Pediatric pharmacology of established antifungal agents

Amphotericin B deoxycholate

For many years, amphotericin B deoxycholate (DAMB) has been the standard agent for systemic antifungal therapy. Amphotericin B primarily acts by binding to ergosterol in the fungal cell membrane, leading to pore formation and ultimately, cell death [189]. Amphotericin B possesses a broad spectrum of antifungal activity that includes most fungi pathogenic in humans. However, some of the emerging pathogens such as A. terreus, Tr. beigelii, Scedosporium prolificans and certain Fusarium spp. may be micro-biologically and clinically resistant [101].

After IV administration of the deoxycholate formulation, amphotericin B rapidly dissociates from its vehicle and becomes highly protein bound before distributing predominantly into liver, spleen, bone marrow, kidney, lung and other sites [190]. Elimination from the body is slow; only small quantities are excreted into urine and bile [191, 192]. Due to the hetero-genicity in underlying disease conditions and differences in the modes of administration, the reported pharmacokinetics of DAMB in pediatric patients are characterized by a high variability among individual patients [193-197]. Infants and children appear to clear the drug more rapidly than adults, as indicated by a significant negative correlation between patient age and clearance of DAMB [194, 195]. Whether this enhanced clearance from the bloodstream has implications for dosing remains to be elucidated as systematic studies correlating pharmacokinetic parameters with measures of outcome or toxicity have not been performed to date.

Infusion-related reactions and nephrotoxicity are major problems associated with the use of DAMB and often limit successful therapy. Infusion-related reactions (fever, rigors, chills, myalgias, arthralgias, nausea, vomiting, and headaches) are thought to be mediated by the release of cytokines from monocytes in response to the drug [198] and can be noted in up to 73% of patients prospectively monitored at the bedside [199]. In a more recent prospective study in pediatric cancer patients, fever and/or rigors associated with the infusion of DAMB were observed in 19 of 78 treatment courses (24%) [200]. Interestingly, however, these so characteristic adverse effects of DAMB are only rarely observed in the neonatal setting [38]. Infusion-related reactions may be blunted by slowing the infusion rate, but often require acetaminophen, hydrocortisone (0.5-1.0 mg/kg) or meperidine (0.2-0.5 mg/kg) premedication [28]. Less common are hypotension, hypertension, flushing and vestibular disturbances; bronchospasm and true ana-phylaxis are rare [201]. Cardiac arrhythmias and cardiac arrest due to acute potassium release may occur with rapid infusion (< 60 min), in particular if there is preexisting hyperkalemia and/or renal impairment [202, 203].

The hallmarks of amphotericin B-associated nephrotoxicity are azote-mia, wasting of potassium and magnesium; tubular acidosis and impaired urinary concentration ability are rarely of clinical significance [201, 204]. As assessed prospectively in a large clinical trials in the setting of empirical therapy in persistently granulocytopenic patients, relevant electrolyte wasting occurs in approximately 12%, and increases in the serum creatinine by more than 100% in 34% of patients [199]. Azotemia can be exacerbated by concomitant nephrotoxic agents, in particular by cyclosporine and tacro-limus, but also by aminoglycosides and glycopeptides [205]. While some data suggest a somewhat lower rate of azotemia in children as compared to adults [206], this has not been a consistent observation [205]. Of note, DAMB-associated azotemia has been reported in only 2% of pediatric cancer patients receiving the drug at 1 mg/kg/day for comparatively short periods as empirical antifungal therapy [200]; in premature neonates, in more contemporary series containing safety data of DAMB (0.5-1.0 mg/ kg), the incidence of azotemia ranged from zero to 15% [38-41], indicat-

Table 2. Medical management of invasive infections by opportunistic yeast

Fungal disease

Management

Uncomplicated candidemia or invasive candidiasis

Acute dissem. candidiasis with hemodynamic instability

Second line therapy of

- refractory infections

- limiting toxicity

Amphotericin B deoxycholate (0.6-1.0 mg/kg/day) (A-I)

- Fluconazole (8-12 mg/kg/day; max. 800 mg/day) (A-I)

- Fluconazole (16 mg/kg/day plus amphotericin B deoxycholate (0.7 mg/kg/day for days 1-5) (A-I)

- Voriconazole (4 mg/kg bid IV; day 1:12 mg/kg)** (A-I)

Amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine*** (100 mg/kg/day in 3-4 dosages) (B-III)

- Liposomal amphotericin B (3-5 mg/kg/day) (A-II) Amphotericin B lipid complex (5 mg/kg/day) (B-II)

- Voriconazole (4 mg/kg bid IV; day 1:12 mg/kg)** (B-II)

