CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS	Section 5 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Clinical presentation

Although, the VLBW infant with candidiasis can present with many of the nonspecific signs and symptoms associated with invasive bacterial infection, symptoms are often more subtle and indolent. Cultures should be obtained whenever sepsis is suspected. Cultures should be repeated after the initial evaluation if the infant does not clinically improve within 48 hours or if the infant's condition worsens. New-onset thrombocytopenia (<100 X 10⁹/L [<100 X 10³/無, or <100,000/mL]) is present in most cases of fungal sepsis and decrease an additional 50% to a mean platelet count of less than 50 X 10⁹/L (<100 X 10³/無, or <100,000/mL) (Guida, 2003). Persistent thrombocytopenia may indicate therapeutic failure.

Signs and symptoms in VLBW infants with candidemia are summarized according to incidence, as follows (Fanaroff, 1998):

• Thrombocytopenia with WBC count of less than 100 X 10⁹/L (<100 X 10³/無, or <100,000/mL) - 84%

• Immature-to-total neutrophil ratio of 0.2 or higher - 77%

• Increase in apnea and/or bradycardia - 63%

• Increase in oxygen requirement - 56%

• Increase in assisted ventilation - 52%

• Lethargy and/or hypotonia - 39%

• GI symptoms (eg, gastric aspirates, distention, bloody stools) - 30%

• Hypotension - 15%

• Glucose concentration of more than 140 mg/dL - 13%

• WBC count of more than 20 X 10⁹/L (>20 X 10³/無, or >20,000/mL) - 12%

• Metabolic acidosis - 11%

• Absolute neutrophil count <1.5 X 10⁹/L (<1500/無) - 3%

Differential diagnosis

• Gram-positive or gram-negative sepsis

• NEC

• FBP

• Abscess

• Intracranial hemorrhage

• Central vascular catheter thrombosis

	MORBIDITY, MORTALITY, AND FOLLOW-UP	Section 6 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Morbidity

Neurodevelopmental impairment (NDI) is more common in infants with fungal sepsis who weigh less than 1000 g than in ELBW infants without infection (Benjamin, 2006; Stoll, 2004; Friedman, 2000). NDI does not appear to be more common in infants who weigh 1000-1500 g.

In the largest study of NDI to date in ELBW infants with infection, Stoll et al examined mental and psychomotor developmental indexes, cerebral palsy (CP), and hearing or visual impairment (Stoll, 2004). Forty-one percent of infected infants (any clinical sepsis, bloodstream infection, or meningitis) and 57% of infants with fungal sepsis had at least one adverse neurodevelopmental outcome. The prevalence of adverse neurodevelopmental outcomes in infants with fungal sepsis were as follows:

• Mental developmental index of less than 70 - 34%

• Psychomotor developmental index of less than 70 - 24%

• CP - 18%

• Visual impairment - 14%

• Hearing impairment - 5%

The rate of NDI in infants with fungal sepsis did not differ significantly from those with bloodstream infection with other microorganisms (coagulase-negative staphylococcus [CONS], non-CONS, and gram-positive and gram-negative organisms).

The effect of invasive fungal infection on other morbidities is still being studied. In ELBW infants, several studies have described an association with retinopathy of prematurity. One study demonstrated an increased incidence of bronchopulmonary dysplasia (Friedman, 2000).

Because of the infants' maturing immune systems, outcomes may better correlate with corrected gestational age at the time of infection. Infants who develop infection later in their hospital stay (ie, after 6 wk) may have better outcomes, but this requires further study.

Mortality

In VLBW infants, candidemia is associated with a mortality rate of 21-32% (Makhoul, 2002; Stoll, 2002; Lopez, 2003; Benjamin, 2004). Less than 26 weeks' gestation and a birth weight of less than 1000 g correlate with increased mortality rates (40-50%). The mortality rate is significantly higher when sepsis is due to C albicans (nearly 44%) than when it is due to C parapsilosis (15%) or other Candida species (Stoll, 2002).

