SPECIAL FOCUS y Invasive pediatric fungal infections

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Review

Anidulafungin: is it a promising option in the treatment of pediatric invasive fungal infections?

Expert Rev. Anti Infect. Ther. 9(3), 339346 (2011)

Anl Tapsz
Department of Pediatric Infectious Disease, Gazi University, Faculty of Medicine, Ankara, Turkey Tel.: +90 505 319 7574 Fax: +90 312 215 0143 anilaktas@gazi.edu.tr

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.
KeYWoRDs : anidulafungin Aspergillus Candida children

Candida species are among the most prevelant causative agents of nosocomial bloodstream infections in the pediatric population [1,2] . The increasing use of uconazole 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 [79,101] . 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 Pzer under the name Eraxis and Ecalta.
Mechanism of action & spectrum of activity

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 TABLE 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 g/ml) Candidaalbicans (0.06), Candidaglabrata (0.12), Candida tropicalis (0.06) and Candidakrusei (0.12) isolates, but less potent against Candida parapsilosis (2 g/ml) and Candidaguilliermondii (2 g/ml) . Moreover, echinocandin potency was greatest for anidulafungin (minimum effective concentration [MEC 90 ]: 0.008 g/ml) against Aspergillus fumigatus species identied in lower respiratory tract infections in the same study [7] .
Mechanism of resistance

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. including 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
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Candida isolates yielding a MIC >2 g/ml are considered non-susceptible to anidula f ungin according to the Clinical and Laboratory Standards Institute [15,16] . Resistance develops when the isolates contain a mutation in the genes that encodes for components of the
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Table 1. In vitro activity of anidulafungin.

In vitro activity
Fungicidal activity Fungistatic activity No activity

Adverse events

Type of fungus
Candida spp. Aspergillus spp. Cryptococcus spp., Trichosporon spp., Fusarium spp., Scedosporium spp., Pseudallescheria spp., Zygomycetes Histoplasma spp., Blastomyces spp., Coccidioides spp. (mycelia form) Histoplasma spp., Blastomyces spp., Coccidioides spp. (yeast form)

Low MIC High MIC

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 (14 g/ml) [19] .
Pharmacokinetics & pharmacodynamics

To date, anidulafungin appears to have an excellent side-effect prole [25,26] . At normal doses, the drug is usually well tolerated. 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 discontinued therapy because of adverse events [28] . Fever, rash, headache, hypotension, dyspnea, ushing, 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

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 candidiasis 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 g/ml, respectively. The route of administration is intravenous due to limited oral bioavailability. The current formulation 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 patients 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 1.53 mg/kg loading dose and 0.751.5 mg/kg/day maintenance 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 chemically in the bloodstream without hepatic metabolism or renal clearance [20] .
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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 [3032] . 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 signicant pharmacokinetic interaction 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 signicant 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 alternative in the future, particularly for prevention and treatment of fungal infections in pediatric transplant patients. General characteristic properties of anidulafungin are shown in TABLE 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 treatment of invasive candidiasis [28,3638] . In an open-label, non-comparative, 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 normally sterile sites. MIC distribution showed that C.albicans and
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Anidulafungin in the treatment of pediatric invasive fungal infections

