Definitions

Invasive Candida infections (ICI) in neonates include: congenital cutaneous candidiasis (CCC) and late-onset cutaneous candidiasis, bloodstream infections (BSIs), urinary tract infections (UTIs), meningitis, peritonitis, and infection of other sterile sites (bone and joint infections). These infections are often classified similar to other neonatal infections into early-onset (<72 hours after birth) and likely vertically transmitted and late-onset (≥72 hours after birth) and potentially horizontally transmitted infections. This is a worthy system to standardize definitions, recognizing that Candida species are slow-growing organisms and some infections in the first weeks of life have been shown by molecular studies to be vertically transmitted.

Microbiology

Candida albicans and C. parapsilosis account for 80% to 90% of invasive Candida infections in centers not using antifungal prophylaxis.¹⁶ Less common Candida species include C. glabrata and C. tropicalis, and a smaller percentage of infections are caused by C. lusitaniae, C. guilliermondii, and C. dubliniensis. C. parapsilosis isolates have been found to be genetically heterogeneous, with 10% being identified as two different species: C. metapsilosis and C. orthopsilosis. These three species are phenotypically indistinguishable, and molecular methods are needed for their detection. Centers using antifungal prophylaxis have a very low incidence of infections, and the few that occur are primarily by non-albicans species in NICUs using fluconazole prophylaxis. The change in epidemiology of Candida species with antifungal prophylaxis is important because fluconazole prophylaxis has virtually eliminated the more virulent C. albicans infections.

Pathogenesis and Pathophysiology

Most Candida species are commensal organisms as part of the normal human microbiome in the skin and gastrointestinal tract. They may exist primarily as budding yeast cells, filamentous hyphal structures, or both. Adherence and colonization are normal, and fungi become pathogenic owing to fungal and host factors (Figure 56-2).

The slow-growing nature of Candida facilitates its ability to progress from colonization to dissemination into the bloodstream and body tissues before clinical signs and symptoms of infection become apparent. In preterm neonates, similar to other hosts, four major steps can be identified in infected infants after exposure to Candida spp: (1) adhesion, (2) colonization, (3) dissemination, and (4) abscess formation (see Figure 56-2). These steps are related to the size of the inoculum (e.g., the number of fungal organisms), their virulence, and the characteristics of the host response.

Adhesion is the key step in colonization. Candidal species can adhere to epithelial and endothelial cells as well as catheters. Biofilm formation limits penetration of antifungals and shielding Candida from the host response. Surface glycoproteins such as INT1p, which binds to beta-integrins present on the endothelium and white blood cells, facilitate fungal adherence. The absence of a functional INT1 gene diminishes adherence in yeast cells but not filamentous forms.

The preterm infant has an immature immune system and is frequently exposed to broad-spectrum antibacterial and other medications that can suppress his or her immune response. Studies examining the effect of steroids and antibiotics have been performed in mice orally inoculated with C. albicans to mimic conditions in the preterm infant.¹¹ Antibiotic treatment alone led to increased Candida colonization but did not affect dissemination. When dexamethasone was added to the antibiotic regimen, both colonization and dissemination increased in these animal models. Additionally, dexamethasone in addition to antibiotics led to an increase in the percentage of filamentous forms in the gastrointestinal tract compared with antibiotics alone. These studies also showed that C albicans strains with two functional copies of the INT1 gene increased the number of fungi colonizing the cecum and disseminating to extraintestinal sites.

Studies consistently demonstrate higher associated mortality in preterm infants with C. albicans compared with non-albicans BSIs. Its virulence encompasses a combination of factors involving adhesion, cytotoxicity, hydrolytic enzymes (aspartyl proteinases, phospholipases, lipases, and hemolysins), morphologic switching, and genes. In addition to the adhesion factors discussed, C. albicans produces higher concentration of hydrolytic enzymes compared to non-albicans species. Morphologic factors are discussed in the following.

C. albicans can alternate its morphology in response to specific environmental cues, and it has an obligate diploid genome, lacking a complete sexual cycle, and has several genes important for virulence. Studies have found a strong correlation between virulence and the ability to alternate among three morphological forms—yeasts, hyphae, and pseudohyphae. The morphologic switch is a complex process involving changes in cellular shape, mechanical properties, interactions with other cells, and differential expression of multiple genes. Because of their size and shape, filamentous forms increase virulence of C. albicans in part by escaping phagocytosis.