Cerebral cryptococcosis

Extracerebral manifestations

- Amphotericin B deoxycholate (0.7 mg/kg/day) plus flucytosine*** (100 mg/kg/day in 3-4 dosages) for a 2 weeks (induction), followed by fluconazole (8-12 mg/kg/day) (consolidation/maintenance) (A-I)

- "Second line" for intolerance of amphotericin B deoxy-cholate: Liposomal amphotericin B (5 mg/kg/day) (B-II); in case of polyene intolerance: Fluconazole (8-12 mg/kg/ day) plus flucytosine*** (B-II)

- Amphotericin B deoxycholate (0.7-1.0 mg/kg/day) (C-III)

- Amphotericin B deoxycholate (0.7 mg/kg/day) plus flucytosine*** (100 mg/kg/d in 3-4 dosages) (C-III)

* Adult dosage, not approved for individuals < 18 years; proposed pediatric dosage: 50 mg/m2/ day (day 1: 70 mg/m2, max.: 70 mg/day).

** IV dosage for patients > 11 years; IV dosage for children from 2 to 11 years: 7 mg/kg/day without loading dose.

*** Monitoring of plasma concentrations recommended (> 40 to < 100 ^g/mL).

ing that DAMB is much better tolerated than previously reported [207]. The renal toxicity associated with DAMB therapy may lead to renal failure and dialysis; however, azotemia most often stabilizes on therapy and is usually reversible after discontinuation of the drug [28]. Avoiding concomitant nephrotoxic agents, and using appropriate hydration and normal saline loading (10-15 mL NaCl/kg/day) [208-210] may lessen the likelihood and severity of azotemia.

With the advent of new antifungal agents and following the completion of pivotal clinical Phase III trials, a few indications are left for antifun-gal treatment of opportunistic mycoses with conventional deoxycholate amphotericin B (Tabs 2-4). These include candidemia and acute disseminated candidiasis, particular in neonates, and induction therapy for crypto-coccal meningitis. The recommended daily dosage in these settings ranges from 0.7 to 1.0 mg/kg/day administered over 2-4 h as tolerated. Treatment

Table 3. Medical management of invasive infections by opportunistic molds

Fungal disease

Management

Invasive aspergillosis

- First line

- Second line for

- refractory infections

- limiting toxicity

Therapy of immediately life-threatening infections

Consolidation therapy

- Voriconazole (4 mg/kg IV bid, day 1: 12 mg/kg) (A-I)*

- Amphotericin B lipid complex (5 mg/kg/day) (A-II)

- Caspofungin (50 mg/day IV; day 1: 70 mg) (A-II)***

- Voriconazole (4 mg/kg bid IV; day 1: 12 mg/kg) (A-II)*

- Liposomal amphotericin B (a 5 mg/kg/day) plus caspofungin (50 mg/day IV; day 1: 70 mg) (C-III)***

- Voriconazole (4 mg/kg/day IV; day 1: 12 mg/kg)** plus caspofungin (50 mg/day IV; day 1: 70 mg) (C-III)***

- Posaconazole (400 mg bid or 200 mg qid PO) (B-III)##

Non-Aspergillus hyalo-hyphomycetes

- Voriconazole (4 mg/kg bid IV; day 1: 12 mg/kg) (B-III)*

- Liposomal amphotericin B (5-10 mg/kg/day IV) (C-III)

- Amphotericin B lipid complex (5 mg/kg/day) (C-III)

- Posaconazole (400 mg bid or 200 mg qid PO) (B-III)##

Zygomyces infections

- Liposomal amphotericin B (5-10 mg/kg/day) (B-II)

- Amphotericin B lipid complex (a 5 mg/kg/day) (B-II)

- Posaconazole (400 mg bid or 200 mg qid PO) for second line therapy only (B-II)##

Infection by pigmented filamentous fungi

- Voriconazole (4 mg/kg bid; day 1: 12 mg/kg) (C-III)*

- Liposomal amphotericin B (a 5 mg/kg/day) (C-III) Amphotericin B Lipid Complex (5 mg/kg/day) (C-III)

- Posaconazole (400 mg bid or 200 mg qid PO) (B-III)##

* IV dosage for patients >11 years; IV dosage for children of 2-11 years: 7 mg/kg/day without loading dose. PO dosages from 2 years onward: 200 mg bid.

** Based on a recently presented clinical trial [345]

*** Adult dosage, not approved for individuals < 18 years; proposed pediatric dosage: 50 mg/ m2/day (day 1:70 mg/m2, max.: 70 mg/day)

# Proposed pediatric dosage, monitoring of plasma trough concentrations recommended (target: > 0.5 ^g/mL)

## Not approved in pediatric patients; 800 mg/day have been safely given to children > 12 years of age.

should be started at the full target dosage with careful bedside monitoring during the first hour of infusion [28, 106]. While better tolerated, continuous infusion over 24 h is not recommended due to the complete lack of efficacy data [211].

