Clinical Infectious Diseases Advance Access published July 21, 2014
1 Antifungal combination therapy for invasive aspergillosis
Almudena Martín-Peña1,2, Manuela Aguilar-Guisado1,2, Ildefonso Espigado2,3, and
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José Miguel Cisneros1,2 1
Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva,
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/ CSIC/Universidad de Sevilla, Seville, Spain
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Red Española para la Investigación en Patología Infecciosa (REIPI)
3
Unidad Clínica de Hematología y Hemoterapia, Instituto de Biomedicina de Sevilla
(IBiS), Hospital Universitario Virgen del Rocío/ CSIC/Universidad de Sevilla, Seville,
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Spain
Corresponding author: José Miguel Cisneros, Unidad de Gestión Clínica de
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Enfermedades Infecciosas, Microbiología y Medicina Preventiva del Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot S/N 41013, Seville. Tel /Fax: +34 955012377, E-mail: [email protected]
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Alternate correspondig author: Almudena Martín-Peña, Unidad de Gestión Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva del Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot S/N 41013, Seville. Tel /Fax: +34 955012185, E-mail: [email protected]
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Summary: Antifungal combined therapy against invasive aspergillosis in primary and salvage indication has been widespread in last years, despite of the limited data
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supporting its efficacy. The available information is analyzed and our viewpoint on this topic is discussed.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
2
2 Abstract The outcome of invasive aspergillosis (IA) continues to be associated with significant
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attributable mortality, especially in patients with hematological malignancies and hematopoietic stem cell transplant (HSCT) recipients. In this context, antifungal
combined therapy (ACT) has become an emerging strategy against IA. In an attempt to evaluate the benefits of ACT, a large number of experimental studies, clinical series and randomized trials have been reported, with varying results. In addition, several
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not been made available. In summary, there is an imbalance between the weak level of published evidence regarding the benefits of ACT and its high and rising use in current
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clinical practice, despite its associated cost. In this viewpoint a critical analysis of the available information regarding ACT for the treatment of IA is discussed and the
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ce
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opinion of the authors with respect to its use is presented.
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controlled trials have been registered, however in most cases their final results have
3 Introduction Invasive aspergillosis (IA) is a life-threatening infection, especially in patients with
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hematological malignancies. Although survival has increased in recent years due to advances in diagnosis and the availability of an arsenal of new antifungals [1], the
outcome of IA remains suboptimal, with an attributable mortality of up to 42%-64% [2,3]. In this context, the combination of different antifungal drugs is attractive for
several reasons: first, to achieve potential synergistic effects due to the action of the
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to achieve broader antifungal coverage for empiric or targeted therapy in centers with high rates of resistance; and third to potentially reduce acquired resistance [4,5]. The
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clinical results that would be expected if ACT provided an added benefit are an increased response rate and improved survival, however it should be noted that ACT
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could also lead to antagonism for some antifungal combinations, enhanced toxicity, and significant additional costs. The scientific evidence supporting the hypothesis that combination therapy could be more effective than monotherapy is mainly based on in
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vitro and experimental studies [5], whereas the studies performed in clinical settings are numerous and quite heterogeneous [5–7]. In this viewpoint we critically review the available information regarding ACT for IA in an attempt to answer the following question: Is ACT more effective and as safe as monotherapy for IA?. To answer this question, we have comprehensively evaluated the
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information available regarding ACT in the treatment of IA from published preclinical studies to current clinical trials that are not yet published in the scientific literature.
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Efficacy and safety of antifungal combined therapy Preclinical studies There are numerous experimental studies on the use of combinations of different antifungals for the treatment of IA, both in vitro studies evaluating antifungal susceptibility and interactions between antifungals or studies in animal models [5].
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drugs on different targets or inhibition of different steps of the same pathway; second,
4 Some of these studies have tested combinations of azoles and amphotericin (AMB) in vitro showing variable effects, from synergy to antagonistic activity [6]. However, the
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true efficacy of these combinations cannot be established due to the lack of a standardized CLSI protocol for in vitro synergy testing of fungi [8], and the lack of
correlation of in vitro synergy data with clinical outcomes, which may indeed make results difficult to interpret.
The most significant results supporting ACT in animal models have been reported
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in animal models of IA was shown with the combination of caspofungin plus
voriconazole and micafungin plus itraconazole [9,10] when compared to echinocandin
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alone, although survival was no better than with triazole monotherapy [11–13]. The combination of anidulafungin with voriconazole results in improved survival compared
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to either monotherapy in some animal models [14,15] whereas other studies using the same combination have shown no differences in outcome regarding either of the monotherapy regimens [16]. In general, these contradictory results suggest that the
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addition of triazoles to echinocandin results in a trend toward improved survival compared to monotherapy with echinocandins, but no measurable benefit compared to monotherapy with voriconazole.
In summary, one must be aware of inherent problems associated with in vitro combinations assays and the different animal models, used for characterizing these
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treatment regimens before translating these results into clinical practice. Clinical studies
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1. Clinical series
In recent years, many clinical studies characterizing ACT for IA have been reported in which the authors attempted to evaluate if ACT offers an advantage in terms of successful response and/or survival. The main characteristics of these studies [1,3,17– 24] are shown in Table 1.