To further examine the role of yeast and filamentous forms, one study intravenously and orally infected antibiotic-treated and dexamethasone-treated mice using three strains of C. albicans: (1) a wild-type strain that had both yeast cell and filamentous forms, (2) a strain with only yeast cells, and (3) a strain that was constitutively filamentous.¹⁰ The mortality rate was significantly greater in both the wild-type (92%) and yeast-cell (56%) strains compared with the filamentous strain alone (0%). The filamentous strain had no dissemination, and cecal colonization was significantly less than that of the other two strains. The wild-type strain had diffuse hyphal invasion with increased tissue necrosis compared with the yeast-cell strain. The researchers speculated that the yeast forms are critically important for adherence and tissue dissemination and that hyphal formation in the tissues contributes to parenchymal destruction.

Prematurity

The immature lymphocyte and antibody system predisposes preterm infants to skin and mucosal fungal colonization, whereas deficient innate host defense mechanisms predispose them to dissemination and overwhelming infection.⁵⁶ With compromise of the barrier defense system, invasive Candida infections may occur, owing to deficient neutrophil number and function. Neutrophils provide the major role in antifungal defense, ingesting and killing Candida in a process requiring production of oxygen metabolites, antibodies, cytokines, and activation of the C3 complement component, all of which are decreased in preterm infants compared with term infants and adults. Also deficient are neutrophil granules and cytokines that play a critical role in the lysis of Candida hyphae and pseudohyphae, which are too large to be engulfed by phagocytosis. Macrophages have impaired adherence, phagocytosis, and oxidative killing in preterm infants, affecting their ability to contain fungal colonization and infection. In addition to cell-mediated defenses, cytokines contribute to innate immunity against fungal infection through enhancement of cell-mediated fungicidal activity. Pulmonary host defense is primarily through alveolar macrophages, cilia and mucous, and surfactant, all of which are deficient in preterm infants.

Additionally, studies in animal models showed that the hypoxic insult that can be common in preterm infants around delivery or with apnea events is associated with increased gut fungal colonization and dissemination to mesenteric lymph nodes.^64a

Candida species produce proteases that may be lytic for the thin keratin layer produced by the immature stratum corneum in the first weeks after birth and phospholipases against lipid membranes that both may facilitate epithelial invasion.⁵⁶ Increased transepidermal water loss from preterm skin creates a moist environment that facilitates fungal colonization and growth. Because of the increased permeability of the preterm skin, substrates such as glucose may diffuse to the epithelial surface, facilitating Candida growth. Candida may alter its surface structure in the presence of high glucose, increasing its adherence and proliferative properties. Skin maturation occurs by 2 weeks of life in extremely preterm infants, after which new fungal skin colonization occurs less frequently.

The microflora of the gastrointestinal tract play an important role in fungal colonization and infection. Buccal candidal adherence is increased in preterm compared with term infants, facilitating colonization. A normal bacterial flora inhibits Candida growth by competing for both adhesion sites and nutrients. The commensal gut microflora can also enhance immunomodulatory activities against the most common pathogens, including Candida spp. Athymic adult neonatal bg/bg-nu/nu mice exposed to Candida spp. prolonged their survival when Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei GG, or Bifidobacterium animalis were present in the gastrointestinal tracts, compared with that of isogenic mice colonized with C. albicans alone. The incidence of systemic candidiasis in the bg/bg-nu/nu mice was significantly reduced by each of the four probiotic bacterial species.¹¹⁶

In another study of athymic mice given an oral challenge with Candida, fungal colonization was attenuated when a normal gut flora was present compared with those with a germ-free microflora.⁴⁷ This highlights the fact that the intestinal microflora may be as important as an intact immune system in preventing fungal colonization and infection.

