Two Cases of Curvularia geniculata Keratitis Successfully Treated with Natamycin-Based Therapy

Two Cases of Curvularia geniculata Keratitis Successfully Treated with Natamycin-Based Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Two Cases of Curvularia geniculata Keratitis Successfully Treated with Natamycin-Based Therapy Atsuhiko Fukuto, Fumiya Miyako, Toshinori Hara, Rie Nagaoka, Takashi Yaguchi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7048594/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Sep, 2025 Read the published version in Mycopathologia → Version 1 posted 6 You are reading this latest preprint version Abstract This report describes two cases of Curvularia geniculata keratitis, a rare form of fungal keratitis successfully managed with natamycin-based therapy. Both patients presented with characteristic feathery corneal infiltrates following ocular trauma. In vivo confocal microscopy and direct microscopy revealed septate filamentous fungi, and the isolates were definitively identified as C. geniculata through sequence analysis of the translation elongation factor 1-alpha ( tef1-α ) gene. Antifungal susceptibility testing showed sensitivity to natamycin at 2 µg/mL for both isolates, with variable sensitivity to other antifungal agents. Patient 1 was treated with a combination of topical natamycin and voriconazole, while Patient 2 received natamycin monotherapy. Both patients achieved complete healing and excellent visual outcomes. These cases underscore the importance of accurate molecular identification for species differentiation within the Curvularia genus and demonstrate the efficacy of natamycin-based therapy for C. geniculata keratitis. The choice between monotherapy and combination therapy may be guided by clinical severity and antifungal susceptibility testing. This report contributes to the understanding of the clinical features, diagnosis, and management of this rare condition and highlights the potential value of susceptibility testing in guiding treatment decisions. Curvularia geniculata Fungal keratitis Natamycin Voriconazole Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Fungal keratitis remains a significant cause of visual impairment worldwide, with dematiaceous fungi—including Curvularia species—emerging as important pathogens [ 1 ]. These pigmented filamentous fungi are widely found in soil and vegetation, and keratitis often follows plant-related trauma, especially in tropical and subtropical regions [ 2 ]. Although several Curvularia species have been implicated in ocular infections, keratitis caused by Curvularia geniculata is relatively rare, and current knowledge of its clinical features and treatment remains limited. We report two cases of C. geniculata keratitis that were successfully treated with medical management. By presenting these cases, we aim to contribute to a better understanding of the clinical features, diagnosis, and management of this relatively uncommon form of fungal keratitis. Case Reports Patient 1 A 29-year-old man who worked at an incineration facility crushing garbage presented with hyperemia and a foreign body sensation in his right eye. After visiting a local ophthalmologist the following day, he was referred to the Department of Ophthalmology at Hiroshima University Hospital 5 days later because of lack of improvement. At the initial examination, his corrected visual acuity in the right eye was 20/20. Conjunctival injection was noted, and slit-lamp examination revealed a corneal ulcer with feathery infiltrate at the 4-o’clock position of the right cornea (Fig. 1a). The initial corneal scraping did not reveal any organisms. Treatment was started with topical antibiotics: 1.5% levofloxacin six times daily, cefmenoxime six times daily, and ofloxacin ointment three times daily. Three days later, the infiltration had expanded. Subsequent epithelial curettage with fluorescent and lactophenol cotton blue staining revealed club-shaped, thick nodular filamentous fungi (Fig. 2a, b), and in vivo confocal microscopy confirmed the presence of similarly shaped filamentous fungi (Fig. 2b). On the basis of these findings, fungal keratitis was diagnosed. The treatment regimen was switched to 5% natamycin twice daily and 1% voriconazole four times daily. After 10 days of antifungal therapy, the lesion had scarred, and the medications were discontinued. Patient 2 A 63-year-old man sustained a right eye injury when foreign material entered his eye while cutting grass. He visited a local ophthalmologist 2 days after the injury and was prescribed levofloxacin and ofloxacin ophthalmic ointments. However, he developed ocular pain and decreased visual acuity with corneal infiltration, and he was referred to the Department of Ophthalmology at Hiroshima University Hospital 4 days after the initial injury. At presentation, the best-corrected visual acuity in the right eye was 20/50. An irregularly shaped infiltrate was observed