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when testing combinations of triazoles with echinocandins. A positive effect on survival
5 The most important drawback of these studies is the limited scientific quality of their design since they fail to establish the true efficacy of ACT, a fact that and also makes
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the generalization of study conclusions challenging. First, most of these studies have a retrospective and monocentric design [1,3,18,20], and two of them were carried out at the same institution over long periods of time during which different antifungal
combinations were analyzed, and both studies involved unbalanced groups study arms in terms of number of patients included [3,18]. Only one study has a prospective and
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ACT with micafungin versus monotherapy for salvage treatment, and a small number of patients in primary therapy. Furthermore, this study had a non-comparative design, and
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analyzed heterogeneous populations and multiple micafungin-based combinations that were determined based on the treating clinician’s discretion [22]. Two additional studies
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have a case-control design, however in both of them the control group data was retrospectively collected [17,19]. Moreover, one of these studies was designed to evaluate posaconazole as salvage therapy and not to analyze the efficacy of ACT [17].
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Therefore, none of the studies are randomized, and the decision to initiate ACT was left to the discretion of the treating physicians in five of seven studies, both for primary and/or salvage study [1,3,17,18,22]. The selection of different combinations of antifungal drugs (caspofungin plus voriconazole in three studies [1,19,20], an echinocandin plus amphotericin B in two studies [3,17], caspofungin or micafungin plus
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a miscellaneous [21,22], and amphotericin plus itraconazole [18]) in primary and/or salvage therapy and the absence of a predefined criteria for initiating ACT indication
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makes it difficult to interpret the results of these studies. In addition to the lack of appropriate design, the major challenge associated with studies evaluating ACT is the absence of an appropriate measure of efficacy. Most of the studies evaluate the satisfactory response (including partial and complete resolution of clinical, radiological and microbiological data) and overall survival [3,17,19,21], whereas others analyze only overall survival or crude and attributable
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multicenter design, although it also includes unbalanced study arm groups sizes for
6 mortality [1,20], or only satisfactory response [18]. The difficulty of accessing clinical data and being able to determine each point of the measure of satisfactory response,
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especially when using retrospective data, further complicates the interpretation of results. In addition, attributable mortality may be difficult to assess since the
contribution of IA to death in hematological patients may not be properly established in the absence of autopsy because of the complexity of these patients. For these
reasons, the impact of ACT on overall survival compared with monotherapy may be the
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six studies evaluating overall survival, three of them found differences between treatment groups: in the first study [19], which compares ACT with voriconazole and
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caspofungin vs. AMB for primary therapy of IA in solid organ transplant recipients, there was a significant difference in survival in patients with renal failure or infection
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due to Aspergillus fumigatus. This is an important finding since the comparator in monotherapy is AMB, which has known higher associated nephrotoxicity and lower efficacy than voriconazole (included in the combination therapy) for IA [25]. The second
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study [17] compares high doses of AMB plus caspofungin vs. posaconazole for salvage therapy of IA, and found higher overall survival in patients receiving monotherapy. This result is not surprising since the study evaluated the compassionate-use of posaconazole and used a historic control group that received high dose of AMB, which has been shown to be more toxic and no more effective than standard doses [26].
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Finally, another study comparing voriconazole plus caspofungin vs. voriconazole for salvage therapy reported better three-month survival for the ACT group [20]. However,
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the study had a retrospective design with a small and unbalanced number of patients in the treatment groups, and the time periods in which treatment groups were compared are different (the monotherapy group was treated between 1997-2001 whereas than the ACT group was treated only in 2001). Since ACT was administered only in the last year of the study, changes in clinical care in this period that would not be detectable by
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most appropriate measure for efficacy when comparing clinical studies. Indeed, of the
7 the observational design of the study could have had an impact on differences in survival.
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An important issue when evaluating the combination of antifungal drugs is toxicity. However, only three out of eight studies include a comparison of toxicity between
monotherapy and ACT [3,17,20]. Overall, the results show that polyenes used alone or in combination with an echinocandin added to renal and hepatic toxicity [3,17],
especially when high doses are used [17], whereas there are no significant differences
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not include a polyene [20]. 2. Published clinical trials
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In comparison with clinical trials evaluating monotherapy, the design of trials evaluating combination therapy presents additional complexities and challenges. Careful
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consideration should be given to the definition of combination therapy, study design (i.e, superiority vs. inferiority), selection of patient populations, control regimens, and endpoints. Two clinical trials evaluating ACT reported to date are detailed in Table 1.
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Both studies, which have different designs, include a small sample size and their statistical design is not appropriate for determining if ACT is superior or equivalent (not calculation of delta factor) than monotherapy, leading to underpowered results. The first study [24] is an open-label, non comparative, and non controlled clinical trial evaluating the efficacy and safety of caspofungin-based combinations for salvage
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therapy of IA. No differences in the end-point (favorable response) in both combination groups were found, but these results were not compared with monotherapy. The
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second study [23] is a pilot, randomized and comparative study, but the monotherapy arm consisted of high dose L-AMB. Taking into account that monotherapy with high dose L-AMB is known to be more toxic and without additional benefits in terms of efficacy than standard doses [26], this is not the optimal comparator, and as expected a higher rate of drug-related adverse events were detected in this group. In this sense, the results showing a higher favorable response rate in the ACT group may be
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in hepatic or renal toxicity between ACT and monotherapy when the combination does
8 debatable due to the use of an inappropriate comparator and the effect of the reduced sample size.
