Published online April 2, 2007
PEDIATRICS Vol. 119 No. 4 April 2007, pp. 772-784 (doi:10.1542/peds.2006-2931)
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REVIEW ARTICLE

Antifungal Therapy in Children With Invasive Fungal Infections: A Systematic Review

Christopher C. Blyth, MBBSa,b, Pamela Palasanthiran, MBBS, FRACP, MDa,b and Tracey A. O'Brien, FRACP, MBChB, MHL, BScb,c

a Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, New South Wales, Australia
b School of Women's and Children's Health, University of New South Wales, Randwick, New South Wales, Australia
c Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, New South Wales, Australia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 CONCLUSIONS
 REFERENCES
 
Invasive fungal infections are associated with significant morbidity and mortality. Differences between children and adults are reported, yet few trials of antifungal agents have been performed in pediatric populations. We performed a systematic review of the literature to guide appropriate pediatric treatment recommendations. From available trials that compared antifungal agents in either prolonged febrile neutropenia or invasive candidal or Aspergillus infection, no clear difference in treatment efficacy was demonstrated, although few trials were adequately powered. Differing antifungal pharmacokinetics between children and adults were demonstrated, requiring dose modification. Significant differences in toxicity, particularly nephrotoxicity, were identified between classes of antifungal agents. Therapy needs to be guided by the pathogen or suspected pathogens, the degree of immunosuppression, comorbidities (particularly renal dysfunction), concurrent nephrotoxins, and the expected length of therapy.

Key Words: antifungal agents • pediatrics • mycoses • candidiasis • aspergillosis • neutropenia

Abbreviations: IFI—invasive fungal infection • CAB—conventional amphotericin B deoxycholate • ABLC—amphotericin B lipid complex • ABCD—amphotericin B colloidal dispersion • RCT—randomized, controlled trial

Invasive fungal infection (IFI) is a significant problem in those at risk. Candida and Aspergillus species are the most frequent fungi responsible for invasive infections in children. Worldwide, the incidence is increasing in at-risk populations.1–4 Furthermore, the increasing incidence of resistant fungi is creating additional therapeutic challenges.1,5–8

Despite improvements in supportive care, IFI is still associated with a significant mortality rate and high health care costs.9 In studies published within the last decade, mortality rates in children with candidemia range from 19% to 31%.10–15 Invasive aspergillosis in children is associated with even greater mortality: 68% to 77%.16–19 A higher mortality rate is seen in those with greater degrees of immunosuppression, particularly after hematopoietic stem cell transplantation.17

Currently, there are 4 classes of drugs for treatment of IFIs: polyenes, triazoles, echinocandins, and nucleoside analogues. The available polyenes include conventional amphotericin B deoxycholate (CAB), liposomal amphotericin B, amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD). Numerous triazoles have been trialled, including fluconazole, itraconazole, voriconazole, posaconazole, and ravuconazole. Both groups of drugs target ergosterol, a key component of the fungal cell membrane.20 Echinocandins (caspofungin, micafungin, and anidulafungin) are a novel class of antifungal agents that interfere with cell wall biosynthesis.21 Finally, the nucleoside analog flucytosine interferes with nucleotide synthesis.

Differences between children and adults with IFI exist. These differences include predisposing factors, infective organism, and site of infection.16,18,22 Significant pharmacokinetic differences occur between pediatric and adult patients with many antifungal agents. Therefore, there is a need for pediatric-specific data to guide antifungal therapy in children.


   METHODS
TOP
 ABSTRACT
 METHODS
CONCLUSIONS
 REFERENCES
 
We performed a systematic review that included all trials in children with IFIs. The aim was to collate evidence for best-practice guidelines. The Medline, Embase, and Cochrane databases were searched from January 1966 to May 2006 for relevant studies. Review of references and conference proceedings led to the identification of additional relevant articles including unpublished data. Pediatric trials or trials with a sufficient number of pediatric subjects were identified and reviewed.

In this review, data on the most frequently encountered clinical problems are presented: antifungal therapy in prolonged fever and neutropenia, candidemia/invasive candidiasis, and invasive aspergillosis. Relative antifungal toxicities are also compared. When pediatric studies have been judged to be insufficient, adult studies have been used to supplement data. Pediatric comparative trial data are listed in Tables 1 and 2; recommended pediatric and adult dosages of antifungal agents are listed in Table 3.


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  		TABLE 1 Data on Efficacy From Comparative Pediatric Trials

 

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  		TABLE 2 Data on Toxicity From Comparative Pediatric Trials

 

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  		TABLE 3 Recommended Antifungal Dosing for Children and Adults With IFI

 
Empiric Antifungal Therapy in Those at Risk (Prolonged Fever and Neutropenia)
IFIs are an important cause of morbidity and death in patients with neutropenia.23 In 1982, Pizzo et al24 conducted an unblinded randomized study in 50 neutropenic children, adolescents, and young adults who remained febrile for 7 days despite broad-spectrum antibiotic treatment. Results demonstrated more rapid fever defervescence and less fungal infections in those who received amphotericin B, but the findings failed to reach significance. Despite the study limitations and those of the European Organisation for Research and Treatment of Cancer trial that followed,25 it has become standard of care to use antifungal agents in neutropenic subjects who remain febrile despite the use of broad-spectrum antibacterial agents.

Prentice et al26 conducted the largest pediatric randomized, controlled trial (RCT) to date. In an RCT that included 202 children with 96 hours of fever and neutropenia that were unresponsive to broad-spectrum antibiotics, liposomal amphotericin B (1 or 3 mg/kg per day) was compared with CAB (1 mg/kg per day). Safety was the primary end point. The study also included 134 adults. Treatment success (fever defervescence without additional antifungal therapy) was observed in 51% of children who received CAB, 64% who received 1 mg/kg per day of liposomal amphotericin B, and 63% who received 3 mg/kg per day of liposomal amphotericin B (P = .22). Although the overall analysis (adults and children inclusive) demonstrated a significant difference in treatment success between CAB and the higher dose of liposomal amphotericin B (49% vs 64%; P = .03), the Kaplan-Meier analysis of time to fever defervescence failed to show any significant difference between these treatment arms.26

In another small trial, CAB (0.8 mg/kg per day) and ABCD (4 mg/kg per day) therapy were compared in 49 children with prolonged fever and neutropenia.27 A composite end point was used to assess treatment success: fever defervescence, survival for at least 7 days after drug cessation, no documented or suspected IFI within 7 days of receipt of the study drug, and no toxicities that required cessation of therapy. The difference in treatment success observed between CAB and ABCD approached significance (41% vs 69%; P = .051), yet the time to fever defervescence was similar with both treatments (P = .654).