Follow-up

All preterm infants with infection should receive neurodevelopmental follow-up in the first few years of life and early intervention services, if needed.

	WORKUP AND EVALUATION AND FUTURE DIAGNOSTICS	Section 7 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Workup and evaluation

Workup and evaluation for fungal infections in preterm infants includes the following tests: blood, urine, and CSF cultures. Clearance of blood stream infection should be documented with 3 or more negative blood culture results. Each negative culture result should be obtained at least 24 hours apart.

• Laboratory studies at presentation
  • Obtain a CBC count with manual differential and platelet count.

  • To assess liver function, measure total and direct bilirubin levels. Also measure the levels of the liver enzymes aspartate amino transferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), and alkaline phosphatase.

  • Measure BUN and creatinine levels to assess renal function.

• Laboratory studies during the infection
  • Thrombocytopenia is extremely common and can persist until clearance of Candida infection and should be closely monitored during treatment until resolution.

  • Liver and renal function should be evaluated at the time of diagnosis (or if candidemia is persistent) because they may suggest liver or renal dissemination and the need for ultrasonography.

  • Antifungal treatment can affect serum electrolytes and the hematologic, hepatic, and renal systems and should be monitored during treatment.

• Screening tests for dissemination
  • Screening for end-organ dissemination should be performed at the time of diagnosis in all sepsis cases and repeated if fungemia persists for longer than 5 days. Dissemination affects length of treatment.

  • The optimal timing of surveillance is not well defined, but persistent fungemia (>5 d) is associated with increased dissemination (Chapman, 2000; Noyola, 2001). Consequently, appropriate cultures and surveillance for end-organ dissemination should occur at onset and after 5-7 days if persistent fungemia is present.

  • The screening for dissemination includes the following:
    • Echocardiography

    • Renal ultrasonography

    • Head ultrasonography

    • Indirect ophthalmoscopy

    • Peritoneal cultures if laparotomy is performed to manage NEC or FBP

• Laboratory testing in patients with persistent candidemia
  • In patients with persistent candidemia that lasts more than 2 days, central catheters should be removed if they still remain (central catheters should be removed when bloodstream infection is diagnosed).

  • In patients with persistent candidemia of longer than 5 days, repeat screening tests for vegetation or abscess, including the following:
    • Echocardiography and renal and head ultrasonography

    • Liver and spleen ultrasonography

    • Lumbar puncture

    • Bone scan or joint aspiration (if clinical symptoms warrant)

    • Ultrasonography or laparotomy of the abdomen (in patients with a history of abdominal surgery, NEC, or FBP, to evaluate for abscesses)

    • Ultrasonography, venography, or magnetic resonance venography (MRV) of the previous location of the catheter tip (if the patient had any vascular catheters prior to or at the time of diagnosis, to evaluate for a thrombus)

Future diagnostic tests

Investigators are studying molecular techniques to identify fungi and other microorganisms and to reveal the diagnosis more rapidly and with higher sensitivity than with blood cultures. Examples include polymerase chain reaction (PCR) and DNA microarray technology. These techniques will hopefully allow for the rapid detection of small numbers of organisms in minute volumes of blood, even after antimicrobial treatment is started.

Fungal PCR to detect the gene for 18S ribosomal RNA (rRNA) in VLBW infants has yielded promising results but requires additional study (Scheffler, 2003). PCR results are positive not only in patients with candidemia but also in those with Candida peritonitis and those with candiduria (Tirodker, 2003).

In addition, investigators are examining the role of monitoring markers of fungal disease to diagnose and evaluate responses to antifungal therapy. These markers include beta-glucan of the cell wall, anti-Candida antibodies, D-arabinitol (candidal metabolite), and fungal chitin synthase (assessed with PCR).

Microarray technology and gene chips are being studied to rapidly determine susceptibility and resistance patterns at the time of diagnosis. These will facilitate the initiation of therapy with an appropriate antifungal agent when resistance occurs and, hopefully, improve outcomes.