in the paracentral cornea, accompanied by a small epithelial defect at the same location (Fig. 3a, b). Anterior segment optical coherence tomography revealed that the infiltrative lesion was confined to the superficial stroma without corneal thinning. Although direct microscopy and in vivo confocal microscopy did not reveal clear fungal elements, filamentous fungal infection was suspected based on the mechanism of injury and anterior segment findings. Topical natamycin was added to the treatment regimen, and the infiltrate had nearly resolved within 2 weeks of the initial visit, with complete epithelialization achieved. Topical betamethasone phosphate was then initiated, leading to healing with minimal scarring. Two months after the initial examination, best-corrected visual acuity in the right eye recovered to 20/16. Microbiological Findings The two isolates were morphologically and molecularly indistinguishable. The conidiogenous cells were terminal, brown, smooth, and bore darkened scars. The conidia were cylindrical to ellipsoidal, slightly curved, 3- to 5-distoseptate, pale brown to brown in color, and rounded at the apex (Fig. 4a). The cultured colonies had velvety surfaces (Fig. 4b). Based on these morphological features, the isolates were identified as belonging to the genus Curvularia . Sequence analysis of the translation elongation factor 1-alpha ( tef1-α ) gene showed 100% identity (929/929 bp) with C. geniculata strain NB871 (GenBank accession no. OP709948). The isolates were preserved as IFM 67522 and IFM 69711 at the Medical Mycology Research Center, Chiba University, through the National Bio-Resource Project, Japan (JPNBRP202228). Antifungal susceptibility testing was conducted for both isolates. In Patient 1’s isolate, amphotericin B, terbinafine, luliconazole, itraconazole, voriconazole, and ravuconazole all showed complete (100%) growth inhibition at concentrations of > 2 µg/mL. At 0.25 µg/mL, luliconazole, itraconazole, and ravuconazole showed 80% growth inhibition, while voriconazole achieved 80% inhibition at 0.5 µg/mL. Natamycin completely inhibited growth at 2 µg/mL. For the isolate from Patient 2, the minimum inhibitory concentrations were as follows: amphotericin B, complete inhibition at 0.25 µg/mL; natamycin, complete inhibition at 2 µg/mL. The 80% growth inhibition concentrations were as follows: terbinafine, 1 µg/mL; luliconazole, 0.06 µg/mL; itraconazole, 0.06 µg/mL; voriconazole, 0.5 µg/mL; and ravuconazole, 0.5 µg/mL. Both isolates were sensitive to natamycin at the same concentration (2 µg/mL), while Patient 2’s isolate demonstrated greater sensitivity to amphotericin B and azole antifungals than did Patient 1’s isolate. Discussion This report describes two cases of keratitis caused by C. geniculata , a relatively uncommon cause of fungal keratitis, confirmed through molecular identification. Although C. geniculata keratitis has been reported in two cases since the 1960s [ 3 , 4 ], our cases represent the first molecularly confirmed instances using genetic analysis. These findings underscore the clinical importance of accurate species identification within the genus Curvularia and offer valuable insights into the management of this rare condition. The clinical presentation of Curvularia keratitis in our cases is consistent with previous reports in the literature. In a comprehensive 30-year study by Wilhelmus and Jones analyzing 43 cases of Curvularia keratitis, the clinical spectrum ranged from superficial feathery infiltrates of the central cornea to suppurative ulceration of the peripheral cornea [ 5 ]. The authors noted that Curvularia keratitis typically presents as a superficial feathery infiltration, rarely with visible pigmentation, which gradually becomes focally suppurative. Both of our patients exhibited characteristic feathery infiltrates—particularly prominent in Patient 1—further supporting these established clinical features. The presence or absence of hypopyon is an important prognostic indicator in Curvularia keratitis. Hypopyon formation is relatively uncommon, occurring in only 12% of cases in the study by Wilhelmus and Jones [ 5 ], but when present, it was associated with a significantly increased risk of complications. Similarly, Khurana et al. reported hypopyon in 16.5% of 97 culture-proven Curvularia keratitis cases in India, with its absence linked to better visual outcomes [ 6 ]. Notably, neither of our patients developed hypopyon, and both achieved excellent final visual acuity (20/20 and 20/16, respectively), further supporting the established correlation between the absence of hypopyon and a favorable prognosis in Curvularia keratitis. Accurate species identification within the genus Curvularia has become increasingly important because of significant taxonomic revisions in recent years. Numerous cryptic species have been revealed through molecular phylogenetic studies [ 7 – 10 ], highlighting the insufficiency of