Other empiric antifungal trials that compared different formulations of amphotericin B have not included children, or pediatric subgroup analysis was not performed. Adult trials have failed to demonstrate a significant difference in treatment success when CAB (0.6–0.8 mg/kg per day) is compared with liposomal amphotericin B (3 mg/kg per day) or ABCD (4 mg/kg per day).28,29 Furthermore, a meta-analysis of RCTs that included 1895 patients failed to demonstrate any difference in mortality between CAB and lipid-agent use.30 Fewer breakthrough fungal infections were seen in those receiving liposomal amphotericin B compared with CAB.30 No difference in treatment success was observed when liposomal amphotericin B was compared with ABLC in persistently febrile and neutropenic adults, although the study was insufficiently powered.31

Kim et al32 compared CAB and itraconazole as empiric therapy in 30 neutropenic children. The trial was inadequately powered, and both cohorts were poorly matched for duration of neutropenia. No difference in response rate was observed. A number of trials have compared fluconazole or itraconazole with CAB in neutropenic patients.33–36 Only 1 trial was adequately powered,34 and 1 was inclusive of children.35 All subjects were azole naive before the study. No pediatric subgroup analysis was performed. All trials showed that azoles were equally effective as CAB. Voriconazole was compared with liposomal amphotericin B in 837 adolescent and adult subjects.37 No difference in treatment success was observed when using a composite end point; however, fewer breakthrough fungal infections were seen in those who were receiving voriconazole.

Khayat et al38 retrospectively compared liposomal amphotericin B and caspofungin in 26 febrile and neutropenic children. The duration of neutropenia and treatment were significantly shorter in those receiving caspofungin. No difference in effectiveness was observed (92% in both cohorts). Liposomal amphotericin B and caspofungin were compared in 1095 febrile neutropenic adults. Despite there being a greater number of patients who survived for ≤7 days after completion of the study therapy in the caspofungin group, no overall difference in treatment success was observed.39

In summary, no clear differences in overall treatment success or mortality have been demonstrated in pediatric or adult trials in which empiric conventional amphotericin B and lipid preparations were compared in subjects with prolonged fever and neutropenia. Fewer breakthrough infections may occur in subjects who receive liposomal amphotericin B. In azole-naive neutropenic subjects, conventional amphotericin B and fluconazole seem equally effective. Furthermore, in febrile neutropenic adults, voriconazole and caspofungin seem to be as effective as liposomal amphotericin B.

Antifungal Therapy in Proven Candidemia or Invasive Candidiasis
In pediatric and neonatal case series, Candida albicans and Candida parapsilosis are the most frequently isolated organisms responsible for invasive disease.1,40–42 Other species such as Candida tropicalis, Candida glabrata, and Candida krusei occur less frequently than in adult cohorts. C tropicalis, C glabrata, C krusei, and Candida guillermondii frequently have reduced susceptibility to fluconazole, and Candida lusitaniae is thought to have variable sensitivity against amphotericin B.43

Higher rates of candidemia with nonalbicans species are seen in those who receive systemic antifungal agents.6 Previous fluconazole therapy is a risk factor for infection with a fluconazole-resistant organism.6 The association between C parapsilosis and central-line infection has been documented by a number of authors.41,44

Numerous antifungal agents have been used in open-label trials in neonates and children with candidemia/invasive candidiasis. Amphotericin B and its lipid preparations,45–52 azoles,53–55 and echinocandins56,57 have all been shown to be effective in neonates with candidal infections. Amphotericin B-based preparations, azoles, and echinocandins have also been shown to be effective in predominantly immunosuppressed pediatric populations.55,58–66 The most frequently used end point is microbiologic clearance of candidemia (CAB: 68%46; lipid preparations of amphotericin B: 83%–100%45–48,51,52; fluconazole: 72%–97%53,55,61,62; itraconazole: 81%58; caspofungin: 85%–100%56,57; micafungin: 72%66). Comparing trials is difficult given the small numbers, mixed patient populations, and varying comorbidities. Furthermore, newer agents are frequently used as salvage therapy in open-label trials after failure of standard agents.

Two small RCTs have compared antifungal agents in pediatric candidemia. Driessen et al67 compared CAB (1 mg/kg per day) with fluconazole (5 mg/kg per day) in 23 predominantly preterm neonates. Although the trial was significantly underpowered, no significant difference in treatment success or mortality rate was demonstrated. Mondal et al68 compared enterally administered fluconazole (10 mg/kg per day) and itraconazole (10 mg/kg per day) in 43 pediatric intensive care patients with candidemia. No significant difference in total mortality rate (18.2% vs 9.5%) or attributable mortality rate (4.8% vs 4.5%) was demonstrated. The time to mycological cure (5.6 ± 1.6 vs 5.5 ± 1.9 days) and clinical cure (7.0 ± 2.6 vs 7.9 ± 1.3 days) was similar for both treatment groups.

The therapeutic equivalence of fluconazole and CAB has been demonstrated in predominantly nonneutropenic adolescents and adults with candidemia or invasive candidiasis.69–71 Furthermore, the therapeutic equivalence of voriconazole compared with CAB followed by fluconazole was demonstrated in 370 nonneutropenic adolescents and adults.72 Voriconazole was superior in subjects with C tropicalis sepsis. Therapeutic equivalence of fluconazole and voriconazole was demonstrated for esophageal candidiasis by Ally et al73 in adult patients with cancer and HIV.

