New Antimycotics in the Pipeline – For Ophthalmology Too?

Abstract

Seven new antimycotics are presented that are at different points of development or approval. These substances are mainly first-in-class drugs. They are primarily developed for systemic administration. However, with the support of a pharmacist, the intravenous formulation may be used as eyedrops. In this short review, the activities of the substances against various fungal infections are described. After unsuccessful conventional therapy of fungal eye infections, one of these new substances might be suitable to cure the mycosis.

Key words

infectious diseases - microbiology - pharmacology

Publikationsverlauf

Eingereicht: 06. Februar 2021

Angenommen: 26. März 2021

Artikel online veröffentlicht:
01. Juli 2021

• References/Literatur

• 1 Ahmed SA, Hofmüller W, Seibold M. et al. Tintelnotia, a new genus in Phaeosphaeriaceae harbouring agents of cornea and nail infections in humans. Mycoses 2017; 60: 244-253
• 2 Habbe KJ, Frings A, Schrader S. et al. Tintelnotia destructans: ein neuer Feind vor dem Tore. Ophthalmologe 2018; 115: 948-950
• 3 Behrens-Baumann WJ, Hofmüller W, Tammer I. et al. Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafin in combination with polyhexamethylene biguanide. Int Ophthalmol 2019; 39: 1379-1385
• 4 Schelenz S, Hagen F, Rhodes JL. et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob Resist Infect Control 2016; 5: 35
• 5 Breazzano MP, Tooley AA, Godfrey KJ. et al. Candida auris and endogenous panophthalmitis: clinical and histopathologic features. Am J Ophthalmol Case Rep 2020; 19: 100738
• 6 Trief D, Gray ST, Jacobiec FA. et al. Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus. Br J Ophthalmol 2016; 100: 184-188
• 7 Bawankar P, Lahane S, Pathak P. et al. Central retinal artery occlusion as the presenting manifestation of invasive rhino-orbital-cerebral mucomycosis. Taiwan J Ophthalmol 2020; 10: 62-65
• 8 Rauseo AM, Coler-Reilly A, Larson L. et al. Hope on the Horizon: Novel Fungal Treatments in Development. Open Forum Infect Dis 2020; 7: ofaa016
• 9 Pfaller MA, Huband MD, Flamm RK. et al. In vitro activity of APX001A (Manogepix) and comparator agents against 1,706 fungal isolates collected during an international surveillance program in 2017. Antimicrob Agents Chemother 2019; 63: e00840-19
• 10 Trzoss M, Covel JA, Kapoor M. et al. Synthesis of analogs of the Gwt1 inhibitor Manogepix (APX001A) and in vitro evaluation against Cryptococcus spp. Bioorg Med Chem Lett 2019; 29: 126713
• 11 Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug Discov 2017; 16: 603-616
• 12 Lima SL, Colombo AL, Almeida JN. Fungal cell wall: emerging antifungals and drug resistance. Front Microbiol 2019; 10: 2573
• 13 Alkhazraji S, Gebremariam T, Alqarihi A. et al. Fosmanogepix (APX001) is effective in the treatment of immunocompromised mice infected with invasive pulmonary scedosporiopsis or disseminated fusariosis. Antimicrob Agents Chemother 2020; 64: e01735-19
• 14 Shaw KJ, Ibrahim AS. Fosmanogepix: A review of a first-in-class broad spectrum agent for the treatment of invasive fungal infections. J Fungi (Basel) 2020; 6: 239
• 15 Wiederhold NP, Najvar LK, Shaw KJ. et al. Efficacy of delayed therapy with Fosmanogepix (APX001) in a murin model of Candida auris invasive Candidiasis. Antimicrob Agents Chemother 2019; 63: e01120-19