Lipid formulations of amphotericin B

During the past decade, three novel formulations of amphotericin B have become available for clinical use: AMB colloidal dispersion (ABCD,

Invasive fungal infections in children: advances and perspectives Table 4. Medical management of invasive infections by endemic molds

Fungal disease

Management

Histoplasmosis

Liposomal amphotericin B (3 mg/kg/day IV) (A-I) Amphotericin B deoxycholate (0.7 mg/kg/day IV) (B-I) Itraconazole*,** (2.5 mg/kg bid) (A-II) Fluconazole*** [(8)-12 mg/kg/day PO/IV] (A-II)

Coccidioidomycosis

Amphotericin B deoxycholate (0.S-1.0 mg/kg/day IV) (A-III) Fluconazole*** [(8)-12 mg/kg/day PO/IV] (A-II) Itraconazole*,** (2.S mg/kg bid) (A-II) Posaconazole (400 mg bid or 200 mg qid PO) (B-III)##

Blastomycosis

Amphotericin B deoxycholate (0.S-1.0 mg/kg/day IV) (A-II) traconazole*,** (2.S mg/kg bid) (A-II)

Paracoccidioidomycosis -Amphotericin B deoxycholate (0.S-1.0 mg/kg/day IV) (A-II) - Itraconazole*,** (2.S mg/kg bid) (B-III)

* Clinically stable patients with mild to moderate disease outside and no CNS involvement, or as consolidation or maintenance therapy. Dosages refer to the cyclodextrin solution.

** Monitoring of trough plasma concentrations is recommended (target: > 0.5 ^g/mL). Intravenous therapy 200 mg BID for 2 days, followed by 200 mg/day for patients > 18 years of age.

*** Agent of first choice in (1) consolidation therapy of meningeal coccidioidomycosis; (2) Coccidioides-meningitis; (3) coccidioidomycosis of stable patients with mild to moderate disease or as consolidation or maintenance therapy.

## Second line therapy; not approved in pediatric patients; 800 mg/day have been safely given to children > 12 years of age.

Amphocil™, or Amphotec™) AMB lipid complex (ABLC or Abelcet™), and a small unilamellar vesicle (SUV) liposomal formulation (LAMB, AmBisome™). In comparison to DAMB, the lipid formulations share a reduced nephrotoxicity, which allows for the safe delivery of higher dosages of AmB [212, 213].

Each of the lipid formulations possesses distinct physicochemical and pharmacokinetic properties (Tab. 5). All three, however, preferentially distribute to the reticuloendothelial system (RES) and functionally spare the kidney. While the micellar dispersion of ABCD behaves very similar as compared to DAMB, the unilamellar liposomal preparation is only slowly taken up by the RES and achieves strikingly high peak plasma concentrations and AUC (area under the plasma concentration time curve) values. In contrast, the large ribbon-like aggregates of ABLC are rapidly taken up by the RES, resulting in lower peak plasma and AUC values [212, 213]. Whether and how the distinct physicochemical and pharmacokinetic features of each formulation translate into different pharmacodynamic properties in vivo is largely unknown.

Safety and antifungal efficacy of ABCD, ABLC, and LAMB have been demonstrated in an array of phase II and III clinical trials in immunocom-

Penicilliosis

Amphotericin B deoxycholate (0.S-1.0 mg/kg /day IV) (A-II) Itraconazole*,** (2.S mg/kg bid) (A-II)

Table 5. Physicochemical properties and multiple-dose pharmacokinetic parameters of the four currently marketed amphotericin B formulations

DAMB ABCD ABLC LAMB

Lipids (molar ratio) Deoxycholate Cholesteryl- DMPC/DMPG HPC/CHOL/

Table 5. Physicochemical properties and multiple-dose pharmacokinetic parameters of the four currently marketed amphotericin B formulations

DAMB ABCD ABLC LAMB

Lipids (molar ratio) Deoxycholate Cholesteryl- DMPC/DMPG HPC/CHOL/

sulfate

(7:3)

DSPG (2:1:

Mol% AMB

34%

50%

50%

10%

Lipid configuration

Micelles

Micelles

Membranelike

suv

Diameter (^m)

0.05

0.12-0.14

1.6-11

0.08

Dosage (mg AMB/kg)

1

5

5

5

Cmax (^g/mL)

2.9

3.1

1.7

58

AUC024 (^g/mL-h)

36

43

14

713

VD (L/kg)

1.1

4.3

131

0.22

Cl (L/h-kg)

0.028

0.117

0.476

0.017

HPC, hydrogenated phosphatidylcholine; CHOL, cholesterol; DSPG, disteaoryl phosphati-dylglycerol; DMPC, dimiristoyl phosphatidylcholine; DMPG, dimiristoyl phosphatidylglyc-erol; suv, small unilamellar vesicles; Cmax, peak plasma concentration; AUC0 24, area under the concentration vs. time curve from 0 to 24 h; VD, volume of distribution; Cl, clearance. Data represent mean values, stem from adult patients and were obtained after different rates of infusion. Modified from [213].