Echinocandins have been compared with CAB and azoles in adults with candidemia and invasive candidal infections. No comparative pediatric trials have been performed. Caspofungin and CAB seem equally effective in adult patients with candidemia and oropharyngeal or esophageal candidiasis.74–76 No difference in treatment success has been demonstrated in adults with esophageal candidiasis treated with fluconazole and caspofungin, micafungin, or anidulafungin.77–79 Caspofungin has been shown to be effective in treating fluconazole-resistant esophageal candidiasis.80

At least 14 days of therapy after the last positive blood-culture result is recommended for children and neonates with candidemia in the absence of disseminated disease.81 Donowitz and Hendley82 retrospectively reviewed short-course therapy in 30 neonatal and pediatric patients with candidemia. Clinical and mycological cure was documented in 58% of subjects administered 7 to 14 days of antifungal therapy after bloodstream sterilization. No comparison has been performed with longer courses of antifungal therapy. An intravascular device is the most frequent source of candidemia in children (D. Marriott, MBBS, T. Sorrell, MD, M. Slavin, MBBS, S. Chen, MBBS, PhD, and D. Ellis, PhD, "The Australian Candidaemia Study: A Prospective Population Based Laboratory Surveillance for Candidaemia in Australia Over a Three Year Period," unpublished work, 2006). Management of intravascular devices is integral in the management of children with candidemia but is beyond the scope of this review (see Nucci and Anaissie83).

Treatment for deep candidal infection frequently requires prolonged therapy. Treatment recommendations are from open-label and observational studies rather than comparative trials. Pappas et al81 recommended at least 4 weeks of therapy in candidal meningitis after resolution of symptoms and signs. Combination therapy (ie, amphotericin B derivative and flucytosine) is often recommended. The role of newer antifungal agents has not yet been fully established. Prolonged antifungal therapy (ie, >6 weeks) is frequently required for chronic disseminated candidiasis, endocarditis, endophthalmitis, and osteomyelitis.81 This prolonged treatment is influenced by the underlying degree of immunosuppression, the presence of prosthetic material, and the response to both medical therapy and surgery where warranted.

In conclusion, no adequately powered comparative trials in pediatric candidemia or invasive candidiasis have been performed. No difference in treatment success has been seen when CAB, azoles, and echinocandins were compared in nonneutropenic adolescents and adults. Previous antifungal therapy may have an impact on the infecting Candida species and should influence empiric therapy.

Antifungal Therapy in Proven or Suspected Invasive Aspergillosis
There is a paucity of comparative data for pediatric aspergillosis. Furthermore, a lack of uniform definitions for diagnosis and treatment response, the relatively small subject numbers in pediatric studies, the lack of pediatric subgroup analysis in larger studies, and differences in the study populations create uncertainty about optimal management.84 Assessment of open-label pediatric trials indicates that the most frequently used end point has been clinical cure and/or improvement. Treatment response rates have varied markedly (CAB: 32%16; ABLC: 39%–78%60,63,85; voriconazole: 60%59; caspofungin: 70%65; micafungin: 45%86). Mixed patient populations and the use of antifungal agents as either primary or salvage therapy make interpretation of the data difficult.

The only comparative trial of antifungal therapy in pediatric aspergillosis compared ABCD with CAB. Children and adults who were given ABCD were compared with a historic cohort treated with CAB.87 ABCD was administered to patients who were intolerant of or refractory to CAB therapy, had preexisting renal impairment, or were enrolled in ABCD dose-escalation trials after hematopoietic stem cell transplantation. Pediatric numbers were small, and no pediatric subgroup analysis was performed. White et al87 found that treatment success and survival were greater in the ABCD group. Those treated with ABCD were younger and less likely to be neutropenic.

Using comparative data from adult trials, a number of conclusions can be drawn regarding the relative efficacy of different antifungal agents. CAB was compared with lipid preparations in 2 underpowered RCTs: no significant difference in treatment outcome was observed when CAB (1.0–1.5 mg/kg per day) was compared with liposomal amphotericin B (5 mg/kg per day) or ABCD (6 mg/kg per day).88,89

Two randomized trials compared different doses of liposomal amphotericin B in proven or probable aspergillosis. No difference in clinical response was observed between 1 and 4 mg/kg per day of liposomal amphotericin B, although the trial was insufficiently powered.90 In patients with proven aspergillosis at group assignment, clinical response was seen in 58% of those who received 4 mg/kg per day compared with 37% who received 1 mg/kg per day. Another trial compared 3 and 10 mg/kg per day of liposomal amphotericin B in 339 subjects with filamentous fungal infection (predominantly aspergillosis). No differences in treatment success at 12 weeks (50% vs 48%, respectively) or survival (72% vs 58%, respectively) were observed.91

Herbrecht et al92 compared CAB (1 mg/kg per day) with voriconazole (6 mg/kg twice daily for 24 hours followed by 4 mg/kg twice daily) in 277 adolescents and adults with proven or probable aspergillosis. Voriconazole was superior with regards to treatment success (53% vs 32%, respectively) and survival (71% vs 58%, respectively). Some of the voriconazole treatment success may be attributable to duration of therapy, because it was significantly longer in the voriconazole group (77 vs 10 days, respectively). Other licensed antifungal agents were used less frequently in those who were administered voriconazole compared with CAB (36% vs 80%, respectively).

Caspofungin and micafungin have been shown to be effective in open-label trials in adults with aspergillosis who were intolerant of or refractory to other antifungal agents.93–95 No comparative trials have been published to date.

The duration of antifungal therapy required for invasive aspergillosis in children and adults has not been determined. Herbrecht et al92 clinically and radiologically evaluated subjects after 12 weeks of antifungal therapy. In an open-label study of voriconazole use in children with IFI (predominately aspergillosis), the median duration of therapy was 93 days (range: 1–880).59 The length of therapy administered needs to influenced by response to therapy and immunologic recovery.

