5-fluorocytosine (5-FC) should be administered in the presence of meningitis. This combination is synergistic for most C albicans isolates, although other species may not be susceptible. The addition of 5-FC compensates at least partially for the relatively poor penetration of amphotericin B into the cerebrospinal fluid. Although clinical decision making may be optimized when levels of 5-FC can be determined in-house, a dose of 25 mg/kg/d (divided every 6 hours) typically is safe unless renal function is compromised. Monitoring for bone marrow toxicity is essential. Treatment of disseminated candidasis typically requires at least four weeks of daily therapy, but a longer course may be necessary if distant foci fail to resolve.
Invasive Candidiasis in Infants Weighing More Than 2,500 g at Birth A single retrospective study has begun to delineate the role of candidal infections in infants weighing more than 2,500 g at birth.1 In a retrospective survey of an 8-year period in a single NICU, 17 of 59 infants with invasive candidiasis weighed more than 2,500 g at birth. Seventy six percent of the infected infants had serious congenital anomalies, whereas the remainder had congenital viral infection or meconium aspiration. All of these conditions prolonged time in the nursery such that the mean age at onset of invasive candidal infection was approximately 47 ⫾ 8.5 days. In contrast to the prevalence of candidemia in infants weighing less than 1,500 g, candidemia was detected in only 0.6 percent of infants weighing more than 2,500 g, an overall reduction of almost 10-fold. The site most frequently infected was the urine (71% of infants). Ten of 17 infants died (60% with C albicans), and mortality was directly attributable to invasive candidiasis in 3 infants. In 2 additional infants, disseminated candidiasis was found at autopsy, but it was not listed as the cause of death.1 These data underscore the ability of Candida species to infect infants of normal or increased gestation, albeit at a considerably lower rate.
Invasive Fungal Dermatitis A novel syndrome described only recently, the entity of invasive fungal dermatitis affects the premature infant, particularly those weighing less than 1,000 g. In 1 series of 16 cases, postnatal steroids and hyperglycemia also were implicated.19 Sixty-nine percent of the infants had disseminated disease from a cutaneous focus, and C albicans was the positive organism in 69 percent of the cases. Other Candida species, Aspergillus fumigatus or Aspergillus niger, Trichosporon beigelii, and Curvularia species were isolated in the remaining 5 cases, and 7 infants (44%) died. Infants present with an erosive, bluish discoloration at sites of pressure, most often on the buttock or back. Biopsy of the tissue often is required to yield the causative organism, which can disseminate to the bloodstream and to deep tissues in approximately two thirds of cases. Treatment of invasive fungal dermatitis requires prompt institution of systemic antifungal therapy with amphotericin B unless susceptibility data dictate a change to another agent.
Intralipid Fungemia The presentation of intralipid fungemia20,21 often is clinically silent or accompanied only by mild, nonspecific symptoms, but when cultures for bacteria or Candida species are negative, the alert clinician should suspect M furfur or M pachydermatis. This organism, previously characterized as Pityrosporum, is widely prevalent on the skin of adults and in large quantity causes the entity known as tinea versicolor.
Margaret K. Hostetter
Approximately 80 percent of NICU infants are colonized with M furfur after 1 week of age by horizontal transmission. The diagnosis typically is missed because the organism requires culture in lipid-supplemented media in order to grow. The addition of an olive oil overlay to fungal cultures often is sufficient. Treatment of the entity requires removal of the catheter and discontinuation of the lipid infusion, but systemic antifungal therapy is not required in the vast majority of cases. Outcome uniformly is good.
References 1. Saiman L, Luddington E, Pfaller M, et al: Risk factors for candidemia in neonatal intensive care unit patients. Pediatr Infect Dis J 19: 319-324, 2000 2. Rabalais GP, Samiec TD, Bryant KK, et al: Invasive candidiasis in infants weighing more than 2500 grams at birth admitted to a neonatal intensive cae unit. Pediatr Infect Dis J 15: 348-352, 1996 3. Botas CM, Kurlat I, Young Sm, et al: Disseminated candidal infections and intravenous hydrocortisone in preterm infants. Pediatrics 95: 883-887, 1995 4. Campbell JR, Zaccaria E, Baker CJ: Systemic candidiasis in extremely low birth weight infants receiving topical petrolatum ointment for skin care: A case-control study. Pediatrics 105: 1041-1045, 2000 5. Zach TL, Hostetter MK: Biochemical abnormalities of the third component of complement in neonates. Pediatr Res 26: 116-120, 1989 6. Wolach B: Neonatal sepsis: Pathogenesis and supportive therapy. Semin Perinatol 21:28-38, 1997 7. Mehr S, Doyle LW: Cytokines as markers of bacterial sepsis in newborn infants: A review. Pediatr Infect Dis J 19:879-887, 2000 8. Garderet L, Dulphy N, Douay C, et al: The umbilical cord blood alphabeta T-cell repertoire: Characteristics of a polyclonal and naive but completely former repertoire. Blood 91: 340-346, 1998
9. Hostetter MK. Integrin-like proteins in Candida spp. and other microorganisms. Fungal Genetics and Biology 28:135-145, 1999 10. Johnson DE, Thompson TR, Ferrieri P: Congenital candidiasis. Am J Dis Child 135:273-275, 1981 11. Kossoff EH, Buescher S, Karlowicz MG: Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases. Pediatr Infect Dis j 7: 504-508, 1998 12. Odds FC: Morphogenesis in Candidaalbicans. CRC Critical Reviews in Microbiology 12:45-93, 1988 13. Faix RG: Invasive neonatal candidiasis: comparison of albicans and parapsilosis infection. Pediatr Infect Dis J 11:88-93, 1992 14. Karlowicz MG, Hashimoto LN, Kelly RE, et al: Should central venous catheters be removed as soon as candidemia is detected in neonates? Pediatrics 106: E63, 2000. 15. Eppes SC, Troutman JL, Gutman LT. Outcome of treatment of candidemia in children whose central catheters were removed or retained. Pediatr Infect Dis J 8:99-104, 1989 16. Foker JE, Bass JL, Thompson T, et al: Management of intracardiac fungal masses in premature infants. J Thorac Cardiovasc Surg. 87:244-250, 1984 17. Augustin J, Lacson S, Raffalli J, et al: Failure of a lipid amphotericin B preparation to eradicate candiduria: Preliminary findings based on three cases. Clin Infect Dis 29:686-687, 1999 18. Chapman RL, Faix RG: Persistently positive cultures and outcome in invasive neonatal candidiasis. Pediatr Infect Dis J 19:822-827, 2000 19. Rowen JL, Atkins JT, Levy ML, et al: Invasive fungal dermatitis in the U1000-Gram neonate. Pediatrics 95:682-687, 1995 20. Aschner JL, Punsalang A Jr, Maniscalco WM, et al: Percutaneous central venous catheter colonization with Malassezia furfur: Incidence and clinical significance. Pediatrics 80:535-539, 1987 21. Marcon MJ, Powell DA: Epidemiology, diagnosis, and management of Malassezia furfur systemic infection. Diagn Microbiol Infect Dis 7:161-175, 1987 22. Larocco M, Dorenbauj A, Robinson A, et al: Recovery of Malassezia pachydermatis from eight infants in a neonatal intensive care nursery: Clinical and laboratory features. Pediatr Infect Dis J 7:398-401, 1988