morphological characteristics alone for reliable species determination. Many Curvularia species share overlapping morphological traits and conidial dimensions, making precise identification particularly challenging. In our cases, both isolates were definitively identified as C. geniculata sensu stricto through sequence analysis of the tef1-α gene, which showed 100% identity with the reference strain. Notably, initial analysis using only the internal transcribed spacer region proved inadequate for definitive species-level identification, underscoring the importance of multi-locus approaches in Curvularia taxonomy. The distinction between sensu lato and sensu stricto classifications is clinically relevant because different Curvularia species may exhibit varying pathogenicity, antifungal susceptibility profiles, and clinical outcomes. The choice of antifungal therapy for Curvularia keratitis remains centered on natamycin, the only topical antifungal agent approved for ophthalmic use by the U.S. Food and Drug Administration [ 11 , 12 ]. In a landmark study by Wilhelmus and Jones, all tested Curvularia isolates were inhibited by ≤ 4 µg/mL of natamycin, demonstrating excellent in vitro activity, and 78% of patients achieved a visual acuity of 20/40 or better [ 9 ]. Recent meta-analyses comparing topical natamycin with voriconazole have shown similar visual acuity outcomes at 2–3 months, although natamycin is associated with a lower risk of corneal perforation and therapeutic penetrating keratoplasty [ 13 ]. Our in vitro susceptibility testing showed that both isolates were sensitive to natamycin at 2 µg/mL, consistent with previous reports. However, there was notable variability in sensitivity to other antifungal agents between the two isolates, with Patient 2’s isolate demonstrating greater sensitivity to amphotericin B and azole antifungals than Patient 1’s isolate. This variability highlights the potential value of susceptibility testing in guiding therapy, particularly in cases that do not respond to initial treatment. In our approach, Patient 1 was treated with a combination of natamycin and voriconazole, while Patient 2 was successfully managed with natamycin alone. Both patients achieved complete healing and excellent visual outcomes, supporting the effectiveness of both strategies. Recent studies have reported synergistic effects between natamycin and voriconazole against Curvularia species in 23.1% of tested isolates [ 14 ], suggesting that combination therapy may be beneficial in selected cases. In conclusion, C. geniculata keratitis, though rare, can be effectively managed with appropriate antifungal therapy. Molecular identification is crucial for accurate diagnosis and species-level differentiation within the Curvularia genus. Both natamycin monotherapy and combination therapy with natamycin and voriconazole appear to be effective treatment options, with the choice potentially guided by clinical severity and antifungal susceptibility testing results. Declarations Funding The authors did not receive support from any organization for the submitted work. Consent for publication Written informed consent was obtained from the patients for the publication of this case report and any accompanying images. Consent for treatment Written informed consent was obtained from the patients before the procedures described in this case report. Ethical Approval This study was an observational study. The Institutional Review Board of Hiroshima University issued approval E2016-0709. Acknowledgment We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript. References Hoffman JJ, Arunga S, Mohamed Ahmed AHA, Hu VH, Burton MJ. Management of Filamentous Fungal Keratitis: A Pragmatic Approach. J Fungi (Basel). 2022;8(10). doi:10.3390/jof8101067 Rai M, Ingle AP, Ingle P, Gupta I, Mobin M, Bonifaz A, et al. Recent advances on mycotic keratitis caused by dematiaceous hyphomycetes. J Appl Microbiol. 2021;131(4):1652–67. doi:10.1111/jam.15008 Georg LK. Curvularia geniculata, A Cause of Mycotic Keratits. J Med Assoc State Ala. 1964;33:234–6. Nityananda K, Sivasubramaniam P, Ajello L. A Case of Mycotic Keratitis Caused by Curvularia geniculata. Archives of ophthalmology (Chicago, Ill. : 1960). 1964;71:456–8. doi:10.1001/archopht.1964.00970010472003 Wilhelmus KR, Jones DB. Curvularia keratitis. Trans Am Ophthalmol Soc. 2001;99:111–30; discussion 30–2. Khurana A, Chanda S, Bhagat P, Aggarwal S, Sharma M, Chauhan L. Clinical characteristics, predisposing factors, and treatment outcome of Curvularia keratitis. Indian J Ophthalmol. 2020;68(10):2088–93. doi:10.4103/ijo.IJO_90_20 Kiss N, Homa M, Manikandan P, Mythili A, Krizsan K, Revathi R, et al. New Species of the Genus Curvularia: C. tamilnaduensis and C. coimbatorensis from Fungal Keratitis Cases in South India. Pathogens. 2019;9(1). doi:10.3390/pathogens9010009 Iturrieta-Gonzalez I, Gene J, Wiederhold N, Garcia D. Three new Curvularia species from clinical and environmental sources. MycoKeys. 