404 Patrick Gerner in children and adolescents with chronic hepatitis C. Hepatology 41: 1013– 1018 18 Gonzalez-Peralta RP, Kelly DA, Haber B, Molleston J, Murray KF, Jonas MM, Shelton M, Mieli-Vergani G, Lurie Y, Martin S et al (2005) Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 42: 1010–1018 19 Ahn J, Flamm S (2004) Peginterferon-alpha(2b) and ribavirin. Expert Rev Anti Infect Ther 2: 17–25 Pediatric Infectious Diseases Revisited 405 ed. by Horst Schroten and Stefan Wirth © 2007 Birkhäuser Verlag Basel/Switzerland Invasive fungal infections in children: advances and perspectives Andreas H. Groll 1 , Julia Koehler 2 and Thomas J. Walsh 3 1 Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children’s Hospital, Münster, Germany; 2 Division of Infectious Diseases, Children’s Hospital Boston, Boston, Massachusetts, USA; 3 Immunocompromised Host Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA Abstract Invasive fungal infections are important causes of morbidity and mortality in immuno- compromised children. The past two decades have seen a dramatic increase in both num- ber and overall relevance of invasive fungal infections in the hospital. At the same time, however, improved microbiological and imaging techniques together with an increased awareness have shifted the diagnosis of fungal infections from the autopsy theatre to the bedside. Major advances have been made in the definition of fungal diseases, the algo- rithms of antifungal interventions, the design and implementation of clinical trials and the development of standardized in vitro susceptibility testing. Most importantly, however, an array of new antifungal agents has entered the clinical arena and has made antifungal therapy more safe, more effective, but also more complicated. This article reviews some unique features of invasive fungal infections in infants and children and provides an update on the pharmacology of antifungal therapeutics in the pediatric population. Introduction Invasive fungal infections are important causes of morbidity and mortal- ity in immunocompromised children. These infections remain difficult to diagnose and the outcome depends critically on the prompt initiation of appropriate antifungal chemotherapy and restoration of host defenses. The past two decades have seen a dramatic increase in both number and overall relevance of invasive fungal infections in the hospital. At the same time, however, improved microbiological and imaging techniques together with an increased awareness have shifted the diagnosis of fungal infections from the autopsy theatre to the bedside. Major advances have been made in the definition of fungal diseases, the algorithms of antifungal interven- tions, the design and implementation of clinical trials and the development of standardized in vitro susceptibility testing. Most importantly, however, an array of new antifungal agents has entered the clinical arena and has made antifungal therapy more safe, more effective, but also more complicated. 406 Andreas H. Groll et al. Children, in particular neonates and young infants, represent a special population not only in a pharmacological sense but also with regard to epidemiology and manifestations of fungal infections. This review there- fore focuses on unique features of invasive fungal infections in infants and children and the pharmacology of antifungal therapeutics in the pediatric population. Host biology: Aspects unique to pediatric patients Anatomical considerations are important throughout infancy, but particu- larly in preterm neonates. Due to the reduced thickness of the skin, the use of medical devices and the moist environment, preterm neonates have a particular susceptibility to developing primary cutaneous aspergillosis and zygomycosis [1, 2]. Similarly, the extremely tenuous gastrointestinal wall structures lead to a unique propensity to primary invasive gastrointestinal mold infections with precipitous perforation, a pattern that is relatively uncommon in other settings [3, 4]. The comparably small diameter of blood vessels provides a nidus for catheter-associated Candida thrombophlebitis, -thrombosis, and endocarditis [5–8]; life-threatening Candida laryngitis and epiglottitis may occur in immunocompromised infants and young children for similar anatomical reasons [9–12]. In neonates, physiological differences such as the larger fractional water content, the smaller plasma protein fraction, relatively larger organ vol- umes, and the functional immaturity of hepatic metabolism and renal excre- tion result in considerable differences in drug distribution, metabolism, and elimination as