<i>In Vitro</i>
            Combination of Isavuconazole with Echinocandins against Azole-Susceptible and -Resistant Aspergillus spp

Echinocandins (caspofungin, micafungin, anidulafungin), targeting ␤-1,3glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other ␤-1,3-glucan synthase inhibitors (ibrexafungerp). KEYWORDS Aspergillus, anidulafungin, calcineurin, caspofungin, heat shock protein 90, ibrexafungerp, micafungin, paradoxical effect, rezafungin M olds of the genus Aspergillus (particularly, Aspergillus fumigatus) are the causal agents of invasive aspergillosis (IA), a life-threatening infection affecting immunocompromised hosts, such as hematological cancer or transplant patients. The current antifungal armamentarium for the treatment of IA is limited to three antifungal drug classes. Fungicidal drugs, such as the triazoles (e.g., voriconazole, posaconazole, or isavuconazole) and the polyenes (amphotericin B formulations) represent the firstchoice treatments, whereas the fungistatic echinocandins (caspofungin, anidulafungin, and micafungin) represent an alternative and are only marginally used as monotherapy (1, 2). However, use of echinocandins is gaining interest because of the emergence of acquired azole resistance in A. fumigatus isolates and the limitations related to drug interactions and/or toxicity with azoles and amphotericin B. The aim of this review is to discuss the role of the echinocandins in the treatment of IA, from the mechanistic point of view of drug-pathogen-host interactions to clinical application and perspectives. ECHINOCANDINS AGAINST ASPERGILLUSMechanisms of action. The echinocandin drugs are lipopeptides derived from fu...

show abstract

“…triazole isavuconazole against Aspergillus spp. was described as indifferent for most cases in one study (78).…”

Section: Echinocandins In Clinical Practicementioning

confidence: 92%

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Aruanno

Glampedakis

Lamoth

2019

Antimicrob Agents Chemother

101

View full text Add to dashboard Cite

show abstract

“…In a comparison of several such techniques (Etest, checkerboard, and time-kill), the Etest was simple to use, time-efficient, reproducible, and was proposed as an alternative method [113]. Moreover, because the Etest is an agar diffusion assay, it can also be used to support or confirm results of antifungal interactions detected by checkerboard or time-kill methods [114][115][116][117][118][119][120][121]. Different protocols can be used for testing antifungal combination of a drug A with a drug B by the Etest.…”

Section: Combination Studiesmentioning

confidence: 99%

“…[114,[116][117][118][119]123,124,127,130], Aspergillus spp. [120][121][122][123][124][125][126]131], and Mucorales [115].…”

Section: Combination Studiesmentioning

confidence: 99%

“…In Aspergillus spp., several studies have reported the used of Etest for testing combination of azoles with echinocandins [120,121,131]. In the first two studies, the combination of voriconazole with anidulafungin and the combination of isavuconazole with the three echinocandins against azole-susceptible and -resistant Aspergillus species showed mainly indifferent interactions by Etest.…”

Section: Combination Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Antifungal Susceptibly Testing by Concentration Gradient Strip Etest Method for Fungal Isolates: A Review

Dannaoui

Espinel-Ingroff

2019

JoF

Self Cite

View full text Add to dashboard Cite

Antifungal susceptibility testing is an important tool for managing patients with invasive fungal infections, as well as for epidemiological surveillance of emerging resistance. For routine testing in clinical microbiology laboratories, ready-to-use commercial methods are more practical than homemade reference techniques. Among commercially available methods, the concentration gradient Etest strip technique is widely used. It combines an agar-based diffusion method with a dilution method that determinates a minimal inhibitory concentration (MIC) in µg/mL. Many studies have evaluated the agreement between the gradient strip method and the reference methods for both yeasts and filamentous fungi. This agreement has been variable depending on the antifungal, the species, and the incubation time. It has also been shown that the gradient strip method could be a valuable alternative for detection of emerging resistance (non-wild-type isolates) as Etest epidemiological cutoff values have been recently defined for several drug-species combinations. Furthermore, the Etest could be useful for direct antifungal susceptibility testing on blood samples and basic research studies (e.g., the evaluation of the in vitro activity of antifungal combinations). This review summarizes the available data on the performance and potential use of the gradient strip method.

show abstract

“…To the best of our knowledge, only two studies to date have investigated the interaction of isavuconazole with an echinocandin and only five azole-resistant A. fumigatus isolates (three with TR 34 /L98H mutation, one with G54W and one with P216L) were tested. 23 , 24 Therefore, we investigated the in vitro interaction between isavuconazole and anidulafungin for 30 A. fumigatus isolates including 18 azole-resistant isolates with various isavuconazole resistance phenotypes.…”

Section: Introductionmentioning

confidence: 99%

In vitro interaction of isavuconazole and anidulafungin against azole-susceptible and azole-resistant Aspergillus fumigatus isolates

Buil

Brüggemann

Denardi

et al. 2020

Journal of Antimicrobial Chemotherapy

View full text Add to dashboard Cite

Background The voriconazole and echinocandin combination has been found to be synergistic in vitro and in vivo against most Aspergillus fumigatus isolates, both with a WT azole phenotype and an azole-resistant phenotype. The interaction between isavuconazole and echinocandins is less well studied. This is especially true for azole-resistant isolates. Objectives We investigated the in vitro interaction between isavuconazole and anidulafungin for 30 A. fumigatus isolates including 18 azole-resistant isolates with various isavuconazole resistance phenotypes. Methods The isavuconazole/anidulafungin interaction was studied by using an adapted EUCAST-based 2D (12 × 8) chequerboard broth microdilution colorimetric assay using XTT. The interaction was analysed by FIC index (FICi) analysis and Bliss independence (BI) interaction analysis. Results Both the FICi analysis and the BI analysis showed synergistic interaction between isavuconazole and anidulafungin for the majority of WT and azole-resistant isolates. As we did not see significant beneficial effects of combination therapy in TR46/Y121F/T289A isolates at clinically achievable drug concentrations, it is unlikely that TR46/Y121F/T289A infections would benefit from isavuconazole and anidulafungin combination therapy. Conclusions In regions with high azole resistance rates this combination may benefit patients with WT disease, azole-resistant invasive aspergillosis and those with mixed azole-susceptible and azole-resistant infection, but may not be beneficial for aspergillosis due to isolates with high isavuconazole resistance, such as TR46/Y121F/T289A isolates.

show abstract

In Vitro Combination of Isavuconazole with Echinocandins against Azole-Susceptible and -Resistant Aspergillus spp

Cited by 13 publications

References 41 publications

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Antifungal Susceptibly Testing by Concentration Gradient Strip Etest Method for Fungal Isolates: A Review

In vitro interaction of isavuconazole and anidulafungin against azole-susceptible and azole-resistant Aspergillus fumigatus isolates

Contact Info

Product

Resources

About