2020;68:1–21. doi:10.3897/mycokeys.68.51667 Ferdinandez HS, Manamgoda DS, Udayanga D, Deshappriya N, Munasinghe MS, Castlebury LA. Molecular phylogeny and morphology reveal three novel species of Curvularia (Pleosporales, Pleosporaceae) associated with cereal crops and weedy grass hosts. Mycological Progress. 2021;20(4):431–51. doi:10.1007/s11557-021-01681-0 Madrid H, da Cunha KC, Gene J, Dijksterhuis J, Cano J, Sutton DA, et al. Novel Curvularia species from clinical specimens. Persoonia. 2014;33:48–60. doi:10.3767/003158514X683538 Qiu S, Zhao GQ, Lin J, Wang X, Hu LT, Du ZD, et al. Natamycin in the treatment of fungal keratitis: a systematic review and Meta-analysis. Int J Ophthalmol. 2015;8(3):597–602. doi:10.3980/j.issn.2222-3959.2015.03.29 Mascarenhas M, Chaudhari P, Lewis SA. Natamycin Ocular Delivery: Challenges and Advancements in Ocular Therapeutics. Adv Ther. 2023;40(8):3332–59. doi:10.1007/s12325-023-02541-x FlorCruz NV, Evans JR. Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015;2015(4):CD004241. doi:10.1002/14651858.CD004241.pub4 Sradhanjali S, Yein B, Sharma S, Das S. In vitro synergy of natamycin and voriconazole against clinical isolates of Fusarium, Candida, Aspergillus and Curvularia spp. Br J Ophthalmol. 2018;102(1):142–5. doi:10.1136/bjophthalmol-2017-310683 Cite Share Download PDF Status: Published Journal Publication published 13 Sep, 2025 Read the published version in Mycopathologia → Version 1 posted Editorial decision: Minor revisions 11 Aug, 2025 Reviewers agreed at journal 11 Jul, 2025 Reviewers invited by journal 11 Jul, 2025 Editor invited by journal 10 Jul, 2025 Editor assigned by journal 05 Jul, 2025 First submitted to journal 04 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7048594","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":484152478,"identity":"8c0f53d2-7435-4f5b-b1b2-7b7971ce18cc","order_by":0,"name":"Atsuhiko 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infiltration.\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7048594/v1/895fedb60c4cf7c2a0eb7807.jpg"},{"id":86777553,"identity":"3d22a6fb-cc07-412a-b0c1-4114c8898e23","added_by":"auto","created_at":"2025-07-15 12:51:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":218499,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea \u003c/strong\u003eFungiflora Y staining of a corneal scraping from Patient 1, showing club-shaped, thick, septate filamentous fungi. \u003cstrong\u003eb\u003c/strong\u003e In vivo confocal microscopy of Patient 1 demonstrating numerous filamentous fungi with morphology similar to that observed on Fungiflora Y staining.\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7048594/v1/61a38a67e4ffa4259c876a91.jpg"},{"id":86779058,"identity":"8a0fbbeb-1a1b-4f53-8db7-5dbcea56695c","added_by":"auto","created_at":"2025-07-15 13:07:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":289088,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e Anterior segment photograph of Patient 2 at the initial examination, showing a 1-mm corneal infiltrate located in the paracentral area. \u003cstrong\u003eb\u003c/strong\u003e Fluorescein staining reveals an epithelial defect smaller than the area of corneal infiltration.\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7048594/v1/69b0d3d218b1128afe83b40e.jpg"},{"id":86778626,"identity":"d1834611-1ca3-4e49-b2f2-a8b9c39b451f","added_by":"auto","created_at":"2025-07-15 12:59:15","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":257924,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e Lactophenol cotton blue staining showing septate hyphae with curved, septate conidia. \u003cstrong\u003eb\u003c/strong\u003e Colony morphology on Sabouraud dextrose agar after 7 days of incubation at 25°C, displaying a cream to pale yellow, velvety colony with a flat surface.\u003c/p\u003e","description":"","filename":"fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7048594/v1/e8dd9f18376a4a90da0a9630.jpg"},{"id":91817647,"identity":"9ee1728d-333c-4ef4-a93b-93b48dabac05","added_by":"auto","created_at":"2025-09-22 07:00:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1516123,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7048594/v1/32d24b4d-5dfe-4e00-875d-6dc9d41c414e.pdf"}],"financialInterests":"","formattedTitle":"Two Cases of Curvularia geniculata Keratitis Successfully Treated with Natamycin-Based Therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFungal keratitis remains a significant cause of visual impairment worldwide, with dematiaceous fungi—including \u003cem\u003eCurvularia\u003c/em\u003e species—emerging as important pathogens [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These pigmented filamentous fungi are widely found in soil and vegetation, and keratitis often follows plant-related trauma, especially in tropical and subtropical regions [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although several \u003cem\u003eCurvularia\u003c/em\u003e species have been implicated in ocular infections, keratitis caused by \u003cem\u003eCurvularia geniculata\u003c/em\u003e is relatively rare, and current knowledge of its clinical features and treatment remains limited.