compared to a standard healthy adult [13–15]. The still incomplete blood-brain barrier, in addition to its pharmacological conse- quences on drug penetration, may also be one reason for the enhanced risk of neonates to develop meningoencephalitis, an otherwise unusual compli- cation of invasive Candida infection [16, 17]. Infants and younger children continue to exhibit differences in the relative proportion of body water, adipose tissue, and organ volumes; of note, as compared to the age-related, decreasing organ function in adult individuals, the functional reserve of both hepatic and renal function is generally larger [15]. Specific immunological characteristics in neonates include a functional immaturity of mono- and polymorphonuclear phagocytes and T lympho- cytes [18] as well as a possibly increased susceptibility to the immunosup- pressive effects of glucocorticosteroids [4], which may render them suscep- tible to nosocomially acquired opportunistic mycoses. The yet-developing cellular immunity may also explain the occurrence of overwhelming infec- tions by Histoplasma capsulatum [19, 20] and possibly other endemic fungi in infants [21]. The pediatrician may also become confronted with neonates and infants who present with superficial or invasive fungal infections as one of the first manifestations of a congenital T cell immunodeficiency [22, 23] Invasive fungal infections in children: advances and perspectives 407 or of chronic granulomatous disease [24, 25]. In older children and adoles- cents, genetic illnesses such as cystic fibrosis or B cell disorders, which lead to chronic recurrent airway infection and lung destruction, may result in fungal airway disease including allergic bronchopulmonary aspergillosis, aspergilloma, and sometimes, invasive mould infections [26, 27]. Pediatric populations at risk for invasive infections The pediatric populations at risk can be defined by specific predisposing defects in host defenses and several additional, non-immunological factors. In general, deficiencies in the number or function of phagocytic cells are associated with invasive infections by opportunistic fungi, such as Candida spp., Aspergillus spp., zygomyces spp. and a large variety of other, less fre- quently encountered yeasts and molds. In contrast, deficiencies or imbalanc- es of T lymphocyte function are linked to mucocutaneous candidiasis and invasive infections by Cryptococcus neoformans and the dimorphic moulds (Fig. 1). Non-immunological factors include the necessary exposure to the organism, preexisting tissue damage, and, limited to Candida spp., the pres- ence of indwelling vascular catheters, colonization of mucous membranes, the use of broad-spectrum antibiotics, parenteral nutrition, and complicated intra-abdominal surgery [28]. In extension of this classification, the pediatric populations at risk for invasive fungal infections include neonates, in particular preterm neonates; pediatric patients with congenital immunodeficiencies involving phagocytic or T lymphocyte functions; pediatric patients with acquired immunodefi- ciencies such as HIV infection, cancer, hematopoietic stem cell transplan- tation (HSCT) or solid organ transplantation, and immunosuppressive treatment with corticosteroids; children of all age groups beyond the neo- natal period that are hospitalized for severe acute illnesses; and those with chronic-destructive lung disease (Tab. 1). Epidemiology and presentation of invasive fungal infections in pediatric patients The neonate Candida spp. colonize the vaginal tract of approximately 30% of pregnant women; very rarely, they can become the cause of chorioamnionitis and intrauterine infection [29, 30]. Candida rapidly colonizes the mucocutane- ous surfaces [31, 32]; in healthy infants, this colonization may result in thrush and diaper dermatitis [31]. In hospitalized, ill neonates, however, Candida has evolved as important cause of life-threatening invasive infections, partic- ularly in very low birth weight infants. Candida spp. now account for 9–13% 408 Andreas H. Groll et al. of all bloodstream isolates in neonatal intensive care units (NICUs) [33, 34]. In the U.S., Candida spp. currently are the third most common cause of late onset sepsis, and second only to polyresistant Enterobacter spp. in mortality [35, 36]. Case series indicate that invasive candidiasis occurs in up to 5% of infants with a birth weight of < 1500 g and in 8–28% of infants with a birth weight of < 1000 g; the crude mortality associated with these infections ranges from 15% to 30% with an attributable mortality of 6–22% despite appropriate therapy [37–50]. Moreover, a