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SPECIAL FOCUS y Invasive pediatric fungal infections Review Anidulafungin: is it a promising option in the treatment of pediatric invasive fungal infections? Expert Rev. Anti Infect. Ther. 9(3), 339–346 (2011) Anıl Tapısız Department of Pediatric Infectious Disease, Gazi University, Faculty of Medicine, Ankara, Turkey Tel.: +90 505 319 7574 Fax: +90 312 215 0143 Cases of invasive fungal infections are increasing globally due to an i
  339 Review ISSN  1478-7210 © 2011 Expert Reviews Ltd10.1586/ERI.11.7 SPECIAL FOCUS   󰁹  Invasive pediatric fungal infections Candida   species are among the most prevelant causative agents of nosocomial bloodstream infections in the pediatric population [1,2] . The increasing use of fluconazole for prevention and treatment of Candida   infections has led to the emergence of non-albicans species resistant to azoles [3,4] . Echinocandins are now considered as a treatment option for these serious fungal infections [5,6] . Anidulafungin, the most recently developed echinocandin, has taken its place in the antifungal armamentarium by virtue of its activity against both Candida and  Aspergillus species [7–9,101] . Anidulafungin, a semi-synthetic echinocandin, is a fermentation product of  Aspergillus nidulans [10]  and was approved by the US FDA in 2006 and is marketed by Pfizer under the name Eraxis ®  and Ecalta  ® . Mechanism of action & spectrum of activity  Anidulafungin exhibits activity by inhibiting 1,3- b - d -glucan synthase leading to lysis of the fungal cell wall [11] . It has fungicidal activity against a broad spectrum of Candida spp. includ-ing those resistant to azoles and polyenes, and also has fungistatic activity against  Aspergillus spp.   [12,13] .   However  Cryptococcus neoformans,   Fusarium , Trichosporon and Rhizopus spp. are resistant to anidulafungin. Anidulafungin has low MICs against mycelia forms of Histoplasma spp., Blastomyces spp.   and  Coccidioides spp., but high MICs against the yeast forms [14] . The in vitro activity of anidulafungin is shown in T  ABLE  1 .The  in vitro  activity of anidulafungin was tested against yeast bloodstream isolates in the SENTRY Antimicrobial Surveillance Program in 2008 [7]  and it was found to be the most active agent against (MIC 90  in µg/ml) Candida albicans (0.06), Candida gla-brata   (0.12), Candida tropicalis (0.06) and Candida krusei   (0.12) isolates, but less potent against Candida parapsilosis (2 µg/ml) and Candida guilliermondii (2 µg/ml) . Moreover,   echinocandin potency was greatest for ani-dulafungin (minimum effective concentration [MEC 90 ]: 0.008 µg/ml) against  Aspergillus  fumigatus species   identified in lower respiratory tract infections in the same study [7] . Mechanism of resistance Candida isolates yielding a MIC   >2 µg/ml are considered non-susceptible to anidula fungin according to the Clinical and Laboratory Standards Institute [15,16] . Resistance devel-ops when the isolates contain a mutation in the genes that encodes for components of the An ı l Tap ı s ı z Department of Pediatric Infectious Disease, Gazi University, Faculty of Medicine, Ankara, Turkey Tel.: +90 505 319 7574 Fax: +90 312 215 0143 Cases of invasive fungal infections are increasing globally due to an increase in the immunosuppressed population, the use of broad-spectrum antibiotics and the invasive instrumentation of patients in intensive care units. Ongoing emergence of resistance and problems with toxicity have resulted in the need for the development of new antifungal agents. Anidulafungin, the most recently developed echinocandin, is approved by the US FDA for treatment of candidemia, other forms of Candida  infection and esophageal candidiasis in non-neutropenic adult patients, but it is not currently licensed for pediatric usage. The drug is projected to be distinctive owing to its unique pharmacokinetics and is already listed in adult antifungal treatment guidelines. In this article, anidulafungin will be reviewed with a focus on pediatric patients. K EYWORDS :  anidulafungin ã  Aspergillus  ã Candida  ã children Anidulafungin: is it a promising option in the treatment of pediatric invasive fungal infections? Expert Rev. Anti Infect. Ther.  9(3), 339–346 (2011)  340 Review Expert Rev. Anti Infect. Ther.  9(3), (2011) Tapısız 1,3- b - d -glucan synthase enzyme complex such as FKS-1  and FKS-2    [17,18] . To date, resistance to anidulafungin is rarely reported because of its limited use. However, some C. glabrata isolates have displayed non-wild-type elevated MIC values for anidulafungin (1–4 µg/ml) [19] . Pharmacokinetics & pharmacodynamics  Anidulafungin is distinguished from other existing antifungal agents by its excellent pharmacokinetics. It has linear pharmaco-kinetics with concentrations achieved proportional to dose. Concentration-dependent fungicidal activity and a long postanti-fungal effect have been observed in vitro  and in animal infection models [20,21] . Recommended adult dosage for esophageal candi-diasis is 100 mg loading dose followed by 50 mg daily, and twice the dose is recommended for invasive candidiasis. The steady state mean maximum and minimum plasma concentrations were 7.2 and 3.3 µg/ml, respectively. The route of administration is intra-venous due to limited oral bioavailability. The current formula-tion of anidulafungin is solubilized in water and the alcohol free injection form of Eraxis is available in the USA under the name Eraxis SWFI (sterile water for injection). Anidulafungin has the longest half-life of all the echinocandins. In children, the mean elimination is approximately 20 h, which is similar to adults. Dose adjustment according to patient’s weight and gender is not needed in adults, but in children, clearance and volume of distribution at steady state are effected by bodyweight only but not age [20] . In a study examining the pharmacokinetics of anidulafungin in pediatric patients, children ranging from 2 to 17 years of age with neutropenia given anidulafungin at 1.5–3 mg/kg loading dose and 0.75–1.5 mg/kg/day mainte-nance dose, had exposures similar to adult patients receiving 50 or 100 mg/day, respectively [22] . Neither end-stage renal impairment nor dialysis changes the pharmacokinetics of anidulafungin and there is no need to adjust doses for patients with renal and/or hepatic impairment [23] . Protein binding is almost 99% and therefore penetration into tissues such as lung, liver, kidney and spleen, which are more affected by invasive infection, is excellent [24] . Unlike caspofungin and micafungin, anidulafungin is degraded chemi-cally in the bloodstream without hepatic metabolism or renal clearance [20] . Adverse events To date, anidulafungin appears to have an excellent side-effect profile [25,26] . At normal doses, the drug is usually well toler-ated. Side effects are usually infusion related with higher doses (130 mg/day) [27] . However, in an invasive candidiasis trial, 15 of 127 patients receiving standard dose anidulafungin discontin-ued therapy because of adverse events [28] . Fever, rash, headache, hypotension, dyspnea, flushing, dizziness, nausea, diarrhea, hypo-kalemia, minor elevations in hepatic parameters, neutropenia and leukopenia are previously reported side effects. No changes of QT intervals have been reported [25] .In a study with a limited number of children older than 2 years of age [20] , anidulafungin was found to be well tolerated. One patient had fever and one patient had facial erythema, which resolved with slowing of the infusion rate. Anidulafungin crossed the placental barrier in animal studies, but no controlled data are available in human pregnancy [29] . Drug interactions Current data indicate that anidulafungin is less likely to have drug interactions due to it not being a substrate, inhibitor or inducer of the cytochrome P450 isozymes involved in drug metabolism [28] . No drug interactions were observed with drugs including rifampicin, antiretrovirals, phenytoin, metranidazol, cyclosporine, tacrolimus, amphotericin B, voriconazole and calcium channel blockers [30–32] .Interactions between immunosupressive drugs and the other two echinocandins, caspofungin and micafungin have previously been reported [33] . For example, a higher incidence of elevated hepatic transaminase levels has been demonstrated in patients receiving caspofungin and cyclosporine concomitantly [34] . On the contrary, there were no significant pharmacokinetic interac-tion between anidulafungin and tacrolimus or anidulafungin and cyclosporine [30,32] . Studies evaluating the concomitant use of anidulafungin and either amphotericin B or voriconazole did not demonstrate significant adverse events [31,35] .This property of the drug provides the opportunity to coadminister anidulafungin with other drugs without requiring dose adjustment of either drug. Anidulafungin may be an alter-native in the future, particularly for prevention and treatment of fungal infections in pediatric transplant patients. General characteristic properties of anidulafungin are shown in T  ABLE  2 . Evaluation of studies with anidulafungin There is an increasing interest regarding