In summary, pediatric data are insufficient to guide therapy in children with invasive aspergillosis. Adult data suggest that in subjects with invasive aspergillosis, voriconazole is superior to conventional amphotericin B and associated with superior survival. Higher doses of liposomal amphotericin B are not superior to 3 mg/kg per day of liposomal amphotericin B. Echinocandins are effective in aspergillosis, although no comparative trials have been completed.

Combination Antifungal Therapy
Given the high morbidity of IFI, the role of combination therapy is frequently considered. To date, no pediatric combination trials have been published, although research is underway. In nonneutropenic adults with candidemia, amphotericin B and fluconazole were compared with amphotericin B alone.96 Clearance of Candida from the bloodstream occurred more frequently with combination therapy; however, no difference in the primary end point or 90-day mortality rate was demonstrated. Combination therapy with voriconazole and caspofungin (n = 16) was retrospectively compared with voriconazole (n = 31) in a population of adults with proven or probable aspergillosis and progression despite treatment with amphotericin B.97 Three-month survival, estimated with Kaplan-Meier curves, demonstrated a reduced mortality rate with combination therapy (hazard ratio: 0.28; P = .011).

In summary, there is insufficient evidence currently to support the routine use of combination therapy in children with candidemia, invasive candidiasis, or aspergillosis. Combination therapy should be reserved for salvage therapy pending additional trial data. Two antifungal agents from different classes should be used for salvage therapy.

Pediatric Antifungal Pharmacokinetics and Drug Interactions
Significant differences between adult and pediatric antifungal pharmacokinetics have been demonstrated with a number of antifungal agents. Pediatric amphotericin B pharmacokinetics differ significantly from adults.59,98–100 Because amphotericin B products do not accumulate in plasma, have large volumes of distribution, and long elimination half-lives, recommended doses are not dissimilar from adult recommendations. Pediatric studies reveal more rapid elimination and larger volumes of distribution in children administered fluconazole compared with adults.101–103 From pharmacokinetic modeling, 12 mg/kg per day of fluconazole is required to achieve comparable plasma concentrations to adults receiving 400 mg/day.101 Neonatal fluconazole elimination is reduced, necessitating less frequent dosing. Voriconazole pharmacokinetics in children are linear compared with the nonlinear pharmacokinetics seen in adults. The area under the curve in children given 4 mg/kg 12-hourly is similar to adults given 3 mg/kg 12-hourly.104 Doses of up to 11 mg/kg twice daily may be required in children to achieve concentrations similar to 4 mg/kg twice daily in adults. Again, pediatric caspofungin pharmacokinetics are different to adults administered the drug. Variations in the pharmacokinetic results with both weight and age suggest that weight-based dosing fails to provide consistent pharmacokinetics across all ages. In children and adolescents, 50 mg/m2 best approximates the area under the curve and trough concentration of adults receiving 50 mg/day.105 In premature neonates, 2 mg/kg or 25 mg/m2 best approximate adult pharmacokinetic data.106

Adult and pediatric pharmacokinetics seem to be similar for itraconazole,107–109 posaconazole,110 micafungin,111,112 and anidulafungin.113 Additional studies are required to define the correct pediatric dosage for newer antifungal agents including posaconazole, ravuconazole, micafungin, and anidulafungin.110–113 Currently recommended pediatric dose ranges are listed in Table 3.

Competition for cytochrome p450 metabolism is a problem with certain antifungal agents. This is of particular relevance to the interaction of azoles with cyclophosphamide and other immunosuppressants (cyclosporine, tacrolimus, and sirolimus). Dose reduction (cyclosporine or tacrolimus with itraconazole or voriconazole) or avoidance (sirolimus with voriconazole) is recommended.21,114–120 Despite initial concerns about cyclosporine and caspofungin coadministration, a number of observational studies in children and adult subjects who received concomitant therapy have demonstrated the safety of this combination.65,121,122

Antifungal Toxicity in Children
The development of new antifungal agents has been driven by the toxicities that occur with CAB. Azoles, lipid preparations, and echinocandins are all associated with significantly less toxicity. The toxicity of CAB,46,123–132 lipid preparations,45,47–51,60,63,85,133,134 fluconazole,54,55,61,62,67,68,102,128,135–138 itraconazole,68,108,109 voriconazole,59,104,139,140 caspofungin,56,57,65,105,141 micafungin,94,111 and anidulafungin113 have been determined in a number of pediatric trials, yet there is a paucity of comparative data. Furthermore, a lack of uniform definitions hinders comparison.

Two pediatric randomized trials that compared CAB to ABCD demonstrated a reduced rate of nephrotoxicity with ABCD (52% vs 12% in both studies; P < .01).27,29 Although Prentice et al26 failed to detect a significant difference in the rates of nephrotoxicity when they compared 1 mg/kg per day of CAB and 1 to 3 mg/kg per day of liposomal amphotericin B (21% vs 8%–11%, respectively; P = .10), their definition of nephrotoxicity was less stringent (see Table 2).

These pediatric data are supported by numerous larger trials. Three meta-analyses demonstrated a 49% to 75% reduction in nephrotoxicity with lipid preparations compared with CAB.30,142,143 If nephrotoxicity secondary to a lipid preparation occurs, it occurs after a longer course of therapy.26,29 Both adult and neonatal studies have demonstrated that lipid preparations are safe in subjects with pretreatment nephrotoxicity.46,144,145 No pediatric studies have compared different lipid preparations. In contrast to the findings of Wingard et al,31 a recent meta-analysis demonstrated no significant difference in rates of nephrotoxicity seen with liposomal amphotericin B and ABLC.143

Both azoles and echinocandins cause less nephrotoxicity than CAB and liposomal amphotericin B when compared in adolescents and adults.34,36,37,71,72,92 No trials comparing ABLC or ABCD to azoles and echinocandins exist to date. In children who were given fluconazole and itraconazole, similar rates of nephrotoxicity have been seen.68 When compared with both CAB and liposomal amphotericin B, less nephrotoxicity is seen in adults who are given caspofungin.39,74,76 No difference in the rates of nephrotoxicity have been seen when caspofungin and fluconazole were compared in adults.77