recent large analysis showed that 73% of extremely low birth weight infants (< 1000 g) with invasive candidia- sis did not survive or had significant neurodevelopmental impairment [51]. Invasive candidiasis in preterm infants is most commonly due to C. albicans and C. parapsilosis [43, 47] and associated with prior mucocutaneous colo- nization, vascular catheters, the use of broad-spectrum antibiotics and cor- ticosteroids, and parenteral hyperalimentation [47, 52–55]. Most neonates with systemic candidiasis are symptomatic at the onset of their disease and present with signs and symptoms that are virtually identical to those of non-fungal etiological agents. Among deeply invasive infections, cutaneous, renal, pulmonary, and cerebral involvement are disproportionally common [28], and Candida is increasingly recognized as causative agent of infec- tions associated ventricular shunts and drains [56]. Fungemia persisting for 14 days and longer despite appropriate management has been reported to occur in as much as 10% of extremely low birth weight infants with candi- demia and poses a particular challenge to the infectious disease specialist [51, 57]. Numerous outbreaks have been reported, which underscores the Figure 1. Clinical classification of fungal pathogens observed in humans. Invasive fungal infections in children: advances and perspectives 409 importance of appropriate infection control measures for prevention of these infections [44, 53]. Malassezia spp. are lipophilic commensal yeasts that colonize the human skin and may cause pityriasis, a skin infection that is only cosmetically rele- vant. However, these organisms also may gain access to the bloodstream via percutaneous vascular catheters to cause a potentially fatal systemic infec- tion in premature infants receiving parenteral nutritional lipid supplements [58, 59]. Similar to Candida, the most probable mode of acquisition is via the hands of health care workers [60], but direct contamination through con- taminated intravenous (IV) solutions and catheters has also been reported [61]. Special media containing olive oil are required for isolation [58]. Infections by Aspergillus species and zygomyces are very rare in the neonatal setting. They tend to have a predilection for the skin, and, in the case of the zygomycetes, for the gastrointestinal tract, resulting in necrotizing skin lesions and devastating necrotizing gastroenterocolitis, respectively. Potential sources of the organism are contaminated water, contaminated ventilation systems and contaminated dressing materials or infusion boards [1–4, 62]. A large literature review in the late 1990 found 44 cases of invasive aspergillosis that were reported in children of ) 3 months of age. Most of these infants had either invasive pulmonary (23%), primary cutaneous (25%), or disseminated aspergillosis (32%). Prematurity, chronic granulomatous disease, and a complex of diarrhea, dehydration, malnutrition, and invasive bacterial infections accounted for the majority of underlying conditions (82%). Only few patients were neutropenic, but at least 41% had received corticosteroids. While all other forms of the disease mainly occurred in term infants, cutaneous as well as alimentary tract aspergillosis occurred almost exclusively in preterm neo- nates. Disseminated disease was uniformly fatal, but patients who received appropriate therapy had over 70% survival [4]. Invasive mould infections in the setting of neonatal medicine should be considered in infants with Table 1. Pediatric populations at risk for invasive fungal infections – Neonates – Infants – Children with congenital immunodeficiencies – defects of phagocytic host defenses – defects of specific cellular host defenses – Children with acquired immunodeficiencies – iatrogenic immunosuppression – treatment for cancer – HIV infection – Children with acute illnesses – Children with chronic airway diseases 410 Andreas H. Groll et al. expanding, necrotizing skin lesions or gastrointestinal perforation. Surgical debridement is essential in most cases [3, 4]. The infant Disseminated histoplasmosis is a classical example for the potentially dismal course of a primary infection by an endemic fungus in apparently healthy infants that were exposed to the organisms. The disease is fatal if not detect- ed and treated. Its clinical manifestations include prolonged fevers, failure to thrive, hepatosplenomegaly, pancytopenia, and ultimately, disseminated intravascular coagulation and multiorgan failure [19, 20, 63]. Not much is known about blastomycosis and cocidioidomycosis in this age group, but ultimately fatal cases have