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Antifungal Combinations in Fungal Infections

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A special issue of Journal of Fungi (ISSN 2309-608X).

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 39223

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Dr. Patrick Schwarz

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Guest Editor

1. Department of Internal Medicine, Respiratory and Critical Care Medicine, University Hospital Marburg, D-35033 Marburg, Germany
2. Center for Invasive Mycoses and Antifungals, Philipps University Marburg, D-35043 Marburg, Germany
Interests: antifungals; antifungal combinations; fungal diagnostics; medical mycology

Dr. Eric Dannaoui

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Guest Editor

1. Unité de Parasitologie-Mycologie, Service de Microbiologie, Hôpital Européen Georges Pompidou, F-75015 Paris, France
2. Faculté de Médecine, Université Paris Cité, F-75006 Paris, France
Interests: human pathogenic fungi; antifungals; mycoses; Aspergillus; in vitro susceptibility testing; antifungal resistance; animal models
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Special Issue Information

Dear Colleagues,

Many fungal infections are difficult to treat, in part because of the intrinsic or acquired resistance of many fungi to currently available antifungal drugs. Antifungal combinations are an interesting tool, not only to overcome this resistance, but also because of the potential synergism obtained, when drugs are acting together. Various methods of assessing antifungal combinations have been used. In vitro, most often used is the checkerboard method based on the EUCAST or CLSI microdilution broth reference techniques. Usually interpreted by the fractional inhibitory concentration index, other ways of analysis and interpretation of the results have also beeing used, as no standardized procedures have been estabilished. The gold standard for assessing antifungal combinations in vivo are survival models in mammals, but fungal burden studies have also been used successfully, and alternative minihost models have been implemented. Indeed, because of ethical reasons, in recent years animal models in invertebrates like the waxmoth Galleria mellonella have become more and more popular. A success story for antifungal combinations has become the combination of amphotericin B with flucytonsine, which is recommended first-line treament for patients with cryptococcosis. For other fungal pathogens (e.g. Candida spp., Aspergillus spp., rare molds), combination therapy are generally not recommend as first-line but can be of interest for species with intrisic or acquired resistance. In view of the fact that drug repurposing has major advantages like the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines, combinations of antifungals with non-antifungal drugs have also become atractive.

In this Special Issue several reviews will address the current status of antifungal combinations against fungi of medical importance. Original works are also wellcome.

Dr. Patrick Schwarz
Dr. Eric Dannaoui
Guest Editors

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Keywords

Antifungal agents
Drug therapy, Combination
In vitro susceptibility testing
Animal models
Mycoses
Human fungal pathogens
Filamentous fungi
Yeasts
Aspergillus
Candida
Fractional Inhibitory Concentration Index (FIC index)
Response surface analysis
Drug synergism
Loewe Additivity
Bliss Independence

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Published Papers (9 papers)

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Research

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13 pages, 1733 KiB

Open AccessArticle

Synergistic In Vitro Interaction of Isavuconazole and Isoquercitrin against Candida glabrata

by Petra V. Schwarz, Ilya Nikolskiy, Eric Dannaoui, Frank Sommer, Gert Bange and Patrick Schwarz

J. Fungi 2022, 8(5), 525; https://doi.org/10.3390/jof8050525 - 20 May 2022

Cited by 3 | Viewed by 2331

Abstract

In vitro interactions of broad-spectrum azole isavuconazole with flavonoid isoquercitrin were evaluated by a broth microdilution checkerboard technique based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference methodology for antifungal susceptibility testing against 60 Candida strains belonging to the species Candida albicans (n = 10), Candida glabrata (n = 30), Candida kefyr (n = 6), Candida krusei (n = 5), Candida parapsilosis (n = 4), and Candida tropicalis (n = 5). The results were analyzed with the fractional inhibitory concentration index and by response surface analysis based on the Bliss model. Synergy was found for all C. glabrata strains, when the results were interpreted by the fractional inhibitory concentration index, and for 60% of the strains when response surface analysis was used. Interaction for all other species was indifferent for all strains tested, whatever interpretation model used. Importantly, antagonistic interaction was never observed. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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13 pages, 6389 KiB

