Triazole use in the nursery: fluconazole, voriconazole, posaconazole, and ravuconazole

Abstract

Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and Ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.

BACKGROUND

Invasive fungal infections in infants admitted to the neonatal intensive care unit (NICU) cause significant morbidity and death. Invasive fungal infections account for ~10% of nosocomial sepsis in very low birth weight (VLBW, <1500 g birth weight) infants [1]. The cumulative incidence is ~1–4% for all NICU admission and affects 20% of infants <750 g birth weight [2–8]. Mortality is high (20–30%) even with appropriate therapy [1, 3, 5] and survivors suffer from high rates (59–73%) of long-term neurodevelopmental impairment [3, 9, 10].

The majority of invasive fungal infections in neonates and infants are due to Candida spp. Other species (e.g. Aspergillus spp. and Malassezia spp.) are rare in this population [3, 5, 7]. C. albicans accounts for the majority of infections, but C. parapsilosis is emerging as a pathogen and accounts for 25% of invasive fungal infections in VLBW infants [11, 12]. Other species such as C. glabrata and C. krusei which are often resistant to azoles are becoming more important in adult populations [13–18] but have not yet emerged as significant pathogens in the NICU [7, 19–21].

The clinical presentation of fungal infections is difficult to distinguish from other invasive bacterial infections [22]. Further, cultures often take a long time for isolates, if any, to grow [23], and may show poor sensitivity even in the presence of confirmed meningoencephalitis [3]. Sensitivity is also limited due to the low volume (<1mL) drawn for most neonatal blood cultures. As a result, infants are frequently exposed to empirical antifungal therapy. Given susceptibility patterns, ease of administration, and excellent safety profile, azole antifungal agents are often used as first line therapy for invasive fungal disease and prophylaxis in infants.

TRIAZOLES

The azole antifungals can be divided into two main classes: imidazoles and triazoles. These two classes differ based on the number of nitrogens in the azole ring which results in different binding affinities for the cytochrome P450 enzyme system [24]. The imidazoles, with the exception of ketoconazole, are primarily used for superficial fungal infections. The triazoles are most commonly used for invasive fungal infections and can further be classified in first generation (e.g. fluconazole, itraconazole) and second generation triazoles (e.g. voriconazole, posaconazole, and ravuconazole).

Mechanism of Action

The triazole antifungals inhibit the cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is necessary for the conversion of lanosterol to ergosterol which is an essential component of the cellular membrane of fungi. Disruption of ergosterol synthesis leads to damage of the cellular membrane by increasing its permeability. The increased permeability of the cellular membrane of fungi results in cell lysis and death [25–27].

FLUCONAZOLE

Fluconazole has excellent activity against Candida spp and a low side-effect profile making it a first-line drug for invasive candidiasis (IC) [28–36]. Unfortunately, with widespread use has come emerging resistance and an alteration of the epidemiology of candidiasis in adult populations [29, 37–47]; Candida glabrata is now the most commonly isolated Candida spp from adult patients with IC [16, 31, 34, 48–51], and some nurseries have reported Candida glabrata as a predominant fungal pathogen [52].

Pharmacology

Fluconazole is available in both intravenous (IV) and oral formulations with rapid absorption from gastrointestinal tract and ~92% bioavailability compared with the IV form. It has low protein binding and excellent penetration into the CSF with concentrations ~80% of those found in the serum. Penetration into other body tissues such as joint spaces, saliva, vaginal secretions, and vitreous humor of the eye also approximate levels found in the serum. Fluconazole is eliminated primarily through the kidneys and excreted largely unchanged resulting in urine concentrations 10–20 times higher than those found in blood [53, 54].

