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  Table of Contents  
Year : 2019  |  Volume : 37  |  Issue : 1  |  Page : 109-112

Combination antifungals as an effective means of salvage in paediatric leukaemia patients with invasive fungal infections

1 Department of Pediatrics, Division of Pediatric Oncology, All Institute of Medical Sciences, New Delhi, India
2 Department of Radiology, All Institute of Medical Sciences, New Delhi, India

Date of Web Publication16-Aug-2019

Correspondence Address:
Dr. Aditya Kumar Gupta
Department of Pediatrics, Division of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_18_157

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 ~ Abstract 

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in paediatric leukaemias. Antifungal combinations to treat these patients are being explored. Fourteen children with leukaemias and IFIs were treated with a combination of antifungal agents at our centre. The first antifungal was amphotericin-B in 13 children and voriconazole in one child. In view of no improvement and clinical deterioration, in nine patients, voriconazole was added as the second antifungal agent and in four, it was caspofungin. All patients completed 4–6 weeks of antifungal therapy. The overall mortality attributable to IFI for the cohort was 4/14 (28%).

Keywords: Combination antifungals, leukaemias, paediatrics

How to cite this article:
Meena JP, Gupta AK, Jana M, Seth R. Combination antifungals as an effective means of salvage in paediatric leukaemia patients with invasive fungal infections. Indian J Med Microbiol 2019;37:109-12

How to cite this URL:
Meena JP, Gupta AK, Jana M, Seth R. Combination antifungals as an effective means of salvage in paediatric leukaemia patients with invasive fungal infections. Indian J Med Microbiol [serial online] 2019 [cited 2020 Aug 11];37:109-12. Available from:

 ~ Introduction Top

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric leukaemia patients. Prolonged and severe neutropenia is a risk factor for IFIs in these patients. The mortality with IFIs has been high even with timely initiation of antifungals. Resistance to the available antifungals is being increasingly encountered, making these patients more vulnerable. Fluconazole resistance is common in non-Candida albicans. Echinocandin and azole resistance is also on the rise in infections with Candida glabrata. Aspergillus fumigatus which can cause severe invasive infections in the immunocompromised patients is increasingly showing azole resistance worldwide. This has triggered the search for new approaches for the treatment of these infections such as the use of antifungal combinations. Antifungal combinations have not been studied in detail for paediatric oncology patients in relation to their efficacy, toxicity and feasibility of administration. We present our experience with the use of combination antifungals as a means of salvage in paediatric leukaemia patients with IFIs.

 ~ Materials and Methods Top

The case records of 197 patients aged <16 years admitted to the Division of Pediatric Oncology of the All India Institute of Medical Sciences, New Delhi, India, between January 2016 and July 2017, with a diagnosis of a haematological malignancy, were reviewed retrospectively. The study and data accumulation were carried out as per the institute's ethical committee standards.

A total of 14 patients who fulfilled the following inclusion criteria were enrolled in the study: (i) a diagnosis of proven, probable or possible IFI according to European organisation for research and treatment of cancer/Mycosis study group (EORTC/MSG) Consensus Group recommendations 2008[1] and (ii) treatment with a combination of antifungal agents.

The criterion for addition of the second antifungal was failure in improvement of the general condition of the patient even after 7 days of addition of the first antifungal drug or a deterioration in the clinical condition after the addition of the first antifungal at any time point that was not attributable to an alternative cause.

Favourable responses were defined as definitive improvement of associated clinical signs and symptoms with complete or partial response of all radiographic evidence of fungal infection. All other responses were classified as unfavourable. The Aspergillus enzyme-linked immunoassay was used to detect the galactomannan antigen. Results with a galactomannan index of 0.5 or greater were reported as positive.

The categorical variables were presented as frequency (percentage). The continuous data were presented as mean ± standard deviation for normally distributed data and as median for skewed data.

 ~ Results Top

Fourteen patients with proven, probable or possible IFI received combination antifungals. The baseline characteristics of the patients are summarised in [Table 1]. Two patients had proven IFIs, nine had probable IFIs and three had possible IFIs. The clinical and investigational parameters of the patients are presented in [Table 2].
Table 1: Baseline characteristics of all patients

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Table 2: Clinical features and outcomes of all patients