\u003c/p\u003e\u003cp\u003eWe report two cases of \u003cem\u003eC. geniculata\u003c/em\u003e keratitis that were successfully treated with medical management. By presenting these cases, we aim to contribute to a better understanding of the clinical features, diagnosis, and management of this relatively uncommon form of fungal keratitis.\u003c/p\u003e"},{"header":"Case Reports","content":"\u003cp\u003ePatient 1\u003c/p\u003e\u003cp\u003eA 29-year-old man who worked at an incineration facility crushing garbage presented with hyperemia and a foreign body sensation in his right eye. After visiting a local ophthalmologist the following day, he was referred to the Department of Ophthalmology at Hiroshima University Hospital 5 days later because of lack of improvement. At the initial examination, his corrected visual acuity in the right eye was 20/20. Conjunctival injection was noted, and slit-lamp examination revealed a corneal ulcer with feathery infiltrate at the 4-o’clock position of the right cornea (Fig.\u0026nbsp;1a). The initial corneal scraping did not reveal any organisms. Treatment was started with topical antibiotics: 1.5% levofloxacin six times daily, cefmenoxime six times daily, and ofloxacin ointment three times daily. Three days later, the infiltration had expanded. Subsequent epithelial curettage with fluorescent and lactophenol cotton blue staining revealed club-shaped, thick nodular filamentous fungi (Fig.\u0026nbsp;2a, b), and in vivo confocal microscopy confirmed the presence of similarly shaped filamentous fungi (Fig.\u0026nbsp;2b). On the basis of these findings, fungal keratitis was diagnosed. The treatment regimen was switched to 5% natamycin twice daily and 1% voriconazole four times daily. After 10 days of antifungal therapy, the lesion had scarred, and the medications were discontinued.\u003c/p\u003e\u003cp\u003ePatient 2\u003c/p\u003e\u003cp\u003eA 63-year-old man sustained a right eye injury when foreign material entered his eye while cutting grass. He visited a local ophthalmologist 2 days after the injury and was prescribed levofloxacin and ofloxacin ophthalmic ointments. However, he developed ocular pain and decreased visual acuity with corneal infiltration, and he was referred to the Department of Ophthalmology at Hiroshima University Hospital 4 days after the initial injury. At presentation, the best-corrected visual acuity in the right eye was 20/50. An irregularly shaped infiltrate was observed in the paracentral cornea, accompanied by a small epithelial defect at the same location (Fig.\u0026nbsp;3a, b). Anterior segment optical coherence tomography revealed that the infiltrative lesion was confined to the superficial stroma without corneal thinning. Although direct microscopy and in vivo confocal microscopy did not reveal clear fungal elements, filamentous fungal infection was suspected based on the mechanism of injury and anterior segment findings. Topical natamycin was added to the treatment regimen, and the infiltrate had nearly resolved within 2 weeks of the initial visit, with complete epithelialization achieved. Topical betamethasone phosphate was then initiated, leading to healing with minimal scarring. Two months after the initial examination, best-corrected visual acuity in the right eye recovered to 20/16.\u003c/p\u003e"},{"header":"Microbiological Findings","content":"\u003cp\u003eThe two isolates were morphologically and molecularly indistinguishable. The conidiogenous cells were terminal, brown, smooth, and bore darkened scars. The conidia were cylindrical to ellipsoidal, slightly curved, 3- to 5-distoseptate, pale brown to brown in color, and rounded at the apex (Fig.\u0026nbsp;4a). The cultured colonies had velvety surfaces (Fig.\u0026nbsp;4b). Based on these morphological features, the isolates were identified as belonging to the genus \u003cem\u003eCurvularia\u003c/em\u003e. Sequence analysis of the translation elongation factor 1-alpha (\u003cem\u003etef1-α\u003c/em\u003e) gene showed 100% identity (929/929 bp) with \u003cem\u003eC. geniculata\u003c/em\u003e strain NB871 (GenBank accession no. OP709948). The isolates were preserved as IFM 67522 and IFM 69711 at the Medical Mycology Research Center, Chiba University, through the National Bio-Resource Project, Japan (JPNBRP202228). Antifungal susceptibility testing was conducted for both isolates. In Patient 1’s isolate, amphotericin B, terbinafine, luliconazole, itraconazole, voriconazole, and ravuconazole all showed complete (100%) growth inhibition at concentrations of \u0026gt; 2 µg/mL. At 0.25 µg/mL, luliconazole, itraconazole, and ravuconazole showed 80% growth inhibition, while voriconazole achieved 80% inhibition at 0.5 µg/mL. Natamycin completely inhibited growth at 2 µg/mL. For the isolate from Patient 2, the minimum inhibitory concentrations were as follows: amphotericin B, complete inhibition at 0.25 µg/mL; natamycin, complete inhibition at 2 µg/mL. The 80% growth inhibition concentrations were as follows: terbinafine, 1 µg/mL; luliconazole, 0.06 µg/mL; itraconazole, 0.06 µg/mL; voriconazole, 0.5 µg/mL; and ravuconazole, 0.5 µg/mL. Both isolates were sensitive to natamycin at the same concentration (2 µg/mL), while Patient 2’s isolate demonstrated greater sensitivity to amphotericin B and azole antifungals than did Patient 1’s isolate.