Incidence

There is variation between rates in different NICUs and the incidence reported in the literature. These differences reflect a wide range of factors and are not a mere indicator of the overall quality of care. Based on patient demographics, use of antifungal prophylaxis, surgical population, resuscitation of extremely preterm infants, and practices related to feeding, medication, and antibiotic usage of individual NICUs, considerable variation exists between rates and risk for invasive Candida infections. Fridkin et al. reported the rate of Candida BSIs ranged between 3% and more than 23% among NICUs in infants less than 1000 g, and other studies have reported similar findings.16,31,39 Centers that care for infants with gastroschisis, NEC, and other complex gastrointestinal diseases have an increased risk for invasive Candida infections.³⁵ Resuscitation practices may be the most significant area of practice variation affecting invasive Candida infection rates; NICUs that do not resuscitate infants less than 25 weeks, for example, would have a lower rate of invasive Candida infections in infants less than 1000 grams compared with centers caring for 23- and 24-week gestation infants.

The literature has limitations owing to definitions of incidence. Studies including all invasive Candida infections in both preterm and full-term infants are limited, and most studies of incidence or risk factors focus on only Candida BSIs. The burden of all invasive Candida infections is nearly twice as high as BSI rates and even greater when empiric and pre-emptive therapy is considered (Figure 56-3 and Figure 56-4).

The incidence of invasive Candida infections in extremely low birth weight (ELBW, <1000 grams at birth) infants, not including congenital cutaneous candidiasis, is around 10%. The highest incidence of invasive Candida infections occurs in the most extremely preterm infants and is greater than 20% for infants less than 25 weeks’ gestation (Figure 56-5).¹⁶ Candida UTIs account for an additional 3% to 4% of invasive Candida infections in ELBW infants.^16,54,120 Multicenter studies have reported that Candida UTIs have a high associated mortality similar to Candida BSIs in ELBW infants, confirming their invasive nature in neonates.^16,93 Finally, meningitis and peritonitis, complicating focal bowel perforation and stage III NEC, contribute an additional 1% to 2% to the incidence of invasive Candida infections in ELBW infants.

Examining candidemia alone, the largest is a report from 128 US NICUs using US National Nosocomial Infections Surveillance (NNIS) system data from 1995 to 2004 (N = 130,523 neonates).³⁹ For infants less than 1000 g, the median infection rate was 7.5%, whereas 25% of NICUs had rates 13.5% or higher. The incidence decreases significantly for infants greater than 1000 g. Candidemia rates for infants of birth weights 1001 to 1500 g is 1.32%, for 1501 to 2500 g is 0.36%, and for those greater than 2501 g is 0.29%. The incidence increases in an inverse linear pattern when examining rates by gestational age. The rate of invasive Candida infections increases from around 3% at 28 weeks’ gestation to 24% at 23 weeks’ gestation.

Outcomes

For preterm infants, invasive Candida infections are associated with neurodevelopmental impairment and high mortality.

Risk Factors

As neonatal candidiasis can be fatal among premature infants, an understanding of the risk factors that lead to infection is critical (Table 56-1). Conditions that facilitate fungal colonization and proliferation and increase the risk for invasive infection include gastrointestinal dysmotility, ileus, antibiotics, acid inhibition, steroids, and the immaturity of the patient’s immune system. Several risk factors have been identified, with gestational age having the strongest effect. This correlates with the degree of underdevelopment of the immune system, and immaturity of the skin and gastrointestinal and respiratory tracts in these infants.

The extremely preterm infant has the unique combination of being immunocompromised, requiring prolonged intensive care (parenteral nutrition, mechanical ventilation, central venous access), being exposed to medications that promote fungal growth (H₂ blocking agents, proton pump inhibiting agents, postnatal corticosteroids, and broad-spectrum antibiotics), and being predisposed to gastrointestinal dysmicrobism, dysmotility, and disease (NEC and focal bowel perforation).16,35,100 Infants, both term and preterm, with complicated gastrointestinal diseases such as gastroschisis or NEC also have multiple risk factors of prolonged ileus, central venous access, parenteral nutrition, surgery, and exposure to prolonged and/or broad-spectrum antibiotics.³⁵

Medications such as broad-spectrum antibiotics and third- and fourth-generation cephalosporin and carbapenem antibiotics are associated with increased risk for candidemia.12,31,100 It is hypothesized that these medications accumulate in high concentrations in bile and alter the balanced gastrointestinal microflora, eradicating competitive gram-negative and anaerobic bacteria, thus facilitating proliferation and dissemination of fungal organisms. Other classes of drugs found to be risk factors for neonatal fungal infection are H₂ antagonists and postnatal corticosteroids.^100,108 In infants less than 1000 g, an association between lack of enteral feedings and infection has been reported.¹⁵ For infants not feeding by day of life 3, 8.7% developed Candida BSI or meningitis, compared with 3.4% of those receiving enteral feedings by day of life 3.