In both in vitro and in vivo studies, fluconazole has shown activity against Cryptococcus neoformans and several Candida spp including C. albicans and C. parapsilosis [55]. C. krusei is inherently resistant to fluconazole. C. glabrata tends to show intermediate to complete resistence with the minimum inhibitory concentration required to kill 90% of organisms (MIC₉₀) ≥ 16 µg/mL. An in vitro time-kill study showed that the rate of fluconazole fungistatic activity was not influenced by concentration once the maximal fungistatic concentration was surpassed (concentration-independent), which is in contrast to the concentration-dependent fungicidal activity of amphotericin B deoxycholate or caspofungin [56, 57].

Pharmacokinetics in Children

Scaling of the corresponding adult dosage of fluconazole on a body weight basis is inappropriate for pediatric patients. A review of 5 separate fluconazole pharmacokinetic (PK) studies in 113 children, including 12 premature neonates [58] showed that fluconazole clearance is generally more rapid in children than adults, with a mean plasma half-life of approximately 20 hours compared to approximately 30 hours in adults. Therefore, to achieve comparable exposure in children, the daily fluconazole dose needs to be essentially doubled. Correct pediatric fluconazole dosing should be proportionately higher than adult doses, generally 12 mg/kg/day.

In neonates the volume of distribution is significantly greater and more variable than in infants and children, and doubling the dose for neonatal patients is also necessary to achieve comparable plasma concentrations. The increased volume of distribution is thought to be due to the larger amount of body water found in the total body volume of neonates [58]. Neonates require approximately 5 days to reach steady-state [59], and maintenance fluconazole doses of 12 mg/kg/day are necessary to achieve exposures similar to older children and adults [60]. Thus, a loading dose of 25 mg/kg to achieve steady state concentrations sooner than the traditional dosing scheme may be appropriate. Preliminary data from a phase 1 trial investigating a fluconazole loading dose in 12 critically ill children showed that the therapeutic target (AUC_0–24 = 400 ug*h/mL) was reached with the loading dose in 72% of subjects with no related adverse events [61].

Toxicities, Side Effects, and Drug Interactions

Side effects of fluconazole are uncommon. Safety studies have found limited hepatotoxicity compared with the other azoles [55]. In one study of 24 immunocompromised children, elevated transaminases were observed in only two cases [62]. A review of 726 children under the age of one year given fluconazole showed that this drug was generally well-tolerated, and reaffirmed the guidelines to increase the interval between doses due to the prolonged elimination during the first month of life [63]. The safety profile of fluconazole was assessed for 562 children ages 0 to 17 years through the review of 12 clinical trials of fluconazole in children [55, 64]. Most children received multiple doses of fluconazole either orally or via IV injection that ranged from 1 to 12 mg/kg. Many of the patients enrolled in the study had a severe underlying illness and were on a variety of concomitant medications, including chemotherapeutic agents. Fluconazole was overall well tolerated. Fifty-eight children (10.3%) reported transient, treatment-related side effects, most commonly vomiting or diarrhea. Only 3 children (0.5%) had liver-related side effects including elevated liver enzymes, elevated bilirubin, or hepatomegaly. All three of these children had leukemia and the chemotherapy was also implicated as a possible cause for the hepatotoxicity. This toxicity did not appear to be related to the dosage or total drug exposure. There have been very few studies specifically looking at the safety of fluconazole among neonates. Most of the data comes from the growing body of literature assessing fluconazole prophylaxis in this population. Five randomized controlled trials addressing this question also looked at the effect of fluconazole on liver function tests [52, 65–68]. These five studies included 726 infants in the NICU and two found statistically though not clinically significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). All of these values returned to baseline after discontinuation of fluconazole in those infants that survived to discharge.

Neonatal Clinical Studies

Several studies have suggested that triazoles may be a better alternative to amphotericin B deoxycholate because they have a similar broad spectrum of coverage with fewer side effects [29]. An early study of 40 neonates and infants (aged 2 days to 3 months) with either non-response or contraindication to standard antifungal therapy were treated with fluconazole and showed a 97% clinical and mycological response [69]. A two-center RCT comparing amphotericin B with fluconazole for the treatment of fungal septicemia showed no difference in outcomes and a trend toward fewer side effects in the fluconazole group but was limited by a sample size of 23 infants and not powered to show differences in mortality or neurodevelopmental outcome. There have been no other clinical trials comparing the azoles with amphotericin in neonates.