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In summary, it is not possible to draw definite conclusions regarding the efficacy and safety of ACT from these clinical trials since their results are limited by small sample sizes and inappropriate design. 3. International guidelines of from scientific societies
Since guidelines published by scientific societies [27–29] are commonly used in clinical
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preclinical and clinical data impacts on the different international societies’
recommendations regarding ACT for IA. It is noteworthy that scientific societies differ in
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their recommendations as well as in the given strength of the evidence supporting the use of ACT in both primary and salvage therapy (Table 2), in spite of the fact that these
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guidelines were published during the same time period (2008-2011) with the availability of similar scientific information. This fact underlines the subjectivity of these guidelines due to the weakness of the data that support them.
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4. Non published clinical trials A global vision of this topic should include both published studies and data from those clinical trials that once started, have never resulted in the publication of the final results (Table 3). In addition to clinical trials that are withdrawn for different reasons without obtaining results, the common practice of stopping clinical trials prematurely may
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overestimate the real effect of the intervention. The results of seven of the nine clinical trials evaluating ACT registered on the web site
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of www.clinicaltrial.gov have not been published. Five of them have been withdrawn,
three before the enrolment of patients and two because of insufficient recruitment. The remaining two studies have been completed. The results of the clinical trial NCT00037206, completed in February 2003, are neither available nor published. The other study identified as NCT00531479 has an optimal design as it is a randomized and double blind clinical trial comparing voriconazole and anidulafungin vs.
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practice, it is essential to determine how the available scientific evidence based on
9 voriconazole monotherapy for primary treatment of IA. The preliminary results reported at the 22nd European Congress of Clinical Microbiology and Infectious Diseases after
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enrolment of the first 277 patients, showed a significant reduction in the six-week crude mortality rate when excluding cases of possible aspergillosis [30]. The study was
completed with 454 treated patients and, pending final peer review, the results in the whole population posted on the clinicaltrial.gov website (dated: April 3, 2012) do not seem to confirm the preliminary results, assuming that no significant differences are
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Economic aspects
A crucial aspect to consider regarding antifungal use is its elevated cost. In recent
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years antifungal consumption has experienced an important increase, often due to misuse [31]. The widespread use of ACT may have contributed to this fact, together
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with the rising incidence of IA and the use of newer and more expensive antifungal drugs. Thus, antifungal drugs account for a high fraction of drug expenditures in hospital settings [32], especially in the hematological setting in which the cost ranges
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from 36% to 57% of total expenditures [33,34]. This has prompted the need for optimization of antifungal use in the hospital settings [32–35]. To our knowledge, only one study has evaluated the cost-effectiveness of ACT vs. monotherapy for salvage therapy of IA in HSCT recipients [36], concluding that salvage monotherapy with caspofungin was the most cost-effective strategy (dominant strategy), in terms of life
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years gained. Although salvage ACT with L-AMB plus caspofungin was the most effective strategy, the financial requirements needed to gain one extra life-year
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exceeded the ceiling ratio usually used to make decisions. Thus, although only this study has analysed the pharmacoeconomics of ACT, and its results are limited by the paucity of published data (including a theorical population of HSCT recipients derived from studies with a time-horizon of 12 weeks), our conclusion is that the increased costs associated with ACT may not be compensated by its effectiveness. Conclusion
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noted.
10 From our point of view the use of antifungal combined therapy has not proven to be more effective than monotherapy and is not justified for the treatment of invasive
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aspergillosis. Although there are no data suggesting increased toxicity using standard doses, the increase in cost may be difficult to assume by the Health Care Systems in the current economic context. Other approaches, including prompt diagnosis which
would allow for the early initiation of therapy and the optimization of current antifungal therapy by therapeutic drug monitoring, may be more effective approaches for
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Acknowledgments
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We thank the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III co-financed by European Development Regional Fund "A way to achieve Europe"
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ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). The authors would also like to thank Michael McConnell for revising the manuscript. AMP have no conflicts of interest to declare, I.E. has received speaking honoraria from
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Merck, Astellas Pharma, Gilead and Pfizer; J.M.C. has received speaking honoraria from Merck, Astellas Pharma and Pfizer; and MAG has received speaking honoraria
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from Gilead.
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improving the outcome of patients with invasive aspergillosis.
11 References
2.
Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006; 91:1068–1075.
3.
Mihu CN, Kassis C, Ramos ER, Jiang Y, Hachem RY, Raad II. Does combination of lipid formulation of amphotericin B and echinocandins improve outcome of invasive aspergillosis in hematological malignancy patients? Cancer 2010; 116:5290–5296.
4.
Sobel JD. Combination therapy for invasive mycoses: evaluation of past clinical trial designs. Clin. Infect. Dis. 2004; 39 Suppl 4:S224–227.
5.
Hatipoglu N, Hatipoglu H. Combination antifungal therapy for invasive fungal infections in children and adults. Expert Rev Anti Infect Ther 2013; 11:523–535.
6.
Vazquez JA. Clinical practice: combination antifungal therapy for mold infections: much ado about nothing? Clin. Infect. Dis. 2008; 46:1889–1901.
7.
Garbati MA, Alasmari FA, Al-Tannir MA, Tleyjeh IM. The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review. Int. J. Infect. Dis. 2012; 16:e76–81.
8.
CLSI 2008. Reference method for broth dilution antifungal suscepti- bility testing of filamentous fungi; approved standard—second edi- tion. CLSI document M38– A2. Clinical and Laboratory Standards In- stitute, Wayne, PA
9.
