Management
Removal of Infected Foci
Removal of medical hardware such as a catheter that is often a focus for Candida, decreases mortality and increases the clearance rate of systemic infection.[86] Surgical resection of infected tissue may be needed, if systemic antifungal therapy is not successful in eradicating the infection, or if the infected tissue causes functional impairment. Functional impairment may be seen in patients with a fungal mass, causing urinary obstruction or hemodynamic compromise of the right atrium.[62]
Systemic Antifungal Therapy
Amphotericin B Deoxycholate Amphotericin B deoxycholate is a polyene, which binds to ergosterol in the fungal cell membrane leading to cell leakage and death, and is the mainstay in the treatment of systemic candidiasis.[87] Most Candida species are susceptible to amphotericin B deoxycholate, and this drug is efficacious and well tolerated in neonates.[88,89] The 2009 Infectious Diseases Society of America guidelines recommend that amphotericin B deoxycholate be used for disseminated infection at a daily dose of 1 mg/kg/day for 3 weeks.[90] In patients with tissue foci, for example, endocarditis, after systemic dissemination, the duration of therapy may have to be prolonged to 4–12 weeks along with surgical removal of the foci.[90,91] Duration of therapy is influenced by sterilization of blood cultures as well as eradication of any foci of infection by imaging studies of the kidney, heart and brain. Renal ultrasonography is used to assess clearance of renal fungal masses, although it poorly correlates with survival or long-term renal function.[67] In patients with CNS(or suspected CNS involvement), flucytosine is not routinely recommended but may be added at 50–150 mg/kg per day divided into four doses if the CSF does not become sterile within a few days, or if the patient is becoming increasingly ill on amphotericin B deoxycholate monotherapy.[90,91]
Adverse effects of amphotericin B deoxycholate appear to be less common in neonates than in older children and adults. 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, dose dependent and resolve with cessation of the drug. Neonates on amphotericin B deoxycholate should have serial monitoring of serum potassium, magnesium and creatinine, liver enzymes and complete blood counts.
Amphotericin B Lipid Formulations Three lipid formulations are available, namely liposomal amphotericin, amphotericin lipid complex and amphotericin colloidal dispersion.[90] 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 conventional amphotericin B deoxycholate. They are typically reserved for neonates who develop intolerant infusion-related reactions or renal dysfunction during amphotericin B deoxycholate administration. The lipid formulations should be avoided if Candida infection involves the urinary tract, because these large-molecule drugs may not penetrate well into the renal parenchyma.[92–94] There is some evidence from a retrospective study that lipid formulations increase mortality.[95]
Triazoles
Triazoles inhibit the 14-α-sterol demethylase of the cytochrome P450 system, which is necessary for the production of ergosterol, a major component of the fungal cell membrane. Several studies have shown that fluconazole, a first-generation triazole, is effective in treating neonatal systemic candidiasis.[96–98] Fluconazole has excellent bioavailability when taken orally, potentially reducing the need for intravenous administration, reaches excellent therapeutic levels throughout the body, including the CSF,[99] and is an excellent agent for the treatment of Candida UTI, since it is excreted unchanged in high concentrations into the urine. As a first-line drug in suspected or non-typed fungal sepsis, fluconazole is limited by its lower efficacy against non-Albicans species compared with amphotericin B. A risk involved with fluconazole therapy is the emergence of fluconazole-resistant Candida species, such as C. krusei and C. glabrata. Fluconazole dosing of 6 mg/kg achieves blood levels higher than the average area under the curve/MICs of most Candida species infecting neonates. Based upon plasma samples of 55 infants (range of gestational age between 23 and 40 weeks gestation), a dose of 12 mg/kg per day during the first 90 days of life is needed to achieve optimal serum fluconazole concentration to treat candidiasis.[100] In a recent cohort study in infants <60 days with suspected systemic candidiasis, a loading dose of fluconazole (25 mg/kg) followed by maintenance dosing of 12 mg/kg/day for 4 days was safe and achieved the therapeutic target more rapidly than traditional dosing.[101] Pharmacokinetic data indicate that a longer dosing interval is required for neonates because fluconazole is renally excreted, and neonates have a low glomerular filtration rate. In addition, if fluconazole is being used for prophylaxis, a different antifungal should be used for treatment in that NICU. Second-generation triazoles, such as voriconazole, have been developed with a broader spectrum of activity and increased potency. In adult trials, they are effective in fluconazole-resistant species, but there is no comparable data in neonates.[102] 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 (i.e., photophobia, blurred vision and color changes). Until further study is completed, administration should be considered only in patients with Aspergillosis. Similar to all azoles, patients on voriconazole should be closely monitored if 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).[103,104]