HPC, hydrogenated phosphatidylcholine; CHOL, cholesterol; DSPG, disteaoryl phosphati-dylglycerol; DMPC, dimiristoyl phosphatidylcholine; DMPG, dimiristoyl phosphatidylglyc-erol; suv, small unilamellar vesicles; Cmax, peak plasma concentration; AUC0 24, area under the concentration vs. time curve from 0 to 24 h; VD, volume of distribution; Cl, clearance. Data represent mean values, stem from adult patients and were obtained after different rates of infusion. Modified from [213].

promised patients. The overall response rates in these trials ranged from 53% to 84% in patients with invasive candidiasis and 34% to 59%, respectively, in patients with presumed or documented invasive aspergillosis [201, 214]. A few randomized, controlled trials have been completed in which one of the new formulations has been compared to DAMB [199, 205, 215]. These studies have consistently shown at least equivalent therapeutic efficacy but reduced nephrotoxicity of the lipid formulations [214].

A considerable number of pediatric patients have been treated with either ABCD, ABLC or LAMB within the above-mentioned protocols, but separately published pediatric data are limited with the exception of ABLC.

Amphotericin B colloidal dispersion

Population-based multiple-dose pharmacokinetic studies with ABCD in bone marrow transplant patients with systemic fungal infections included the compartmental analysis of five children < 13 years of age who received the compound at 7.0 and 7.5 mg/kg/day. Estimated pharmacokinetic parameters in these children were not significantly different from those obtained in a dose-matched cohort of adult patients [216]. Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with DAMB; an additional 70 children with presumed or proven fungal infection were treated on five different open-label Phase II trials of ABCD. In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4%; p = 0.003); other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12%; there were no other unexpected severe toxicities [217].

Amphotericin B lipid complex

The pharmacokinetics of ABLC have been studied in pediatric cancer patients who received the compound at 2.5 mg/kg over 6 weeks for hepato-splenic candidiasis; ABLC was effective and well tolerated, and no pharma-cokinetic differences were observed as compared to those in adults [218].

Safety and antifungal efficacy of ABLC were studied in 111 treatment episodes in pediatric patients (21 days to 16 years of age) refractory of or intolerant to conventional antifungal agents through an open label, emergency use protocol. ABLC was administered at a mean daily dosage of 4.85 mg/kg (range, 1.1-9.5 mg/kg/day) for a mean duration of 38.9 days (range, 1-198 days). The mean serum creatinine for the entire study population did not significantly change between baseline (1.23 ± 0.11 mg/100 mL) and cessation of ABLC therapy (1.32 ± 0.12 mg/100 mL) over 6 weeks. No significant differences were observed between baseline and end-of-therapy levels of serum potassium, magnesium, hepatic transaminases, alkaline phospha-tase, and hemoglobin. However, there was an increase in the mean total bilirubin (3.66 ± 0.73-5.13 ± 1.09 mg/100 mL) at the end of therapy (p = 0.054). In 7 patients (6%), ABLC therapy was discontinued because of one or more adverse effects. Among 54 cases fulfilling criteria for evaluation of antifun-gal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy [219]. The safety and efficacy of ABLC was also assessed in 548 children and adolescents who were enrolled in the Collaborative Exchange of Antifungal Research (CLEAR) registry of the manufacturer between 1996 and 2000. Most patients were either intolerant of or refractory to conventional antifungal therapy. Response data were evaluable for 255 of the 285 patients with documented single or multiple pathogens. A complete (cured) or partial (improved) response was achieved in 54.9% of patients. There was no significant difference between the rates of new hemodialysis versus baseline hemodialysis. Elevations in serum creatinine of > 1.5x baseline and > 2.5x baseline values were seen in 24.8% and 8.8% of all patients, respectively. The overall response rate and safety profile in pediatric patients were consistent with earlier reported findings of smaller trials [220].

A population pharmacokinetic study in 28 mostly immature neonates with invasive Candida infections has demonstrated that the disposition of ABLC in neonates is similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on the results of this study and a cure rate of > 80%, a dosage of 2.5-5.0 mg/kg is recommended for treatment of neonatal candidiasis [221].