Clemons KV, Parmar R, Martinez M, Stevens DA. Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosis. J. Antimicrob. Chemother. 2006; 58:466–469.
pt ed
M
an
us
cr ipt
Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin. Infect. Dis. 2007; 44:531–540.
ce
10. Clemons KV, Espiritu M, Parmar R, Stevens DA. Comparative efficacies of conventional amphotericin b, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis. Antimicrob. Agents Chemother. 2005; 49:4867–4875. 11. Luque JC, Clemons KV, Stevens DA. Efficacy of micafungin alone or in combination against systemic murine aspergillosis. Antimicrob. Agents Chemother. 2003; 47:1452–1455.
Ac
12. Kirkpatrick WR, Perea S, Coco BJ, Patterson TF. Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob. Agents Chemother. 2002; 46:2564–2568.
13. MacCallum DM, Whyte JA, Odds FC. Efficacy of caspofungin and voriconazole combinations in experimental aspergillosis. Antimicrob. Agents Chemother. 2005; 49:3697–3701.
14. Petraitis V, Petraitiene R, Hope WW, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
1.
12 concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis. Antimicrob. Agents Chemother. 2009; 53:2382–2391.
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15. Calvo E, Pastor FJ, Salas V, Mayayo E, Guarro J. Combined therapy of voriconazole and anidulafungin in murine infections by Aspergillus flavus. Mycopathologia 2012; 173:251–257.
16. Van de Sande WWJ, Mathot RAA, ten Kate MT, et al. Combination therapy of advanced invasive pulmonary aspergillosis in transiently neutropenic rats using human pharmacokinetic equivalent doses of voriconazole and anidulafungin. Antimicrob. Agents Chemother. 2009; 53:2005–2013.
us
an
18. Kontoyiannis DP, Boktour M, Hanna H, Torres HA, Hachem R, Raad II. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis. Cancer 2005; 103:2334– 2337.
M
19. Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81:320–326. 20. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin. Infect. Dis. 2004; 39:797–802.
pt ed
21. Cesaro S, Giacchino M, Locatelli F, et al. Safety and efficacy of a caspofunginbased combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients. BMC Infect. Dis. 2007; 7:28. 22. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J. Infect. 2006; 53:337–349.
ce
23. Caillot D, Thiébaut A, Herbrecht R, et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer 2007; 110:2740–2746.
Ac
24. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006; 107:2888–2897.
25. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 2002; 347:408– 415. 26. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
17. Raad II, Hanna HA, Boktour M, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia 2008; 22:496–503.
13 dose regimen with standard dosing (AmBiLoad trial). Clin. Infect. Dis. 2007; 44:1289–1297.
cr ipt
27. ECIL-5 Antifungal therapy - ECIL5 Antifungal Therapy.pdf. Available at: http://www.kobe.fr/ecil/telechargements2013/ECIL5%20Antifungal%20Therapy.pd f. Accessed 10 June 2014. 28. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis. 2008; 46:327–360.
us
an
30. Marr K, Schlamm H, Rottinghaus ST, et al. A Randomized Double Blind Study of Combination Antifungal Therapy with Voriconazole and Anidulafungin Versus Voriconazole Monotherapy for Primary Treatment of Invasive Aspergillosis. London, UK: ECCMID: 2012. 31. Martín-Peña A, Aguilar-Guisado M, Cisneros JM. Does the current treatment of invasive fungal infection need to be reviewed? Enferm. Infecc. Microbiol. Clin. 2013;
M
32. Zarb P, Amadeo B, Muller A, et al. Antifungal therapy in European hospitals: data from the ESAC point-prevalence surveys 2008 and 2009. Clin. Microbiol. Infect. 2012; 18:E389–E395.
pt ed
33. Rieger CT, Cornely OA, Hoppe-Tichy T, et al. Treatment cost of invasive fungal disease (Ifd) in patients with acute myelogenous leukaemia (Aml) or myelodysplastic syndrome (Mds) in German hospitals. Mycoses 2012; 55:514– 520. 34. Martín-Peña A, Gil-Navarro MV, Aguilar-Guisado M, et al. Cost-effectiveness analysis comparing two approaches for empirical antifungal therapy in hematological patients with persistent febrile neutropenia. Antimicrob. Agents Chemother. 2013; 57:4664–4672.
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35. Mondain V, Lieutier F, Hasseine L, et al. A 6-year antifungal stewardship programme in a teaching hospital. Infection 2013; 41:621–628.
Ac
36. Ament AJHA, Hübben MWA, Verweij PE, et al. Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach. J. Antimicrob. Chemother. 2007; 60:385–393.
