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Vol. 29. Núm. S2.
Micafungina: nuevos retos y nuevas posibilidades en el tratamiento de la infección fúngica invasora
Páginas 38-42 (Marzo 2011)
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Vol. 29. Núm. S2.
Micafungina: nuevos retos y nuevas posibilidades en el tratamiento de la infección fúngica invasora
Páginas 38-42 (Marzo 2011)
Enfermedades Infecciosas y Microbiología Clínica
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Tratamiento combinado de la aspergilosis invasora. ¿Una oportunidad para micafungina?
Combination therapy for invasive aspergillosis
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Isabel Ruiz-Camps
Servicio de Enfermedades Infecciosas, Hospital Universitario Vall d’Hebron, Barcelona, España
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Resumen
Bibliografía
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Resumen

Las infecciones fúngicas invasoras, y en concreto la aspergilosis invasora, han aumentado en frecuencia en las últimas décadas, y pese a la aparición de nuevos antifúngicos se asocian a una elevada mortalidad que oscila entre el 40 y el 80%, dependiendo del paciente en el que incida y de la localización de ésta. Para intentar disminuir esta elevada tasa, se han planteado nuevas estrategias terapéuticas, entre las que se encuentra la terapia combinada. La mayoría de los datos disponibles sobre la eficacia de las combinaciones proceden de modelos experimentales, datos in vitro y estudios observacionales retrospectivos o con un número reducido de pacientes donde además mezclan pacientes en tratamiento de primera línea con pacientes en rescate, y hay muchas aspergilosis posibles y pocas probadas o probables. De momento, no se ha demostrado que el tratamiento combinado tenga una eficacia significativamente superior a la monoterapia; sin embargo, podría estar indicado en formas de aspergilosis grave, que cursen con afectación del sistema nervioso central o afectación pulmonar extensa con insuficiencia respiratoria, etc. Entre las combinaciones, la asociación de una equinocandina, grupo al que pertenece la micafungina, con voriconazol o anfotericina B liposomal parece mostrar sinergia y ha sido la más ensayada en estudios clínicos y, por tanto, aunque con escaso grado de evidencia, es la recomendada por las diferentes sociedades científicas.

Palabras clave:
Terapia combinada
Aspergilosis Micafungina
Abstract

The frequency of invasive fungal infections, and specifically invasive aspergillosis, has increased in the last few decades. Despite the development of new antifungal agents, these infections are associated with high mortality, ranging from 40% to 80%, depending on the patient and the localization of the infection. To reduce these figures, several therapeutic strategies have been proposed, including combination therapy. Most of the available data on the efficacy of these combinations are from experimental models, in vitro data and retrospective observational studies or studies with a small number of patients that have included both patients in first-line treatment and those receiving rescue therapy; in addition there are many patients with possible forms of aspergillosis and few with demonstrated or probable forms. To date, there is no evidence that combination therapy has significantly higher efficacy than monotherapy; however, combination therapy could be indicated in severe forms of aspergillosis, or forms with central nervous involvement or extensive pulmonary involvement with respiratory insufficiency, etc. Among the combinations, the association of an echinocandin – the group that includes micafungin – with voriconazole or liposomal amphotericin B seems to show synergy. These combinations are those most extensively studied in clinical trials and therefore, although the grade of evidence is low, are recommended by the various scientific societies.

Keywords:
Combination therapy
Aspergillosis Micafungin
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Bibliografía
[1]
L. Pagano, M. Caira, A. Nosari, M.T. Van Lint, A. Candoni, M. Offidani, et al.
Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study-Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne.
Clin Infect Dis, 45 (2007), pp. 1161-1170
[2]
J. Morgan, K.A. Wannemuehler, K.A. Marr, S. Hadley, D.P. Kontoyiannis, T.J. Walsh, et al.
Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program.
Med Mycol, 43 (2005), pp. S49-58
[3]
J. Gavaldá, O. Len, R. San Juan, J.M. Aguado, J. Fortun, C. Lumbreras, et al.
Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study.
Clin Infect Dis, 41 (2005), pp. 52-59
[4]
R. Herbrecht, D.W. Denning, T.F. Patterson, J.E. Bennett, R.E. Greene, J.W. Oestmann.
Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
N Engl J Med, 347 (2002), pp. 408-415
[5]
O.A. Cornely, J. Maertens, M. Bresnik, R. Ebrahimi, A.J. Ullmann, E. Bouza.
Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial).
Clin Infect Dis, 44 (2007), pp. 1289-1297
[6]
J. Mensa, R. De La Cámara, E. Carreras, M. Cuenca Estrella, J.A. García Rodríguez, M. Gobernado, et al.
Treatment of fungal infections in patients with hematologic neoplasia.
Med Clin (Barc), 132 (2009), pp. 507-521
[7]
C.M. Van der Horst, M.S. Saag, G.A. Cloud, R.J. Hamill, J.R. Graybill, J.D. Sobel, et al.
Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group.
N Engl J Med, 337 (1997), pp. 15-21
[8]
M. Cuenca-Estrella.
Combinations of antifungal agents in therapy -what value are they?.
J Antimicrob Chemother, 54 (2004), pp. 854-869
[9]
J.A. Vázquez.
Clinical practice: combination antifungal therapy for mold infections: much ado about nothing?.
Clin Infect Dis, 46 (2008), pp. 1889-1901
[10]
D.T. Te Dorsthorst, P.E. Verweij, J.F. Meis, N.C. Punt, J.W. Mouton.
In vitro interactions between amphotericin B, itraconazole, and flucytosine against 21 clinical Aspergillus isolates determined by two drug models.
Antimicrob Agents Chemother, 48 (2004), pp. 2007-2013
[11]
S. Maesaki, S. Kawamura, Y. Miyazaki, K. Tomono, T. Tashiro, S. Kohno.
Effect of sequential combination of amphotericin B and azole antifungal agents against Aspergillus fumigatus.
J Infect Chemother, 5 (1999), pp. 125-129
[12]
S. Perkhofer, H. Lugger, M.P. Dierich, C. Lass-Florl.
Posaconazole enhances the activity of amphotericin B against Aspergillus hyphae in vitro.
Antimicrob Agents Chemother, 51 (2007), pp. 791-793
[13]
N.S. Ryder, I. Leitner.
Synergistic interaction of terbinafine with triazoles or amphotericin B against Aspergillus species.
Med Mycol, 39 (2001), pp. 91-95
[14]
S. Perea, G. González, A.W. Fothergill, W.R. Kirkpatrick, M.G. Rinaldi, T.F. Patterson.
In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp.
Antimicrob Agents Chemother, 46 (2002), pp. 3039-3041
[15]
E.K. Manavathu, G.J. Alangaden, P.H. Chandrasekar.
Differential activity of triazoles in two-drug combinations with the echinocandin caspofungin against Aspergillus fumigatus.
J Antimicrob Chemother, 51 (2003), pp. 1423-1425
[16]
J. Meletiadis, T. Stergiopoulou, E.M. O'Shaughnessy, J. Peter, T.J. Walsh.
Concentrationdependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: analysis by a new response surface model.
Antimicrob Agents Chemother, 51 (2007), pp. 2053-2064
[17]
M. Cuenca-Estrella, A. Gómez-López, G. García-Effron, L. Alcázar-Fuoli, E. Mellado, M.J. Buitrago, et al.
Combined activity in vitro of caspofungin, amphotericin B, and azole agents against itraconazole-resistant clinical isolates of Aspergillus fumigatus.
Antimicrob Agents Chemother, 49 (2005), pp. 1232-1235
[18]
Y.F. Brun, C.G. Dennis, W.R. Greco, R.J. Bernacki, P.J. Pera, J.J. Bushey, et al.
Modeling the combination of amphotericin B, micafungin, and nikkomycin Z against Aspergillus fumigatus in vitro using a novel response surface paradigm.
Antimicrob Agents Chemother, 51 (2007), pp. 1804-1812
[19]
R.E. Lewis, D.P. Kontoyiannis.
Micafungin in combination with voriconazole in Aspergillus species: a pharmacodynamic approach for detection of combined antifungal activity in vitro.
J Antimicrob Chemother, 56 (2005), pp. 887-892
[20]
A. Philip, Z. Odabasi, J. Rodríguez, V.L. Paetznick, E. Chen, J.H. Rex, et al.
In vitro synergy testing of anidulafungin with itraconazole, voriconazole, and amphotericin B against Aspergillus and fusarium spp.
Antimicrob Agents Chemother, 49 (2005), pp. 3572-3574
[21]
W.R. Kirkpatrick, S. Perea, B.J. Coco, T.F. Patterson.
Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis.
Antimicrob Agents Chemother, 46 (2002), pp. 2564-2568
[22]
V. Petraitis, R. Petraitiene, W.W. Hope, J. Meletiadis, D. Mickiene, J.E. Hughes, et al.
Combination therapy in treatment of experimental pulmonary spergillosis: in vitro and in vivo correlations of the concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis.
Antimicrob Agents Chemother, 53 (2009), pp. 2382-2391
[23]
V. Petraitis, R. Petraitiene, A.A. Sarafandi, A.M. Kelaher, C.A. Lyman, H.E. Casler, et al.
Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin.
J Infect Dis, 187 (2003), pp. 1834-1843
[24]
W.J. Steinbach, D.A. Stevens, D.W. Denning.
Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001.
Clin Infect Dis, 37 (2003), pp. S188-224
[25]
P.H. Chandrasekar, J.L. Cutright, E.K. Manavathu.
Efficacy of voriconazole plus amphotericin B or micafungin in a guinea-pig model of invasive pulmonary aspergillosis.