Given the high morbidity and mortality associated with neonatal IC even in the face of appropriate therapy and the association of Candida colonization with subsequent IC [70–72], there has been considerable interest in fluconazole prophylaxis as a strategy to reduce the overall burden of IC in the nursery. To date there have been five randomized controlled trials (RCTs) [52, 65–68], eight retrospective reviews [19, 20, 73–78], and a Cochrane review [79] examining fluconazole prophylaxis in neonates.

The first of the RCT’s was performed by Kicklighter, et al [67] and found that rectal colonization was significantly lower in VLBW infants receiving fluconazole 6 mg/kg/d versus placebo [15 vs. 46%, p<0.001]. In a prospective, randomized double-blind trial over a 30-month period of 100 infants with birth weights < 1000 g, those infants who received fluconazole for 6 weeks had a decrease in fungal colonization (22% versus 60%) as well as a decrease in the development of invasive fungal infection compared to placebo (0% versus 20%) [65]. A prospective, randomized, double-blind trial by the same group comparing a twice weekly regimen with the regimen used in the previous study found no significant difference in fungal colonization (p=0.83) or invasive disease (p=0.68) [66]. A larger prospective, randomized double-blind, controlled trial conducted in 8 NICUs in Italy among 322 infants with birth weight <1500 g showed that a fluconazole prophylaxis regimen of 3 or 6 mg/kg every second day for 4–6 weeks significantly reduced the incidence of both Candida colonization [incidence of 9.8% in the 6 mg group, 7.7% in the 3 mg group, and 29.2% in the placebo group (P<0.001)] and invasive fungal infections [incidence of 2.7% in the 6 mg group (P=0.005), 3.8% in the 3 mg group (P=0.02), and 13.2% in the placebo group] [68]. In contrast to the other studies, Parikh et al [52] randomized 120 infants <1500g to fluconazole prophylaxis 6 mg/kg/d every three days for the first week then daily for up to four weeks versus placebo. They found increased rates of fungal colonization in the placebo group [30% versus 8.3% (p=0.003)] but no difference in rate of IC [25% versus 26.7% (p=0.835)]. As opposed to most other reports in this population, C. glabrata, not C. albicans, was the dominant pathogen (71% versus 3.2%).

A Cochrane review meta-analysis of the five RCTs [79] showed a significantly lower incidence of invasive fungal infection in neonates treated with prophylactic fluconazole [relative risk 0.48 (95% CI 0.31, 0.73); number needed to treat (NNT): 11 (95% CI 7, 33)]. There was no significant difference in mortality between the fluconazole prophylaxis and placebo groups.

Use of a drug with limited data regarding dosing and safety in a vulnerable population such as premature neonates always involves weighing risks and benefits. Given the morbidity and mortality associated with invasive candidiasis and the number of fluconazole studies conducted to date, this drug is a possible choice for first line therapy. However, depending on local resistance patterns, other classes of antifungals (e.g. echinocandins, lipid-based amphotericin B formulations) might be better choices for first-line treatment due to their broader Candida spp coverage. In addition, fluconazole use in treatment is not recommended in settings where this drug is used routinely for prophylaxis. Related to this, the decision to use fluconazole for prophylaxis is more complicated and needs to carefully consider several variables. On one hand, exposing a large number of neonates to a drug for the benefit of a relative few is always a critical decision: in this view, evaluating the number-needed-to-treat is a correct approach. The prophylaxis studies above were conducted in centers with high baseline rates of candidemia [80]: obviously, in these centers there may be a solid benefit in adoption of prophylaxis. On the other hand, no clear benefit in reduction of mortality has been shown to date, and no assessment of the neurodevelopmental outcomes of premature neonates exposed to fluconazole is currently available. Pending this, universal prophylaxis cannot be recommended, but its use has to be considered on a center-to-center basis.