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
29. Fortún J, Carratalá J, Gavaldá J, et al. [Guidelines for the treatment of invasive fungal disease by Aspergillus spp. and other fungi issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2011 Update]. Enferm. Infecc. Microbiol. Clin. 2011; 29:435–454.
rip t
Therapy category Study design
Indication
Clinical series
MT
(N)
(N)
HD LF-AMB + Caspofungin
Cases and controls
ACT vs. MT
(1999-2005 vs. 1994-2005)
Salvage
Crude mortality ACT vs. MT
- Non randomized - Retrospective control groups - ACT group is control group
(N=53)
11% vs. 40%, p
1 Antifungal combination therapy for invasive aspergillosis
Almudena Martín-Peña1,2, Manuela Aguilar-Guisado1,2, Ildefonso Espigado2,3, and
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José Miguel Cisneros1,2 1
Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva,
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/ CSIC/Universidad de Sevilla, Seville, Spain
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Red Española para la Investigación en Patología Infecciosa (REIPI)
3
Unidad Clínica de Hematología y Hemoterapia, Instituto de Biomedicina de Sevilla
(IBiS), Hospital Universitario Virgen del Rocío/ CSIC/Universidad de Sevilla, Seville,
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Spain
Corresponding author: José Miguel Cisneros, Unidad de Gestión Clínica de
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Enfermedades Infecciosas, Microbiología y Medicina Preventiva del Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot S/N 41013, Seville. Tel /Fax: +34 955012377, E-mail: [email protected]
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Alternate correspondig author: Almudena Martín-Peña, Unidad de Gestión Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva del Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot S/N 41013, Seville. Tel /Fax: +34 955012185, E-mail: [email protected]
ce
Summary: Antifungal combined therapy against invasive aspergillosis in primary and salvage indication has been widespread in last years, despite of the limited data
Ac
supporting its efficacy. The available information is analyzed and our viewpoint on this topic is discussed.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
2
2 Abstract The outcome of invasive aspergillosis (IA) continues to be associated with significant
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attributable mortality, especially in patients with hematological malignancies and hematopoietic stem cell transplant (HSCT) recipients. In this context, antifungal
combined therapy (ACT) has become an emerging strategy against IA. In an attempt to evaluate the benefits of ACT, a large number of experimental studies, clinical series and randomized trials have been reported, with varying results. In addition, several
us
not been made available. In summary, there is an imbalance between the weak level of published evidence regarding the benefits of ACT and its high and rising use in current
an
clinical practice, despite its associated cost. In this viewpoint a critical analysis of the available information regarding ACT for the treatment of IA is discussed and the
Ac
ce
pt ed
M
opinion of the authors with respect to its use is presented.
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controlled trials have been registered, however in most cases their final results have
3 Introduction Invasive aspergillosis (IA) is a life-threatening infection, especially in patients with
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hematological malignancies. Although survival has increased in recent years due to advances in diagnosis and the availability of an arsenal of new antifungals [1], the
outcome of IA remains suboptimal, with an attributable mortality of up to 42%-64% [2,3]. In this context, the combination of different antifungal drugs is attractive for
several reasons: first, to achieve potential synergistic effects due to the action of the
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to achieve broader antifungal coverage for empiric or targeted therapy in centers with high rates of resistance; and third to potentially reduce acquired resistance [4,5]. The
an
clinical results that would be expected if ACT provided an added benefit are an increased response rate and improved survival, however it should be noted that ACT
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could also lead to antagonism for some antifungal combinations, enhanced toxicity, and significant additional costs. The scientific evidence supporting the hypothesis that combination therapy could be more effective than monotherapy is mainly based on in
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vitro and experimental studies [5], whereas the studies performed in clinical settings are numerous and quite heterogeneous [5–7]. In this viewpoint we critically review the available information regarding ACT for IA in an attempt to answer the following question: Is ACT more effective and as safe as monotherapy for IA?. To answer this question, we have comprehensively evaluated the
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information available regarding ACT in the treatment of IA from published preclinical studies to current clinical trials that are not yet published in the scientific literature.
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Efficacy and safety of antifungal combined therapy Preclinical studies There are numerous experimental studies on the use of combinations of different antifungals for the treatment of IA, both in vitro studies evaluating antifungal susceptibility and interactions between antifungals or studies in animal models [5].
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drugs on different targets or inhibition of different steps of the same pathway; second,
4 Some of these studies have tested combinations of azoles and amphotericin (AMB) in vitro showing variable effects, from synergy to antagonistic activity [6]. However, the
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true efficacy of these combinations cannot be established due to the lack of a standardized CLSI protocol for in vitro synergy testing of fungi [8], and the lack of
correlation of in vitro synergy data with clinical outcomes, which may indeed make results difficult to interpret.
The most significant results supporting ACT in animal models have been reported
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in animal models of IA was shown with the combination of caspofungin plus
voriconazole and micafungin plus itraconazole [9,10] when compared to echinocandin
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alone, although survival was no better than with triazole monotherapy [11–13]. The combination of anidulafungin with voriconazole results in improved survival compared
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to either monotherapy in some animal models [14,15] whereas other studies using the same combination have shown no differences in outcome regarding either of the monotherapy regimens [16]. In general, these contradictory results suggest that the
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addition of triazoles to echinocandin results in a trend toward improved survival compared to monotherapy with echinocandins, but no measurable benefit compared to monotherapy with voriconazole.
In summary, one must be aware of inherent problems associated with in vitro combinations assays and the different animal models, used for characterizing these
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treatment regimens before translating these results into clinical practice. Clinical studies
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1. Clinical series
In recent years, many clinical studies characterizing ACT for IA have been reported in which the authors attempted to evaluate if ACT offers an advantage in terms of successful response and/or survival. The main characteristics of these studies [1,3,17– 24] are shown in Table 1.