A number of authors have identified specific risk factors for amphotericin B–induced nephrotoxicity. Amphotericin B dose, preexisting renal impairment, hyponatremia, hypovolemia, and the concurrent use of nephrotoxic medications are associated with an increased risk of amphotericin B nephrotoxicity.28,129,146–151 Age and underlying disease are not associated with increased risk. When nephrotoxic medications are assessed independently, cyclosporine and diuretics increase the rate of nephrotoxicity, whereas aminoglycosides and vancomycin in isolation seem not to increase the risk.147–149In a study by Walsh et al,28 the risk of nephrotoxicity more than doubled when ≥2 concurrent nephrotoxins (cyclosporine, aminoglycosides, or foscarnet) were used. Avoidance of nephrotoxins and hypovolemia as well as sodium loading before amphotericin B use may decrease the risk of nephrotoxicity. Wingard et al146 determined that hematopoietic stem cell recipients were >5 times more likely to require hemodialysis when administered amphotericin B for aspergillosis than solid organ transplant- and nontransplant-related chemotherapy recipients. Dialysis was a significant risk factor for death.

Infusional toxicity (most frequently chills, rigors, fever, nausea, and vomiting) is a frequent complication of amphotericin B treatment in children and adults. Despite premedication and the development of tolerance, infusional toxicities continue to pose a problem.152,153 Infusional toxicities are rarely reported in neonates.46,127 Comparative trials with adult and pediatric patients have demonstrated that liposomal amphotericin B is the amphotericin B product associated with the least infusional reactions.143 CAB, ABLC, and ABCD have similar rates of infusional reactions.143

Newer agents have been compared with both conventional and lipid preparations of amphotericin B. Compared with amphotericin B products, fluconazole, itraconazole, voriconazole, and caspofungin are responsible for less infusional reactions.34,36,74,92 Furthermore, both voriconazole and caspofungin are associated with less infusional toxicity than liposomal amphotericin B.37,39 No difference in infusional toxicity has been seen when fluconazole and micafungin were compared.78

Continuous amphotericin B infusions result in less nephrotoxicity and infusional toxicity compared with intermittent infusion.154,155 No adult or pediatric trials have compared continuous CAB infusions with lipid preparations. Experimental in vitro and in vivo studies support concentration-dependant killing with a prolonged postantibiotic effect, which suggests that a large daily dose will be most effective and that achieving an optimal peak concentration is important.20 The limitations of vascular access in children with multiple comorbidities and therapies pose significant problems with continuous infusions.

Hepatotoxicity has been assessed in a number of pediatric and adult trials. No significant difference between CAB and any lipid preparation of amphotericin B has been demonstrated.26,28,156 No significant difference has been detected between azoles and conventional or liposomal amphotericin B.33,34,37,67,68,71,92 Furthermore, no significant difference has been observed between caspofungin, CAB, and fluconazole.74,76,77

Rash is seen more frequently in adults who are given fluconazole or voriconazole compared with amphotericin B.34,92 Visual disturbance or eye symptoms are reported more frequently in both adults and children taking voriconazole.37,92

In conclusion, pediatric and adult toxicity data demonstrate clear differences when comparing different agents. Lipid preparations of amphotericin B cause less nephrotoxicity than CAB, yet azoles and echinocandins are less nephrotoxic than all amphotericin B preparations. Preexisting renal impairment, concurrent nephrotoxins, or those receiving large cumulative doses have a higher risk of nephrotoxicity. Hematopoietic stem cell recipients are at the greatest risk of needing dialysis. Rates of infusional toxicity also vary widely: liposomal amphotericin B is associated with less infusional toxicity compared with CAB, yet both azoles and echinocandins seem to result in lower rates than all amphotericin B preparations. Rash, visual disturbances (with voriconazole), and drug interactions with azoles create additional complexity when administering antifungal therapy.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 CONCLUSIONS
REFERENCES
 
IFIs continue to be associated with significant mortality and morbidity. Despite significant differences in pediatric antifungal pharmacokinetics, few adequately powered pediatric trials have been conducted to compare the efficacy and toxicity of different antifungal agents. Pediatricians often rely on adult data with results extrapolated to children.

No consistent differences in treatment success or mortality rate have been demonstrated in comparative trials in patients with fever with neutropenia, candidemia, and invasive candidiasis. Initial therapy with voriconazole is superior to conventional amphotericin B in aspergillosis, with an associated survival advantage. Numerous differences in antifungal toxicity have been observed in children and adults when conventional amphotericin B is compared with newer antifungal agents. Insufficient evidence is available to recommend routine use of combination therapy for candidemia or aspergillosis.

Additional research on antifungal agents in children to assess pharmacokinetics and toxicity of newer agents, relative efficacy, and cost is needed. Given the difficulties in performing adequately powered efficacy trials in children, in whom the incidence of IFIs is low, the ongoing extrapolation of adult data to pediatric practice is likely to be required.


   ACKNOWLEDGMENTS
 
We thank Professor Tania Sorrell, Dr Monica Slavin, Associate Professor David Ellis, Dr Nicky Gilroy, Dr Tony Allworth, Dr Karin Thursky, and Dr Leon Worth for assistance and guidance. We also thank Dr Kate Hale for assisting with literature searches and Sally Blyth for her assistance and critical review.


   FOOTNOTES
 
Accepted Dec 12, 2006.