VORICONAZOLE

Voriconazole is a synthetic derivative of fluconazole. Voriconazole has the spectrum of activity of itraconazole, yet the bioavailability of fluconazole. Importantly, it has both fungicidal and fungistatic activity against Aspergillus [81–83].

Pharmacology

Voriconazole is available in both intravenous and oral formulations with approximately 90% oral bioavailability. It is extensively metabolized by the liver with less than 5% excreted unchanged in the urine. Voriconazole is 58% protein bound, has a large volume of distribution and penetrates well into the CSF. Dosing with 3–6mg/kg intravenously twice daily and 200mg orally twice daily results in serum trough concentrations of 2–6µg/ml and 2–3µg/ml respectively. Steady state concentrations for both intravenous and oral dosing are typically achieved after 5–6 days unless a loading dose is given in which case steady state concentrations are achieved in one day [84]. However, wide interpatient variability of drug exposure has been noted in adults following standard dosing.

There are several factors that are thought to contribute to this variability including nonlinear PK of voriconazole, genetic polymorphisms of CYP2C19, drug-drug interactions, liver disease, and patient age. Studies in both healthy volunteers [85–87] and critically ill adults [88, 89] have demonstrated non-linear PK that is thought to be due to saturable first-pass metabolism and decreased systemic clearance. Consequently small changes in dose may affect large changes in serum drug levels. Liver metabolism is primarily mediated by CYP2C19 of which several allelic polymorphisms have been identified. Individuals with poor metabolizing phenotypes have a roughly two-fold higher drug exposure than heterozygous extensive metabolizers and four-fold higher exposure than homozygous extensive metabolizers [90, 91]. Poor metabolizers may be found in up to 20% of non-Indian Asians while this trait is uncommon in white and black populations [84]. Like other azoles, voriconazole has the potential to interact with drugs metabolized by the CYP450 enzyme system. Similarly, any liver injury affecting this metabolism has the potential to alter voriconazole drug exposure.

In contrast to adults, the PK of voriconazole in children is linear at lower doses and patient weight rather than age seems to play a larger role in determining drug exposure making extrapolation of adult data problematic. Based on PK/PD analysis in a prospective multicenter study of 39 immunocompromisedchildren or children with documented invasive fungal disease age 2–11y, a dose of 4mg/kg intravenously was found to be equivalent to the recommended dose of 3mg/kg in adults [92]. Similar to adults, drug elimination correlated with CY2C19 phenotype, but children were found to have higher elimination rates than those found in adults, which at least partially explains the linear kinetics at lower doses. In a population PK analysis of 3 open label pediatric studies involving 82 children 2–11 years of age, an intravenous dose of 7mg/kg or 200mg orally twice daily was found to be equivalent to adult dosing [92].

Toxicities, Side Effects, and Drug Interactions

Voriconazole’s main side effects include reversible dose-dependent visual disturbances (increased brightness, blurred vision) in as many as one-third of treated patients [93, 94], elevated hepatic transaminases with increasing doses [95, 96], and occasional skin reactions likely due to photosensitization [81, 97–99].

As with other azoles the potential exists to modify the metabolism of other drugs, including a contraindication for concomitant use with sirolimus. In one study coadministration of voriconazole and tacrolimus elevated trough tacrolimus levels in one liver transplant patient nearly ten-fold [100], and in another study tacrolimus levels were significantly increased 2.2-fold when coadministered with voriconazole [101]. In a study of renal transplant patients, concomitant administration of voriconazole with cyclosporine also resulted in a 1.7-fold increase in the geometric mean for cyclosporine area under the plasma concentration-time curve, so it is recommended that the cyclosporine dose be halved and levels monitored frequently [102].