both in vivo  and in vitro  activity of anidulafungin in various conditions. Invasive candidiasis  Anidulafungin has been demonstrated to be effective in the treat-ment of invasive candidiasis [28,36–38] . In an open-label, non-com-parative, dose ranging, Phase II study in 123 adults with invasive candidiasis, anidulafungin was effective in eradicating C. albicans   and other species of Candida from the bloodstream and other nor-mally sterile sites. MIC distribution showed that C. albicans   and Table 1. In vitro  activity of anidulafungin. In vitro  activityType of fungus Fungicidal activity Candida spp.Fungistatic activity  Aspergillus spp.No activity Cryptococcus spp., Trichosporon spp., Fusarium  spp., Scedosporium spp., Pseudallescheria  spp., ZygomycetesLow MIC Histoplasma spp., Blastomyces spp.  , Coccidioides spp. (mycelia form)High MIC Histoplasma spp., Blastomyces spp.  , Coccidioides spp. (yeast form)  341 Review Anidulafungin in the treatment of pediatric invasive fungal infections C. glabrata  were the most susceptible species whereas C. parap-silosis  was the least. Cure or improvement was obtained in 73 out of 83 patients [37] .The results of comperative studies with fluconazole demon-strated superiority of anidulafungin [28,38] . A therapeutic trial in adult patients with invasive candidiasis comparing anidu-lafungin (200 mg loading dose followed by 100 mg/day) with fluconazole (800 mg loading dose followed by 400 mg/day) found a significant difference in favor of anidulafungin (75.6 vs 60.2%; p = 0.01). The rate of death from all causes was found to be 31.4% in the fluconazole group and 22.8% in the anidulafungin group. During follow-up, lower persistent infec-tion was present in patients treated with anidulafungin (6.3 vs 14.4%; p = 0.06). Adverse events and tolerability profiles  were similar [28] . In other comperative studies, anidulafungin  was associated with higher response rates and a trend toward decreased mortality in critically ill patients with acute organ dysfunction and shorter intensive care unit and total length of hospital stay [38] . Data about the efficacy of anidulafungin in pediatric patients are extremely limited. It was evaluated in one study and found to be superior to standard fluconazole in patients 16 years of age or older with invasive candidiasis [28] . Seriously ill or immunocompromised children are at increased risk of invasive fungal infections, particularly candidemia, but fungal epidemiology in children is markedly different from adults. C. albicans   and C. parapsilosis   are the two most frequent causes of candidemia, whereas incidence of species such as C. krusei   and C. glabrata  , which interfere with fluconazole treatment, are not frequently seen in pediatric patients. C. parapsilosis is particularly associated with bloodstream infections in very low-birth-weight neonates and is also seen in children with catheters, prosthetic devices and those receiving intravenous hyperalimentation in pediatric units [1–3] . Decreased susceptibility of C. parapsilosis   isolates to echinocandins has been demon-strated in previous studies [39–43] . Although the mechanism of action of echinocandins is similar, there are clues indicating that differences exist in both antifungal activity and fungal resistance mechanisms among the three echinocandins [44] . In a recent study determining the activity of three echino candins against C. parapsilosis   isolates obtained from burn unit patients, healthcare  workers and the hospital environment, it was found that isolates obtained from health-care workers and environmental sources  were susceptible to all antifungals, whereas anidulafungin had more potent antifungal activity than the other two echinocandins against the C. parapsilosis   isolates obtained from burn unit patients [44] . The ability of caspofungin and anidulafungin to effect the ultrastructure of C. parapsilosis   was deter-mined by using scanning electron microscopy. Equivalent activity in one caspofungin-susceptible isolate was observed, but in one caspofungin-nonsusceptible isolate, anidulafungin was sufficient to induce cellular damage and distort the cellular morphology at lower concentrations [44] . The reason for these differences is unknown and no role of different mutations in the FKS-1  gene could be shown in the study [44] . Similar results had been reported by Moudgal et al.  in which isolates of C. parapsilosis   with reduced susceptibility to caspofungin and micafungin remained susceptible to anidulafungin [45] . Candida parapsilosis   has previously been separated into