Clin Microbiol Infect, 10 (2004), pp. 925-928
[26]
K.V. Clemons, M. Espiritu, R. Parmar, D.A. Stevens.
Comparative efficacies of conventional amphotericin B, liposomal amphotericin B (Am-Bisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis.
Antimicrob Agents Chemother, 49 (2005), pp. 4867-4875
[27]
K.V. Clemons, R. Parmar, M. Martínez, D.A. Stevens.
Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosis.
J Antimicrob Chemother, 58 (2006), pp. 466-469
[28]
K.V. Clemons, D.A. Stevens.
Efficacy of micafungin alone or in combination against experimental pulmonary aspergillosis.
Med Mycol, 44 (2006), pp. 69-73
[29]
Y. Nagasaki, Y. Eriguchi, Y. Uchida, N. Miyake, Y. Maehara, M. Kadowaki, et al.
Combination therapy with micafungin and amphotericin B for invasive pulmonary aspergillosis in an immunocompromised mouse model.
J Antimicrob Chemother, 64 (2009), pp. 379-382
[30]
T.B. Aliff, P.G. Maslak, J.G. Jurcic, M.L. Heaney, K.N. Cathcart, K.A. Sepkowitz, et al.
Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin.
Cancer, 97 (2003), pp. 1025-1032
[31]
K.A. Marr, M. Boeckh, R.A. Carter, H.W. Kim, L. Corey.
Combination antifungal therapy for invasive aspergillosis.
Clin Infect Dis, 39 (2004), pp. 797-802
[32]
A. Upton, K.A. Kirby, P. Carpenter, M. Boeckh, K.A. Marr.
Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality.
Clin Infect Dis, 44 (2007), pp. 531-540
[33]
J. Maertens, A. Glasmacher, R. Herbrecht, A. Thiebaut, C. Cordonnier, B.H. Segal, et al.
Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis.
Cancer, 107 (2006), pp. 2888-2897
[34]
D.P. Kontoyiannis, R. Hachem, R.E. Lewis, G.A. Rivero, H.A. Torres, J. Thornby, et al.
Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies.
Cancer, 98 (2003), pp. 292-299
[35]
D. Caillot, A. Thiébaut, R. Herbrecht, S. De Botton, A. Pigneux, F. Bernard, et al.
Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial).
Cancer, 110 (2007), pp. 2740-2746
[36]
I.I. Raad, H. Hanna, M. Boktour, H. Torres, D. Kontoyiannis, R. Hachem, et al.
The combination of caspofungin (C) and voriconazole (V) as primary and salvage therapy of invasive aspergillosis (IA) in hematologic malignancy patients (HMP). Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy.
American Society for Microbiology, (2006),
[37]
N. Singh, A.P. Limaye, G. Forrest, N. Safdar, P. Muñoz, K. Pursell, et al.
Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.
Transplantation, 81 (2006), pp. 320-326
[38]
D.W. Denning, K.A. Marr, W.M. Lau, D.P. Facklam, V. Ratanatharathorn, C. Becker, et al.
Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.
J Infect, 53 (2006), pp. 337-349
[39]
D.P. Kontoyiannis, V. Ratanatharathorn, J.A. Young, J. Raymond, M. Laverdière, D.W. Denning, et al.
Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis.
Transpl Infect Dis, 11 (2009), pp. 89-93
[40]
T.J. Walsh, E.J. Anaissie, D.W. Denning, R. Herbrecht, D.P. Kontoyiannis, K.A. Marr, et al.
Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America.
Clin Infect Dis, 46 (2008), pp. 327-360
[41]
European Leukemia Net Antifungal prophylaxis. European Conference on Infections in Leukemia. Disponible en: http://www.ichs.org/Ecilslides/ECIL%203%20Antifungal%20therapy%20Update%202009.pdf
[42]
C. Girmenia, G. Barosi, F. Aversa, A. Bacigalupo, T. Barbui, D. Baronciani, et al.
Prophylaxis and treatment of invasive fungal diseases in allogeneic stem cell transplantation: results of a consensus process by Gruppo Italiano Trapianto di Midollo Osseo (GITMO).
Clin Infect Dis, 49 (2009), pp. 1226-1236
[43]
A. Böhme, M. Ruhnke, D. Buchheidt, O.A. Cornely, H. Einsele, R. Enzensberger, et al.
Treatment of invasive fungal infections in cancer patients-recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).
Ann Hematol, 88 (2009), pp. 97-110
[44]
U. Flückiger, O. Marchetti, J. Bille, P. Eggimann, S. Zimmerli, A. Imhof, et al.
Fungal Infection Network of Switzerland (FUNGINOS). Treatment options of invasive fungal infections in adults.
Swiss Med Wkly, 136 (2006), pp. 447-463
[45]
T.J. Walsh, S. Goutelle, R.W. Jelliffe, J.A. Golden, E.A. Little, C. Devoe, et al.
Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients.
Antimicrob Agents Chemother, 54 (2010), pp. 3451-3459
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