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when testing combinations of triazoles with echinocandins. A positive effect on survival
5 The most important drawback of these studies is the limited scientific quality of their design since they fail to establish the true efficacy of ACT, a fact that and also makes
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the generalization of study conclusions challenging. First, most of these studies have a retrospective and monocentric design [1,3,18,20], and two of them were carried out at the same institution over long periods of time during which different antifungal
combinations were analyzed, and both studies involved unbalanced groups study arms in terms of number of patients included [3,18]. Only one study has a prospective and
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ACT with micafungin versus monotherapy for salvage treatment, and a small number of patients in primary therapy. Furthermore, this study had a non-comparative design, and
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analyzed heterogeneous populations and multiple micafungin-based combinations that were determined based on the treating clinician’s discretion [22]. Two additional studies
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have a case-control design, however in both of them the control group data was retrospectively collected [17,19]. Moreover, one of these studies was designed to evaluate posaconazole as salvage therapy and not to analyze the efficacy of ACT [17].
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Therefore, none of the studies are randomized, and the decision to initiate ACT was left to the discretion of the treating physicians in five of seven studies, both for primary and/or salvage study [1,3,17,18,22]. The selection of different combinations of antifungal drugs (caspofungin plus voriconazole in three studies [1,19,20], an echinocandin plus amphotericin B in two studies [3,17], caspofungin or micafungin plus
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a miscellaneous [21,22], and amphotericin plus itraconazole [18]) in primary and/or salvage therapy and the absence of a predefined criteria for initiating ACT indication
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makes it difficult to interpret the results of these studies. In addition to the lack of appropriate design, the major challenge associated with studies evaluating ACT is the absence of an appropriate measure of efficacy. Most of the studies evaluate the satisfactory response (including partial and complete resolution of clinical, radiological and microbiological data) and overall survival [3,17,19,21], whereas others analyze only overall survival or crude and attributable
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multicenter design, although it also includes unbalanced study arm groups sizes for
6 mortality [1,20], or only satisfactory response [18]. The difficulty of accessing clinical data and being able to determine each point of the measure of satisfactory response,
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especially when using retrospective data, further complicates the interpretation of results. In addition, attributable mortality may be difficult to assess since the
contribution of IA to death in hematological patients may not be properly established in the absence of autopsy because of the complexity of these patients. For these
reasons, the impact of ACT on overall survival compared with monotherapy may be the
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six studies evaluating overall survival, three of them found differences between treatment groups: in the first study [19], which compares ACT with voriconazole and
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caspofungin vs. AMB for primary therapy of IA in solid organ transplant recipients, there was a significant difference in survival in patients with renal failure or infection
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due to Aspergillus fumigatus. This is an important finding since the comparator in monotherapy is AMB, which has known higher associated nephrotoxicity and lower efficacy than voriconazole (included in the combination therapy) for IA [25]. The second
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study [17] compares high doses of AMB plus caspofungin vs. posaconazole for salvage therapy of IA, and found higher overall survival in patients receiving monotherapy. This result is not surprising since the study evaluated the compassionate-use of posaconazole and used a historic control group that received high dose of AMB, which has been shown to be more toxic and no more effective than standard doses [26].
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Finally, another study comparing voriconazole plus caspofungin vs. voriconazole for salvage therapy reported better three-month survival for the ACT group [20]. However,
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the study had a retrospective design with a small and unbalanced number of patients in the treatment groups, and the time periods in which treatment groups were compared are different (the monotherapy group was treated between 1997-2001 whereas than the ACT group was treated only in 2001). Since ACT was administered only in the last year of the study, changes in clinical care in this period that would not be detectable by
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most appropriate measure for efficacy when comparing clinical studies. Indeed, of the
7 the observational design of the study could have had an impact on differences in survival.
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An important issue when evaluating the combination of antifungal drugs is toxicity. However, only three out of eight studies include a comparison of toxicity between
monotherapy and ACT [3,17,20]. Overall, the results show that polyenes used alone or in combination with an echinocandin added to renal and hepatic toxicity [3,17],
especially when high doses are used [17], whereas there are no significant differences
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not include a polyene [20]. 2. Published clinical trials
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In comparison with clinical trials evaluating monotherapy, the design of trials evaluating combination therapy presents additional complexities and challenges. Careful
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consideration should be given to the definition of combination therapy, study design (i.e, superiority vs. inferiority), selection of patient populations, control regimens, and endpoints. Two clinical trials evaluating ACT reported to date are detailed in Table 1.
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Both studies, which have different designs, include a small sample size and their statistical design is not appropriate for determining if ACT is superior or equivalent (not calculation of delta factor) than monotherapy, leading to underpowered results. The first study [24] is an open-label, non comparative, and non controlled clinical trial evaluating the efficacy and safety of caspofungin-based combinations for salvage
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therapy of IA. No differences in the end-point (favorable response) in both combination groups were found, but these results were not compared with monotherapy. The
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second study [23] is a pilot, randomized and comparative study, but the monotherapy arm consisted of high dose L-AMB. Taking into account that monotherapy with high dose L-AMB is known to be more toxic and without additional benefits in terms of efficacy than standard doses [26], this is not the optimal comparator, and as expected a higher rate of drug-related adverse events were detected in this group. In this sense, the results showing a higher favorable response rate in the ACT group may be
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in hepatic or renal toxicity between ACT and monotherapy when the combination does
8 debatable due to the use of an inappropriate comparator and the effect of the reduced sample size.