Liposomal amphotericin B

The pharmacokinetics of LAMB in pediatric patients beyond the neonatal period have been investigated in a formal Phase II dose-escalation trial investigating dosages of 2.5, 5.0, and 7.5 mg/kg in immunocompromised patients and using a population-based approach; the results of these studies indicate that the disposition of LAMB in pediatric patients is not fundamentally different from that in adults and that weight is covariate that determines clearance and volume of distribution [222, 223]. Many pediatric patients have been enrolled on clinical trials with LAMB but were not separately evaluated [199, 224]. Two hundred-four children (mean age, 7 years) with neutropenia and fever of unknown origin were randomized in an open label, multicenter trial to receive either DAMB 1 mg/kg/day (n = 63), LAMB 1 mg/kg/day (n=70) or LAMB 3 mg/kg/day (n=71) for empirical antifungal therapy [206]. Twenty-nine percent of patients treated with 1 mg/kg/day LAMB, 39% of patients treated with 3 mg/kg/day LAMB, and 54% of patients treated with DAMB experienced adverse effects (p = 0.01); nephrotoxicity, defined as 100% or more increase in serum creatinine from baseline, was noted in 8, 11, and 21%, respectively (n.s.). Hypokalemia (< 2.5 mmol/L) occurred 10%, 11%, and 26% of patients (p=0.02), increases in serum transaminase levels (a 110 U/L) in 17%, 23%, and 17% and increases in serum bilirubin (a 35 ^mol/L) in 11%, 12%, and 10% of patients, respectively. Efficacy assessment by intent-to-treat analysis indicated successful therapy in 51% of children treated with DAMB and 64% and 63% in children treated with LAMB at either 1 or 3 mg/kg/day (p = 0.22). LAMB at either 1 or 3 mg/kg/day was significantly safer and at least equivalent to DAMB with regard to resolution of fever of unknown origin [206]. LAMB was well tolerated and effective in small cohorts of immunocompromised children requiring antifungal therapy for proven or suspected infections, including patients with bone marrow transplant for primary immunodeficiencies [225] and cancer patients [226]. A Phase IV analysis of 141 courses of LAMB administered for a mean of 17 days duration at a mean maximum dosage of 2.5 mg/kg for various indications to pediatric cancer/HSCT patients revealed a low rate of adverse events (4%) necessitating discontinuation. While mean GOT, GPT and AP values were slightly higher at end of treatment (p < 0.01), bilirubin and creatinine values were not different from baseline. LAMB had acceptable safety and tolerance and displayed efficacy in prevention and treatment of invasive fungal infections [227].

LAMB (2.5-7 mg/kg/day) was evaluated prospectively in 24 very low birth weight infants (mean birth weight 847 ± 244 g, mean gestational age 26 weeks) with systemic candidiasis. Thirteen infants failed previous antifun-gal therapy with amphotericin B (with or without 5-flucytosine). Candida spp. were isolated from the blood in all 25 episodes and from skin abscesses and urine in four infants each, respectively. The mean duration of therapy was 21 days; the cumulative LAMB dose was 94 mg/kg. Fungal eradication was achieved in 92% of the episodes; 20 (83%) infants were considered clinically cured at the end of treatment. No major adverse effects were recorded; one infant developed increased bilirubin and hepatic transaminase levels during therapy. Four (17%) infants died; in two of them (8%) the cause of death was directly attributed to systemic candidiasis [228]. In a second study undertaken by the same investigators, high-dose (5-7 mg/kg/day) LAMB was evaluated prospectively in 41 episodes of systemic candidiasis occurring in 37 neonates (36 of the 37 were premature infants with very low birth weights). Candida spp. were isolated from blood in all patients and from urine, skin abscesses and peritoneal fluid in 6, 5 and 1 neonates, respectively; 28, 5 and 8 infants received 7, 6-6.5 and 5 mg/kg/day, respectively. Median duration of therapy was 18 days; median cumulative dose was 94 mg/kg. Fungal eradication was achieved in 39 of 41 (95%) episodes; one patient died due to systemic candidiasis on day 12 of therapy. High-dose LAMB was effective and safe in the treatment of neonatal candidiasis. Fungal eradication was more rapid in patients treated early with high doses and in patients who received high-dose LAMB as first-line therapy [229].

The lipid formulations of AMB have less renal toxicity as defined by development of azotemia than conventional AMB; distal tubular toxicity also may be somewhat reduced. Infusion-related side effects of fever, chills, and rigor appear to be substantially less frequent with LAMB. The infusion-related reactions of ABCD and ABLC appear to be similar to those of DAMB. Several individual cases of substernal chest discomfort, respiratory distress and of sharp flank pain have been noted during infusion of LAMB [230, 231]. Similarly, in comparative studies, hypoxic episodes associated with fever and chills were more frequent in ABCD recipients than in DAMB recipients [205, 232]. Mild increases in serum bilirubin and alkaline phosphatase have been registered with all three formulations, and mild increases in serum transaminases with LAMB. However, no case of fatal liver disease has occurred. Pharmacokinetic and safety data from children so far indicate no fundamental differences in these parameters as compared to those obtained in the adult population.