	TREATMENT, EMPIRIC TREATMENT, AND PROPHYLAXIS	Section 8 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Treatment

Prompt initiation of systemic antifungal therapy (see Image 6) and central vascular catheter removal (in cases of sepsis) at the time of diagnosis are needed to optimize successful eradication, prevent dissemination, and improve outcomes.

Antifungal therapy

Amphotericin B deoxycholate (Fungizone) remains the primary antimicrobial medication for invasive fungal infection. This drug binds to the sterol component (ergosterol) of the cell membrane, creating a pore that leads to cell death. Although test doses have preceded administration in the past, enough safety data now support initiating administration with a starting dose of 1 mg/kg/d without need for lower test doses (Kingo, 1997). Poor outcomes may be related to the delay in reaching appropriate antifungal dosing. It should be intravenously administered once daily over 2-6 hours.

Several studies have examined lipid formulations of amphotericin B (Juster-Reicher, 2000; Linder, 2003). Lipid formulations distribute to the mononuclear phagocytic system, and doses of 5 mg/kg are required for efficacy similar to that of amphotericin B deoxycholate. One study examined doses of 5-7 mg/kg of lipid amphotericin B formulations in 36 VLBW infants and reported no adverse effects (Juster-Reicher, 2003). Lipid formulations include liposomal amphotericin, amphotericin B colloidal dispersion (ABCD), and amphotericin B lipid complex (ABLC).

One special circumstance is worth discussing. In patients with urinary tract infections or renal abscesses, amphotericin B deoxycholate has higher renal penetration compared with the lipid preparations and may be more effective.

Amphotericin resistance is extremely rare. Most C lusitaniae strains are susceptible, and infections due to these organisms clear with amphotericin. However, C lusitaniae resistance has been reported. Susceptibility testing can help guide therapeutic choices.

Fluconazole, an azole that inhibits the enzyme C-14 lanosterol demethylase in the formation of ergosterol, has demonstrated similar efficacy to amphotericin B deoxycholate. Fluconazole has excellent tissue penetration. The dose is 6 mg/kg/d. Fluconazole is available as a parenteral for intravenous infusion or as a powder for oral suspension. The oral products are 100% bioavailable; therefore, the same dose may be used for oral or intravenous administration. The frequency of dosing varies with the patient's gestational and postnatal age. Resistance can occur, and susceptibility testing should be performed if resistance is a concern. Most C krusei isolates are intrinsically resistant to fluconazole. As with all azoles, the drug has many potential interactions and should not be concomitantly administered with cisapride, cotrimoxazole, cyclosporine, phenytoin, rifampin, or macrolides.

Voriconazole is an azole derived from fluconazole with a broader spectrum of antifungal activity. To date, it has not been studied in neonates. Unlike fluconazole, voriconazole is 58% protein bound and contains a cyclodextrin carrier that is cleared by the kidney and can accumulate in infants with renal insufficiency. A rare complication is torsades de pointes, and 13% of pediatric patients have reported visual disturbances (ie, photophobia, blurred vision, color changes). Until further study is completed, administration should be considered only in patients with aspergillosis. Similar to all azoles, voriconazole should not be concomitantly administered with cisapride or macrolides. Drug levels should be monitored because pharmacokinetic studies in this population are currently lacking and exact dosing may vary by gestational and postconceptional age and birth weight (4-6 mg/kg/dose every 12 h) (Muldrew, 2005; Frankenbusch, 2006).

A new class of antifungals is the echinocandins, which inhibit 1,3-beta-glucan synthesis of the cell wall. Caspofungin acetate (Cancidas) and micafungin sodium (Mycamine) were recently approved in the United States. Caspofungin is approved to treat aspergillosis and infection with Candida species. Micafungin is approved for prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and for treatment of esophageal candidiasis. Another drug in this class undergoing study is anidulafungin (Eraxis). Because these agents inhibit an enzyme, resistance and safety need to be studied along with efficacy.