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Thirteen patients were started on empirical therapy with liposomal amphotericin-B, out of which, in two, it was changed to caspofungin due to the side effects of amphotericin-B (patient no. 8 and patient no. 10). In one patient (patient no. 14), voriconazole was used as the initial antifungal as this child had hypokalaemia at that time in nine patients, voriconazole was added as the second antifungal, in four, it was caspofungin and for the patient who was on voriconazole, upfront amphotericin-B was added. In two patients, there was evidence of hepatic dysfunction (transaminitis) due to which caspofungin was added as the second antifungal rather than voriconazole although galactomannan was positive in them (patient no. 5 and patient no. 9). The same brand of drugs were used for all the patients, and it was obtained from the hospital's pharmacy. Liposomal amphotericin-B was given at a dose of 3–5 mg/kg/day; voriconazole was administered at a dose of 9 mg/kg/dose, 12 hourly and caspofungin at a dose of 70 mg/m2/day on day 1 followed by 50 mg/m2/day with a capping dose of 70 mg/day. Drug-level monitoring was not done due to non-availability. All patients completed 4–6 weeks of antifungal therapy. Antifungal therapy was stopped in these patients if they were asymptomatic, had demonstrated absolute neutrophil count recovery, the imaging showed healing of the lesions and if galactomannan had become negative (if positive initially). Four patients out of the 14 died [Table 2]. Of the ten patients who survived, one died later due to progressive leukaemia. Of the ten patients who were discharged initially, three were discharged on intravenous caspofungin which they got on a day-care basis, and the rest on oral voriconazole.

 ~ Discussion Top

IFIs lead to significant morbidity and mortality in paediatric cancer patients. The degree and duration of neutropenia are of prognostic significance in cancer patients with IFI.[2] Martin et al. found that, in the USA, the incidence of fungal sepsis in these patients increased by approximately 200% between 1979 and 2000.[3]

Mor et al. found the incidence of IFIs to be about 7.2% among 1047 children diagnosed with malignancies between 1998 and 2006, and the causative organism was Candida in 20% and moulds in 60%.[2]Aspergillus species have emerged as an important cause of IFIs. Pneumonia is the most frequent clinical manifestation of these opportunistic fungal infections, and other manifestations include sinusitis and deep-seated abscesses such as brain abscesses.[4]

Early initiation of antifungal therapy is crucial because delay is associated with increased mortality.[5],[6] Despite timely antifungal therapy, IFIs may have dismal outcomes. Mortality related to IFI has been high varying from 43% to 87% in various studies.[7],[8],[9] A cause-specific mortality due to IFI of 35% has been found in patients of acute leukaemia.[10] This has led to the development of new strategies in their management, such as immune therapies and nanoparticle formulations of antifungal agents. The benefits of the use of combination antifungals as a strategy to manage these patients have not been explored much.In vitro and animal studies have demonstrated synergistic effects of combining a triazole (itraconazole, voriconazole or posaconazole) or amphotericin-B with an echinocandin (caspofungin, micafungin or anidulafungin).[11] The benefits of combination antifungals for IFI are increased drug synergy and efficacy and decreased resistance to antifungal drugs.[12]

Mor et al. had found an increased association of IFIs with acute myeloid leukaemia in comparison to acute lymphoblastic leukaemia, and 80% of these were due to moulds, out of which 55% were due to non-Aspergillus species.[2] Observations in our group of patients were similar [Table 2]. All of our patients received combination antifungals. The overall mortality attributable to IFI for the group was four out of 14 (28%).

Evidence for the use of combination antifungals is emerging. Marr et al. recently found evidence favouring combination therapy with voriconazole and anidulafungin over voriconazole for primary invasive aspergillosis among galactomannan-positive patients. Six-week all-cause mortality was 15.7% (17 of 108) in the combination group compared with 27.3% (30 of 110) in the monotherapy group.[13] Panackal et al. in a systematic review and meta-analysis to compare mould-active triazoles or lipid amphotericin-B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis found improved 12-week survivals and success with combination antifungals, for salvage treatment of invasive aspergillosis.[14] Similarly, Yilmaz et al. in 19 episodes of IFI in 17 children found that, with combination antifungals, there was a favourable response rate of 68.4% and a 12-week survival of 75% without any serious side effects.[15] In the Combistrat randomised pilot trial on adults, Caillot et al. found more favourable responses with lesser side effects with amphotericin-B and caspofungin combination compared to high-dose monotherapy.[16] Cesaro et al. used caspofungin-based antifungal combination therapy on forty children and adolescents and reported a favourable response in 53% of the patients and a 100-day survival rate of 70%.[17]

Retrospective studies on adults have found that the combination of caspofungin and amphotericin-B is well tolerated and can be administered safely to high-risk patients with haematological malignancies. However, contrary to the above observations, a retrospective study by Mihu et al. involving 159 adult patients with haematological malignancies and invasive aspergillosis showed that the combination of amphotericin-B and an echinocandin did not offer any advantage in terms of improving response or reducing mortality.[18],[19],[20]