• 16 Gebremariam T, Alkhazraji S, Algarihi A. et al. Fosmanogepix (APX001) is effective in the treatment of pulmonary murine mucormycosis due to Rhizopus arrhizus . Antimicrob Agents Chemother 2020; 64: e00178-20
• 17 Aruanno M, Glampedakis E, Lamoth F. Echinocandins for the treatment of aspergillosis: from laboratory to bedside. Antimicrob Agents Chemother 2019; 63: e00399-19
• 18 Arendrup MC, Jørgensen KM, Hare KR. et al. In vitro activity of Ibrexafungerp (SCY-078) against Candida auris isolates as determined by EUCAST methodology and comparison with activity against C. albicans and C. glabrata and with activities of six comparator agents. Antimicrob Agents Chemother 2020; 64: e02136-19
• 19 Pfaller MA, Messer SA, Rhomberg PR. et al. Differential activity of the oral glucan synthase inhibitor SCY-078 against wild-type and echinocandin-resistant strains of Candida species. Antimicrob Agents Chemother 2017; 61: e00161-17
• 20 Gintjee T, Donnelly MA, Thompson 3rd GR. Aspiring antifungals: review of current antifungal pipeline developments. J Fungi (Basel) 2020; 6: 28
• 21 Lamoth F, Alexander BD. Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates. Antimicrob Agents Chemother 2015; 59: 4308-4311
• 22 Larkin E, Hager C, Chandra J. et al. The emerging pathogen Candida auris: Growth phenotype, virulence factors, activity of antifungals and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob Agents Chemother 2017; 61: e02396-16
• 23 Petraitis V, Petraitiene R, Katragkou A. et al. Combination therapy with Ibrexafungerp (formerly SCY-078), a first-in-class triterpenoid inhibitor (1 → 3)-β-D-glucan synthesis, and Isavuconazole for treatment of experimental invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2020; 64: e02429-19
• 24 Wring S, Borroto-Esoda K, Solon E. et al. SCY-078, a novel fungicidal agent, demonstrates distribution to tissues associated with fungal infections during mass balance studies with intravenous and oral [¹⁴C]SCY-078 in albino and pigmented rats. Antimicrob Agents Chemother 2019; 63: e02119-18
• 25 Oliver JD, Sibley GEM, Beckmann M. et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci U S A 2016; 113: 12809-12814
• 26 Wiederholt NP. Review of the novel investigational antifungal olorofim. J Fungi (Basel) 2020; 6: 122
• 27 Abe M, Nakamura S, Kinjo Y. Efficacy of T-2307, a novel arylamidine, against ocular complications of disseminated candidiasis in mice. J Antimicrob Chemother 2019; 74: 1327-1332
• 28 Mroczyńska M, Brillowska-Dąbrowska A. Review on current status of echinocandins use. Antibiotics (Basel) 2020; 9: 227
• 29 Garcia-Effron G. Rezafungin – Mechanisms of action, susceptibility and resistance: Similarities and differences with other echinocandins. J Fungi (Basel) 2020; 6: 262
• 30 Aigner M, Lass-Flörl C. Encochleated Amphotericin B: Is the oral availability of Amphotericin B finally reached?. J Fungi (Basel) 2020; 6: 66
• 31 Roth M, Daas L, Renner-Wilde A. et al. Das Deutsche Pilzkeratitisregister: Erste Ergebnisse einer Multicenterstudie. Ophthalmologe 2019; 116: 957-966
• 32 Benson H. Permeability of the cornea to topically applied drugs. Arch Ophthalmol 1974; 91: 313-327
• 33 Vorwerk CK, Streit F, Binder L. et al. Aqueous humor concentration of voriconazole after topical administration in rabbits. Graefes Arch Clin Exp Ophthalmol 2008; 246: 1179-1183