Open AccessArticle

Metrics of Antifungal Effects of Ciprofloxacin on Aspergillus fumigatus Planktonic Growth and Biofilm Metabolism; Effects of Iron and Siderophores

by Gabriele Sass, Lynn Scherpe, Marife Martinez, Julianne J. Marsh and David A. Stevens

J. Fungi 2022, 8(3), 240; https://doi.org/10.3390/jof8030240 - 28 Feb 2022

Cited by 2 | Viewed by 3361

Abstract

Pseudomonas aeruginosa and Aspergillus fumigatus frequently coexist in the airways of immunocompromised patients or individuals with cystic fibrosis. Ciprofloxacin (CIP) is a synthetic quinolone antibiotic commonly used to treat bacterial infections, such as those produced by Pseudomonas aeruginosa. CIP binds iron, and it is unclear what effect this complex would have on the mycobiome. The effects of CIP on Aspergillus were dependent on the iron levels present, and on the presence of Aspergillus siderophores. We found that CIP alone stimulated wildtype planktonic growth, but not biofilm metabolism. At high concentrations, CIP antagonized a profungal effect of iron on wildtype Aspergillus metabolism, presumably owing to iron chelation. CIP interfered with the metabolism and growth of an Aspergillus siderophore mutant, with the effect on metabolism being antagonized by iron. CIP acted synergistically with iron on the growth of the mutant, and, to a lesser extent, the wildtype. In summary, CIP can increase fungal growth or affect fungal metabolism, depending on the local iron concentration and available siderophores. Therefore, high local CIP concentrations during treatment of Pseudomonas–Aspergillus co-infections may increase the fungal burden. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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16 pages, 3026 KiB

Open AccessArticle

Improved In Vitro Anti-Mucorales Activity and Cytotoxicity of Amphotericin B with a Pegylated Surfactant

by Kévin Brunet, Cheikh A. B. Diop, Alexia Chauzy, Noémie Prébonnaud, Sandrine Marchand, Blandine Rammaert and Frédéric Tewes

J. Fungi 2022, 8(2), 121; https://doi.org/10.3390/jof8020121 - 27 Jan 2022

Cited by 4 | Viewed by 2731

Abstract

The aim of this study was to evaluate the effect of the combination of amphotericin B (AmB) and various non-ionic surfactants on the anti-Mucorales activity of AmB, the toxicity of the combination on eukaryotic cells and the modification of AmB aggregation states. Checkerboards were performed on five genera of Mucorales (12 strains) using several combinations of different surfactants and AmB. These data were analyzed by an E_max model. The effect of surfactants on the cytotoxic activity of AmB was then evaluated for red blood cells and two eukaryotic cell lines by absorbance and propidium iodide internalization. Finally, the effect of polyethylene glycol (15)-hydroxystearate (PEG15HS) on the aggregation states of AmB was evaluated by UV-visible spectrometry. PEG15HS increased the efficacy of AmB on four of the five Mucorales genera, and MICs of AmB were decreased up to 68-fold for L. ramosa. PEG15HS was the only surfactant to not increase the cytotoxic activity of AmB. Finally, the analysis of AmB aggregation states showed that the increased efficacy of AmB and the absence of toxicity are related to an increase in monomeric and polyaggregated forms of AmB at the detriment of the dimeric form. In conclusion, PEG15HS increases the in vitro efficacy of AmB against Mucorales at low concentration, without increasing its toxicity; this combination could therefore be evaluated in the treatment of mucormycosis. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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17 pages, 4020 KiB

Open AccessArticle

Real-Life Considerations on Antifungal Treatment Combinations for the Management of Invasive Mold Infections after Allogeneic Cell Transplantation

by Emmanouil Glampedakis, Romain Roth, Stavroula Masouridi-Levrat, Yves Chalandon, Anne-Claire Mamez, Federica Giannotti, Christian Van Delden and Dionysios Neofytos