Studies are underway to determine the effectiveness of echinocandins in pediatric and neonatal patients. In 2 small studies, the drug has shown promise and some efficacy, but its optimal dosage and safety needs further study. Caspofungin therapy was studied in 10 neonates with candidemia that persisted 13-49 days despite treatment with amphotericin (Odio, 2004). Nine infants survived, including 1 who had a relapse after 15 days of treatment that cleared after caspofungin was administered for another 15 days. Central venous catheters were removed as soon as blood-culture results were known. The dosage was 1 mg/kg/d for 2 days then 2 mg/kg/d. The limitations of the study included small size, lack of pharmacokinetic data, and lack of attempted combination therapy. Another study of 13 patients had a much lower success rate, with 1 mg/kg/d of caspofungin combined with other antifungals (Natarajan, 2005). This study was complicated by delayed catheter removal.

A randomized study to compare micafungin with amphotericin B deoxycholate is currently underway. In the future, agents such as nikkomycins, which inhibit chitin synthase of the cell wall, may be added to the antifungal armamentarium.

Central catheter removal

Central catheter removal is critical in the treatment of neonatal candidemia. The catheter should be removed upon the first positive blood culture result. Prompt removal, within 24 hours of documented positive blood culture results, is associated with lowered mortality rates, reduced end-organ dissemination, improved neurodevelopmental outcomes, and increased scores on the Bayley scale (Chapman, 2000; Noyola, 2001; Benjamin, 2006).

Combination therapy

Amphotericin B with the addition of flucytosine (Ancobon) has been used to treat meningitis in infants who can tolerate the oral formulation of flucytosine. However, efficacy of this regimen has not been shown to be superior to that of amphotericin B alone. Flucytosine is a fluorine analog of cytosine that is converted to 5-fluorouracil, leading to inhibition of thymidylate synthetase and disruption of DNA synthesis. Flucytosine monotherapy rapidly leads to resistance, so flucytosine cannot be used alone. For meningitis in patients with CNS abscess or persistent CSF cultures, the addition of fluconazole (because of its excellent CSF penetration) is a therapeutic option.

One study examined the use of a second antifungal agent (fluconazole) in combination with amphotericin B in patients with fungal sepsis. The second agent was administered immediately upon discovery of an abscess or a positive urine culture result and also administered in patients with a persistent culture-positive infection for longer than 10 days (Linder, 2003). Infants received 1 mg/kg of amphotericin B deoxycholate (n=34) if their creatinine level was less than 1.2. If the creatinine level was more than 1.2, they received 5 mg/kg of liposomal amphotericin B (n=6) or ABCD (n=14). Patients were treated for 14 days after negative culture result or until radiographic resolution of abscess. Sterilization occurred in 36 patients (67%) with monotherapy and increased to 52 patients (96%) with polytherapy.

Another issue is the treatment of presumed invasive fungal infection in the absence of positive fungus culture results. Although postmortem diagnosis of invasive candidiasis was common in the past, 2 recent studies demonstrated that only 2.7% of cases were diagnosed at autopsy (Noyola, 2001; Lopez, 2003).

Empiric Treatment

In the VLBW infant, an evaluation for signs and symptoms of late-onset sepsis is typically accompanied by antibacterial treatment for at least 48 hours. Some studies have reported on the use of empiric antifungals pending culture results. Fungal cultures generally take 2-3 days to demonstrate positive results; therefore, empiric therapy may need to be longer than its antibacterial counterpart (Schelonka, 2003). Some authors propose that starting empiric antifungal therapy while culture results are pending may decrease the high mortality rate associated with candidemia in VLBW infants, especially those born at less than 28 weeks' gestation (Makhoul, 2002; Benjamin and DeLong, 2003). In other studies, empiric therapy may have improved outcomes in VLBW infants, but this result has not been studied in a prospective controlled trial (Makhoul, 2001; Schelonka, 2003).