been reported [21, 64, 65]. Conceptually, primary infection by endemic fungi during infancy is reminiscent of the infantile form of pulmonary pneumocystosis, which is associated with young age, malnutrition, and endemic exposure [66]. Candida albicans is a ubiquitous agent of diaper dermatitis, which may be precipitated by moisture, occlusion, fecal contact and urinary pH. Its classical presentation is that of an erythema bordered by a collarette of scale with satellite papules and pustules. Concomitant dermatophytosis may occasionally be present. Treatment consists of the correction of physiologi- cal factors and topical antifungal treatment [28]. Children with congenital immunodeficiencies Among the phagocyte-defect syndromes, myeloperoxidase (MPO) deficien- cy is the most common entity. While MPO-deficient cells have only minor microbicidal abnormalities against bacteria in vitro, killing of Candida spp is highly deficient and may serve as explanation for invasive Candida infec- tions reported in some patients with this disorder [67, 68]. Chronic granu- lomatous disease of childhood (CGD) is a genetically diverse congenital disorder of the NADPH oxidase complex that is associated with an inability of phagocytic cells to provide antimicrobial oxidants and to kill ingested microorganisms [69]. It is the prime example for an inherited immune dis- order with a high risk of invasive mycoses; at the same time, it serves as a paradigm for the importance of phagocytosis in the defense of infections by opportunistic moulds. Invasive mycoses, particularly invasive aspergil- losis, may repeatedly complicate the course of this disorder, accounting for an estimated lifetime incidence of between 16% and 40% [24, 25, 70, 71]. Interferon-a (IFN-a) or prophylactic antifungal triazoles may reduce the fre- quency of these infections [72, 73]. Treatment is protracted and consists of antifungal chemotherapy, IFN-a, and appropriate surgical interventions; the precise role of gene therapies and HSCT has yet to be defined [28, 74–76]. Invasive fungal infections in children: advances and perspectives 411 The role of immunoglobulins in host defenses against fungi is important against cryptococcosis and possibly mucosal and invasive candidiasis [77], but it is not well understood for other mycoses. Children with inherited defi- cits of B lymphocytes appear to be not at increased risk for fungal infection, unless there is a concomitant disorder of T lymphocytes or phagocytosis. This includes individuals with the x-linked hyper-IgM syndrome [78], and patients with the hyper-IgE syndrome, which is associated with chronic mucocutaneous candidiasis, and possibly with cryptococcosis and aspergil- losis [79]. Inherited immunodeficiencies involving the number or function of T lymphocytes predispose to mucocutaneous and, occasionally, invasive candidiasis, and conceptually, to cryptococcosis and histoplasmosis [22, 77]. Severe combined immunodeficiency (SCID) and severe types of thymic hypoplasia (DiGeorge syndrome) are medical emergencies of the neonatal period that can be managed successfully only with HSCT or thymus trans- plantation, respectively [80–82]. Refractory mucocutaneous candidiasis is a hallmark of these disorders and can therefore be an important clue to the appropriate immunological work-up. Chronic mucocutaneous candidiasis is a less severe congenital immunodeficiency with an impaired T cell response to Candida antigens [83]. It is characterized by chronic recurrent candidiasis of nails, skin, perineum, and oropharynx and may be idiopathic or associ- ated with either the polyendocrinopathy syndrome type I or the hyper-IgE syndrome [79, 84]. Children with acquired immunodeficiencies Iatrogenic immunosuppression Treatment with pharmacological dosages of glucocorticosteroids rapidly provides a functional impairment of phagocytosis by mono- and polymor- phonuclear leukocytes. Similar to adults, such therapy is one of the most important reasons for the increased susceptibility to invasive mycoses of children with immunosuppressive therapy for immunological disorders, solid organ transplantation, and for graft-vs host disease (GVHD) follow- ing HSCT [28, 85, 86]. Cancer While current treatment for pediatric cancers is curative in most instances, highly dose-intensive chemotherapy regimens and aggressive support- ive care measures also result in profound impairments of host defenses. Prolonged, profound granulocytopenia is the single most important risk factor for opportunistic fungal infections in children and adolescents with 412 Andreas H. Groll et al. cancer [87, 88]. Other well-known, but