Address correspondence to Pamela Palasanthiran, MBBS, FRACP, MD, Department of Immunology and Infectious Diseases, Sydney Children's Hospital, High Street, Randwick, New South Wales 2130, Australia. E-mail: pamela.palasanthiran{at}sesiahs.health.nsw.gov.au

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
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 REFERENCES
 

  1. Kossoff EH, Buescher ES, Karlowicz MG. Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases. Pediatr Infect Dis J. 1998;17 :504 –508[CrossRef][ISI][Medline]
  2. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34 :909 –917[CrossRef][ISI][Medline]
  3. Asmundsdottir LR, Erlendsdottir H, Gottfredsson M. Increasing incidence of candidemia: results from a 20-year nationwide study in Iceland. J Clin Microbiol. 2002;40 :3489 –3492[Abstract/Free Full Text]
  4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348 :1546 –1554[Abstract/Free Full Text]
  5. Manno G, Scaramuccia A, Rossi R, Coppini A, Cruciani M. Trends in antifungal use and species distribution among Candida isolates in a large paediatric hospital. Int J Antimicrob Agents. 2004;24 :627 –628[CrossRef][ISI][Medline]
  6. Nguyen MH, Peacock JE Jr, Morris AJ, et al. The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. Am J Med. 1996;100 :617 –623[CrossRef][ISI][Medline]
  7. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP; National Nosocomial Infections Surveillance System Hospitals. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989–1999. Clin Infect Dis. 2002;35 :627 –630[CrossRef][ISI][Medline]
  8. Baran J Jr, Muckatira B, Khatib R. Candidemia before and during the fluconazole era: prevalence, type of species and approach to treatment in a tertiary care community hospital. Scand J Infect Dis. 2001;33 :137 –139[CrossRef][ISI][Medline]
  9. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis. 2005;41 :1232 –1239[CrossRef][ISI][Medline]
  10. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110 :285 –291[Abstract/Free Full Text]
  11. Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 1996;129 :63 –71[CrossRef][ISI][Medline]
  12. Benjamin DK, DeLong E, Cotten CM, Garges HP, Steinbach WJ, Clark RH. Mortality following blood culture in premature infants: increased with Gram-negative bacteremia and candidemia, but not Gram-positive bacteremia. J Perinatol. 2004;24 :175 –180[CrossRef][Medline]
  13. Saiman L, Ludington E, Pfaller M, et al. Risk factors for candidemia in neonatal intensive care unit patients. The National Epidemiology of Mycosis Survey study group. Pediatr Infect Dis J. 2000;19 :319 –324[CrossRef][ISI][Medline]
  14. Pappas PG, Rex JH, Lee J, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37 :634 –643[CrossRef][ISI][Medline]
  15. Rodriguez-Nunez A. Incidence and mortality of proven invasive Candida infections in pediatric intensive care patients. Infect Control Hosp Epidemiol. 2001;22 :477 –478[CrossRef][ISI][Medline]
  16. Walmsley S, Devi S, King S, Schneider R, Richardson S, Ford-Jones L. Invasive Aspergillus infections in a pediatric hospital: a ten-year review. Pediatr Infect Dis J. 1993;12 :673 –682[ISI][Medline]
  17. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32 :358 –366[CrossRef][ISI][Medline]
  18. Abbasi S, Shenep JL, Hughes WT, Flynn PM. Aspergillosis in children with cancer: a 34-year experience. Clin Infect Dis. 1999;29 :1210 –1219[CrossRef][ISI][Medline]
  19. Shetty D, Giri N, Gonzalez CE, Pizzo PA, Walsh TJ. Invasive aspergillosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1997;16 :216 –221[CrossRef][ISI][Medline]
  20. Groll AH, Kolve H. Antifungal agents: in vitro susceptibility testing, pharmacodynamics, and prospects for combination therapy. Eur J Clin Microbiol Infect Dis. 2004;23 :256 –270[CrossRef][ISI][Medline]
  21. Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis. 2003;37(suppl 3) :S157 –S187[CrossRef]
  22. Krupova Y, Sejnova D, Dzatkova J, et al. Prospective study on fungemia in children with cancer: analysis of 35 cases and comparison with 130 fungemias in adults. Support Care Cancer. 2000;8 :427 –430[CrossRef][ISI][Medline]
  23. Bodey G, Bueltmann B, Duguid W, et al. Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis. 1992;11 :99 –109[CrossRef][ISI][Medline]
  24. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med. 1982;72 :101 –111[CrossRef][ISI][Medline]
  25. Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group. Am J Med. 1989;86 :668 –672[CrossRef][ISI][Medline]
  26. Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98 :711 –718[CrossRef][ISI][Medline]
  27. Sandler ESM, Mustafa MM, Tkaczewski IRN, et al. Use of amphotericin B colloidal dispersion in children. J Pediatr Hematol Oncol. 2000;22 :242 –246[CrossRef][ISI][Medline]
  28. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340 :764 –771[Abstract/Free Full Text]
  29. White MH, Bowden RA, Sandler ES, et al. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis. 1998;27 :296 –302[ISI][Medline]
  30. Johansen HK, Gotzsche PC. Amphotericin B lipid soluble formulations vs amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev. 2000;(3) :CD000969
  31. Wingard JR, White MH, Anaissie E, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis. 2000;31 :1155 –1163[CrossRef][ISI][Medline]
  32. Kim SY, Park JS, Jeong NG, Jeong DC, Cho B, Kim HW. Amphotericin B and itraconazole as empirical antifungal therapy in children with acute leukemia with neutropenic fever [abstract (not selected for publication)]. Presented at: American Society of Hematology 47th annual meeting and exposition; December 10–13, 2005; Atlanta, GA
  33. Malik IA, Moid I, Aziz Z, Khan S, Suleman M. A randomized comparison of fluconazole with amphotericin B as empiric anti-fungal agents in cancer patients with prolonged fever and neutropenia. Am J Med. 1998;105 :478 –483[CrossRef][ISI][Medline]
  34. Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med. 2000;108 :282 –289[CrossRef][ISI][Medline]