A scoring system has been proposed that includes thrombocytopenia, a gestational age of less than 28 weeks, and broad-spectrum antibiotic treatment; however, this system has not been prospectively studied for safety or efficacy (Benjamin and DeLong, 2003). Infants with NEC or FBP are also at increased risk. Further study is needed to investigate the efficacy and safety of empiric antifungal therapy.

Most fungi are isolated from cultures within 48 hours (Schelonka, 2003). Therefore, some experts do not recommend empiric antifungal therapy. They recommend prompt initiation of antifungal treatment and removal of any central venous catheters upon positive culture results. In a study by Noyola et al (2001), the start of antifungal therapy and the removal of central vascular catheters within 2 days after blood cultures were obtained was not associated with increased morbidity or mortality in episodes of fungal sepsis.

In certain circumstances, empiric antifungal therapy for 48-72 hours may be warranted in infants with negative initial culture results who still have signs and symptoms of sepsis after 48 hours of antibacterial treatment and who are recultured. In addition, the infants must have one of the following criteria:

• Thrombocytopenia (<100 X 10⁹/L [<100 X 10³/無, or <100,000/mL])

• NEC or FBP

• Weight of less than 750 g or a gestational age of less than 26 weeks

Prophylaxis

Because of the high mortality rate and NDI associated with fungal sepsis in VLBW infants, prevention with nystatin, miconazole, and fluconazole has been studied in the highest-risk patients. In randomized placebo-controlled trials, oral prophylaxis with both nystatin and miconazole decreased fungal colonization and nystatin decreased candiduria, but neither decreased candidemia.

One recent retrospective study of nystatin prophylaxis (administered orally or via nasogastric tube 3 times daily) reported a lower frequency of candidemia in infants who weighed less than 1500 g during the treatment period; however, few infants in the study group weighed less than 750 g (Ozturk, 2006). In that study, prophylaxis initiated after birth was more effective in preventing infection than treatment begun after colonization was detected. A randomized controlled trial of nystatin prophylaxis is needed in high-risk infants because other studies have reported conflicting results (Kaufman, Clin Microbiol Rev, 2004). To date, studies of human milk, intravenous immunoglobulins, and granulocyte-macrophage colony-stimulating factor have not demonstrated a decrease in fungal sepsis.

In a randomized controlled trial, prophylaxis with intravenous fluconazole in high-risk infants who weighed less than 1000 g and had an endotracheal tube or central vascular catheter was effective in preventing invasive fungal infection (Kaufman, 2001). Investigators studied prophylaxis using 3 mg/kg of intravenous fluconazole every 72 hours on days 1-14, every 48 hours on days 15-28, and then daily administration on days 29-42 for as long as 6 weeks if intravenous access is not required. No adverse effect or fungal resistance was detected during the 30-month study period. The same authors examined dosing with 3 mg/kg twice a week compared with the regimen described above and found similar efficacy (Kaufman, 2005).

Fluconazole is an excellent drug for prophylaxis because of its long half-life, high tissue concentration, low lipophilicity, and low protein binding. One concern with fluconazole prophylaxis is the potential for the emergence of resistance over time, and this issue is under further study.

Several observational studies have been completed to examine fluconazole prophylaxis in both ELBW and VLBW infants (Bertini, 2005; Healy, 2005; Manzoni, 2006; Aghai, 2006). A meta-analysis of randomized and observational studies with control subjects using Mantel-Haenszel methods demonstrated an 84% reduction in invasive fungal infections among 2111 preterm infants (OR, 0.16; 95% CI, 0.08-0.31; P <.001) (Kaufman, 2001; Kicklighter, 2001; Bertini, 2005; Healy, 2005; Manzoni, 2006; Aghai, 2006). For high-risk ELBW infants, the studies demonstrated an 88% reduction in invasive fungal infections (OR, 0.12; 95% CI, 0.05-0.29; P <.001).