notable risk factors include chemo- therapy-induced mucositis, extended courses of broad-spectrum antibiotics, the presence of indwelling central venous lines, and, particularly in children with acute leukemia, the therapeutic use of glucocorticosteroids [89]. Oropharyngeal candidiasis (OPC) may occur in up to 15% of chil- dren undergoing intensive chemotherapy or bone marrow transplantation despite various forms of topical or systemic antifungal prophylaxis [90]. Esophageal candidiasis is also not uncommon, even in the absence of con- spicuous OPC [28], and Candida epiglottitis and laryngeal candidiasis may emerge in neutropenic children as life-threatening causes of airway obstruc- tion [9, 10, 91]. Similar to the adult cancer population, Candida- and Aspergillus spp are the most common causes of invasive fungal infections in children with cancer [88, 92]. Invasive candidiasis in neutropenic children may present as catheter-associated candidemia, acute disseminated candidiasis, and deep single organ candidiasis. Its overall frequency in children with high-risk leu- kemias and/or bone marrow transplantation is between 5% and 10%; the crude mortality associated with these infections is at least 20% and close to 100% in patients with persistent neutropenia [88, 93–100]. Catheter-associ- ated fungemia is most commonly caused by C. albicans, but non-albicans Candida spp., particularly C. parapsilosis, and previously uncommon yeast pathogens are increasingly encountered [88, 100–102]. Whether the primary source of fungemia or a target for attachment of circulating organisms, the intravascular catheter serves as a source for continued seeding of the bloodstream and should be removed whenever feasible [103–106]. Acute disseminated candidiasis occurs typically in granulocytopenic children and manifests with persistent fungemia, hemodynamic instability, multiple cuta- neous and visceral lesions and high mortality despite antifungal therapy [28, 97]. Candida albicans is the most frequent cause, although C. tropicalis has been increasingly implicated as an important pathogen in neutropenic children. Flynn et al. [107] reported 19 children treated for leukemia in whom C. tropicalis infections developed. Fungemia without meningitis in 11 children was treated successfully, whereas meningitis in 7 children was uniformly fatal, underscoring that meningitis is a critical factor for outcome of this infection. Chronic disseminated candidiasis typically presents with fever despite granulocyte recovery, often coupled with right upper quad- rant abdominal pain, and increased alkaline phosphatase levels [108, 109]. Imaging studies demonstrate multiple lesions in liver, spleen, and other organs that correspond morphologically to large granulomas with extensive chronic inflammatory reaction [110]. Treatment is protracted [28], but may not necessarily require the interruption of anticancer therapy, provided that the disseminated infection has stabilized or is resolving [111]. Invasive aspergillosis has emerged as important cause for morbidity and mortality in children with hematological malignancies or undergoing bone marrow transplantation; more recent pediatric series indicate a frequency Invasive fungal infections in children: advances and perspectives 413 of 4.5–10% in this setting with an associated crude mortality of 40–94% [88, 94, 102, 112–114]. The disease is rather rare in children treated for solid tumors, underscoring the role of prolonged neutropenia and corticosteroid therapy in its pathogenesis [94, 112]. Similar to the adult setting, the lungs are the most frequently affected site, and disseminated disease is found in approximately 30% of cases [113]. While paranasal sinus aspergillosis appears to be less common than in adults [112, 115, 116], primary cutane- ous aspergillosis has been preferentially reported in the pediatric setting in association with lacerations by armboards, tape, and electrodes and at the insertion site of peripheral or central venous catheters [115, 117–120]. With combined surgical and medical therapy, primary cutaneous aspergil- losis has a comparatively more favorable prognosis [115]. The outcome of invasive aspergillosis children with hematological malignancies may not be as dismal as in adults [88, 112]. In a recent small series, all patients who were treated with amphotericin B for a minimum of 10 days responded to medi- cal or combined medical and surgical therapy, and 64% were cured [112]. Nevertheless, the overall long-term survival was merely 31% after a median follow-up of 5.6 years. Apart from recurrent or refractory cancer, in that study, the main