The lipid formulations of amphotericin B are currently licensed for the treatment of patients with invasive mycoses refractory of or intolerant to

DAMB, and, limited to LAMB, for empirical therapy of persistently neu-tropenic patients. Evidence-based, but not formally licensed indications for first-line therapy exist for LAMB for treatment of invasive aspergillosis [233], invasive candidiasis [234], and zygomycosis (all formulations) [106]. The currently recommended therapeutic dosages are 3 (to 5) mg/kg/day for LAMB, and 5 mg/kg for ABCD and ABLC, respectively [106]; the therapeutic dosage for treatment of zygomycosis should not be less than 5 mg/kg/day (Tabs 2-4). Similar to conventional amphotericin B (DAMB), treatment should be started with the full calculated dosage at the infusion rate recommended by the manufacturer.

Antifungal triazoles

The antifungal triazoles have become an important component of the anti-fungal armamentarium. They are associated with overall less toxicity than DAMB, possess a suitable spectrum of activity, and have demonstrated clinical efficacy under many circumstances. The triazoles function by inhibiting the cytochrome P450-dependent conversion of lanosterol to ergosterol, which leads to altered membrane properties and inhibition of cell growth and replication. Whereas fluconazole and itraconazole are now available for more than a decade, new triazoles such as voriconazole and posaconazole have entered the clinical arena only recently [201, 214].

Fluconazole

The availability of fluconazole has been a major advance in antifungal therapy. Its spectrum of activity includes Candida spp, Cryptococcus neoformans, Trichosporon asahii, and endemic dimorphic fungi, but not Aspergillus spp. and the other opportunistic moulds. C. krusei, and to a lesser extent, C. gla-brata are considered intrinsically resistant to fluconazole in vitro [235].

Available as oral and parenteral formulation, fluconazole possesses almost ideal pharmacokinetic properties. Independent of food or intra-gastric pH, oral bioavailability is > 90%. Due to its free solubility in water, protein binding is low and penetration into CSF and tissues is excellent; most of the drug is excreted in an unchanged form into the urine [236]. The plasma pharmacokinetics of fluconazole in pediatric age groups exhibit changes in the volume of distribution and clearance that are characteristic for a water-soluble drug with minor metabolism and predominantly renal elimination. Except for premature neonates, where clearance is decreased, pediatric patients tend to have an increased normalized plasma clearance and a shorter half-life in comparison to adults [237-242] (Tab. 6). As a consequence, dosages at the higher end of the recommended dosage range are necessary for the treatment of invasive mycoses in children. Because

Table 6. Pharmacokinetic parameters of fluconazole in pediatric patients

Age group

VD (L/kg)

Cl (L/h-kg)

T1/2 (h)

Preterm <1500 g

day 1

1.18

0.010

88

day 6

1.84

0.019

67

day 12

2.25

0.031

55

Term neonates

1.43

0.036

28

Infants > 1-6 months

1.02

0.037

19

Children, 5-15 years

0.84

0.031

18

Adult volunteers

0.65

0.015

30

Data represent mean values and are compiled from six studies; VD, volume of distribution; Cl, total clearance; T1/2, elimination half-life. Modified from [211].

Data represent mean values and are compiled from six studies; VD, volume of distribution; Cl, total clearance; T1/2, elimination half-life. Modified from [211].

exposure over time appears to be the pharmacodynamic parameter that is most predictive of antifungal activity [243, 244], fractionating the daily dose is not required in infants and children despite the shorter half-life in these age groups.

In adults, dosages of up to 1200 mg/kg/day have been safely administered over prolonged periods of time [245]. In pediatric patients of all age groups, at dosages of up to 12 mg/kg/day, fluconazole is generally well tolerated [246]. The most common reported side effects in pediatric patients include gastrointestinal disturbances (8%), increases in hepatic transaminases (5%) and skin reactions (1%); toxicity-related discontinuation of therapy with fluconazole occurs in approximately 3% of patients [246]. Severe side effects, including relevant hepatoxicity and exfoliative skin reactions have been reported anectodically in association with fluconazole therapy [201]. Fluconazole undergoes minimal cytochrome P450 (CYP) metabolism but inhibits CYP3A4 and several other isoforms and interacts with enzymes involved in glucuronidation, thereby leading to numerous drug-drug interactions. Due to a lesser affinity for human CYP450 3A, however, number and frequency of relevant drug-drug interactions are lower than those of ketokonazole or itraconazole [214, 247, 248].