Dosing with 3 mg/kg twice weekly is effective and limits exposure, cost, and potential adverse effects. When initiated around birth, prophylaxis should be administered for 6 weeks or less in patients with a birth weight of less than 1000 g or less than 6 weeks if intravenous access is no longer needed. For patients with a birth weight of more than 1000 g, continue prophylaxis until intravenous access is no longer needed and until adequate enteral feedings are achieved.

If antifungal prophylaxis with fluconazole is administered, using a different antifungal agent (eg, amphotericin B) for primary treatment of an invasive fungal infection is important. This ensures treatment with a susceptible antifungal agent and possibly decreases the risk of fungal resistance. Surveillance cultures for fungal resistance are recommended when fluconazole prophylaxis is completed.

Patients may have a combination of risk factors for fungemia and associated mortality. For some neonatal ICUs (NICUs) with high acuity, those with a high rate of infection, and those with large populations of ELBW infants, prophylaxis may be appropriate. For NICUs with a low incidence of candidemia, the relatively select group of infants who weigh less than 750 g and were born at less than 27 weeks' gestation are likely to be at high risk and may benefit from prophylaxis (Benjamin and DeLong, 2003; Johnsson, 2004).

Prophylaxis should be administered only while high-risk infants require intravenous access during the first 6 weeks of life. When intravenous access is no longer required, the risk for invasive fungal infection decreases because the additional risk factors for fungemia (eg, parenteral nutrition, use of lipid emulsions or broad-spectrum antibiotics, central venous access) are no longer present. After 6 weeks of life, the frequency of candidemia is reduced in preterm infants, and the disease may be associated with better survival rates (Kossoff, 1998; Kaufman, 2001). Further study is needed in other high-risk preterm and full-term infants with complicated GI disease who require prolonged periods without enteral feedings.

Until further information is available, prophylaxis in the highest-risk patients in NICUs is still being studied for safety and optimal patient selection (Long, 2005; Fanaroff, 2006). The highest-risk patients who may benefit include the following:

• All infants with a birth weight of less than 750 g

• Patients with a birth weight of 750-1000 g and 2 or more additional risk factors (eg, presence of a central venous catheter, not receiving full enteral feedings, receiving antibiotics for a bloodstream infection, receiving a third- or fourth-generation cephalosporins or carbapenems, steroid therapy)

• Preterm and full-term infants with GI disease, such as NEC, FBP, or complicated cases of gastroschisis, omphalocele, intestinal atresia, and Hirschsprung disease (eg, not receiving or expected to receive enteral feedings for >7 d).

For patients who receive fluconazole prophylaxis, the dose should be 3 mg/kg twice weekly until intravenous access is no longer required (<6 wk). In patients with suspected or documented fungal infection who receive prophylaxis, amphotericin B should be administered as the initial antifungal therapy until Candida species infection and fungal susceptibility is determined.

	MALASSEZIA INFECTIONS, ASPERGILLOSIS, ZYGOMYCOSIS (MUCORMYCOSIS)	Section 9 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Malassezia infections

Presentation of infection with Malassezia organisms is similar to that seen with invasive candidiasis. Infection does not routinely disseminate; therefore, end-organ surveillance is needed only if species are persistently isolated from several cultures.

Malassezia furfur is a lipid-dependent fungus that may colonize central venous catheters when lipid emulsions are infused. It can also colonize the skin and GI tract. Horizontal transmission is common. These fungi readily grow in Sabouraud medium coated with sterile olive oil. Treatment can include any one of the following measures:

• Stopping lipid infusions for 48-72 hours

• Stopping lipid infusions for 48-72 hours and administering amphotericin B for 7 days

• Stopping lipid infusion for 48-72 hours and removing the central venous catheter

• Removing a central venous catheter

Malassezia pachydermatis is not an obligate lipophilic organism. It has been reported to cause sepsis, urinary tract infection, and meningitis in VLBW infants but not in other neonates. Horizontal transmission occurs and can be prevented with hand washing.