• 34 Lau D, Fedinands M, Leung L. et al. Penetration of voriconazole 1 % eyedrops into human aqueous humor. A prospective open-label study. Arch Ophthalmol 2008; 126: 343-346
• 35 Vorwerk CK, Tuchen S, Streit F. et al. Aqueous humor concentrations of topically administered caspofungin in rabbits. Ophthalmic Res 2009; 41: 102-105
• 36 Behrens-Baumann W, Finis D, MacKenzie C. et al. Keratomykose – Therapiestandards und aktuelle Entwicklungen. Klin Monbl Augenheilkd 2015; 232: 754-764
• 37 Liston SD, Whitesell L, Kapoor M. et al. Enhanced efflux pump expression in Candida mutants results in decreased manogepix susceptibility. Antimicrob Agents Chemother 2020; 64: e00261-20
• 38 Song J, Zhou J, Zhang L. et al. Mitochondria-mediated azole drug resistance and fungal pathogenicity: opportunities for therapeutic development. Microorganisms 2020; 8: 1574
• 39 Doft BH, Weiskopf J, Nilsson-Ehle I. et al. Amphotericin clearance in vitrectomized versus nonvitrectomized eyes. Ophthalmology 1985; 92: 1601-1605
• 40 Hariprasad SM, Wieler WF, Holz ER. et al. Determination of vitreous, aqueous and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol 2004; 122: 42-47
• 41 Prajna NV, Krishnan T, Rajaraman R. et al. Effect of oral voriconazole in fungal keratitis in the Mycotic Ulcer Treatment Trial (MUTT II): a randomized clinical trial. JAMA Ophthalmol 2016; 134: 1365-1372
• 42 Sponsel WE, Graybill JR, Nevarez HL. et al. Ocular and systemic posaconazole (SCH-56592) treatment of invasive Fusarium solani keratitis and endophthalmitis. Br J Ophthalmol 2002; 86: 829-830
• 43 Tu EY, McCartney DL, Beatty RF. et al. Successful treatment of resistant ocular fusariosis with posaconazole (SCH-56592). Am J Ophthalmol 2007; 143: 222-227
• 44 Tu EY, Park AJ. Recalcitrant Beauveria bassiana keratitis: confocal microscopy findings and treatment with posaconazole (Noxafil). Cornea 2007; 26: 1008-1010
• 45 Altun A, Kurna SA, Sengor T. et al. Effectiveness of posaconazole in recalcitrant fungal keratitis resistant to conventional antifungal drugs. Case Rep Ophthalmol Med 2014; 2014: 701653
• 46 Pleyer U, Mondino BJ, Adamu SA. et al. Immune response to Staphylococcus epidermidis-induced endophthalmitis in a rabbit model. Invest Ophthalmol Vis Sci 1992; 33: 2650-2663
• 47 Behrens-Baumann W. Kortikosteroide als Additiv zur antimikrobiellen Therapie. Ophthalmologe 2016; 113: 964-965
• 48 Kramer A, Behrens-Baumann W. eds. Antiseptic Prophylaxis and Therapy in ocular Infections – Principles, Clinical Practice and Infection Control. Developments in Ophthalmology Vol. 33. Basel: Karger; 2002
• 49 Roth M, Steindor E, Kurzai O. et al. Mykotische Keratitis: Klinische Zeichen, Diagnose, Therapie. Augenheilkunde up2date 2020; 10: 8-16
• 50 Rahman MR, Johnson GJ, Husain R. et al. Randomised trial of 0,2 % chlorhexidine gluconate and 2,5 % natamycin for fungal keratitis in Bangladesh. Br J Ophthalmol 1998; 82: 919-925
• 51 Oliveira dos Santos C, Kolwijck E, van der Lee HA. et al. In vitro activity of chlorhexidine compared with seven antifungal agents against 98 Fusarium isolates recovered from fungal keratitis patients. Antimicrob Agents Chemother 2019; 63: e02669-18
• 52 Behrens-Baumann W. Keratomykose. In: Pleyer U. Hrsg. Entzündliche Augenerkrankungen. 2. Aufl.. Berlin, Heidelberg: Springer; 2021. [in press]