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In summary, it is not possible to draw definite conclusions regarding the efficacy and safety of ACT from these clinical trials since their results are limited by small sample sizes and inappropriate design. 3. International guidelines of from scientific societies
Since guidelines published by scientific societies [27–29] are commonly used in clinical
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preclinical and clinical data impacts on the different international societies’
recommendations regarding ACT for IA. It is noteworthy that scientific societies differ in
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their recommendations as well as in the given strength of the evidence supporting the use of ACT in both primary and salvage therapy (Table 2), in spite of the fact that these
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guidelines were published during the same time period (2008-2011) with the availability of similar scientific information. This fact underlines the subjectivity of these guidelines due to the weakness of the data that support them.
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4. Non published clinical trials A global vision of this topic should include both published studies and data from those clinical trials that once started, have never resulted in the publication of the final results (Table 3). In addition to clinical trials that are withdrawn for different reasons without obtaining results, the common practice of stopping clinical trials prematurely may
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overestimate the real effect of the intervention. The results of seven of the nine clinical trials evaluating ACT registered on the web site
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of www.clinicaltrial.gov have not been published. Five of them have been withdrawn,
three before the enrolment of patients and two because of insufficient recruitment. The remaining two studies have been completed. The results of the clinical trial NCT00037206, completed in February 2003, are neither available nor published. The other study identified as NCT00531479 has an optimal design as it is a randomized and double blind clinical trial comparing voriconazole and anidulafungin vs.
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practice, it is essential to determine how the available scientific evidence based on
9 voriconazole monotherapy for primary treatment of IA. The preliminary results reported at the 22nd European Congress of Clinical Microbiology and Infectious Diseases after
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enrolment of the first 277 patients, showed a significant reduction in the six-week crude mortality rate when excluding cases of possible aspergillosis [30]. The study was
completed with 454 treated patients and, pending final peer review, the results in the whole population posted on the clinicaltrial.gov website (dated: April 3, 2012) do not seem to confirm the preliminary results, assuming that no significant differences are
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Economic aspects
A crucial aspect to consider regarding antifungal use is its elevated cost. In recent
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years antifungal consumption has experienced an important increase, often due to misuse [31]. The widespread use of ACT may have contributed to this fact, together
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with the rising incidence of IA and the use of newer and more expensive antifungal drugs. Thus, antifungal drugs account for a high fraction of drug expenditures in hospital settings [32], especially in the hematological setting in which the cost ranges
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from 36% to 57% of total expenditures [33,34]. This has prompted the need for optimization of antifungal use in the hospital settings [32–35]. To our knowledge, only one study has evaluated the cost-effectiveness of ACT vs. monotherapy for salvage therapy of IA in HSCT recipients [36], concluding that salvage monotherapy with caspofungin was the most cost-effective strategy (dominant strategy), in terms of life
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years gained. Although salvage ACT with L-AMB plus caspofungin was the most effective strategy, the financial requirements needed to gain one extra life-year
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exceeded the ceiling ratio usually used to make decisions. Thus, although only this study has analysed the pharmacoeconomics of ACT, and its results are limited by the paucity of published data (including a theorical population of HSCT recipients derived from studies with a time-horizon of 12 weeks), our conclusion is that the increased costs associated with ACT may not be compensated by its effectiveness. Conclusion
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noted.
10 From our point of view the use of antifungal combined therapy has not proven to be more effective than monotherapy and is not justified for the treatment of invasive
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aspergillosis. Although there are no data suggesting increased toxicity using standard doses, the increase in cost may be difficult to assume by the Health Care Systems in the current economic context. Other approaches, including prompt diagnosis which
would allow for the early initiation of therapy and the optimization of current antifungal therapy by therapeutic drug monitoring, may be more effective approaches for
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Acknowledgments
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We thank the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III co-financed by European Development Regional Fund "A way to achieve Europe"
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ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). The authors would also like to thank Michael McConnell for revising the manuscript. AMP have no conflicts of interest to declare, I.E. has received speaking honoraria from
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Merck, Astellas Pharma, Gilead and Pfizer; J.M.C. has received speaking honoraria from Merck, Astellas Pharma and Pfizer; and MAG has received speaking honoraria
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from Gilead.
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improving the outcome of patients with invasive aspergillosis.
11 References
2.
Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006; 91:1068–1075.
3.
Mihu CN, Kassis C, Ramos ER, Jiang Y, Hachem RY, Raad II. Does combination of lipid formulation of amphotericin B and echinocandins improve outcome of invasive aspergillosis in hematological malignancy patients? Cancer 2010; 116:5290–5296.
4.
Sobel JD. Combination therapy for invasive mycoses: evaluation of past clinical trial designs. Clin. Infect. Dis. 2004; 39 Suppl 4:S224–227.
5.
Hatipoglu N, Hatipoglu H. Combination antifungal therapy for invasive fungal infections in children and adults. Expert Rev Anti Infect Ther 2013; 11:523–535.
6.
Vazquez JA. Clinical practice: combination antifungal therapy for mold infections: much ado about nothing? Clin. Infect. Dis. 2008; 46:1889–1901.
7.
Garbati MA, Alasmari FA, Al-Tannir MA, Tleyjeh IM. The role of combination antifungal therapy in the treatment of invasive aspergillosis: a systematic review. Int. J. Infect. Dis. 2012; 16:e76–81.
8.
CLSI 2008. Reference method for broth dilution antifungal suscepti- bility testing of filamentous fungi; approved standard—second edi- tion. CLSI document M38– A2. Clinical and Laboratory Standards In- stitute, Wayne, PA
9.