Clinical Studies in Adults

Voriconazole has been approved by the FDA as initial therapy for the treatment of invasive aspergillosis and candidemia [103]. The largest prospective clinical trial of voriconazole as primary therapy for invasive aspergillosis in adults showed better clinical response and improved survival in subjects receiving voriconazole versus those receiving amphotericin B deoxycholate [104]. A multicenter trial of voriconazole versus fluconazole in treating esophageal candidiasis in 391 immunocompromised patients showed similar success rates with voriconazole (98.3%) and fluconazole (95.1%) [105]. While overall safety and tolerability of both antifungals was acceptable in this study, fewer patients discontinued voriconazole than fluconazole due to poor clinical response, but more patients discontinued voriconazole because of laboratory abnormalities or adverse events.

Because of the non-linear PK in adults and high interpatient variability, investigators support voriconazole therapeutic drug monitoring to improve efficacy and limit toxicity. Studies in adults have shown that under-dosing voriconazole in patients with invasive fungal disease results in significant morbidity and mortality while high serum levels result in more frequent side effects [93, 94, 106–108]. In children the data are more limited. A recent retrospective study of 46 children aged 0.8–20.5 years showed that a trough concentration of 1 µg/mL was associated with increased survival and that serum levels based on a dosage of 7 mg/kg IV and 200mg oral twice daily were highly variable [109].

Pediatric Clinical Studies

The only pediatric-devoted study with voriconazole was an open-label evaluation of 58 children with a proven or probable invasive fungal infection who received voriconazole on a compassionate basis if they were refractory or intolerant to conventional antifungal therapies [110]. Most patients (72%) had aspergillosis, but the group also included scedosporiosis (14%), candidiasis (7%), and others. At the end of therapy (median duration 93 days), a total of 45% of children had a complete or partial response, and only 7% were discontinued from voriconazole because of intolerance. Stratifying outcome by pathogen revealed a complete or partial response of 43% against apsergillosis, 50% against candidemia, and 63% against scedosporiosis. The most commonly reported adverse events in these children included elevation in hepatic transaminases, skin rash and photosensitivity reaction, and abnormal vision.

The studies in neonates are limited to case reports. IV administered voriconazole has been used successfully in preterm infants of very low birth weight with primary cutaneous aspergillosis [111] and fluconazole-resistant Candida albicans [112]. Kohli et al [113] report successful use of oral voriconazole in two term newborns with cardiac disease. Voriconazole’s known ocular side effects and concern over how it might affect the developing retina, make it unlikely that clinical trials are forthcoming in premature infants. Given the availability of other agents with better safety data in neonates (e.g. echinocandins [114–116], lipid-based amphotericin [117]) ,we recommend that voriconazole in this population is used only as salvage therapy for refractory fungal disease and for documented cases of cutaneous or invasive aspergillosis.

Therapeutic Drug Monitoring (TDM) of Voriconazole

Because of the non-linear PK observed in adults and high interpatient exposure variability, it is likely that voriconazole TDM will be implemented to improve efficacy and limit toxicity. Observational studies have noted therapeutic failure with voriconazole plasma levels <1 µg/ml and increase in side effects when levels exceed 5–6µg/ml [93, 107, 108, 118, 119]. Transient hepatotoxicity and visual disturbances are most commonly reported.[93, 94, 120] but serious neurological disturbances and liver failure have also been associated with levels >5µg/ml [106, 119].

Studies in children are more limited, but retrospective studies show that children also experience high interpatient variability in voriconazole concentrations [121] and that mortality decreases when voriconazole serum trough concentrations >1µg/ml are achieved [109]. Case studies in infants suggest that even higher voriconazole doses are needed to achieve this target trough concentration, underscoring the need for TDM [112, 122, 123]. Even though the data acquired thus far support the use of TDM, prospective studies are lacking in children and need to be conducted to answer this question. With increasing availability of voriconazole TDM in the clinical setting, practicing clinicians have an excellent tool with which to guide dosing in infants admitted to the nursery.

POSACONAZOLE

In September of 2006 the FDA approved posaconazole for the prophylaxis and treatment of disseminated candidiasis and aspergillosis in severely immunocompromised patients and for the treatment of oropharyngeal candidiasis. Posaconazole is a second-generation triazole antifungal agent available as a suspension for oral administration. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited.

