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Objective: The role of combination regimens in the treatment of invasive fungal infections (IFIs) in hematologic malignancies remains unclear. We aimed to demonstrate data about combined antifungal therapy (CAT) in pediatric leukemia patients with IFI. Method: Between January 2014 and December 2018, a total of 33 IFI episodes in 28 leukemia patients were analyzed retrospectively. Results: The study patients had acute lymphoblastic leukemia (n=19), acute myeloblastic leukemia (n=9), leukemia relapse (n=21; 75%) and remission (n=7; 25%). The patients were classified as having possible (n=26; 78.8%), probable (n=5; 15.1%) and proven IFI (n=2; 6.1%). Liposomal amphotericin B (LamB) was the most preferred agent (50%) in monotherapy. Mean duration of monotherapy was 12.84+-4.28 (5-24) days. LamB plus voriconazole (54.5%) was the most commonly preferred CAT. Mean duration of CAT was 42.36+-36.4 days, and this combination regimen was not changed throughout the treatment period (p=0.571). Total and IFI-related mortality rates were 60.7% vs 46.4%, respectively. Mortality rates were significantly higher in patients with relapse (p=0.006). Complete response was obtained in 81.8% of surviving patients. Side effects of CAT were observed at quite a low level. Conclusion: CAT has been found to be safe in the treatment of IFI episodes of pediatric leukemia. Uncontrolled underlying disease is the most important factor affecting the mortality rates in IFI.

Objective: The role of combination regimens in the treatment of invasive fungal infections (IFIs) in hematologic malignancies remains unclear. We aimed to demonstrate data about combined antifungal therapy (CAT) in pediatric leukemia patients with IFI. Method: Between January 2014 and December 2018, a total of 33 IFI episodes in 28 leukemia patients were analyzed retrospectively. Results: The study patients had acute lymphoblastic leukemia (n=19), acute myeloblastic leukemia (n=9), leukemia relapse (n=21; 75%) and remission (n=7; 25%). The patients were classified as having possible (n=26; 78.8%), probable (n=5; 15.1%) and proven IFI (n=2; 6.1%). Liposomal amphotericin B (LamB) was the most preferred agent (50%) in monotherapy. Mean duration of monotherapy was 12.84±4.28 (5-24) days. LamB plus voriconazole (54.5%) was the most commonly preferred CAT. Mean duration of CAT was 42.36±36.4 days, and this combination regimen was not changed throughout the treatment period (p=0.571). Total and IFI-related mortality rates were 60.7% vs 46.4%, respectively. Mortality rates were significantly higher in patients with relapse (p=0.006). Complete response was obtained in 81.8% of surviving patients. Side effects of CAT were observed at quite a low level. Conclusion: CAT has been found to be safe in the treatment of IFI episodes of pediatric leukemia. Uncontrolled underlying disease is the most important factor affecting the mortality rates in IFI. [ABSTRACT FROM AUTHOR]

Drug resistance commonly occurs when treating immunocompromized patients with fungal infections. Dehydrozingerone—a phenolic compound isolated from the rhizome of Zingiber officinale —inhibits drug efflux in Saccharomyces cerevisiae by overexpression of the ATP-binding cassette (ABC) transporter Pdr5p. We aimed to investigate whether dehydrozingerone enhances the antifungal activity of glabridin—an isoflavan isolated from the roots of Glycyrrhiza glabra L.—by attenuating multidrug resistance through the intrinsic expression system of multidrug-efflux-related genes in a wild-type strain of the model yeast. The antifungal activity of 50 μmol l−1 glabridin alone was weak and temporary against S. cerevisiae ; however, cell viability was significantly inhibited when the cells were co-treated with glabridin and dehydrozingerone. This enhancement was also observed in human pathogenic Candida albicans. Glabridin efflux did not depend on a particular drug efflux pump; instead, the transcription factors PDR1 and PDR3 —regulating the transcription of multiple genes encoding drug efflux pumps—were involved in the antifungal activity and efflux of glabridin. qRT–PCR analysis revealed that dehydrozingerone reduced glabridin-induced overexpression of the ABC transporter-related genes PDR1, PDR3 , and PDR5 to the levels observed in untreated cells. Our findings indicated that dehydrozingerone potentiates the efficacy of plant-derived antifungals through its effects on ABC transporters. [ABSTRACT FROM AUTHOR]

Fungal infections occurring in immunocompromised patients after immuno-chemotherapy treatment, are often difficult to eradicate and capable of even being fatal. Systemic mycoses affecting severely immunocompromised patients often manifest acutely with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination. Opportunistic fungal infections (mycoses) include several pathogens elements, as Candidiasis, Aspergillosis, Mucormycosis (zygomycosis) and Fusariosis. Prompt diagnosis and effective therapy are needed to improve the associated morbidity and mortality, especially in cases with non-canonical fungal localizations and not responsive to the available antifungal drugs.

This multicentre observational study evaluated the feasibility, efficacy and toxicity of antifungal combination therapy (combo) as treatment of proven or probable invasive fungal diseases ( IFDs) in patients with haematological malignancies. Between January 2005 and January 2010, 84 cases of IFDs (39 proven and 45 probable) treated with combo were collected in 20 Hematological Italian Centres, in patients who underwent chemotherapy or allogeneic haematopoietic stem cell transplantation for haematological diseases. Median age of patients was 34 years (range 1-73) and 37% had less than 18 years. Acute leukaemia was the most common underlying haematological disease (68/84; 81%). The phase of treatment was as follows: first induction in 21/84 (25%), consolidation phase in 18/84 (21%) and reinduction/salvage in 45/84 (54%). The main site of infection was lung with or without other sites. The principal fungal pathogens were as follows: Aspergillus sp. 68 cases (81%), Candida sp. six cases (8%), Zygomycetes four cases (5%) and Fusarium sp. four cases (5%). The most used combo was caspofungin+voriconazole 35/84 (42%), caspofungin + liposomal amphotericin B (L-AmB) 20/84 (24%) and L-AmB+voriconazole 15/84 (18%). The median duration of combo was 19 days (range 3-180). The overall response rate ( ORR) was 73% (61/84 responders) without significant differences between the combo regimens. The most important factor that significantly influenced the response was granulocyte ( PMN) recovery ( P 0.009). Only one patient discontinued therapy (voriconazole-related neurotoxicity) and 22% experienced mild and reversible adverse events (hypokalaemia, ALT/ AST increase and creatinine increase). The IFDs-attributable mortality was 17%. This study indicates that combo was both well tolerated and effective in haematological patients. The most used combo regimens were caspofungin + voriconazole ( ORR 80%) and caspofungin + L-AmB ( ORR 70%). The ORR was 73% and the mortality IFD related was 17%. PMN recovery during combo predicts a favourable outcome. Clinical Trials Registration: NCT00906633. [ABSTRACT FROM AUTHOR]

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5-17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3-69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3-14) days and 91 patient days for LAmB + caspofungin combination and 49 (7-126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve-week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies. [ABSTRACT FROM AUTHOR]