obstacles to a successful outcome were failure to diagnose the invasive aspergillosis during lifetime and, in patients with established diagnosis, catastrophic pulmonary or cerebral hemorrhage. Similar to histoplasmosis [121, 122], cryptococcal meningoencephalitis or pneumonitis are rare opportunistic infections in children with cancer [19]. In patients with pediatric sarcomas, however, pulmonary cryptococcosis may be a differential diagnosis of lung metastasis [123] and case reports such as that from a child with acute leukemia in remission that died suddenly from unrecognized disseminated cryptococcosis may serve as a reminder of the risk for this potentially life-threatening infection [124]. During the last decade, previously uncommon fungal pathogens have been increasingly recognized to cause systemic infection in neutropenic patients [101, 125] (Fig. 1). Particularly notable among the yeast-like organ- isms is Trichosporon beigelii, a normal human commensal and the agent of White Piedra. Trichosporonosis in neutropenic patients presents in a similar way as systemic candidiasis with fungemia and disseminated infection and carries a high mortality [126, 127]. Tr. beigelii is often resistant to the fungi- cidal effects of amphotericin B, but may be amenable to antifungal azoles [128–131]. Among the filamentous fungi, the zygomycetes are notorious for their propensity to invade blood vessels, a rapidly deteriorating clinical course, and clinical refractoriness to antifungal therapy; the most common clinical presentations in the neutropenic host are rhinocerebral, pulmo- nary, cutaneous, and disseminated infection therapy [132, 133]. Fusarium has emerged in some institutions as the second most common filamentous pathogen after Aspergillus [134, 135]. Like the latter, the airborne organ- ism is highly angioinvasive and leads to hemorrhagic infarction. Fusarium is among the few filamentous fungi that cause detectable fungemia and [...]... 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... PO (IV) IV IV IV Dose linearity No Yes Yes Yes Yes Oral bioavailability (%) > 90 > 50 n/a n/a n/a Protein binding (%) 58 > 95 97 84 99 Volume of distribution (L/kg) 2 >5 n/a 0.7–0 .9 0.24 Formulation Caspofungin Anidulafungin Micafungin Elimination half-life (h) 6 25 8–10 24 15 Substrate / inhibitor of CYP450 3A4, 2C9, 2C 19 3A4 n/a n/a n/a feces... 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 (0.5–1.0 mg/kg/day IV) (A-III) – Fluconazole*** [(8)–12 mg/kg/day PO/IV] (A-II) – Itraconazole*,** (2.5 mg/kg bid) (A-II) – Posaconazole (400 mg bid or 200 mg qid PO) (B-III)## Blastomycosis... 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... 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)*** Consolidation therapy – Voriconazole (4200 mg bid PO) (B-III)* – Itraconazole (2.5 mg/kg bid PO) (B-III)# – Posaconazole (400 mg bid or 200 mg qid PO) (B-III)## Non-Aspergillus hyalohyphomycetes – Voriconazole (4 mg/kg bid IV; day 1: 12 mg/kg) (B-III)* – Liposomal... [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... 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 [2 29] The lipid formulations... Blastomycosis – Amphotericin B deoxycholate (0.5–1.0 mg/kg/day IV) (A-II) – traconazole*,** (2.5 mg/kg bid) (A-II) Paracoccidioidomycosis – Amphotericin B deoxycholate (0.5–1.0 mg/kg/day IV) (A-II) – Itraconazole*,** (2.5 mg/kg bid) (B-III) Penicilliosis – Amphotericin B deoxycholate (0.5–1.0 mg/kg /day IV) (A-II) – Itraconazole*,** (2.5 mg/kg bid) (A-II) * Clinically stable patients with mild to moderate disease... mg/kg/day) (B-II); in case of polyene intolerance: Fluconazole (8–12 mg/kg/ day) plus flucytosine*** (B-II) Extracerebral manifestations – Amphotericin B deoxycholate (0.7–1.0 mg/kg/day) (C-III) – Fluconazole (8–12 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. .. 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- -cyclodextrin solution of itraconazole improves oral bioavailability [287, 288] and, in conjunction with the IV formulation [2 89 291 ], has enhanced . pharmacokinetics. Hepatology 42: 1010–1018 19 Ahn J, Flamm S (2004) Peginterferon-alpha(2b) and ribavirin. Expert Rev Anti Infect Ther 2: 17–25 Pediatric Infectious Diseases Revisited 405 ed. by Horst Schroten. Other well-known, but notable risk factors include chemo- therapy-induced mucositis, extended courses of broad-spectrum antibiotics, the presence of indwelling central venous lines, and, particularly. may emerge in neutropenic children as life-threatening causes of airway obstruc- tion [9, 10, 91 ]. Similar to the adult cancer population, Candida- and Aspergillus spp are the most common causes