In vitro interactions between isavuconazole and tacrolimus, cyclosporin A or sirolimus against Mucorales

Schwarz, Patrick; Schwarz, Petra V; Felske-Zech, Heike; Dannaoui, Éric

doi:10.1093/jac/dkz102

Cited by 19 publications

(18 citation statements)

References 44 publications

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“…Similarly, corroborating a report on MMF [25], the administration of CsA was associated with a four-fold risk of invasive fungal infection within the first 6 months after kidney transplantation compared to corticosteroid and azathioprine therapy [26]. On the other hand, potent synergisms in the activity against a variety of fungi has been described for CsA when combined with azoles, which affected even azole resistant isolates [9,10,27,28]. In conclusion, our data show that 1) MPA and CsA exhibit a species-specific inhibitory effect on the growth Aspergillus, 2) higher fungal damage is observed when MPA and CsA are added to growing conidia than to mycelium, and 3) mPRED increases the growth of A. niger, but has no major impact on the growth and viability of the other Aspergillus species tested.…”

Section: Discussionsupporting

confidence: 78%

Immunosuppressive Compounds Affect the Fungal Growth and Viability of Defined Aspergillus Species

et al. 2019

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Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds—cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)—on the growth and viability of five clinically important Aspergillus species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all Aspergillus spp. tested, although growth inhibition by MPA was highest in A. niger, A. flavus and A. brasiliensis. Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of A. niger, but had no major impact on the growth and viability of any of the other Aspergillus species tested. Our findings may help to better understand the interaction of drugs with Aspergillus species and ultimately may have an impact on individualizing immunosuppressive therapy.

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Section: Discussionsupporting

confidence: 78%

Immunosuppressive Compounds Affect the Fungal Growth and Viability of Defined Aspergillus Species

et al. 2019

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“…Combinations of sirolimus with azoles showed more likely indifferent interactions . Antagonism was even reported for some isolates in two studies, and for most of the tested isolates in another study . Chequerboard combination of cyclosporine A with caspofungin revealed mostly indifferent interactions when interpreted by the FIC index, while synergy was found more frequently when an alternate endpoint (a fourfold reduction in MEC (minimum effective concentration)) was used .…”

Section: Combinations Between Antifungals and Non‐antifungal Drugsmentioning

confidence: 86%

“…In vitro combination of sirolimus with caspofungin showed mostly indifferent interactions, while combination with amphotericin B was able to demonstrate mostly synergy . Combinations of sirolimus with azoles showed more likely indifferent interactions . Antagonism was even reported for some isolates in two studies, and for most of the tested isolates in another study .…”

Section: Combinations Between Antifungals and Non‐antifungal Drugsmentioning

confidence: 87%

“…Chequerboard combination of cyclosporine A with caspofungin revealed mostly indifferent interactions when interpreted by the FIC index, while synergy was found more frequently when an alternate endpoint (a fourfold reduction in MEC (minimum effective concentration)) was used . Combination of cyclosporin A with amphotericin B was synergistic, and combination with azoles mostly synergistic or indifferent . For combinations of tacrolimus, discordant results were obtained.…”

Section: Combinations Between Antifungals and Non‐antifungal Drugsmentioning

confidence: 95%

“…One author mainly found indifferent interactions whatever combination was tested, while another reported synergism, indifference and antagonism for the combination of tacrolimus with posaconazole . Recently, combination of tacrolimus with isavuconazole exhibited synergy for 50% of the tested isolates . Combination of cyclosporin A with caspofungin was synergistic or indifferent depending on the method used for interpretation .…”

Section: Combinations Between Antifungals and Non‐antifungal Drugsmentioning

confidence: 99%

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Antifungal combinations in Mucorales: A microbiological perspective

Schwarz

Cornely

Dannaoui

2019

Mycoses

Self Cite

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Summary Mucormycosis mostly affects immunocompromised patients and is associated with a high morbidity and mortality despite currently available treatments. In that context, combination therapy might be the key to a better outcome for these patients. Purpose of this review is to summarise and to discuss the current combination data obtained in vitro, in vivo in animal models of mucormycosis, and in patients. In vitro combination studies showed that most of the interactions between antifungal drugs were indifferent, even though that some synergistic interactions were achieved for the combination of echinocandins with either azoles or amphotericin B. Importantly, antagonism was never observed. Animal models of mucormycosis focused on infections caused by Rhizopus arrhizus, neglecting most other species responsible for human disease. In these experimental animal models, no strong interactions have been demonstrated, although a certain degree of synergism has been reported in some instances. Combinations of antifungals with non‐antifungal drugs have also been largely explored in vitro and in animal models and yielded interesting results. In patients with ketoacidosis and rhino‐orbito‐cerebral infection, combination of polyene with caspofungin was effective. In contrast, despite promising experimental data, adjunctive therapy with the iron chelator deferasirox was unfavourable and was associated with a higher mortality than monotherapy with liposomal amphotericin B. More combinations have to be tested in vitro and a much larger panel of Mucorales species has to be tested in vivo to give a valuable statement if antifungal combination therapy could be an effective treatment strategy in patients with mucormycosis.

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