Clemons KV, Parmar R, Martinez M, Stevens DA. Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosis. J. Antimicrob. Chemother. 2006; 58:466–469.
pt ed
M
an
us
cr ipt
Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin. Infect. Dis. 2007; 44:531–540.
ce
10. Clemons KV, Espiritu M, Parmar R, Stevens DA. Comparative efficacies of conventional amphotericin b, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis. Antimicrob. Agents Chemother. 2005; 49:4867–4875. 11. Luque JC, Clemons KV, Stevens DA. Efficacy of micafungin alone or in combination against systemic murine aspergillosis. Antimicrob. Agents Chemother. 2003; 47:1452–1455.
Ac
12. Kirkpatrick WR, Perea S, Coco BJ, Patterson TF. Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob. Agents Chemother. 2002; 46:2564–2568.
13. MacCallum DM, Whyte JA, Odds FC. Efficacy of caspofungin and voriconazole combinations in experimental aspergillosis. Antimicrob. Agents Chemother. 2005; 49:3697–3701.
14. Petraitis V, Petraitiene R, Hope WW, et al. Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
1.
12 concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis. Antimicrob. Agents Chemother. 2009; 53:2382–2391.
cr ipt
15. Calvo E, Pastor FJ, Salas V, Mayayo E, Guarro J. Combined therapy of voriconazole and anidulafungin in murine infections by Aspergillus flavus. Mycopathologia 2012; 173:251–257.
16. Van de Sande WWJ, Mathot RAA, ten Kate MT, et al. Combination therapy of advanced invasive pulmonary aspergillosis in transiently neutropenic rats using human pharmacokinetic equivalent doses of voriconazole and anidulafungin. Antimicrob. Agents Chemother. 2009; 53:2005–2013.
us
an
18. Kontoyiannis DP, Boktour M, Hanna H, Torres HA, Hachem R, Raad II. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primary treatment of invasive aspergillosis. Cancer 2005; 103:2334– 2337.
M
19. Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81:320–326. 20. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. Clin. Infect. Dis. 2004; 39:797–802.
pt ed
21. Cesaro S, Giacchino M, Locatelli F, et al. Safety and efficacy of a caspofunginbased combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients. BMC Infect. Dis. 2007; 7:28. 22. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J. Infect. 2006; 53:337–349.
ce
23. Caillot D, Thiébaut A, Herbrecht R, et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer 2007; 110:2740–2746.
Ac
24. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006; 107:2888–2897.
25. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 2002; 347:408– 415. 26. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
17. Raad II, Hanna HA, Boktour M, et al. Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Leukemia 2008; 22:496–503.
13 dose regimen with standard dosing (AmBiLoad trial). Clin. Infect. Dis. 2007; 44:1289–1297.
cr ipt
27. ECIL-5 Antifungal therapy - ECIL5 Antifungal Therapy.pdf. Available at: http://www.kobe.fr/ecil/telechargements2013/ECIL5%20Antifungal%20Therapy.pd f. Accessed 10 June 2014. 28. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis. 2008; 46:327–360.
us
an
30. Marr K, Schlamm H, Rottinghaus ST, et al. A Randomized Double Blind Study of Combination Antifungal Therapy with Voriconazole and Anidulafungin Versus Voriconazole Monotherapy for Primary Treatment of Invasive Aspergillosis. London, UK: ECCMID: 2012. 31. Martín-Peña A, Aguilar-Guisado M, Cisneros JM. Does the current treatment of invasive fungal infection need to be reviewed? Enferm. Infecc. Microbiol. Clin. 2013;
M
32. Zarb P, Amadeo B, Muller A, et al. Antifungal therapy in European hospitals: data from the ESAC point-prevalence surveys 2008 and 2009. Clin. Microbiol. Infect. 2012; 18:E389–E395.
pt ed
33. Rieger CT, Cornely OA, Hoppe-Tichy T, et al. Treatment cost of invasive fungal disease (Ifd) in patients with acute myelogenous leukaemia (Aml) or myelodysplastic syndrome (Mds) in German hospitals. Mycoses 2012; 55:514– 520. 34. Martín-Peña A, Gil-Navarro MV, Aguilar-Guisado M, et al. Cost-effectiveness analysis comparing two approaches for empirical antifungal therapy in hematological patients with persistent febrile neutropenia. Antimicrob. Agents Chemother. 2013; 57:4664–4672.
ce
35. Mondain V, Lieutier F, Hasseine L, et al. A 6-year antifungal stewardship programme in a teaching hospital. Infection 2013; 41:621–628.
Ac
36. Ament AJHA, Hübben MWA, Verweij PE, et al. Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach. J. Antimicrob. Chemother. 2007; 60:385–393.
Downloaded from http://cid.oxfordjournals.org/ at Memorial Univ. of Newfoundland on August 2, 2014
29. Fortún J, Carratalá J, Gavaldá J, et al. [Guidelines for the treatment of invasive fungal disease by Aspergillus spp. and other fungi issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2011 Update]. Enferm. Infecc. Microbiol. Clin. 2011; 29:435–454.
rip t
Therapy category Study design
Indication
Clinical series
MT
(N)
(N)
HD LF-AMB + Caspofungin
Cases and controls
ACT vs. MT
(1999-2005 vs. 1994-2005)
Salvage
Crude mortality ACT vs. MT
- Non randomized - Retrospective control groups - ACT group is control group
(N=53)
11% vs. 40%, p