Feja et al. examined risk factors in 2001-2002 and using multivariate analysis found that catheter use (OR = 1.06 per day of use; 95% CI = 1.02 to 1.10), previous bacterial BSIs (OR = 8.02; 95% CI = 2.76 to 23.30) and gastrointestinal pathology (OR = 4.57; 95% CI = 1.62 to 12.92) were significantly associated with candidemia.³⁵ Gastrointestinal pathology was defined in the study as tracheoesophageal fistula, gastroschisis, omphalocele, Hirschsprung disease, intestinal atresias, or episodes of NEC.

There are some differences in risk factors for infection by species. Risk factors for C. albicans and C. parapsilosis include exposure to third-generation cephalosporins, central vascular catheters, parental nutrition and lipid emulsions, and high acuity while additionally vaginal delivery increases risk for C. albicans and H₂ antagonists for C. parapsilosis infection.¹⁰⁰ Risk for C. glabrata infections is increased with gastrointestinal disease, exposure to fluconazole or antibiotics, prolonged hospitalization, and prior infection with other fungi. C. tropicalis infections are associated with gastrointestinal mucosal injury, antibiotic suppression of bacterial flora, neutropenia, and parenteral nutrition.

Congenital cutaneous candidiasis (CCC) (Table 56-3, Figure 56-6) presents at or within a few days of birth most commonly as an erythematous maculopapular rash but can also manifest itself as skin erythema, pustules, vesicles, abscesses, exfoliation, a diffuse burn-like erythematous rash, and/or papulopustular rash.⁵⁶ The skin involvement covers one or more of the following areas: face/scalp, chest, abdomen, perineal area, one or more extremity, and/or back. These lesions occasionally lead to desquamation. CCC can occur with or without dissemination such as pneumonia or BSI. For affected term infants, it is reasonable to discuss the need for evaluation of the infant’s immune system for a primary immunodeficiency. Also, ELBW infants with congenital cutaneous candidiasis are at greater risk of developing dissemination to the blood, urine, or cerebrospinal fluid (CSF, 66%) compared with 33% in those 1000 to 2500 g or term infants (11%).³³ For this reason, preterm and term infants should be treated with systemic antifungal therapy.

The skin involvement with CCC is invasive, with a high burden of yeast, and should be treated similarly to other invasive fungal infections. Dissemination occurs if not treated for 14 days. In a study examining the pathogenesis and pathology of these infections, skin biopsies demonstrated invasion into the epidermis with an inflammatory process ranging from dermal invasion and granuloma formation to focal necrosis and hemorrhage. These data from biopsies give insight into the invasive nature of the cutaneous involvement, demonstrating the need for prompt IV antifungal therapy. By culturing for both fungal and bacterial organisms, the source of infection can be determined promptly and treatment started in a timely fashion. Differential diagnosis includes staphylococcal as well as other bacterial and fungal skin infections. Pathology with fungal staining of the umbilical cord and placenta can also aid in diagnosis.

End-Organ Dissemination

At the time fungal infection is clinically apparent, the organisms have often disseminated from the blood, urine, or CSF to adhere and proliferate in body fluids, tissues, and organs. Candida species can cause endocarditis, endophthalmitis, dermatitis, peritonitis, osteomyelitis, and septic arthritis, and fungal abscesses may form in the central nervous system, kidneys, liver, spleen, skin, bowel, and peritoneum (see Figure 56-2). Fungal end-organ dissemination has been noted since the earliest reports of Candida sepsis in neonates, being as high as 66% in the 1970s, reflecting prolonged periods of fungemia, uncertainty of significance of positive fungal cultures, underdosing of antifungals, and poor diagnostics, as many infections were diagnosed late or at the time of autopsy. A meta-analysis of studies reporting fungal end-organ dissemination in neonates spanning various practices from 1979 to 2002 found median prevalence of cardiac vegetations or thrombi was 5%, endophthalmitis 3%, renal involvement 5%, and central nervous system abscesses 4%.¹³ Dissemination may be higher in the more extremely preterm infant.