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis report describes two cases of keratitis caused by \u003cem\u003eC. geniculata\u003c/em\u003e, a relatively uncommon cause of fungal keratitis, confirmed through molecular identification. Although \u003cem\u003eC. geniculata\u003c/em\u003e keratitis has been reported in two cases since the 1960s [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], our cases represent the first molecularly confirmed instances using genetic analysis. These findings underscore the clinical importance of accurate species identification within the genus \u003cem\u003eCurvularia\u003c/em\u003e and offer valuable insights into the management of this rare condition.\u003c/p\u003e\u003cp\u003eThe clinical presentation of \u003cem\u003eCurvularia\u003c/em\u003e keratitis in our cases is consistent with previous reports in the literature. In a comprehensive 30-year study by Wilhelmus and Jones analyzing 43 cases of \u003cem\u003eCurvularia\u003c/em\u003e keratitis, the clinical spectrum ranged from superficial feathery infiltrates of the central cornea to suppurative ulceration of the peripheral cornea [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The authors noted that \u003cem\u003eCurvularia\u003c/em\u003e keratitis typically presents as a superficial feathery infiltration, rarely with visible pigmentation, which gradually becomes focally suppurative. Both of our patients exhibited characteristic feathery infiltrates\u0026mdash;particularly prominent in Patient 1\u0026mdash;further supporting these established clinical features.\u003c/p\u003e\u003cp\u003eThe presence or absence of hypopyon is an important prognostic indicator in \u003cem\u003eCurvularia\u003c/em\u003e keratitis. Hypopyon formation is relatively uncommon, occurring in only 12% of cases in the study by Wilhelmus and Jones [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], but when present, it was associated with a significantly increased risk of complications. Similarly, Khurana et al. reported hypopyon in 16.5% of 97 culture-proven \u003cem\u003eCurvularia\u003c/em\u003e keratitis cases in India, with its absence linked to better visual outcomes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, neither of our patients developed hypopyon, and both achieved excellent final visual acuity (20/20 and 20/16, respectively), further supporting the established correlation between the absence of hypopyon and a favorable prognosis in \u003cem\u003eCurvularia\u003c/em\u003e keratitis.\u003c/p\u003e\u003cp\u003eAccurate species identification within the genus \u003cem\u003eCurvularia\u003c/em\u003e has become increasingly important because of significant taxonomic revisions in recent years. Numerous cryptic species have been revealed through molecular phylogenetic studies [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], highlighting the insufficiency of morphological characteristics alone for reliable species determination. Many \u003cem\u003eCurvularia\u003c/em\u003e species share overlapping morphological traits and conidial dimensions, making precise identification particularly challenging. In our cases, both isolates were definitively identified as \u003cem\u003eC. geniculata\u003c/em\u003e sensu stricto through sequence analysis of the \u003cem\u003etef1-α\u003c/em\u003e gene, which showed 100% identity with the reference strain. Notably, initial analysis using only the internal transcribed spacer region proved inadequate for definitive species-level identification, underscoring the importance of multi-locus approaches in \u003cem\u003eCurvularia\u003c/em\u003e taxonomy. The distinction between sensu lato and sensu stricto classifications is clinically relevant because different \u003cem\u003eCurvularia\u003c/em\u003e species may exhibit varying pathogenicity, antifungal susceptibility profiles, and clinical outcomes.