Review

Decreased susceptibility of C.parapsilosis isolates to echinocandins has been demonClass Echinocandin strated in previous studies [3943] . Although the mechanism of action of echinocandins Indications for use Candidemia and other Candida infections including: is similar, there are clues indicating that esophageal candidiasis, intra-abdominal abscess and peritonitis in non-neutropenic adult patients differences exist in both antifungal activity and fungal resistance mechanisms among Recommended doses (for adults): the three echinocandins [44] . In a recent Invasive candidiasis and candidemia 200 mg iv. loading dose followed by 100 mg iv. daily Esophageal candidasis 100 mg iv. loading dose followed by 50 mg iv. daily study determining the activity of three echino candins against C.parapsilosis isolates Method of administration iv. only obtained from burn unit patients, healthcare Protein binding ~99% workers and the hospital environment, it was Penetration into tissues Excellent found that isolates obtained from healthMetabolism Not metabolized care workers and environmental sources were susceptible to all antifungals, whereas Dosage adjustment for Not needed anidulafungin had more potent antifungal organ dysfunction activity than the other two echinocandins Drug interaction Not reported against the C.parapsilosis isolates obtained requiring dose alteration from burn unit patients [44] . The ability of Main side effects Fever, rash, headache, gastrointestinal caspofungin and anidulafungin to effect the iv.: Intravenously. ultrastructure of C.parapsilosis was deterC.glabrata were the most susceptible species whereas C.parap mined by using scanning electron microscopy. Equivalent activity silosis was the least. Cure or improvement was obtained in 73 out in one caspofungin-susceptible isolate was observed, but in one of 83 patients [37] . caspofungin-nonsusceptible isolate, anidulafungin was sufcient The results of comperative studies with uconazole demon- to induce cellular damage and distort the cellular morphology strated superiority of anidulafungin [28,38] . A therapeutic trial at lower concentrations [44] . The reason for these differences is in adult patients with invasive candidiasis comparing anidu- unknown and no role of different mutations in the FKS-1 gene lafungin (200 mg loading dose followed by 100 mg/day) with could be shown in the study [44] . Similar results had been reported uconazole (800 mg loading dose followed by 400 mg/day) by Moudgal et al. in which isolates of C.parapsilosis with reduced found a signicant difference in favor of anidulafungin (75.6 susceptibility to caspofungin and micafungin remained susceptible vs 60.2%; p = 0.01). The rate of death from all causes was to anidulafungin [45] . found to be 31.4% in the uconazole group and 22.8% in the Candidaparapsilosis has previously been separated into three anidulafungin group. During follow-up, lower persistent infec- distinct groups: C.parapsilosis sensu stricto, C.orthopsilosis and tion was present in patients treated with anidulafungin (6.3 C.metapsilosis. C.parapsilosis sensu stricto is the predominant spevs 14.4%; p=0.06). Adverse events and tolerability proles cies among clinical isolates (~90%) with an enhanced ability to were similar [28] . In other comperative studies, anidulafungin form biolms [46,47] and is also commonly isolated from different was associated with higher response rates and a trend toward environmental sources presenting potential routes for nosocomial decreased mortality in critically ill patients with acute organ transmission. C.orthopsilosis and C.metapsilosis constitute 10% of dysfunction and shorter intensive care unit and total length of C.parapsilosis isolates, and are obtained from biological products hospital stay [38] . such as urine, respiratory tract samples and mucosal surfaces in Data about the efcacy of anidulafungin in pediatric patients particular, and were not found to produce a biolm in vitro [46,47] . are extremely limited. It was evaluated in one study and found In the majority of pediatric invasive candidiasis cases, intra to be superior to standard uconazole in patients 16 years of age vascular devices are the dominant risk factor and C.parapsilosis or older with invasive candidiasis [28] . is one of the most frequent species associated with catheter-related Seriously ill or immunocompromised children are at increased bloodstream infection [1] . Patients requiring prolonged use of central risk of invasive fungal infections, particularly candidemia, but venous catheters and parenteral nutrition are at high risk because fungal epidemiology in children is markedly different from adults. of the ability of C.parapsilosis to form biolms on the surface of C.albicans and C.parapsilosis are the two most frequent causes indwelling devices and prosthetic materials [40,42] . Formation of of candidemia, whereas incidence of species such as C. krusei and biolms in intravascular catheters is problematic, since biolms C.glabrata, which interfere with uconazole treatment, are not can confer antifungal resistance and protect the yeast cells from frequently seen in pediatric patients. C.parapsilosis is particularly host immune responses [48] . Hence, when the bloodstream infecassociated with bloodstream infections in very low-birth-weight tion is associated with a catheter, removal of intravascular catheters is neonates and is also seen in children with catheters, prosthetic strongly advised because not removing the catheter is associated with devices and those receiving intravenous hyperalimentation in poor outcome. Recently, activity of anidulafungin has been demonpediatric units [13] . strated against both C.albicans and C.parapsilosis biolms [49,50] . Table 2. Characteristics of anidulafungin.
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Because of the difculty in treating biolm formation, anidulafungin 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 signicant differences in antifungal susceptibility among the sibling species of C.parapsilosis. In a study comparing susceptibility of these strains to uconazole, anidulafungin and caspofungin, it was found that C.parapsilosis sensu stricto was signicantly 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 uconazole, voriconazole, posaconazole, amphotericin 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 anidulafungins MICs were less than those of caspofungin [46] . In a very recent study, antifungal susceptibility proles 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 biolm of C.parapsilosis sensu stricto, where as voriconazole was ineffective [47] . Furthermore, efcacy of anidulafungin against C.albicans mature biolms has recently been demonstrated in a novel rat model of catheter-associated candidiasis. Catheters retrieved from rats, treated with daily intraperitoneal injections of anidulafungin for 7 days, showed reduced cell numbers compared to untreated and uconazole-treated animals. It has been shown that systemic administration of anidulafungin is promising for the treatment of mature C.albicans biolms in vivo [51] . It is unclear whether the results of in vitro studies may effect decisions on therapeutic and prophylactic choices or inuence 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 biolms should be conrmed with further in vivo studies. Selection of antifungal agent in the pediatric population may one day be due to the subtype of the strain determined as a biolm producer or not. Further clinical studies are warranted.
Other Candida infections

