Combination Antifungal Therapy for Invasive Mold Infections Among Pediatric Patients with Hematological Malignancies: Data from A Real-Life Case-Series

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Anna Maria Peri
Marta Verna
Stefano Biffi
Laura Alagna
Benedetta Longhi
Guglielmo Marco Migliorino
Sergio Foresti
Attilio Rovelli
Carmelo Rizzari
Andrea Gori
Antonella Colombini

Abstract

Background: Invasive mold infections in children with hematological malignancies are associated with high mortality rates. The use of combination antifungal therapy in cases with a severe clinical course is increasing, although information on the efficacy and safety of this approach is limited.

Methods: We present a case series of 13 children affected by hemato-oncological disorders who received combination antifungal therapy for invasive mold infections at our center (Pediatric Hematology, San Gerardo Hospital, Monza, Italy) from 2011 to 2016, with the aim of describing their clinical characteristics, types of infections, treatment regimens, clinical outcomes, and treatment safety. Medical records were retrospectively reviewed in order to describe patients’ characteristics.

Results: Combination antifungal therapy included liposomal amphotericin associated with caspofungin (5/13, 38.4%), voriconazole (5/13, 38.4%), or posaconazole (3/13, 23.1%). The 12-week treatment response rate was 69.2% (6/13 patients showed complete response, 3/13 partial response). The crude mortality was 30.7% (4/13): half was related to invasive mold infections (2/13, 15.38%) and half to disease progression (2/13, 15.38%). Overall, treatment was well tolerated, and we did not observe any permanent discontinuation of antifungals due to related side effects.

Conclusions: In our experience, combination antifungal therapy seems to be a safe option in immunocompromised children with invasive mold infections. Well-designed studies are needed to confirm the safety of this approach and to better understand its efficacy in the pediatric setting.

Keywords: antifungal therapy; mold; hematological malignancies

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1. Burgos A, Zaoutis TE, Dvorak CC, Hoffman JA, Knapp KM, Nania JJ, Prasad P, Steinbach WJ. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121(5):e1286-94. PubMed PMID: 18450871. doi: 10.1542/peds.2007-2117

2. Georgiadou SP, Pongas G, Fitzgerald NE, Lewis RE, Rytting M, Marom EM, Kontoyiannis DP. Invasive Mold Infections in Pediatric Cancer Patients Reflect Heterogeneity in Etiology, Presentation, and Outcome: A 10-Year, Single-Institution, Retrospective Study. J Pediatric Infect Dis Soc. 2012;1(2):125-35. PubMed PMID: 26619165. doi: 10.1093/jpids/pis042

3. Al-Rezqi A, Hawkes M, Doyle J, Richardson SE, Allen U. Invasive mold infections in iatrogenically immunocompromised children: an eight-yr review. Pediatr Transplant. 2009;13(5):545-52. PubMed PMID: 18992060. doi: 10.1111/j.1399-3046.2008.01056.x

4. Domenech C, Leick-Courtois C, Bienvenu AL, Pracros JP, Picot S, Bleyzac N, Bertrand Y. Improvement in the Outcome of Invasive Aspergillosis in a Pediatric Hematology Department: A 10-Year Review. J Pediatr Hematol Oncol. 2015 Oct;37(7):560-5.

5. Wattier RL, Dvorak CC, Hoffman JA, Brozovich AA, Bin-Hussain I, Groll AH, Castagnola E, Knapp KM, Zaoutis TE, Gustafsson B, Sung L, Berman D, Halasa NB, Abzug MJ, Velegraki A, Sharma TS, Fisher BT, Steinbach WJ. A Prospective, International Cohort Study of Invasive Mold Infections in Children. J Pediatric Infect Dis Soc. 2015;4(4):313-22. PubMed PMID: 26582870. Pubmed Central PMCID: 4681382. doi: 10.1093/jpids/piu074

6. Pana ZD, Seidel D, Skiada A, Groll AH, Petrikkos G, Cornely OA, Roilides E, Collaborators of Zygomyco.net and/or FungiScope R. Invasive mucormycosis in children: an epidemiologic study in European and non-European countries based on two registries. BMC Infect Dis. 2016;16(1):667. PubMed PMID: 27832748. Pubmed Central PMCID: 5105268. doi: 10.1186/s12879-016-2005-1

7. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Munoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE, European Organization for R, Treatment of Cancer/Invasive Fungal Infections Cooperative G, National Institute of A, Infectious Diseases Mycoses Study Group Consensus G. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-21. PubMed PMID: 18462102. Pubmed Central PMCID: 2671227. doi: 10.1086/588660

8. Common Terminology Criteria for Adverse Events (CTCAE) May 28, 2009 (v4.03: June 14, 2010). Version 4.0:[Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40

9. Abbasi S, Shenep JL, Hughes WT, Flynn PM. Aspergillosis in children with cancer: A 34-year experience. Clin Infect Dis. 1999;29(5):1210-9. PubMed PMID: 10524965. doi: 10.1086/313445

10. Crassard N, Hadden H, Piens MA, Pondarre C, Hadden R, Galambrun C, Pracros JP, Souillet G, Basset T, Berthier JC, Philippe N, Bertrand Y. Invasive aspergillosis in a paediatric haematology department: a 15-year review. Mycoses. 2008;51(2):109-16. PubMed PMID: 18254746. doi: 10.1111/j.1439-0507.2007.01449.x

11. Groll AH, Kurz M, Schneider W, Witt V, Schmidt H, Schneider M, Schwabe D. Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses. 1999;42(7-8):431-42. PubMed PMID: 10546484

12. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, Maertens JA. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162(2):81-9. PubMed PMID: 25599346. doi: 10.7326/M13-2508

13. Patterson TF, Thompson GR, 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. PubMed PMID: 27365388. Pubmed Central PMCID: 4967602. doi: 10.1093/cid/ciw326

14. Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A, Lass-Florl C, Calandra T, Viscoli C, Herbrecht R. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102(3):433-44. PubMed PMID: 28011902. Pubmed Central PMCID: 5394968. doi: 10.3324/haematol.2016.152900

15. Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, Lanternier F, Pagano L, Skiada A, Akova M, Arendrup MC, Boekhout T, Chowdhary A, Cuenca-Estrella M, Freiberger T, Guinea J, Guarro J, de Hoog S, Hope W, Johnson E, Kathuria S, Lackner M, Lass-Florl C, Lortholary O, Meis JF, Meletiadis J, Munoz P, Richardson M, Roilides E, Tortorano AM, Ullmann AJ, van Diepeningen A, Verweij P, Petrikkos G, European Society of Clinical M, Infectious Diseases Fungal Infection Study G, European Confederation of Medical M. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20 Suppl 3:5-26. PubMed PMID: 24479848. doi: 10.1111/1469-0691.12371

16. Yilmaz D, Balkan C, Ay Y, Akin M, Karapinar B, Kavakli K. A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections. Mycoses. 2011;54(3):234-42. PubMed PMID: 19906090. doi: 10.1111/j.1439-0507.2009.01808.x

17. Rubio PM, Sevilla J, Gonzalez-Vicent M, Lassaletta A, Cuenca-Estrella M, Diaz MA, Riesco S, Madero L. Increasing incidence of invasive aspergillosis in pediatric hematology oncology patients over the last decade: a retrospective single centre study. J Pediatr Hematol Oncol. 2009;31(9):642-6. PubMed PMID: 19684521. doi: 10.1097/MPH.0b013e3181acd956

18. Cesaro S, Giacchino M, Locatelli F, Spiller M, Buldini B, Castellini C, Caselli D, Giraldi E, Tucci F, Tridello G, Rossi MR, Castagnola E. Safety and efficacy of a caspofungin-based combination therapy for treatment of proven or probable aspergillosis in pediatric hematological patients. BMC Infect Dis. 2007;7:28. PubMed PMID: 17442100. Pubmed Central PMCID: 1871594. doi: 10.1186/1471-2334-7-28

19. Cesaro S, Tridello G, Castagnola E, Calore E, Carraro F, Mariotti I, Colombini A, Perruccio K, Decembrino N, Russo G, Maximova N, Baretta V, Caselli D. Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high-risk pediatric onco-hematological patients. Eur J Haematol. 2017;99(3):240-8. PubMed PMID: 28556426. doi: 10.1111/ejh.12910

20. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother. 2002;46(1):245-7. PubMed PMID: 11751145. Pubmed Central PMCID: 127002. doi: 10.1128/aac.46.1.245-247.2002

21. Lignell A, Lowdin E, Cars O, Sjolin J. Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model. J Antimicrob Chemother. 2008;62(1):142-8. PubMed PMID: 18408237. doi: 10.1093/jac/dkn154

22. 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(12):4867-75. PubMed PMID: 16304147. Pubmed Central PMCID: 1315954. doi: 10.1128/AAC.49.12.4867-4875.2005

23. 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(2):466-9. PubMed PMID: 16760192. doi: 10.1093/jac/dkl236

24. Kirkpatrick WR, Coco BJ, Patterson TF. Sequential or combination antifungal therapy with voriconazole and liposomal amphotericin B in a Guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother. 2006;50(4):1567-9. PubMed PMID: 16569887. Pubmed Central PMCID: 1426916. doi: 10.1128/AAC.50.4.1567-1569.2006

25. Spader TB, Venturini TP, Cavalheiro AS, Mahl CD, Mario DN, Lara VM, Santurio J, Alves SH. In vitro interactions between amphotericin B and other antifungal agents and rifampin against Fusarium spp. Mycoses. 2011;54(2):131-6. PubMed PMID: 19780977. doi: 10.1111/j.1439-0507.2009.01773.x

26. Guzman-Cottrill JA, Zheng X, Chadwick EG. Fusarium solani endocarditis successfully treated with liposomal amphotericin B and voriconazole. Pediatr Infect Dis J. 2004;23(11):1059-61. PubMed PMID: 15545866.

27. Durand-Joly I, Alfandari S, Benchikh Z, Rodrigue M, Espinel-Ingroff A, Catteau B, Cordevant C, Camus D, Dei-Cas E, Bauters F, Delhaes L, De Botton S. Successful outcome of disseminated Fusarium infection with skin localization treated with voriconazole and amphotericin B-lipid complex in a patient with acute leukemia. J Clin Microbiol. 2003;41(10):4898-900. PubMed PMID: 14532255. Pubmed Central PMCID: 254322. doi: 10.1128/jcm.41.10.4898-4900.2003

28. Ho DY, Lee JD, Rosso F, Montoya JG. Treating disseminated fusariosis: amphotericin B, voriconazole or both? Mycoses. 2007;50(3):227-31. PubMed PMID: 17472622. doi: 10.1111/j.1439-0507.2006.01346.x

29. Al-Hatmi AMS, Bonifaz A, Ranque S, Sybren de Hoog G, Verweij PE, Meis JF. Current antifungal treatment of fusariosis. Int J Antimicrob Agents. 2018;51(3):326-32. PubMed PMID: 28705676. doi: 10.1016/j.ijantimicag.2017.06.017

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