\u003c/p\u003e\u003cp\u003eThe choice of antifungal therapy for \u003cem\u003eCurvularia\u003c/em\u003e keratitis remains centered on natamycin, the only topical antifungal agent approved for ophthalmic use by the U.S. Food and Drug Administration [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In a landmark study by Wilhelmus and Jones, all tested \u003cem\u003eCurvularia\u003c/em\u003e isolates were inhibited by \u0026le;\u0026thinsp;4 \u0026micro;g/mL of natamycin, demonstrating excellent in vitro activity, and 78% of patients achieved a visual acuity of 20/40 or better [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recent meta-analyses comparing topical natamycin with voriconazole have shown similar visual acuity outcomes at 2\u0026ndash;3 months, although natamycin is associated with a lower risk of corneal perforation and therapeutic penetrating keratoplasty [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur in vitro susceptibility testing showed that both isolates were sensitive to natamycin at 2 \u0026micro;g/mL, consistent with previous reports. However, there was notable variability in sensitivity to other antifungal agents between the two isolates, with Patient 2\u0026rsquo;s isolate demonstrating greater sensitivity to amphotericin B and azole antifungals than Patient 1\u0026rsquo;s isolate. This variability highlights the potential value of susceptibility testing in guiding therapy, particularly in cases that do not respond to initial treatment. In our approach, Patient 1 was treated with a combination of natamycin and voriconazole, while Patient 2 was successfully managed with natamycin alone. Both patients achieved complete healing and excellent visual outcomes, supporting the effectiveness of both strategies. Recent studies have reported synergistic effects between natamycin and voriconazole against \u003cem\u003eCurvularia\u003c/em\u003e species in 23.1% of tested isolates [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], suggesting that combination therapy may be beneficial in selected cases.\u003c/p\u003e\u003cp\u003eIn conclusion, \u003cem\u003eC. geniculata\u003c/em\u003e keratitis, though rare, can be effectively managed with appropriate antifungal therapy. Molecular identification is crucial for accurate diagnosis and species-level differentiation within the \u003cem\u003eCurvularia\u003c/em\u003e genus. Both natamycin monotherapy and combination therapy with natamycin and voriconazole appear to be effective treatment options, with the choice potentially guided by clinical severity and antifungal susceptibility testing results.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients for the publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003eConsent for treatment\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients before the procedures described in this case report.\u003c/p\u003e\n\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eThis study was an observational study. The Institutional Review Board of Hiroshima University issued approval E2016-0709.\u003c/p\u003e\n\u003cp\u003eAcknowledgment\u003c/p\u003e\n\u003cp\u003eWe thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoffman JJ, Arunga S, Mohamed Ahmed AHA, Hu VH, Burton MJ. Management of Filamentous Fungal Keratitis: A Pragmatic Approach. J Fungi (Basel). 2022;8(10). doi:10.3390/jof8101067\u003c/li\u003e\n\u003cli\u003eRai M, Ingle AP, Ingle P, Gupta I, Mobin M, Bonifaz A, et al. Recent advances on mycotic keratitis caused by dematiaceous hyphomycetes. J Appl Microbiol. 2021;131(4):1652\u0026ndash;67. doi:10.1111/jam.15008\u003c/li\u003e\n\u003cli\u003eGeorg LK. Curvularia geniculata, A Cause of Mycotic Keratits. J Med Assoc State Ala. 1964;33:234\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eNityananda K, Sivasubramaniam P, Ajello L. A Case of Mycotic Keratitis Caused by Curvularia geniculata. Archives of ophthalmology (Chicago, Ill. : 1960). 1964;71:456\u0026ndash;8. doi:10.1001/archopht.1964.00970010472003\u003c/li\u003e\n\u003cli\u003eWilhelmus KR, Jones DB. Curvularia keratitis. Trans Am Ophthalmol Soc. 2001;99:111\u0026ndash;30; discussion 30\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003eKhurana A, Chanda S, Bhagat P, Aggarwal S, Sharma M, Chauhan L. Clinical characteristics, predisposing factors, and treatment outcome of Curvularia keratitis. Indian J Ophthalmol. 2020;68(10):2088\u0026ndash;93. doi:10.4103/ijo.IJO_90_20\u003c/li\u003e\n\u003cli\u003eKiss N, Homa M, Manikandan P, Mythili A, Krizsan K, Revathi R, et al. New Species of the Genus Curvularia: C. tamilnaduensis and C. coimbatorensis from Fungal Keratitis Cases in South India. Pathogens. 2019;9(1). doi:10.3390/pathogens9010009\u003c/li\u003e\n\u003cli\u003eIturrieta-Gonzalez I, Gene J, Wiederhold N, Garcia D. Three new Curvularia species from clinical and environmental sources. MycoKeys. 2020;68:1\u0026ndash;21. doi:10.3897/mycokeys.68.51667\u003c/li\u003e\n\u003cli\u003eFerdinandez HS, Manamgoda DS, Udayanga D, Deshappriya N, Munasinghe MS, Castlebury LA. Molecular phylogeny and morphology reveal three novel species of Curvularia (Pleosporales, Pleosporaceae) associated with cereal crops and weedy grass hosts. Mycological Progress. 2021;20(4):431\u0026ndash;51. doi:10.1007/s11557-021-01681-0\u003c/li\u003e\n\u003cli\u003eMadrid H, da Cunha KC, Gene J, Dijksterhuis J, Cano J, Sutton DA, et al. Novel Curvularia species from clinical specimens. Persoonia. 