Pharmacology

Posaconazole is currently available only as an oral formulation and reaches maximum plasma concentrations 3 to 5 hours after ingestion. Dose proportional increases in plasma exposure (AUC) to posaconazole were observed following single oral doses from 50 mg to 800 mg and following multiple dose administration from 50 mg to 400 mg twice daily. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration [124]. When administered with a non-fat and high fat diet posaconazole exposure and maximum concentration are 3 to 4 times higher than with the fasting state [125]. In addition, posaconazole exposure is maximized with acidic beverages, administration in divided doses, and the absence of proton pump inhibitors [126]. Posazonazole distributes well into tissues; is 98% protein bound; and is not a substrate for the cytochrome P-450 enzymatic system. However, about 20% of the parent drug is glucuronidated by phase 2 enzymes. Posaconazole is eliminated with a mean half-life of 25 hours (19–31 hours) with a total body clearance (CL/F) of 4.1 to 6.6 ml/min/kg[127]; it is predominantly eliminated in the feces with renal clearance playing a minor role. Therefore, no dose adjustment is necessary in mild to moderate renal insufficiency. Posaconazole is fungicidal in vitro with likely time-dependent killing [128].

Toxicities, Side Effects, and Drug Interactions

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers (i.e. rifabutin, phenytoin) of these clearance pathways may affect posaconazole plasma concentrations [129]. Posaconazole is also a CYP34A inhibitor and therefore, coadministration results in increased plasma concentrations of the following products: cyclosporine (75% dose reduction required), tacrolimus (60% dose reduction required), rifabutin, midazolam and phenytoin [129]. Similar to the other azoles, posaconazole causes transient hepatic reactions including mild to moderate elevations in ALT, AST, alkaline phosphatase, and total bilirubin [129].

Clinical Studies in Adults

In a multicenter (89 sites), international, randomized, single-blinded study of posaconazole (n=304) versus fluconazole or itraconazole (n=298) in neutropenic patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes, posaconazole was superior in preventing invasive fungal infections [130]. Another multicenter, international, randomized, double-blinded study in patients with allogeneic hematopoietic stem-cell transplantation and graft versus hosts disease showed that posaconazole was not-inferior to fluconazole in the prevention of invasive fungal infections [130].

Pediatric Clinical Studies

In a study of 8 patients (7 pediatric patients 9 to 18 years of age) with chronic granulomatous disease and proven or possible invasive mould infection refractory to standard therapy, posaconazole (n=6, 400 mg orally twice per day; n=1, 200 mg orally three times per day) was well tolerated. Further, 6 of the 7 patients experienced complete resolution of infection [131]. Another report including data from 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections showed that 2 children ages 7 and 17 years of age had partial response to posaconazole and 1 child age 18 had a complete response [132]. To our knowledge, there are no reports on the use of posaconazole in neonates, and we would only consider its use as salvage therapy.

RAVUCONAZOLE

Ravuconazole is structurally more similar to fluconazole and voriconazole, containing a thiazole instead of a second triazole. It is often fungicidal [133, 134], has 47–74% bioavailability with linear PK, and a long half-life of approximately 100 hours [135]. The drug is well-absorbed following oral administration, and its absorption is enhanced by food [134]. Penetration of ravuconazole into healthy rat tissue showed that concentration of drug in the lungs was 2–6 times higher than the corresponding blood concentration [136]. Ravuconazole has not been approved by the FDA.

Pharmacology

Ravuconazole is well tolerated, with headache a main side effect, and urine studies suggest no CYP isoenzyme induction [137]. Ravuconazole was also well-tolerated in healthy human subjects in single [135] and multiple doses [138]. Ravuconazole and coadministration with simvastatin was well-tolerated in 20 health subjects and showed ravuconazole was a less potent inhibitor of the CYP3A4 enzyme than other triazole antifungals [139]. Ravuconazole did not affect nelfinavir in 14 healthy volunteers [140].