  35. Viscoli C, Castagnola E, Van Lint MT, et al. Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial. Eur J Cancer. 1996;32A :814 –820[CrossRef]
  36. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized, controlled trial. Ann Intern Med. 2001;135 :412 –422[Abstract/Free Full Text]
  37. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346 :225 –234[Abstract/Free Full Text]
  38. Khayat N, Amsallem D, Nerich V, et al. Caspofungin versus liposomal amphotericin B for empirical therapy in children with persistently febrile neutropenia [abstract G-939]. Presented at: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16–19, 2005; Washington, DC
  39. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351 :1391 –1402[Abstract/Free Full Text]
  40. Zaoutis TE, Greves HM, Lautenbach E, Bilker WB, Coffin SE. Risk factors for disseminated candidiasis in children with candidemia. Pediatr Infect Dis J. 2004;23 :635 –641[ISI][Medline]
  41. Levy I, Rubin LG, Vasishtha S, Tucci V, Sood SK. Emergence of Candida parapsilosis as the predominant species causing candidemia in children. Clin Infect Dis. 1998;26 :1086 –1088[ISI][Medline]
  42. Chen S, Slavin M, Nguyen Q, et al. Active surveillance for candidemia, Australia. Emerg Infect Dis. 2006;12 :1508 –1516[ISI][Medline]
  43. Ellis D. Laboratory methods: antifungal susceptibility profiles. 2006. Available at: www.mycology.adelaide.edu.au/Laboratory_Methods/Antifungal_Susceptibility_Testing/astprofiles.htm. Accessed November 29, 2006
  44. Faix RG. Invasive neonatal candidiasis: comparison of albicans and parapsilosis infection. Pediatr Infect Dis J. 1992;11 :88 –93[ISI][Medline]
  45. Juster-Reicher A, Flidel-Rimon O, Amitay M, Even-Tov S, Shinwell E, Leibovitz E. High-dose liposomal amphotericin B in the therapy of systemic candidiasis in neonates. Eur J Clin Microbiol Infect Dis. 2003;22 :603 –607[CrossRef][ISI][Medline]
  46. Linder N, Klinger G, Shalit I, et al. Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J Antimicrob Chemother. 2003;52 :663 –667[Abstract/Free Full Text]
  47. Adler-Shohet F, Waskin H, Lieberman JM. Amphotericin B lipid complex for neonatal invasive candidiasis. Arch Dis Child Fetal Neonatal Ed. 2001;84 :F131 –F133[Abstract/Free Full Text]
  48. Juster-Reicher A, Leibovitz E, Linder N, et al. Liposomal amphotericin B (AmBisome) in the treatment of neonatal candidiasis in very low birth weight infants. Infection. 2000;28 :223 –226[CrossRef][ISI][Medline]
  49. Scarcella A, Pasquariello MB, Giugliano B, Vendemmia M, de Lucia A. Liposomal amphotericin B treatment for neonatal fungal infections. Pediatr Infect Dis J. 1998;17 :146 –148[CrossRef][ISI][Medline]
  50. Lopez Sastre JB, Coto Cotallo GD, Fernandez CB, Grupo dHC. Neonatal invasive candidiasis: a prospective multicenter study of 118 cases. Am J Perinatol. 2003;20 :153 –163[CrossRef][ISI][Medline]
  51. Weitkamp JH, Poets CF, Sievers R, et al. Candida infection in very low birth-weight infants: outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome). Infection. 1998;26 :11 –15[ISI][Medline]
  52. Cetin H, Yalaz M, Akisu M, Hilmioglu S, Metin D, Kultursay N. The efficacy of two different lipid-based amphotericin B in neonatal Candida septicemia. Pediatr Int. 2005;47 :676 –680[CrossRef][ISI][Medline]
  53. Schwarze R, Penk A, Pittrow L. Treatment of candidal infections with fluconazole in neonates and infants. Eur J Med Res. 2000;5 :203 –208[Medline]
  54. Huttova M, Hartmanova I, Kralinsky K, et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J. 1998;17 :1012 –1015[CrossRef][ISI][Medline]
  55. Fasano C, O'Keeffe J, Gibbs D. Fluconazole treatment of neonates and infants with severe fungal infections not treatable with conventional agents. Eur J Clin Microbiol Infect Dis. 1994;13 :351 –354[CrossRef][ISI][Medline]
  56. Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J. 2004;23 :1093 –1097[ISI][Medline]
  57. Natarajan G, Lulic-Botica M, Rongkavilit C, Pappas A, Bedard M. Experience with caspofungin in the treatment of persistent fungemia in neonates. J Perinatol. 2005;25 :770 –777[CrossRef][Medline]
  58. Singhi SC, Reddy TC, Chakrabarti A. Oral itraconazole in treatment of candidemia in a pediatric intensive care unit. Indian J Pediatr. 2004;71 :973 –977[Medline]
  59. Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J. 2002;21 :240 –248[CrossRef][ISI][Medline]
  60. Herbrecht R, Auvrignon A, Andres E, et al. Efficacy of amphotericin B lipid complex in the treatment of invasive fungal infections in immunosuppressed paediatric patients. Eur J Clin Microbiol Infect Dis. 2001;20 :77 –82[CrossRef][ISI][Medline]
  61. Presterl E, Graninger W. Efficacy and safety of fluconazole in the treatment of systemic fungal infections in pediatric patients. Multicentre Study Group. Eur J Clin Microbiol Infect Dis. 1994;13 :347 –351[CrossRef][ISI][Medline]
  62. Fasano C, O'Keeffe J, Gibbs D. Fluconazole treatment of children with severe fungal infections not treatable with conventional agents. Eur J Clin Microbiol Infect Dis. 1994;13 :344 –347[CrossRef][ISI][Medline]
  63. Wiley JM, Seibel NL, Walsh TJ. Efficacy and safety of amphotericin B lipid complex in 548 children and adolescents with invasive fungal infections. Pediatr Infect Dis J. 2005;24 :167 –174[CrossRef][ISI][Medline]
  64. Ostrosky-Zeichner L, Oude Lashof AM, Kullberg BJ, Rex JH. Voriconazole salvage treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis. 2003;22 :651 –655[CrossRef][ISI][Medline]
  65. Groll AH, Attarbaschi A, Schuster FR, et al. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother. 2006;57 :527 –535[Abstract/Free Full Text]
  66. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, et al. International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia. Eur J Clin Microbiol Infect Dis. 2005;24 :654 –661[CrossRef][ISI][Medline]