2014;33:48\u0026ndash;60. doi:10.3767/003158514X683538\u003c/li\u003e\n\u003cli\u003eQiu S, Zhao GQ, Lin J, Wang X, Hu LT, Du ZD, et al. Natamycin in the treatment of fungal keratitis: a systematic review and Meta-analysis. Int J Ophthalmol. 2015;8(3):597\u0026ndash;602. doi:10.3980/j.issn.2222-3959.2015.03.29\u003c/li\u003e\n\u003cli\u003eMascarenhas M, Chaudhari P, Lewis SA. Natamycin Ocular Delivery: Challenges and Advancements in Ocular Therapeutics. Adv Ther. 2023;40(8):3332\u0026ndash;59. doi:10.1007/s12325-023-02541-x\u003c/li\u003e\n\u003cli\u003eFlorCruz NV, Evans JR. Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015;2015(4):CD004241. doi:10.1002/14651858.CD004241.pub4\u003c/li\u003e\n\u003cli\u003eSradhanjali S, Yein B, Sharma S, Das S. In vitro synergy of natamycin and voriconazole against clinical isolates of Fusarium, Candida, Aspergillus and Curvularia spp. Br J Ophthalmol. 2018;102(1):142\u0026ndash;5. doi:10.1136/bjophthalmol-2017-310683\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"mycopathologia","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"myco","sideBox":"Learn more about [Mycopathologia](https://www.springer.com/journal/11046)","snPcode":"11046","submissionUrl":"https://submission.nature.com/new-submission/11046/3","title":"Mycopathologia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Curvularia geniculata, Fungal keratitis, Natamycin, Voriconazole","lastPublishedDoi":"10.21203/rs.3.rs-7048594/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7048594/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis report describes two cases of \u003cem\u003eCurvularia geniculata\u003c/em\u003e keratitis, a rare form of fungal keratitis successfully managed with natamycin-based therapy. Both patients presented with characteristic feathery corneal infiltrates following ocular trauma. In vivo confocal microscopy and direct microscopy revealed septate filamentous fungi, and the isolates were definitively identified as \u003cem\u003eC. geniculata\u003c/em\u003e through sequence analysis of the translation elongation factor 1-alpha (\u003cem\u003etef1-α\u003c/em\u003e) gene. Antifungal susceptibility testing showed sensitivity to natamycin at 2 \u0026micro;g/mL for both isolates, with variable sensitivity to other antifungal agents. Patient 1 was treated with a combination of topical natamycin and voriconazole, while Patient 2 received natamycin monotherapy. Both patients achieved complete healing and excellent visual outcomes. These cases underscore the importance of accurate molecular identification for species differentiation within the \u003cem\u003eCurvularia\u003c/em\u003e genus and demonstrate the efficacy of natamycin-based therapy for \u003cem\u003eC. geniculata\u003c/em\u003e keratitis. The choice between monotherapy and combination therapy may be guided by clinical severity and antifungal susceptibility testing. This report contributes to the understanding of the clinical features, diagnosis, and management of this rare condition and highlights the potential value of susceptibility testing in guiding treatment decisions.\u003c/p\u003e","manuscriptTitle":"Two Cases of Curvularia geniculata Keratitis Successfully Treated with Natamycin-Based Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 12:51:10","doi":"10.21203/rs.3.rs-7048594/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revisions","date":"2025-08-12T02:03:58+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-07-12T02:45:36+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-11T15:31:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Mycopathologia","date":"2025-07-10T13:12:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-05T12:58:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Mycopathologia","date":"2025-07-04T12:46:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"mycopathologia","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"myco","sideBox":"Learn more about [Mycopathologia](https://www.springer.com/journal/11046)","snPcode":"11046","submissionUrl":"https://submission.nature.com/new-submission/11046/3","title":"Mycopathologia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bd63971c-dcfd-4d43-a138-a2668078a788","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T06:51:01+00:00","versionOfRecord":{"articleIdentity":"rs-7048594","link":"https://doi.org/10.1007/s11046-025-00997-9","journal":{"identity":"mycopathologia","isVorOnly":false,"title":"Mycopathologia"},"publishedOn":"2025-09-13 15:56:54","publishedOnDateReadable":"September 13th, 2025"},"versionCreatedAt":"2025-07-15 12:51:10","video":"","vorDoi":"10.1007/s11046-025-00997-9","vorDoiUrl":"https://doi.org/10.1007/s11046-025-00997-9","workflowStages":[]},"version":"v1","identity":"rs-7048594","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7048594","identity":"rs-7048594","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}