J. Fungi 2021, 7(10), 811; https://doi.org/10.3390/jof7100811 - 28 Sep 2021

Cited by 4 | Viewed by 2146

Abstract

Background: Antifungal combination treatment is frequently administered for invasive mold infections (IMIs) after allogeneic hematopoietic cell transplantation (HCT). Here, we describe the indications, timing, and outcomes of combination antifungal therapy in post-HCT IMI. Methods: A single-center, 10-year, retrospective cohort study including all adult HCT recipients with proven/probable IMI between 1 January 2010 and 1 January 2020 was conducted. Results: During the study period, 515 patients underwent HCT, of whom 47 (9.1%) presented 48 IMI episodes (46 patients with one IMI episode and 1 patient with two separate IMI episodes): 33 invasive aspergillosis (IA) and 15 non-IA IMIs. Almost half (51%) of the patients received at least one course of an antifungal combination (median: 2/patient): 23 (49%), 20 (42%), and 4/47 (9%) patients received pure monotherapy, mixed monotherapy/combination, and pure combination treatment, respectively. Combination treatment was started at a median of 8 (IQR: 2, 19) days post-IMI diagnosis. Antifungal management was complex, with 163 treatment courses prescribed overall, 48/163 (29.4%) concerning antifungals in combination. The clinical reasons motivating the selection of initial combination antifungal therapy included severe IMI (18, 38%), lack of antifungal susceptibility data (14, 30%), lack of pathogen identification (5, 11%), and combination treatment until reaching a therapeutic azole serum level (6, 13%). The most common combination treatments were azole/liposomal amphotericin-B (28%) and liposomal amphotericin-B/echinocandin (21%). Combination treatment was administered cumulatively for a median duration of 28 days (IQR: 7, 47): 14 (IQR: 6, 50) days for IA and 28 (IQR: 21, 34) days for non-IA IMI (p = 0.18). Overall, 12-week mortality was 30%. Mortality was significantly higher among patients receiving ≥50% of treatment as combination (logrank = 0.04), especially those with non-IA IMI (logrank = 0.03). Conclusions: Combination antifungal treatment is frequently administered in allogeneic HCT recipients with IMI to improve clinical efficacy, albeit in an inconsistent and variable manner, suggesting a lack of relevant data and guidance, and an urgent need for new studies to improve therapeutic options. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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11 pages, 1212 KiB

Open AccessArticle

Synergistic Antifungal Activity of Chito-Oligosaccharides and Commercial Antifungals on Biofilms of Clinical Candida Isolates

by Monica Ganan, Silje B. Lorentzen, Peter Gaustad and Morten Sørlie

J. Fungi 2021, 7(9), 718; https://doi.org/10.3390/jof7090718 - 1 Sep 2021

Cited by 9 | Viewed by 2279

Abstract

The development of yeast biofilms is a major problem due to their increased antifungal resistance, which leads to persistent infections with severe clinical implications. The high antifungal activity of well-characterized chitosan polymers makes them potential alternatives for treating yeast biofilms. The activity of a chito-oligosaccharide with a depolymerization degree (DP_n) of 32 (C32) and a fraction of acetylation (F_A) of 0.15 on Candida sp. biofilms was studied. The results showed a concentration-dependent reduction in the number of viable cells present in C. albicans, C. glabrata, and C. guillermondii preformed biofilms in the presence of C32, especially on intermediate and mature biofilms. A significant decrease in the metabolic activity of yeast biofilms treated with C32 was also observed. The antifungals fluconazole (Flu) and miconazole (Mcz) decreased the number of viable cells in preformed early biofilms, but not in the intermediate or mature biofilms. Contrary to Flu or Mcz, C32 also reduced the formation of new biofilms. Interestingly, a synergistic effect on yeast biofilm was observed when C32 and Flu/Mcz were used in combination. C32 has the potential to become an alternative therapeutic agent against Candida biofilms alone or in combination with antifungal drugs and this will reduce the use of antifungals and decrease antifungal resistance. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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10 pages, 2181 KiB

Open AccessArticle

Antifungal Combination Therapy in Children with Cancer—A 4-Year Analysis of Real-Life Data of Two Major Pediatric Cancer Centers

by Stefan Schöning, Konrad Bochennek, Kathrin Gordon, Andreas H. Groll and Thomas Lehrnbecher