Several controlled studies including both neutropenic and non-neutrope-nic adult patients have demonstrated that IV fluconazole (400-800 mg/day) is as effective as DAMB (0.5-1.0 mg/kg/day) against candidemia and other forms of documented or suspected invasive candidiasis, and that it is better tolerated [249-252]. Apart from oropharyngeal and esophageal candidiasis [253-256], fluconazole can thus be used for invasive Candida infections caused by susceptible organisms in patients who are in stable condition and who have not received prior azole therapy [106, 257] (Tab. 2). This also applies to the neonatal setting: In six published series including a 10 patients with proven invasive Candida infections, treatment with fluconazole at a daily dosage of 5-6 mg/kg was successful in 83-97% and crude mortality ranged from 10% to 33%; in none of the altogether 125 patients was flu-conazole discontinued due to toxicity [258-263]. The recommended dosage range for pediatric patients of all age groups is 6-12 mg/kg/day; in view of the faster clearance rate, however, 12 mg/kg/day may be most appropriate dosage for treatment of life-threatening infections in infants and children. Because of an initially decreased clearance in preterm neonates of < 1500 g, we advocate every other day dosing with 6-12 mg/kg during the first week of life in this specific setting.

Further potential indications for fluconazole include consolidation therapy for chronic disseminated candidiasis [264, 265] and cryptococcal meningitis [266, 267]. High dose fluconazole has been used for infections by the yeast Tr. beigelii in non-neutropenic hosts; because of the potential for breakthrough infections by other opportunistic fungi, the addition of DAMB is recommended in persistently neutropenic patients [28]. Fluconazole has become the drug of choice for treatment of coccidioidal meningitis [268] and has proven effectiveness in nonmeningeal coccidioidal infections [269]. However, fluconazole appears comparatively less active than itraconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis, blastomycosis, histoplasmosis and sporotrichosis [270-275] (Tab. 4).

Fluconazole is also active in preventing mucosal candidiasis in patients with HIV infection or cancer [276-278] and has proven efficacy in preventing invasive Candida infections in patients undergoing bone marrow transplantation [279, 280]. Fluconazole has been shown to reduce Candida infections in low birth weight infants [281-286]. Thus, fluconazole prophylaxis is a valid option for centers with a high frequency (> 10%) of invasive Candida infections in premature infants of < 1000 g birth weight or in the setting of a nosocomial outbreak by a fluconazole-susceptible Candida species.

Itraconazole

Itraconazole has antifungal activity comparable to fluconazole but also possesses activity against Aspergillus spp. and certain dematiaceous moulds [201, 214]. In contrast to fluconazole, however, itraconazole is water-insoluble, highly protein-bound and undergoes extensive metabolism in the liver. Absorption from the capsule form is highly dependent on a low intragastric pH, compromised in the fasting state and thus often erratic [201, 247]. The hydroxypropyl-p-cyclodextrin solution of itraconazole improves oral bioavailability [287, 288] and, in conjunction with the IV formulation [289-291], has enhanced the clinical utility of itraconazole.

Itraconazole is usually well tolerated with a similar pattern and an approximately identical frequency of adverse effects as fluconazole [247]. However, both propensity and extent of drug-drug interactions through interference with mammalian cytochrome P450-dependent drug metabolism appear greater [201, 214].

The safety and pharmacokinetics of cyclodextrin itraconazole solution in immunocompromised pediatric patients have been studied in two Phase II clinical trials [292, 293]. The solution was well tolerated and safe in 26 infants and children with cancer (n = 20) or liver transplantation who received the compound at 5 mg/kg/day for documented mucosal candidiasis or as antifungal prophylaxis for 2 weeks [292]. Treatment with cyclodextrin itraconazole achieved potentially therapeutic concentrations of itraconazole in plasma; these levels, however, were substantially lower than those reported in adult cancer patients [294]. In a cohort of 26 HIV-infected children and adolescents, cyclodextrin itraconazole was safe and effective for treatment of OPC at dosages of 2.5 mg/day or 2.5 mg twice a day (bid) given for at least 14 days. Both dosage regimens resulted in higher peak plasma concentrations and AUC 0-24-h values than reported in the above referenced study in pediatric cancer patients. Based on safety and efficacy, a dosage of 2.5 mg/kg bid was recommended for the treatment of OPC in pediatric patients a 5 years old. [293]. Vomiting (12%), abnormal liver function tests (5%) and abdominal pain (3%) were the most common adverse effects considered definitely or possibly related to cyclodextrin itraconazole solution in an open study in 103 neutropenic pediatric patients who received the drug at 5 mg/kg/day for antifungal prophylaxis; 18% of patients withdrew from the study because of adverse events [295]. No experience with the IV formulation in pediatric patients has been reported. Similarly, only anecdotal reports have been published on the use of itraconazole in the neonatal setting.