Noyola et al. and Chapman et al. found that infants with candidemia for more than 5 and 7 days, respectively, were more likely to demonstrate ophthalmologic, renal, or cardiac abnormalities than those with a shorter duration of candidemia.24,85 When amphotericin B was administered and central vascular catheters removed within 2 days of the first positive blood culture, outcomes such as end-organ dissemination and mortality were decreased.⁸⁵

Endocarditis and Infected Vascular Thrombi

Candida endocarditis or infected vascular thrombi have been reported in 5.5% to 15.2% of cases of fungal sepsis, with equal prevalence for C. albicans and C. parapsilosis. Fungal endocarditis may be associated with higher mortality than fungemia alone.24,85 Central vascular catheters place neonates at increased risk. Catheters can cause local trauma to valvular, endocardial, or endothelial tissue, creating a nidus for thrombus and infection at insertion and while in situ. When antifungal therapy alone is unsuccessful in resolution of the endocarditis or thrombus, thrombolytic or anticoagulation therapy may be indicated in some cases, depending on infant’s gestational age and accompanying conditions.

Endophthalmitis and Retinopathy of Prematurity

Endophthalmitis represents intraocular dissemination from the bloodstream. Exogenous infection can also occur secondary to retinopathy of prematurity (ROP) surgery or trauma. Endophthalmitis begins as a chorioretinal lesion that gradually elevates and breaks free in the vitreous, appearing as a white fluffy ball. The infection appears as solitary or multiple yellow-white elevated lesions with indistinct borders that are most often seen in the posterior retina and vitreous.⁸ The clear cell-free vitreous becomes hazy, owing to an influx of inflammatory cells. This vitreous reaction is more difficult to recognize in preterm infants because of the vitreous haze that is present in the first weeks of life. The most immature infants appear to be at highest risk for fungal endophthalmitis. The incidence of retinal endophthalmitis with candidemia has decreased over the years, likely because of more rapid diagnosis, treatment, and prevention of invasive Candida infections. Incidence may be affected by timing of screening, as antifungal treatment effectively treats this infection. The incidence ranges from 0.8% to 6% of preterm infants with candidemia who had indirect ophthalmoscopic examination.^36,85

Even in the absence of visible retinal abscesses or chorioretinitis, there is some epidemiologic evidence that Candida sepsis may predispose preterm infants to severe ROP. Noyola and colleagues, in a case control study of VLBW infants and less than 28 weeks’ gestation, found that 52% (24 of 46) of infants with candidemia developed threshold ROP compared with 24% (11 of 46) of controls without candidemia (p = .008).⁸⁴ Although this has been shown only as an association between fungal sepsis and ROP, early and frequent screening for retinal pathology is recommended in preterm infants with candidemia.

Evaluation and Diagnosis

Cultures of blood, urine, cerebrospinal, and peritoneal fluid or other sterile body fluids remain the best method for diagnosing invasive Candida infections (Figure 56-7). Focus on obtaining sufficient blood culture volumes (≥1 mL) and performing urine and cerebrospinal fluid cultures at the time of evaluation for sepsis remains critical to making prompt diagnoses. One study of neonates demonstrated that isolation of fungus in blood cultures occurred at 37 ± 14 hours, and 97% of blood cultures were positive by 72 hours.¹⁰² Laboratory capabilities to culture fungi, identify Candida species, and perform susceptibility testing are critical to diagnosis and management of invasive Candida infections.