Aspergillosis

Aspergillus infections are rare in neonates but are associated with a high morbidity and mortality rate. Aspergillus species are ubiquitous filamentous fungi (eg, molds) that form spores in the air, soil, decaying vegetation, and dust. For the neonate, transmission usually involves airborne spores. The site of entry may be the respiratory tract, skin, or central vascular catheter. Infection is usually due to exposure to contaminated dust. Invasive aspergillosis in infants can be cutaneous, pulmonary, or systemic infections, with occasional dissemination to the CNS.

Diagnosis is difficult, and a high index of suspicion is needed. Any culture that is positive for Aspergillus must be considered serious in preterm infants. Any skin or oral rashes or lesions should be cultured. Pulmonary presentation should be considered if infection is suspected with negative culture results and persistent signs despite antibacterial treatment.

One presentation involves injured skin areas that rapidly (over 24 h) progress to necrotic eschars. Diagnosis is made by demonstrating septate hyphae with 45° angles characteristic of Aspergillus species. Spores do not readily grow in blood cultures. The organism can be isolated from lung or skin samples when they are cultured on Sabouraud dextrose agar. Bronchoalveolar lavage fluid can also be microscopically examined and cultured.

Treatment has routinely involved amphotericin B, but with little success. Studies in adults have shown that newer antifungals, including voriconazole and echinocandins (eg, caspofungin or micafungin), are more effective than amphotericin B. Because the efficacy, safety, and optimal dosing of these antifungals is currently being determined, consultation with a pediatric infectious disease specialist and pharmacologist is important.

Prevention is crucial and involves filtration of NICU ventilation systems and containment of dust, especially during hospital renovation and construction. High-efficiency particulate air (HEPA) filters are excellent in clearing almost all of these fungi. NICUs should have continuous surveillance programs for mold, especially in and around windows, which can lead to good preventative measures. Ensuring that all ceiling tiles are in proper alignment is critical because all ceilings have some degree of mold.

Any construction in the surrounding area outside of the hospital can also increase the air spore count. During renovation or construction, the air should be tested for Aspergillus with the aid of infection control and microbiology services. HEPA filters should be used to prevent infection if significant levels of Aspergillus are detected.

Zygomycosis

Zygomycotic infections initially present as a black eschar at a site of local trauma or intravenous catheter insertion or infiltrate and progress to a necrotizing soft tissue infection (Oh, 2002; Scheffler, 2003). Early diagnosis, treatment with amphotericin B, and surgical debridement are needed to prevent ulceration, necrosis, and rapidly fatal dissemination. A high degree of suspicion is needed, and tissue biopsy must be performed to identify the nonseptate hyphae with right-angled branches. The mortality rate associated with these infections is reported to be 61% (Oh, 2002; Scheffler, 2003).

	PICTURES	Section 10 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

Caption: Picture 1. Pathogenesis and invasive fungal infections in very low birth weight infants. From Kaufman and Fairchild 2004, with permission.
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Caption: Picture 2. Percutaneous intravenous central catheter and fungal biofilm formation.
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Caption: Picture 3. Risk factors for candidemia. PICC = peripherally inserted central catheter.
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Caption: Picture 4. Congenital cutaneous candidiasis in a 26-week-old infant.
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Caption: Picture 5. Hepatic candidiasis. Note the white pustules of Candida albicans on the surface of the liver.
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Caption: Picture 6. Antifungal mechanisms. Yeast cell and targets of antifungal therapy. From Kaufman 2004, with permission.
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	BIBLIOGRAPHY	Section 11 of 11
Author Information Introduction And Pathogenesis Risk Factors Candidal Infections Clinical Presentation And Differential Diagnosis Morbidity, Mortality, And Follow-up Workup And Evaluation And Future Diagnostics Treatment, Empiric Treatment, And Prophylaxis Malassezia Infections, Aspergillosis, Zygomycosis (mucormycosis) Pictures Bibliography

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