Combination antifungals have been found to be effective in the subset of patients with invasive aspergillosis that are galactomannan positive. Its role in refractory fungal infections is worth exploring in the context of these preliminary studies. In settings where drug levels are not available or there is suspicion of drug resistance, combination antifungal therapy is an attractive alternative. Toxicity with echinocandins is lesser compared to other groups, and this makes it a good option for a broader antifungal coverage in the setting of a poor response.[14]

The use of combination antifungals carries the risk of increased adverse effects and escalation in the cost of care. Combination antifungals could be used in refractory IFIs in case antifungal resistance is suspected or as an empiric broad-spectrum cover followed by rapid de-escalation after pathogen identification. More studies and trials needed to establish their role in the algorithm of management of IFIs in paediatric oncology practice.

 ~ Conclusions Top

IFIs are an important cause of mortality and morbidity in paediatric leukaemia patients, and Aspergillus species are the predominant cause. Invasive fungal pneumonias are the most common manifestation in these children. Combining antifungal drugs is a feasible and effective way to salvage non-responders to antifungal monotherapy. More trials and studies are needed to determine whether these drug combinations could be used upfront in IFIs.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. 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;46:1813-21.  Back to cited text no. 1
Mor M, Gilad G, Kornreich L, Fisher S, Yaniv I, Levy I, et al. Invasive fungal infections in pediatric oncology. Pediatr Blood Cancer 2011;56:1092-7.  Back to cited text no. 2
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.  Back to cited text no. 3
Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 aspergillus study group. Medicine (Baltimore) 2000;79:250-60.  Back to cited text no. 4
Taur Y, Cohen N, Dubnow S, Paskovaty A, Seo SK. Effect of antifungal therapy timing on mortality in cancer patients with candidemia. Antimicrob Agents Chemother 2010;54:184-90.  Back to cited text no. 5
Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47:503-9.  Back to cited text no. 6
Choi SH, Lee SY, Hwang JY, Lee SH, Yoo KH, Sung KW, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer 2013;60:82-7.  Back to cited text no. 7
Rubio PM, Sevilla J, González-Vicent M, Lassaletta A, Cuenca-Estrella M, Díaz MA, et al. Increasing incidence of invasive aspergillosis in pediatric hematology oncology patients over the last decade: A retrospective single centre study. J Pediatr Hematol Oncol 2009;31:642-6.  Back to cited text no. 8
Crassard N, Hadden H, Piens MA, Pondarré C, Hadden R, Galambrun C, et al. Invasive aspergillosis in a paediatric haematology department: A 15-year review. Mycoses 2008;51:109-16.  Back to cited text no. 9
Auberger J, Lass-Flörl C, Ulmer H, Nogler-Semenitz E, Clausen J, Gunsilius E, et al. Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol 2008;88:508-15.  Back to cited text no. 10
Panackal AA. Combination antifungal therapy for invasive aspergillosis revisited. Med Mycol Open Access 2016;2. pii: 12.  Back to cited text no. 11
Lee KH, Lim YT, Hah JO, Kim YK, Lee CH, Lee JM, et al. Voriconazole plus caspofungin for treatment of invasive fungal infection in children with acute leukemia. Blood Res 2017;52:167-73.  Back to cited text no. 12
Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination Antifungal Therapy for Invasive Aspergillosis: A Randomized Trial. Ann Intern Med 2015;162:81–89.  Back to cited text no. 13
Panackal AA, Parisini E, Proschan M. Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: A systematic review and meta-analysis. Int J Infect Dis 2014;28:80-94.  Back to cited text no. 14
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;54:234-42.  Back to cited text no. 15
Caillot D, Thiébaut A, Herbrecht R, de Botton S, Pigneux A, Bernard F, 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;110:2740-6.  Back to cited text no. 16
Cesaro S, Giacchino M, Locatelli F, Spiller M, Buldini B, Castellini C, et al. 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.  Back to cited text no. 17
Mihu CN, Kassis C, Ramos ER, Jiang Y, Hachem RY, Raad II, et al. Does combination of lipid formulation of amphotericin B and echinocandins improve outcome of invasive aspergillosis in hematological malignancy patients? Cancer 2010;116:5290-6.  Back to cited text no. 18
Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, et al. Refractory aspergillus pneumonia in patients with acute leukemia: Successful therapy with combination caspofungin and liposomal amphotericin. Cancer 2003;97:1025-32.  Back to cited text no. 19
Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, 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 2003;98:292-9.  Back to cited text no. 20


  [Table 1], [Table 2]


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