Most commonly, with bloodstream infections, an initial end-organ dissemination (EOD) screen including an echocardiogram, renal ultrasound, cranial ultrasound, and ophthalmologic examination should be performed. This could be performed at presentation or after 5 to 7 days of antifungal therapy. If there is significant bowel pathology such as NEC or focal bowel perforation, a complete abdominal ultrasound should be performed to rule out peritoneal, liver, or splenic involvement. If signs and symptoms of septic arthritis (joint swelling) or osteomyelitis (swelling or immobility) are present, a clinical diagnosis can be made, and evaluation with joint aspiration, bone scan, or magnetic resonance image (MRI) may help define the extent of involvement, but should not be used to rule out joint or bone involvement in neonates. If candidemia persists, end-organ dissemination is even more likely, and surveillance after 5 to 7 days should also include: (1) ultrasound at location of the tip of any central catheters for infected thrombus, (2) complete abdominal ultrasound for abscesses (laparotomy is sometimes considered if high clinical suspicion), and (3) cranial ultrasound/MRI to detect brain dissemination. Abscesses that are amenable to drainage should be drained.

Molecular techniques to identify fungi and their antifungal susceptibilities more rapidly and with higher sensitivity than with blood cultures are being studied. Examples include polymerase chain reaction (PCR) and DNA microarray technology. One challenge is that these tests are mainly compared only with blood culture results, but often detect infection or only colonization at other sites. Fungal PCR to detect the gene for 18S ribosomal RNA in VLBW infants has yielded promising results but requires additional study.¹⁰⁹ Results of PCR tests showed a broader number of infections because they not only detect patients with candidemia but are also positive in those with Candida peritonitis, candiduria, previous candidal infections, and endotracheal colonization.

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. Similar to PCR, these markers are challenging to study because they may be present with bloodstream infections, nonbloodstream infections, previous infections, or with colonization alone.

An area in which PCR and markers such as beta-glucan can be extremely helpful is in the diagnosis and treatment of fungal infections that are not in the bloodstream. They may be useful in detecting fungal infections at other sites (urine, peritoneum, abscesses complicating NEC, or focal bowel perforation) when fungal infection suspicion is high despite negative cultures and trending treatment response. Beta-glucan levels decrease over time with antifungal therapy.

Treatment

Adequate dosing of antifungal therapy has been understudied in neonates and remains a critical issue (Table 56-4). Most of the literature lacks good data on dosing and outcomes. As more data are emerging, we have learned that we were underdosing and delaying optimal therapy for our patients, which may have contributed to delayed clearance, treatment failures, and increased dissemination, morbidity, and mortality. Almost all Candida species have favorable susceptibility to amphotericin B; 97% of neonatal isolates are susceptible to fluconazole, with NICU echinocandin susceptibilities emerging. In addition to dosing, prompt central line removal with Candida bloodstream infections is needed for clearance and to improve outcomes. Information on central line removal is often lacking in studies of antifungal efficacy, making it difficult to assess the efficacy of the agents being studied. In the area of pharmacokinetics, premature neonates, full-term neonates, pediatric patients, and adults often have different plasma clearance rates and drug half-lives, which affect dosing decisions as well as drug efficacy, safety, and toxicity for each of those groups.

Amphotericin B Preparations

Amphotericin B deoxycholate should be the first choice for treatment because of its excellent coverage for almost all Candida species causing invasive Candida infections in neonates, efficacy, low cost compared with other antifungals, safety, and possible better renal penetration compared with lipid preparations. Resistance to amphotericin B is rare, and it is the best choice to start with, pending speciation. When fluconazole is being used for prophylaxis in a NICU for any patient, a different antifungal should be used for treatment of invasive Candida infections in that NICU to decrease antifungal pressure that may lead to azole resistance.

Amphotericin B deoxycholate binds to the sterol component (ergosterol) of the cell membrane, creating pores that lead to cell death. Amphotericin B is combined with deoxycholate to make it soluble in water. In the bloodstream, it dissociates from deoxycholate, and 90% of it binds with lipoproteins. The drug distributes and binds to most tissues, with higher accumulation in the reticuloendothelial system.