  67. Driessen M, Ellis JB, Cooper PA, et al. Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective randomized trial. Pediatr Infect Dis J. 1996;15 :1107 –1112[CrossRef][ISI][Medline]
  68. Mondal RK, Singhi SC, Chakrabarti AMJ. Randomised comparison between fluconazole and itraconazole for the treatment of candidaemia in a pediatric intensive care unit: a preliminary study. Pediatr Crit Care Med. 2004;5 :561 –555[CrossRef][Medline]
  69. Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis. 1996;23 :964 –972[ISI][Medline]
  70. Phillips P, Shafran S, Garber G, et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group. Eur J Clin Microbiol Infect Dis. 1997;16 :337 –345[CrossRef][ISI][Medline]
  71. Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med. 1994;331 :1325 –1330[Abstract/Free Full Text]
  72. Kullberg BJ, Sobel J, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet. 2005;366 :1435 –1442[CrossRef][ISI][Medline]
  73. Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 2001;33 :1447 –1454[CrossRef][ISI][Medline]
  74. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347 :2020 –2029[Abstract/Free Full Text]
  75. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, Dinubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother. 2002;46 :451 –457[Abstract/Free Full Text]
  76. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, Dinubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33 :1529 –1535[CrossRef][ISI][Medline]
  77. Villanueva A, Gotuzzo E, Arathoon EG, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113 :294 –299[CrossRef][ISI][Medline]
  78. de Wet NT, Bester AJ, Viljoen JJ, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther. 2005;21 :899 –907[CrossRef][ISI][Medline]
  79. Krause DS, Simjee AE, van Rensburg C, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis. 2004;39 :770 –775[CrossRef][ISI][Medline]
  80. Kartsonis N, Dinubile MJ, Bartizal K, Hicks PS, Ryan D, Sable CA. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J Acquir Immune Defic Syndr. 2002;31 :183 –187[ISI][Medline]
  81. Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38 :161 –189[CrossRef][ISI][Medline]
  82. Donowitz LG, Hendley JO. Short-course amphotericin B therapy for candidemia in pediatric patients. Pediatrics. 1995;95 :888 –891[Abstract/Free Full Text]
  83. Nucci M, Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidence-based review. Clin Infect Dis. 2002;34 :591 –599[CrossRef][ISI][Medline]
  84. Kontoyiannis DP, Bodey GP. Invasive aspergillosis in 2002: an update. Eur J Clin Microbiol Infect Dis. 2002;21 :161 –172[CrossRef][ISI][Medline]
  85. Walsh TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J. 1999;18 :702 –708[CrossRef][ISI][Medline]
  86. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect. 2006;53 :337 –349[CrossRef][ISI][Medline]
  87. White MH, Anaissie EJ, Kusne S, et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis. 1997;24 :635 –642[ISI][Medline]
  88. Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2002;35 :359 –366[CrossRef][ISI][Medline]
  89. Leenders AC, Daenen S, Jansen RL, et al. Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol. 1998;103 :205 –212[CrossRef][ISI][Medline]
  90. Ellis M, Spence D, de Pauw B, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis. 1998;27 :1406 –1412[ISI][Medline]
  91. Cornely OA, Maertens J, Bresnik M, Herbrecht R. Liposomal amphotericin B (L-AMB) as initial therapy for invasive filamentous fungal infections (IFFI): a randomised prospective trial of a high loading regimen vs standard dosing (AmBiLoad Trial) [poster 3222]. Presented at: American Society of Haematology 47th annual meeting and exposition; December 10–13, 2005; Atlanta, GA
  92. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347 :408 –415[Abstract/Free Full Text]
  93. Maertens J, Raad II, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39 :1563 –1591[CrossRef][ISI][Medline]
  94. Kohno S, Masaoka T, Yamaguchi H, et al. A multicenter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan. Scand J Infect Dis. 2004;36 :372 –379[CrossRef][ISI][Medline]
  95. Kartsonis NA, Saah AJ, Joy LC, Taylor AF, Sable CA. Salvage therapy with caspofungin for invasive aspergillosis: results from the caspofungin compassionate use study. J Infect. 2005;50 :196 –205[CrossRef][ISI][Medline]
  96. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis. 2003;36 :1221 –1228[CrossRef][ISI][Medline]
  97. Marr KA, Boeckh M, Carter RA, Kim HW. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004;39 :797 –802[CrossRef][ISI][Medline]
  98. Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978;13 :271 –276[Abstract/Free Full Text]
  99. Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother. 1989;33 :1989 –1993[Abstract/Free Full Text]
  100. Nath CE, McLachlan AJ, Shaw PJ, Gunning R, Earl JW. Population pharmacokinetics of amphotericin B in children with malignant diseases. Br J Clin Pharmacol. 2001;:671 –680
  101. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis. 1994;13 :325 –329[CrossRef][ISI][Medline]
  102. Lee JW, Seibel NL, Amantea M, Whitcomb P, Pizzo PA, Walsh TJ. Safety and pharmacokinetics of fluconazole in children with neoplastic diseases. J Pediatr. 1992;120 :987 –993[CrossRef][ISI][Medline]
  103. Seay RE, Larson TA, Toscano JP, Bostrom BC, O'Leary MC, Uden DL. Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseases. Pharmacotherapy. 1995;15 :52 –58[ISI][Medline]
  104. Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48 :2166 –2172[Abstract/Free Full Text]
  105. Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49 :4536 –4545[Abstract/Free Full Text]
  106. Odio CM, Pinto LE, Alfaro B, et al. Pharmacokinetics (PK) of caspofungin (CAS) in six premature neonates (PNN) with invasive candidiasis (IC) at a neonatal intensive care unit (NNICU) [abstract LB-16]. Presented at: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16–19, 2005; Washington, DC
  107. Schmitt C, Perel Y, Harousseau JL, et al. Pharmacokinetics of