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Micafungin: a Review in the Prophylaxis and Treatment of Invasive Candida Infections in Paediatric Patients

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Micafungin: a Review in the Prophylaxis and Treatment of Invasive Candida Infections in Paediatric Patients Pediatr Drugs (2017) 19:81–90 DOI 10.1007/s40272-016-0211-3 ADIS DRUG EVALUATION Micafungin: A Review in the Prophylaxis and Treatment of Invasive Candida Infections in Paediatric Patients Lesley J. Scott1 Published online: 13 January 2017 Ó Springer International Publishing Switzerland 2017 Abstract Intravenous micafungin (MycamineÒ; Fun- treatment of invasive Candida infections in paediatric and guardÒ), an echinocandin, is approved in the EU for the adult patients. treatment of invasive candidiasis in children (including neonates) and adolescents (\16 years of age) and as pro- phylaxis against Candida infections in patients undergoing Micafungin: clinical considerations in prophylaxis haematopoietic stem cell transplantation (HSCT) or who and treatment of invasive Candida infections are expected to have neutropenia for C10 days. This nar- rative review focuses on the use of micafungin in paediatric Micafungin, a 1,3-b-D-glucan synthase inhibitor, indications approved in the EU, which may vary from those exhibits a broad spectrum of activity against approved elsewhere in the world. Micafungin has a broad clinically relevant Candida spp. and other fungal spectrum of in vitro activity against clinically relevant pathogens isolates of Candida spp. (including fluconazole-resistant Candida glabrata isolates), a low propensity for emergence High clinical cure rates in the treatment of of resistant isolates and a convenient once-daily regimen. candidaemia and other types of invasive candidiasis In paediatric substudies and a small multinational, phase 3 in paediatric patients (aged \16 years), including trial in neonates with proven invasive candidiasis, intra- neonates (aged 2 days to \4 months) venous micafungin was effective and generally well tol- Provides effective prophylaxis against invasive erated in the treatment of candidaemia and other types of fungal infections in paediatric patients, including in invasive candidiasis and as prophylaxis against fungal neonates infections in patients undergoing HSCT. Hence, mica- fungin remains an important option for the prophylaxis and Generally well tolerated; paediatric patients (especially those aged \1 year) appear to be more likely to develop drug-related liver function test The manuscript was reviewed by: A.C. Arrieta, Pediatric Infectious abnormalities than adult patients Diseases and Infectious Diseases Clinical Research, Children’s Hospital of Orange County, Orange, CA, USA; M.U. Kocak, Department of Dermatology, Kirikkale University, Kirikkale, Turkey; C. Korfitis, Department of Dermatology, 401 General Army Hospital, Athens, Greece; N. Maximova, Bone Marrow Transplant Unit, IRCCS Burlo Garofolo, Trieste, Italy; E. Roilides, Infectious Diseases Unit, 3rd Department of Paediatrics, Faculty of Medicine, Aristotle 1 Introduction University School of Health Sciences, Thessaloniki, Greece. Globally, Candida infections remain a major cause of & Lesley J. Scott [email protected] morbidity and mortality in immunocompromised and crit- ically ill patients, especially in patients with significant 1 Springer, Private Bag 65901, Mairangi Bay, Auckland 0754, comorbidities who are hospitalized for prolonged periods, New Zealand 82 L. J. Scott very young (aged \1 year) and elderly (aged [70 years) krusei, C. guilliermondii and other Candida spp. can be patients, and those with haematological malignancies and/ considered susceptible to micafungin [6]. The epidemio- or neutropenia [1, 2]. However, despite the addition of logical cutoff value (ECV) is being increasingly used to several broad-spectrum antifungal agents over the last harmonize national differences in clinical breakpoints, with couple of decades [such as azoles (e.g. fluconazole, ECV values considered the most sensitive measure for voriconazole, itraconazole) and echinocandins (anidula- assessing the emergence of strains with reduced suscepti- fungin, caspofungin, micafungin)], the frequency of inva- bility versus the wild-type strain [7, 8]. sive candidiasis and associated mortality have not been Micafungin exhibited very good in vitro activity against significantly altered [1, 2]. Moreover, the increasing use of a broad spectrum of clinical isolates of Candida spp. fluconazole has played a key role in the shift in the primary causing invasive candidiasis, based on worldwide surveil- causative pathogen of invasive candidiasis from Candida lance studies of isolates collected from 2001–2006 [9] and albicans to non-C. albicans isolates, with Candida glab- in 2013 [10] (Table 1). MIC values at which 90% of iso- rata and Candida parapsilosis becoming the key pathogens lates were inhibited (MIC90) showed minimal or no change in northern and southern Europe, respectively [1]. Given for Candida spp. isolates collected between 2001–2006 and the shift in causative pathogens and the increase in drug- those collected more recently in 2013 (Table 1). For resistant pathogens (especially fluconazole-resistant C. Candida spp. isolates collected in 2013, 97–100% had an glabrata isolates), judicious antifungal stewardship is MIC that did not exceed the ECV for micafungin, with imperative in the management of these serious, potentially similar rates observed with anidulafungin and caspofungin life-threatening infections [1, 2]. (Table 1)[10]. For 2001–2006 isolates, 100, 92.5–100 and Intravenous micafungin (MycamineÒ; FunguardÒ)is 90.2–100% of individual Candida spp. isolates were sus- approved in many countries worldwide, including in the EU, ceptible to micafungin, caspofungin and anidulafungin, USA and Japan, for the prophylaxis and treatment of inva- respectively, at an MIC of B2 lg/mL [9]. Like all sive Candida infections. Its use in paediatric and/or adult echinocandins, micafungin exhibits less in vitro activity patients has been reviewed previously in Pediatric Drugs [3] against C. parapsilosis and C. guilliermondii isolates, than and Drugs [4, 5]. This narrative review, written from an EU against other Candida spp. (Table 1). perspective, summarizes the pharmacological properties of Candida biofilm-related vascular catheter infections, a micafungin and discusses its clinical use in children (in- typical characteristic of which is antifungal resistance, cluding neonates) and adolescents (aged\16 years) for the significantly impact on patient management and care, prophylaxis and treatment of invasive Candida infections. increasing the length of hospital stay and costs of treatment (reviewed by Ghannoum et al. [11]). Like liposomal amphotericin B formulations and other echinocandins, 2 Pharmacodynamic Properties of Micafungin micafungin exhibits very good in vitro and in vivo activity against Candida biofilms, including those resistant to other Micafungin is a noncompetitive, concentration-dependent antifungal drugs [12–15]. Conversely, conventional inhibitor of the enzyme 1,3-b-D-glucan synthase and, amphotericin B deoxycholate (CAB) and triazoles (e.g. consequently, inhibits the synthesis of 1,3-b-D-glucan (an voriconazole and fluconazole) showed no activity against integral component of the fungal cell wall, but not present Candida biofilm infections [12, 14]. in mammalian cells) [3–5]. Inhibition of 1,3-b-D-glucan In in vitro studies, micafungin exhibited time-depen- synthesis, leads to increased susceptibility of fungal cells to dent, concentration-independent, fungicidal activity and osmotic pressures and ultimately results in cell lysis [3–5]. produced a post-antifungal effect against several clinical Given micafungin is approved for the prophylaxis and and laboratory strains of Candida spp. (as reviewed pre- treatment of invasive Candida infections, this section viously [3–5]). focuses on its in vitro activity against Candida spp. Euro- There appeared to be a low potential for the emergence pean Committee on Antimicrobial Susceptibility Testing of resistance to echinocandins, including micafungin, (EUCAST) susceptibility breakpoints against C. albicans, amongst clinical Candida spp. isolates collected since 2001 C. glabrata and C. parapsilosis are B0.016, B0.03 and in large global surveillance studies (including the two B0.002 lg/mL, respectively [6]. Minimum inhibitory con- studies [9, 10] summarized in Table 1)[8–10, 16, 17]. centrations (MICs) for Candida tropicalis are 1–2 twofold Nonetheless, Candida spp. isolates with reduced suscepti- dilution steps higher than for C. albicans and C. glabrata, bility to echinocandins have emerged, with mutations and those for Candida krusei and Candida guilliermondii conferring reduced susceptibility to echinocandins mapped are &3 and &8 twofold dilution steps higher than those for to the FSK1 and/or FSK2 genes encoding 1,3-b-D-glucan C. glabrata. This means that there is insufficient evidence to synthase [8, 17–21]. In a recent single-centre, retrospective indicate whether the wild-type isolates of C. tropicalis, C. study of 293 episodes (313 isolates) of C. glabrata Micafungin: A Review 83 Table 1 Comparative in vitro activity of echinocandins against clinical isolates of Candida spp. collected in two large, global surveillance studies Candida spp. Isolates collected 2001–2006 [9] Isolates collected 2013 [10] a a a No. of isolates MIC90 (lg/mL) No. of isolates MIC90 (lg/mL) % of isolates susceptible (CLSI/ECV) MFG CAS ANI MFG CAS ANI MFG CAS ANI C. albicans 2869 0.03 0.06 0.06 712 0.03 0.03 0.06 100/100 100/100 100/100 C. glabrata 747 0.015 0.06 0.12 251 0.03 0.06 0.12 98.8/97.6 98/98 96/96 C. guilliermondii 61 1 1 2 16 1 1 4 100/100 100/100 97.5/100 C. krusei 136 0.12 0.25 0.06 49 0.12 0.25 0.06
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