three distinct groups: C. parapsilosis sensu stricto , C. orthopsilosis and  C. metapsilosis  . C. parapsilosis sensu stricto  is the predominant spe-cies among clinical isolates ( ~ 90%) with an enhanced ability to form biofilms [46,47]  and is also commonly isolated from different environmental sources presenting potential routes for nosocomial transmission. C. orthopsilosis and C. metapsilosis constitute 10% of   C. parapsilosis isolates, and are obtained from biological products such as urine, respiratory tract samples and mucosal surfaces in particular, and were not found to produce a biofilm in vitro   [46,47] .In the majority of pediatric invasive candidiasis cases, intra-vascular devices are the dominant risk factor and C. parapsilosis   is one of the most frequent species associated with catheter-related bloodstream infection [1] . Patients requiring prolonged use of central venous catheters and parenteral nutrition are at high risk because of the ability of C. parapsilosis   to form biofilms on the surface of indwelling devices and prosthetic materials [40,42] . Formation of biofilms in intravascular catheters is problematic, since biofilms can confer antifungal resistance and protect the yeast cells from host immune responses [48] . Hence, when the bloodstream infec-tion is associated with a catheter, removal of intravascular catheters is strongly advised because not removing the catheter is associated with poor outcome. Recently, activity of anidulafungin has been demon-strated against both C. albicans and  C. parapsilosis biofilms [49,50] . Table 2. Characteristics of anidulafungin. ClassEchinocandinIndications for useCandidemia and other Candida  infections including: esophageal candidiasis, intra-abdominal abscess and peritonitis in non-neutropenic adult patientsRecommended doses (for adults): ã Invasive candidiasis and candidemiaã Esophageal candidasis 200 mg iv. loading dose followed by 100 mg iv. daily100 mg iv. loading dose followed by 50 mg iv. dailyMethod of administrationiv. onlyProtein binding~99%Penetration into tissuesExcellentMetabolismNot metabolizedDosage adjustment for organ dysfunctionNot neededDrug interaction requiring dose alterationNot reportedMain side effectsFever, rash, headache, gastrointestinaliv.: Intravenously.  Expert Rev. Anti Infect. Ther.  9(3), (2011) 342 Review Tapısız Because of the difficulty in treating biofilm formation, anidulafun-gin may provide promising results in these cases. However, there are few reports into this action of anidulafungin [43,46,47] .It has been demonstrated that there are significant differences in antifungal susceptibility among the sibling species of C. parapsilosis  . In a study comparing susceptibility of these strains to fluconazole, anidulafungin and caspofungin, it was found that C. parapsilosis sensu stricto  was significantly less susceptible to caspofungin or anidulafungin than isolates of C. orthopsilosis   and C. metapsilosis  . In addition, C. parapislosis sensu stricto  was more susceptible to caspofungin than to anidulafungin [43] . In another study, in vitro  susceptibilities to fluconazole, voriconazole, posaconazole, ampho-tericin B, caspofungin and anidulafungin were evaluated. The rate of C. parapsilosis sensu stricto  isolates nonsusceptible to caspofungin and anidula fungin was found to be 38 and 29%, respectively, but anidulafungin’s MICs were less than those of caspofungin [46] . In a very recent study, antifungal susceptibility profiles of planktonic and sessile cells of C. parapsilosis isolates to voriconazole, amphotericin B and anidulafungin were evaluated separately. Although overall activities of the three antifungal agents were similar with regards to planktonic cells, amphotericin B and anidulafungin were found to be moderately effective against the biofilm of C. parapsilosis    sensu stricto ,  where as voriconazole was ineffective [47] . Furthermore, efficacy of anidulafungin against C. albicans   mature biofilms has recently been demonstrated in a novel rat model of catheter-associated candidia-sis. Catheters retrieved from rats, treated with daily intraperitoneal injections of anidulafungin for 7 days, showed reduced cell numbers compared to untreated and fluconazole-treated animals. It has been shown that systemic administration of anidulafungin is promising for the treatment of mature C. albicans   biofilms in vivo   [51] .It is unclear whether the results of in vitro  studies may effect decisions on therapeutic and prophylactic choices or influence the clinical outcome of patients in the future. To support the primary