J. Fungi 2021, 7(8), 604; https://doi.org/10.3390/jof7080604 - 26 Jul 2021

Cited by 1 | Viewed by 2137

Abstract

Clinical data on antifungal combination therapy are limited, in particular in the pediatric setting. We analyzed real-life data collected in two major pediatric cancer centers over a period of 4 years. Patients were identified in an observational study on children with acute leukemia and lymphoma or undergoing hematopoietic cell transplantation. Out of 438 patients, 19 patients received 21 episodes of antifungal combination therapy. Therapy was mostly started for sepsis (n = 5) or clinical deterioration with pulmonary infiltrates (n = 10), and less often for periorbital swelling with suspected mold infection (n = 2), clinical deterioration and new skin lesions, secondary antifungal prophylaxis, a persistently elevated galactomannan index, or as pre-emptive treatment (n = 1 each). Diagnostics revealed proven, probable, and possible invasive fungal disease in two, seven and four episodes, respectively. Most regimens included caspofungin (n = 19), and treatment was initiated as first line therapy in 10 episodes. The median duration was 13 days (4–46 days). Nine of the 13 patients with proven, probable, or possible invasive fungal disease survived, which was comparable to patients receiving antifungal monotherapy. Our analysis demonstrates that combination therapy has mainly been prescribed in selected immunocompromised patients with clinical deterioration due to suspected invasive fungal disease or those with sepsis, and is well tolerated. Future studies need to better characterize clinical settings in which patients may benefit from antifungal combination therapy. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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Review

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15 pages, 325 KiB

Open AccessReview

Combination Therapy for HIV-Associated Cryptococcal Meningitis—A Success Story

by William J. Hurt, Thomas S. Harrison, Síle F. Molloy and Tihana A. Bicanic

J. Fungi 2021, 7(12), 1098; https://doi.org/10.3390/jof7121098 - 20 Dec 2021

Cited by 4 | Viewed by 4119

Abstract

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

12 pages, 301 KiB

Open AccessReview

Role of Antifungal Combinations in Difficult to Treat Candida Infections

by Roxana G. Vitale

J. Fungi 2021, 7(9), 731; https://doi.org/10.3390/jof7090731 - 6 Sep 2021

Cited by 28 | Viewed by 6838

Abstract

Candida infections are varied and, depending on the immune status of the patient, a life-threatening form may develop. C. albicans is the most prevalent species isolated, however, a significant shift towards other Candida species has been noted. Monotherapy is frequently indicated, but the patient’s evolution is not always favorable. Drug combinations are a suitable option in specific situations. The aim of this review is to address this problem and to discuss the role of drug combinations in difficult to treat Candida infections. A search for eligible studies in PubMed and Google Scholar databases was performed. An analysis of the data was carried out to define in which cases a combination therapy is the most appropriate. Combination therapy may be used for refractory candidiasis, endocarditis, meningitis, eye infections and osteomyelitis, among others. The role of the drug combination would be to increase efficacy, reduce toxicity and improve the prognosis of the patient in infections that are difficult to treat. More clinical studies and reporting of cases in which drug combinations are used are needed in order to have more data that support the use of this therapeutic strategy. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

16 pages, 577 KiB

Open AccessReview

Antifungal Combinations in Dermatophytes

by Lucia Brescini, Simona Fioriti, Gianluca Morroni and Francesco Barchiesi

J. Fungi 2021, 7(9), 727; https://doi.org/10.3390/jof7090727 - 5 Sep 2021

Cited by 33 | Viewed by 11684

Abstract

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations against dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies and 31 articles referring to case reports or clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts or essential oils, calcineurin inhibitors, peptides, disinfectant agents, and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections, an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e., terbinafine, griseofulvin, or azole—mainly itraconazole) plus a topical medication (i.e., azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful to accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available so far, it is desirable to continue the research in this field. Full article

(This article belongs to the Special Issue Antifungal Combinations in Fungal Infections)

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