Itraconazole is a useful agent for dermatophytic infections and pityiasis versicolor [296, 297]. It is effective in the treatment of OPC and esophageal candidiasis including adult and pediatric patients who have developed resistance to fluconazole [292, 293, 298]. The clinical efficacy of itraconazole in candidemia and deeply invasive Candida infections has not been systematically evaluated. However, itraconazole is used for long-term treatment of cryptococcal meningitis in patients with HIV infection [266, 267].

Itraconazole is approved as second line agent for treatment of invasive Aspergillus infections; two separate uncontrolled studies that have investigated oral itraconazole for treatment of proven or probable invasive asper-gillosis suggest a response rate comparable to that reported for amphoteri-cin B [299, 300] (Tab. 3). Current experience with the IV formulation for this indication is promising but limited [291]. Itraconazole may also be indicated for treatment of invasive infections by dematiaceous moulds [301], but it has no documented activity against zygomycosis and fusariosis.

Itraconazole is the current treatment of choice for lymphocutaneous sporotrichosis [302] and non-life-threatening, nonmeningeal paracoccidioi-domycosis, blastomycosis, and histoplasmosis in non-immunocompromised patients [63, 303-305]. It also has established efficacy in both induction and maintenance therapy of mild-to-moderate, non-meningeal histoplasmosis in HIV-infected patients [306, 307]. The activity of itraconazole against nonmeningeal and meningeal cocidioidomycosis appears somewhat inferior to that of fluconazole [308-310]. It should be emphasized, however, that amphotericin B remains the treatment of choice for most immunocompro-mised patient and those with life-threatening infections by the endemic fungi [201, 214] (Tab. 4).

Prophylactic itraconazole may reduce the incidence of proven or suspected invasive fungal infections in patients with hematological malignancies [311] and following HSCT [312, 313]. Efficacy in the prevention of invasive aspergillosis is supported by a large meta analysis [314] but not by a randomized, comparative trial. Finally, itraconazole was at least as effective as conventional amphotericin B, and was superior with respect to its safety profile when investigated as empirical antifungal therapy in persistently neutropenic cancer patients [290].

The recommended dosage range for oral itraconzole in pediatric patients beyond the neonatal period is 5-8 (12) mg/kg/day [corresponding to dosages of 200-400 (600) mg/day recommended for adults] with a loading dose of 4 mg/kg three times a day (tid) for the first 3 days. Achievement of adequate plasma levels is important, and drug monitoring is strongly recommended in patients with serious disease. The recommended target level is > 0.5 ^g/mL before the next dose, as measured by HPLC [106]. Data on the use of IV itraconazole in pediatric patients are currently lacking; the dosage regimen utilized in the published adult studies is 200 mg bid for 2 days, followed by 200 mg/day for a maximum of 12 days [290, 291].

5-Fluorocytosine (5-FC)

5-Fluorocytosine (5-FC) is a fungus-specific synthetic base-analog that acts by causing RNA-miscoding and inhibition of DNA synthesis. Its antifungal activity in vitro is essentially limited to yeasts and certain dematiaceous fungi [315].

In the U.S., 5-FC is available only as oral formulation; in several European countries, 5-FC is also marketed as IV solution. The low-molecular-weight, water-soluble compound is readily absorbed from the gastrointestinal tract. 5-FC has negligible protein binding and distributes well into all tissues and body fluids, including the CSF. In humans, less than 1% of a given dose of 5-FC is believed to undergo hepatic metabolism; approximately 90% is excreted into the urine in an unchanged form by glomerular filtration with an elimination half-life from plasma of 3-6 h in patients with normal renal function [201]. In neonates, an extreme interindividual variability in clearance and distribution volume has been reported [196]; separate pharmaco-kinetic data for infants and children are lacking.

Due to the propensity of susceptible organisms to develop resistance in vitro [316], 5-FC is traditionally not administered as a single agent. An established indication is its use in combination with DAMB for induction therapy of cryptococcal meningitis [317, 318] (Tab. 2). The combination with DAMB may also be recommended for the treatment of Candida infections involving deep tissues, in particular for Candida meningitis, infections by certain non-albicans Candida species, and critically ill patients [28]. 5-FC in combination with fluconazole may be used for cryptococcal meningitis, when treatment with DAMB or LAMB is not feasible [319].

The major potential toxicities of 5-FC are gastrointestinal intolerance and hematopoietic toxicity, which is possibly due to the conversion of 5-FC into fluorouracil by intestinal bacteria [201]. Close monitoring of plasma levels and adjustment of the dosage is recommended, in particular when there is evidence for impaired renal function; peak plasma levels between 40 and 60 ^g/mL correlate with antifungal activity but are seldom associated with marrow toxicity [315]. A starting dosage for both adults and children of 100 mg/kg daily divided in three or four doses is currently recommended.

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