Antifungal Pipeline

McCarty, Todd P; Pappas, Peter G.

doi:10.3389/fcimb.2021.732223

Cited by 33 publications

(20 citation statements)

References 98 publications

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“…The further search for new classes of antifungals is essential taking into account the potential multi-drug resistance in C. glabrata , demonstrating an increasing frequency of resistance to echinocandins and azoles. Moreover, C. krusei has an intrinsic fluconazole resistance, combined with a reported decreased susceptibility to amphotericin B and flucytosine, and pan-drug resistance is emerging in C. auris [ 29 , 193 , 194 , 195 , 196 , 197 , 198 , 199 ].…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Treatment of Invasive Candidiasis

Barantsevich

2022

Antibiotics

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Candida species, belonging to commensal microbial communities in humans, cause opportunistic infections in individuals with impaired immunity. Pathogens encountered in more than 90% cases of invasive candidiasis include C. albicans, C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis. The most frequently diagnosed invasive infection is candidemia. About 50% of candidemia cases result in deep-seated infection due to hematogenous spread. The sensitivity of blood cultures in autopsy-proven invasive candidiasis ranges from 21% to 71%. Non-cultural methods (beta-D-glucan, T2Candida assays), especially beta-D-glucan in combination with procalcitonin, appear promising in the exclusion of invasive candidiasis with high sensitivity (98%) and negative predictive value (95%). There is currently a clear deficiency in approved sensitive and precise diagnostic techniques. Omics technologies seem promising, though require further development and study. Therapeutic options for invasive candidiasis are generally limited to four classes of systemic antifungals (polyenes, antimetabolite 5-fluorocytosine, azoles, echinocandins) with the two latter being highly effective and well-tolerated and hence the most widely used. Principles and methods of treatment are discussed in this review. The emergence of pan-drug-resistant C. auris strains indicates an insufficient choice of available medications. Further surveillance, alongside the development of diagnostic and therapeutic methods, is essential.

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Section: Discussionmentioning

confidence: 99%

Diagnosis and Treatment of Invasive Candidiasis

Barantsevich

2022

Antibiotics

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“…Olorofim is a novel antifungal agent. It belongs to a new class of drugs, the orotomides, which target dihydroorotate dehydrogenase, an important enzyme for pyrimidine biosynthesis [ 109 , 110 ]. This new antifungal has shown potent in vitro activity against both Scedosporium spp.…”

Section: The Most Frequent Non- Aspergillus Imis A...mentioning

confidence: 99%

Non-Aspergillusmould lung infections

Puerta‐Alcalde

García-Vidal²

2022

Eur Respir Rev

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Non-Aspergillusfilamentous fungi causing invasive mould infections have increased over the last years due to the widespread use of anti-Aspergillusprophylaxis and increased complexity and survival of immunosuppressed patients. In the few studies that have reported on invasive mould infection epidemiology, Mucorales are the most frequently isolated group, followed by eitherFusariumspp. orScedosporiumspp. The overall incidence is low, but related mortality is exceedingly high. Patients with haematological malignancies and haematopoietic stem cell transplant recipients comprise the classical groups at risk of infection for non-Aspergillusmoulds due to profound immunosuppression and the vast use of anti-Aspergillusprophylaxis. Solid organ transplant recipients also face a high risk, especially those receiving lung transplants, due to direct exposure of the graft to mould spores with altered mechanical and immunological elimination, and intense, associated immunosuppression. Diagnosing non-Aspergillusmoulds is challenging due to unspecific symptoms and radiological findings, lack of specific biomarkers, and low sensitivity of cultures. However, the advent of molecular techniques may prove helpful. Mucormycosis, fusariosis and scedosporiosis hold some differences regarding clinical paradigmatic presentations and preferred antifungal therapy. Surgery might be an option, especially in mucormycosis. Finally, various promising strategies to restore or enhance the host immune response are under current evaluation.

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“…AMR, among fungi, is of particular concern due to the limited number of classes of drugs available to treat invasive fungal infections (i.e., fungistatic azoles as well as fungicidal polyenes and echinocandins) [ 7 ]. This threat is exacerbated by the fact that no new class of antifungal drugs has reached the market in over a decade [ 8 , 9 ]. Climate change is also predicted to increase the prevalence of fungal infections, as fungi adapt to warmer temperatures to increase their geographic range and overcome the thermal protection barrier of their warm-blooded hosts [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and Elimination of Antifungal Tolerance in Candida auris

et al. 2023

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Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen C. auris is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in C. auris has been recently attributed to antifungal “tolerance”. Tolerance is a phenomenon whereby a slow-growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays, together with image analysis, to investigate antifungal tolerance in C. auris to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1) C. auris is tolerant to several common fungistatic and fungicidal drugs, which in some cases can be detected after 24 h, as well as after 48 h, of antifungal drug exposure; (2) the tolerant phenotype reverts to the susceptible phenotype in C. auris; and (3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine in some cases reduces or eliminates tolerance and resistance in patient-derived C. auris isolates. These results suggest that tolerance contributes to treatment failure in C. auris infections for a broad range of antifungal drugs, and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.

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Antifungal Pipeline

Cited by 33 publications

References 98 publications

Diagnosis and Treatment of Invasive Candidiasis

Diagnosis and Treatment of Invasive Candidiasis

Non-Aspergillusmould lung infections

Identification and Elimination of Antifungal Tolerance in Candida auris

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