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

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 uid 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, osteomyelitis, urinary tract infections and meningitis are also documented 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 signicantly reduced mortality and fungal burden in brain tissue to a greater extent than voriconazole, suggesting a potential role of anidulafungin as an alternative choice for the treatment of candidal CNS infection [54] .
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Results of several clinical trials indicate that anidulafungin is effective in treating esophageal candidiasis, including azole refractory disease [5658] . 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 ucon azole, 200 mg administered on day 1 followed by 100 mg daily for 1421 days. The overall clinical and mycological efcacy of anidulafungin was found to be noninferior to that of uconazole as reported previously. However, at 2-week follow-up, the relapse rate for anidulafungin and uconazole was 35.6 and 10.5%, respectively [56] . The cause of higher relapse rates is unknown. The efcacy and safety of anidulafungin has also been demonstrated in patients with azole-refractory oropharyngeal and esophageal 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 efcacy of anidulafungin versus oral uconazole 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 MIC90 was 0.06 g/ml and 99% of strains were inhibited by 0.12 g/ml. There were six uconazoleresistant strains with MICs ranging between 0.015 and 0.06 for anidulafungin [58] . Oropharyngeal and esophageal candidiasis are the most common 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, uconazole still seems to be a better choice in mucosal candidiasis but poor tolerance to uconazole or uconazole-resistant Candida would make anidulafungin an alternative 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 efcacies 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 efcacy 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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Anidulafungin in the treatment of pediatric invasive fungal infections

Review

In a very recent study, in vivo efcacy of anidulafungin during the early phase of disseminated candidiasis in a neutropenic murine model was investigated and the results were compared with uconazole. Fungal burden in tissues of animals was measured at multiple time points within the rst 24 h of therapy. Anidulafungin reduced the fungal burden rapidly and exhibits an excellent antifungal activity at the tissue level [60] . This result may offer promise in critically ill immunocompromised neutropenic patients with disseminated candidiasis. However, anidulafungin is not currently recommended as primary antifungal therapy for invasive candidiasis and candidemia in neutropenic patients because of insufcient clinical data.
Aspergillus infections

demonstrated synergy at a dosage of 5 mg/kg/day, but antagonism at 10 mg/kg/day [66] . A prospective, randomized, double-blinded trial comparing anidulafungin and voriconazole in combination with voriconazole monotherapy for treatment of invasive aspergillosis in adults is projected to complete enrollment by May 2011 [103] . The target enrollment is 405 subjects and this study will hopefully provide an answer to the question of whether combination therapy with voriconazole and anidulafungin is really better than voriconazole alone. Since clinical trials are scarce, routine administration of combinations is not recommended, but may be considered in severe invasive fungal infections associated with high mortality rates in the future.
Expert commentary & ve-year view