Nucleoside Analogues
Flucytosine leads to rapid development of resistance when used as monotherapy and is reserved for use in combination with amphotericin B in neonates with CNS candidiasis, if the CSF does not become sterile within a few days or if the patient's health is deteriorating on amphotericin B deoxycholate monotherapy. Flucytosine has excellent penetration into the CSF and is synergistic with amphotericin B deoxycholate.[105] However, routine use is not recommended in CNS infections because of the difficulty in maintaining appropriate serum concentrations and the risk of toxicity.[90] Serum levels of flucytosine should be monitored to avoid reversible bone marrow suppression, which has been associated with serum levels >100 µg/ml.[88]
Echinocandins
The echinocandins (micafungin, caspofungin and anidulafungin) prevent the formation of glycan polymers, a major component of the fungal cell wall, by inhibiting the 1,3-β-d-glucan synthase enzyme complex. Echinocandins are not routinely used and may be considered in infants for whom the use of fluconazole and amphotericin is precluded because of drug toxicity or resistance.[106] Echinocandins may have higher MICs with C. parapsilosis; speciation and susceptibility testing should be performed with their use in neonates.[107] Micafungin is the only echinocandin authorized for neonatal use by the EMA, based on efficacy and pharmacokinetic data from neonatal populations.[108] A micafungin randomized controlled trial is currently in progress.[201] In a repeated dose, open-label pharmacokinetic and safety study of a 5-day course of 15 mg/kg/day of intravenous micafungin on 12 premature neonates for suspected fungal sepsis, micafungin dosing of 15 mg/kg in premature neonates corresponded to an exposure of approximately 5 mg/kg in adults.[109] No adverse events related to micafungin were observed in this study. In another small open-label study (n = 13) on the safety and pharmacokinetics of micafungin with suspected candidemia or invasive candidiasis, micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure levels that have been shown (in animal models) to be adequate for CNS coverage.[110] In a small randomized double blinded study of 32 infants, caspofungin was a more effective and safer alternative to amphotericin B deoxycholate for the treatment of invasive candidiasis in newborn infants.[111] Case reports, small case series and open-label studies of caspofungin suggest that this echinocandin is well tolerated in neonates.[112–114] Although echinocandins appear to be a promising class of antifungal agents in the treatment of neonatal candidemia, further data and larger studies on efficacy, safety, CNS penetration and dosing regimen in neonates are needed before they can be recommended for routine use.
Empiric Antifungal Therapy There are no established recommendations for initiating empiric therapy for invasive candidiasis like those that exist for group B Streptococcus infections. The goal of empiric therapy is to target the infection when CFU/ml would be low compared with 24–48 h later, when the cultures most commonly become positive. If empiric therapy is to be administered, or studied in the context of a prospective trial, systematic risk-factor modeling may help in patient selection.[4] In a cohort study assessing the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants <1000 g, empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn.[115,116] The incidence of death or neurodevelopmental impairment was lower in infants who received empiric antifungal therapy (19 out of 38; 50%) compared with those who had not (55 out of 86; 64%; odds ratio: 0.27; 95% CI: 0.08–0.86). Empiric antifungal therapy was associated with increased survival without neurodevelopmental impairment.[115,116] Empiric antifungal therapy for 48–72 h may be considered in infants with negative initial culture results who still have signs and symptoms of sepsis after 48 h of antibacterial treatment and have one of the following risk factors: thrombocytopenia, NEC or focal bowel perforation, or <750 g weight/<26 weeks gestational age.[115,117] On the flipside, we must consider the issue of additional exposure to antifungal agents and the risk of antifungal resistance. Although postmortem diagnosis of invasive candidiasis was common in the past, two recent studies demonstrated that only 2.7% of cases were diagnosed at autopsy (Table 2).[66,118]
Expert Rev Anti Infect Ther. 2013;11(7):709-721. © 2013 Expert Reviews Ltd.