There are three lipid preparations of amphotericin B.¹¹⁰ Liposomal amphotericin B is produced by incorporation of amphotericin B into tiny unilamellar liposomes (<100 nm in diameter). Liposomal amphotericin B is small in size and has a negative charge, which prevents significant uptake with the mononuclear phagocyte system. Its properties lead to high peak plasma levels and a larger area under the concentration-time curve. Tissue concentrations are highest in the liver and spleen and lower in the kidney and lungs. In the amphotericin B lipid complex, the drug is complexed in a 1 : 1 ratio with two lipids in a sheet-like formation (500-5000 nm). Its size facilitates rapid uptake by the mononuclear phagocyte system and sequestration in tissues such as the lung, liver, and spleen. This increased volume of distribution is associated with lower serum levels. Amphotericin B colloidal dispersion is a complex with cholesteryl sulfate in a 1 : 1 ratio with amphotericin B in a disclike structure (100 nm). These lipid complexes remain intact and are rapidly taken up by the macrophage phagocyte system. Lipases at the sites of infection then aid in the release of the drug. Liposomes can also bind to the fungal cell membrane, with fungal phospholipases aiding in its release. It is theorized that there are fewer side adverse effects if there is more targeted release of drug at the sites of infection.

Amphotericin B deoxycholate should be started at 1 mg/kg and lipid preparations at 5 mg/kg.⁸⁸ Serum electrolytes and urine output should be monitored, as additional sodium and potassium supplementation is often required. Fluids and enteral feedings should be adjusted to maintain urine output of 2 mL/kg/hour.

Several studies in the past decade have demonstrated no adverse renal or systemic effects of daily amphotericin B deoxycholate at 1 mg/kg. Linder et al. demonstrated that dosing of 1 mg/kg of amphotericin B deoxycholate (N = 34) did not affect renal function.⁶⁸ Creatinine levels (mg/dL) remained unchanged from the start of treatment (0.8 ± 0.4), at 24 hours after beginning treatment (0.8 ± 0.4), through the end of therapy (0.6 ± 0.2). This is an important difference compared to older children and adults for whom infusion-related reactions and nephrotoxicity are frequent concerns with amphotericin B deoxycholate. Lower “test” dosages of amphotericin B deoxycholate are not needed in neonates, as renal and other adverse effects commonly seen in older patients do not occur in neonates. Moreover, lower dosages in neonates only delay the time to achieve optimal therapy and may contribute to morbidity and mortality by delaying clearance of Candida species. If the initial treatment is ineffective, studies have demonstrated safety with increasing the dosing of amphotericin B deoxycholate to 1.5 mg/kg per day.⁵⁰

Lipid preparations starting with doses of 5 to 7 mg/kg are effective and safe with an eradication rate of 95%.⁵¹ Juster-Reicher et al. reported that eradication was achieved more rapidly when liposomal amphotericin B was started at the target dose of 5 to 7 mg/kg per day.

A few retrospective studies have examined whether lipid formulations are better than amphotericin B deoxycholate, but none has shown superiority.5,68 Some studies help guide treatment, whereas other studies may raise questions. Antifungal studies in which the dosing and specific antifungal were known have not found a difference in mortality between lipid preparations of amphotericin B and other antifungals, whereas one study from an administrative database found higher mortality when examining all amphotericin B lipid products grouped together compared with amphotericin B deoxycholate or fluconazole.^5,52,68,77 It is probable that the lipid preparations were underdosed in the later study. Without knowing dosing and the specific antifungal used, as well as controlling for line removal, the data are difficult to interpret, as these factors affect mortality. Additionally, the three lipid products may be associated with different outcomes and should not necessarily be combined into one group.

Other major differences that still need to be evaluated in prospective studies include risk for phlebitis when given via peripheral IV, and whether amphotericin B deoxycholate has an advantage in treating UTIs and renal abscesses. Animal studies have demonstrated significantly higher renal concentrations of deoxycholate, which has led most experts to recommend preference over lipid formulations for UTIs and renal candidiasis. None of the studies have compared optimal dosing of 1 to 1.5 mg/kg of amphotericin deoxycholate with 5 to 7 mg/kg of lipid preparations of amphotericin B. A rodent study examining 1 mg/kg of both amphotericin B deoxycholate and liposomal amphotericin B found kidney tissue concentrations of 735 ng/gram compared with 298 ng/gram, respectively. With dosing having a linear concentration for liposomal amphotericin B, a fivefold increase would be expected with dosing of 5 mg/kg, and kidney concentrations would be equivalent or even higher.^118a Studies examining efficacy for the treatment of UTIs are needed because many treatment studies have focused only on bloodstream infections.

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