Anidulafungin is active against Aspergillus spp. in vitro [7] . The results of the SENTRY Antimicrobial Survelliance Programme in 2008 demonstrated the expanded utility of anidulafungin against the most common mold species identied in lower respiratory tract infections. Echinocandin potency against A. fumigatus was greatest for anidulafungin (MEC90 : 0.002 g/ml) [7] . In experimental animal models, anidulafungin prolonged the survival and reduced antigenemia in rabbits with disseminated aspergillosis [61] . In a comperative study investigating the in vitro pharmacodynamics of caspofungin, micafungin and anidulafungin, anidulafungin exhibited the lowest MEC values and caspofungin exhibited the highest MEC values against nongerminated conidia of Aspergillus spp. Against germinated Aspergillus conidia, however, micafungin and anidulafungin had comparable MEC values lower than caspofungin [62] . The clinical utility of these results remains undened. Although anidulafungin is approved for the treatment of candi diasis like other echinocandins, its role in invasive aspergillosis requires more clinical evaluation. No prospective controlled data are available for the treatment of pediatric invasive aspergillosis with echinocandins as yet. Based on data in adults, echinocandins are not accepted as a rst-line therapeutic option for pediatric invasive aspergillosis.
Combination therapy

Owing to the high mortality rate of invasive aspergillosis, efcacy of combined antifungal therapy has been considered as an option to improve the results obtained with monotherapy. Anidulafungin differs from the remaining antifungal agents as it does not induce cross-resistance with other classes of antifungals. This characteristic is benecial in combination therapy. However, most of the data about the efcacy of different combinations are usually from animal models, case reports and in vitro studies [31,6366] . Anidulafungin in combination with amphotericin B against A.fumigatus species was not more active than anidulafungin alone and did not improve the outcome [63] . Studies evaluating the concomitant use of anidulafungin with either amphotericin B or voriconazole did not demonstrate signicant drugdrug interactions [31,6366] . The combination of anidulafungin and voriconazole did not signicantly improve survival in a transiently neutropenic rat model with advanced pulmonary aspergillosis [65] . Data on combination of anidulafungin and voriconazole in persistently neutropenic rabbits with experimental invasive pulmonary aspergillosis
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In recent years, there has been a signicant improvement in the development of antifungal agents. Anidulafungin, the newest echinocandin, attracts attention with its unique pharmacokinetics among these agents. It has shown promising results in treating invasive infections due to either Candida or Aspergillus spp. Given the safety and efcacy of anidulafungin and its novel pharmaco kinetics, it seems to have several advantages in patients who are subject to drug interactions because of HIV infection, malignancy and post-transplant immunosuppressive therapy. Although it seems to have more potent activity against C.parapsilosis, especially strains causing biolms in vitro, its in vivo activity to C.parapsilosis strains, its efcacy in neutropenic patients and its role in combination therapy for invasive aspergillosis need to be investigated in further studies. An upcoming study comparing the safety, tolerability and efcacy of voriconazole and anidulafungin in combination versus voriconazole alone in pediatric subjects aged 217 years with invasive aspergillosis will provide data on combination therapy in pediatric subjects [104] . Since the characteristics, risk factors, pathophysiology, pathogen epidemiology, susceptibility pattern of the pathogen, pharmacokinetics of antifungal agents and outcomes exhibit substantial differences in pediatric invasive fungal infections when compared with adults, it is not reliable to extrapolate the results of adult studies to pediatric populations. An ongoing study to assess the safety and pharmacokinetics, and evaluate the response to anidulafungin in 60 children with invasive candidiasis will provide pediatric data from a prospective trial [105] . However, further investigations are required to assess clinical relevance in pediatric patients. Otherwise, owing to a lack of large prospective comperative studies in pediatric patients, we will still be trying to nd an answer to the question which one is a better choice for the treatment of pediatric invasive fungal infections.
Financial & competing interests disclosure

The author has no relevant afliations or nancial involvement with any organization or entity with a nancial interest in or nancial conict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 343

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Key issues

Tapsz

Anidulafungin is the latest echinocandin to be developed with antifungal activity against Candida and Aspergillus spp. It is approved for use in candida infections in non-neutropenic adult patients, but not currently licensed for pediatric usage. It is projected to be distinctive with its unique pharmacokinetics. It seems to have several advantages in patients who are subject to drug interactions because of HIV infection, malignancy and post-transplant immunosuppressive therapy. It seems to have more potent activity against C.parapsilosis, especially strains causing biolms in vitro, however, this needs to be supported with in vivo studies. Its efcacy in neutropenic patients and its role in combination therapy for invasive aspergillosis needs to be investigated with further studies. Further investigations are required to assess clinical relevance in pediatric patients.

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