use of anidulafungin, especially in patients who are exposed to catheter-related Candida   infections, its activity against  Candida biofilms should be confirmed with further in vivo  stud-ies . Selection of antifungal agent in the pediatric population may one day be due to the subtype of the strain determined as a biofilm producer or not. Further clinical studies are warranted. Other Candida  infections Pediatric patients, especially neonates, are prone to involvement of other sites such as the CNS, retina, GI tract, liver and spleen when physiologically sterile body fluid cultures show positive results with Candida spp. Although the FDA approves the use of anidulafungin in candidal peritonitis and intra-abdominal abscess, the European Medicines Agency does not [101,102] .   Candida   endocarditis, osteo-myelitis, urinary tract infections and meningitis are also docu-mented as nonindications for anidulafungin because of the poor penetration of the drug to these sites [52,53,101,102] .However, in a murine model of C. albicans   CNS infection, anidulafungin 10 mg/kg/day significantly reduced mortality and fungal burden in brain tissue to a greater extent than voricona-zole, suggesting a potential role of anidulafungin as an alternative choice for the treatment of candidal CNS infection [54] .  Although pulmonary infection caused by Candida   spp. is a very rare disease, two cases of bilateral septic pulmonary candidiasis successfully treated with anidulafungin were recently reported [55] , supporting the use of anidulafungin for the treatment of Candida   lung infections. Mucocutaneous candidiasis Results of several clinical trials indicate that anidulafungin is effective in treating esophageal candidiasis, including azole refrac-tory disease [56–58] . In a double-blind comperative clinical trial involving 601 patients with documented esophageal candidiasis, a 50 mg daily dose of anidulafungin was compared with oral flucon-azole, 200 mg administered on day 1 followed by 100 mg daily for 14–21 days. The overall clinical and mycological efficacy of anidulafungin was found to be noninferior to that of fluconazole as reported previously. However, at 2-week follow-up, the relapse rate for anidulafungin and fluconazole was 35.6 and 10.5%, respectively [56] . The cause of higher relapse rates is unknown. The efficacy and safety of anidulafungin has also been demon-strated in patients with azole-refractory oropharyngeal and esopha-geal candidiasis. A total of 19 patients of whom 89% had advanced HIV infection received 100 mg of intravenous anidulafungin on day 1 followed by daily doses of 50 mg on day 2 through day 14 or for a maximum of 21 days. Clinical success was 95% in oropharyngeal candidiasis and 92% in esophageal candidiasis. At follow-up, clinical success was maintained in 47% of patients [57] . The efficacy of anidulafungin versus oral fluconazole in treating esophageal candidiasis was tested in a double-blind study. C. albicans   represented >90% of baseline isolates and anidulafungin had potent activity against these isolates. Its MIC 90  was 0.06 µg/ml and 99% of strains were inhibited by 0.12 µg/ml. There were six fluconazole-resistant strains with MICs ranging between 0.015 and 0.06 for anidulafungin [58] .Oropharyngeal and esophageal candidiasis are the most com-mon opportunistic infections in patients infected with HIV.  Anidulafungin may offer promise especially in HIV-positive children with oral candidiasis who are on multiple medications and subject to drug interactions with its low potential for drug–drug interactions. When the cost of anidulafungin is taken into consideration, fluconazole still seems to be a better choice in mucosal candidiasis but poor tolerance to fluconazole or fluco-nazole-resistant Candida   would make anidulafungin an alterna-tive therapy. Since recurrent disease is an important dilemma in these patients, further clinical studies are needed to determine the optimal prophylactic therapy in these patients. Febrile neutropenia  Anidulafungin has been evaluated in a neutropenic murine model  with subacute disseminated candidiasis, and MIC ratios were strongly predictive of treatment success and efficacies were similar among C. albicans, C. tropicalis   and C. glabrata   isolates [59] . In a study evaluating pharmocokinetics, safety and tolerability of anidulafungin in neutropenic children, without the efficacy as a primary component, no child at high risk for invasive fungal infection was diagnosed with a breakthrough fungal infection [22] .
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