Clinical Studies

A randomized trial of 76 patients with ravuconazole cured 76% of esophageal candidiasis patients 7 days after administration, with a safety profile similar to fluconazole [141]. A substudy analysis of HIV-positive patients with oropharyngeal candidiasis showed a 95% response rate after 5 days of therapy [142]. Ravuconazole was evaluated in a multicenter, phase I/II randomized, double-blind, placebo controlled trial, dose-ranging study of toenail onychomycosis. For 12 weeks participants (n=151) received one of the following dosing regimens: 200 mg/day; 100 mg/week; 400 mg/week or placebo. Clinical, microbiological cure, and clinical response was greater in those who received ravuconazole 200 mg/day [143].

Pediatric Clinical Studies

There are no clinical trials of ravuconazole in children, and we do not believe it currently has a role in the nursery.

TRIAZOLES AND EXTRACOPOREAL MEMBRANE OXYGENATION

Extracorporeal Membrane Oxygenation (ECMO) provides life-saving support for children with refractory cardiorespiratory failure. ECMO is a cardiopulmonary bypass device that provides complete respiratory and cardiac support and is used in intensive care units (ICU) when conventional modes of support have failed. Mechanically, blood is drained from the venous system, pumped through an artificial lung where oxygen is added and carbon dioxide removed, and then, depending on the configuration of the circuit, returned to either the venous or arterial circulation (Figure 1). ECMO has been used successfully in multiple pediatric disease states including meconium aspiration syndrome (MAS), acute respiratory distress syndrome (ARDS), pneumonia, post-cardiac surgery, post-heart and lung transplant with graft failure, fulminant myocarditis, and sepsis [144–149].

Figure 1.

Schematic of ECMO circuit.

Children supported with ECMO are at high risk for nosocomial infections [150]. Risk factors for these infections include presence of large indwelling catheters, alterations in immune function, use of broad spectrum antibiotics, and frequent access of the ECMO circuit. The vast majority of pediatric patients on ECMO are covered with broad spectrum antibiotics, but antifungal use is much less consistent. In small epidemiological studies in ECMO patients, Candida spp are responsible for up to 50% of nosocomial infections [150–153]. Since treatment of IC involves both antifungals and removal of indwelling catheters [154], in children on ECMO where removal of indwelling catheters is often clinically contraindicated, antifungal prophylaxis could potentially reduce the burden of disease.

There are relatively few studies evaluating the pharmacokinetics/ pharmacodynamics (PK/PD) of drugs in patients on ECMO. However, the data suggest that the ECMO circuit can substantially alter the PK of antimicrobials resulting in changes to elimination and volume of distribution [155–163]. In addition, the critical condition of the patients in need of ECMO and the number of days on ECMO may further impact the PK changes observed.

No antifungals have been studied in any population of patients on ECMO. However, one ex vivo study using blood primed ECMO circuits demonstrated a dramatic decrease in voriconazole levels of 60% over 3 hours [157]. Since the circuit was not connected to a patient and the result was compared to a control specimen, drug loss was attributed to interactions between the drug and circuit [157]. Preliminary data from a phase 1 clinical trial investigating an IV fluconazole loading dose of 25mg/kg in children included one subject on ECMO [61]. While 72% of the subjects in this trial achieved the desired AUC_0–24 of 400, the child on ECMO did not, suggesting the need for higher dosing in this population. A phase 1 clinical trial evaluating the PK/PD of fluconazole in children supported with ECMO is currently underway.

CONCLUSIONS

Infants in the NICU are at increased risk of invasive fungal disease. Management has evolved tremendously over the last decade with the azole antifungals playing a significant role. Areas for future research include the use of fluconazole for prophylaxis in vulnerable populations (e.g. VLBW infants and infants on ECMO) and to better delineate the PK/PD of the newer antifungals such as voriconazole, posaconazole, and ravuconazole.