Skip to main content
NCBI home page
International Journal of Ophthalmology logoLink to International Journal of Ophthalmology
. 2016 Nov 18;9(11):1676–1683. doi: 10.18240/ijo.2016.11.23

Review of clinical and basic approaches of fungal keratitis

Jie Wu 1, Wen-Song Zhang 2, Jing Zhao 1, Hong-Yan Zhou 1
PMCID: PMC5145100  PMID: 27990375

Abstract

Fungal keratitis (FK) is a serious disease which can cause blindness. This review has current information about the pathogenesis, limitations of traditional diagnosis and therapeutic strategies, immune recognition and the diagnosis and therapy of FK. The information of this summary was reviewed regularly and updated as what we need in the diagnosis and therapy of FK nowadays.

Keywords: fungal keratitis, pathogenesis, diagnosis, treatment

INTRODUCTION

Fungal keratitis (FK) is well known as a severe infected ocular disease that causes cornea opacity and blindness, and even loss of the eyeball[1]–[6]. In China, the primary cause is vegetable corneal trauma after agricultural work and the most common pathogens are Fusarium solani and Aspergillus fumigatus[1],[3],[6]. Although new therapies have been excogitated in clinical, FK remains a challenge to ophthalmologists because of the delay of diagnosis and shortness of standard guidelines of treatments. At the same time, the pathogenesis of FK has still not been clarified. Therefore, a better understanding of the pathogenesis of FK is imperative for diagnosis and effective therapy.

PATHOGENESIS OF FUNGAL KERATITIS

Detail pathogenesis of FK has not been clarified. Recent studies and advances have broadened the approach to FK. Previous studies[6]–[8] have revealed that immune system plays an essential role in the pathogenesis of FK. The corneal epithelium, the frontier of cornea against pathogen infection, plays an important role in innate immunity[2]–[3]. When the integrity of ocular surface has been breached due to damage or trauma, it will be more vulnerable to be infected by fungi and other microbes resulting to FK. Innate immunity is the first line of defense in the immunity defenses. The dynamic balance between the host defenses and the virulence of invasive fungus is critical in the development of FK. It can specifically identify the pathogen-associated molecular patterns (PAMPs) on the surface of fungus through pattern recognition receptors (PRRs), including C-type lectin-like receptors (CLRs), toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (leucine-rich repeat-containing receptors, NLRs), scavenger receptor (SR) family[2]–[15]. PRRs play a critical role in innate immunity, which can mediate the secretion of cytokines and chemokines and the infiltration of neutrophils, macrophages, T cells, and ultimately fungal clearance.

LIMATATIONS OF TRADITIONAL DIAGNOSIS AND THERAPEUTIC STRATEGIES

The diagnosis of FK remains challenging and elusive[16]. Culture and microscopic examination are still the reference standard for pathogens diagnosis[17]–[18]. However, they are time-consuming and may delay the treatment[18]. Currently, the rapid and reliable diagnosis of FK has attarcted more and more attention, which including confocal microscopy, anterior segment optical coherence tomography (OCT), polymerase chain reaction (PCR). They are effective but expensive and not readily used in all facilities. If the diagnosis can be made in a short time, it will result in better outcome. Therefore, it is imperative to develop the quick, sensitive, non-invasive and more convenient ways for effective diagnosis[16]–[21].

In developing countries, because of the lack of effective antifungal agents, the treatment of FK is still a challenge[16],[22]–[24]. Two main typical classes of antifungal agents are azoles (voriconazole, fluconazole, ketoconazole, posaconazole, itraconazole) and polyenes (natamycin, amphotericin B)[16],[25]. Topical natamycin (5%) is considered to be the first-line therapy for superficial infection among antifungal agents and is the only available antifungal eye drop[24],[26]–[27]. Natamycin is preferable choice in treatment against Fusarium and Aspegillus, especially in the early period[16],[28]. Currently, other effective medical therapy has attracted attention, include antimicrobial peptides (AMPs)[23], terbinafine[27], micafungin (MCFG)[29], caspofungin[24], immunosuppressant like tacrolimus (FK506)[30] and vitamine D receptor agonist (VDRA)[31]. Corneal collagen cross-linking (CXL) has been suggested to be a promising alternative option in treatment of infectious keratitis[25],[32]–[36]. Surgical intervention is needed for those refractory to medical means to control severe and deep ulcer, like debridment, penetrating keratoplasty (PK), amniotic membrane transplantation (AMT), lamellar keratoplasty (LK), deep anterior lamellar keratoplasty (DALK)[16],[26]. However, more randomized controlled trails should be needed to assess their efficacy.

IMMUNE RECOGNITION

Pattern Recognition Receptors

The corneal epithelium is the fist line[3]. The adhesion of pathogens to epithelial or endothelial cells is the first step with surface open to accessible pathegens. This may be associated with the binding between pathogen ligands and host receptors[37]–[38]. After being invaded, PRRs of the host indentifies specifically PAMPs on fungal surface and triggers innate immunity[3]–[5],[8]–[13],[39]–[40]. PRRs include TLR, CLRs, NLRs, and SR family[3],[8],[40]. TLRs, expressed on immune cells, like neutrophils, monocytes, macrophages, dendritic cells, are the main PRRs, especially TLR2 and TLR4[12]–[13],[41]–[43]. The interaction between PRRs and PAMPs plays an important role in innate immune response[5],[11]. Dectin-1, one of the CLRs, can recognize fungal β-glucans and α-mannose[3],[41],[44]. Dectin-1 is expressed in macrophages, dendritic cells, neutrophils, and corneal eptithelial cells[3],[12]. The recognition activates NF-κB by Syk-CARD9 and RAF pathways[3],[41]. Dectin-1 can also increase the production of IL1-β and IL-18 through NLRP3 inflammasome pathway[41]. Syk pathway is the most important signaling ways of Dectin-1[40]. A study showed that in early period of fungal defenses, Dectin-1 and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) are important[5]. Dectin-1 takes part in anti-fungal activities through recognizing fungi, recruiting neutrophils and macrophages, releasing pro-inflammatory cytokines and starting an adaptive immune response[4],[8],[41]. Therefore, Dectin-1 plays an essential role in pathogenesis of FK. Surfactant protein D (SP-D), a member of CLRs, plays an important role in early innate immunity of Fusarium solani infection[7],[45]. SP-D activates through TLR4-MyD88 signaling pathway. And through the interaction with TLRs, SP-D regulates immune function by down regulating the expression of cytokines[7],[45]. Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), belonging to SR family and also structurally CLRs, expresses in normal corneal epithelium, macrophages, neutrophils, etc. The special structure enables LOX-1 to have many diverse activities, recognizing substances widely. LOX-1 plays a pro-inflammatory role in host defense during FK. However, further study is needed for more detail roles of LOX-1 in FK[10]. NOD2, a kind of NLRs, takes part in the innate immunity by increasing the proinflammatory cytokines[7],[46]. A recent study proposed that NOD2 triggers the inflammatory responses in aspergillums fumigates keratitis through the interaction with TLRs. There are a negative regulation described in the study, “tolerance” between diverse PRR families, avoiding excessive inflammatory responses[9]. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a surface receptor and amplifies the inflammation induced by Aspergillums Fumigatus. TREM-1 has been classified that functioned synergistically with TLRs and NLRs[6],[39],[47].

Cytokines, Chemokines and Cellular Immunity

Macrophages play a critical role in innate immunity against fungal infections. It serves as antigen presenting cells as well as phagocytes. The activation of macrophages can promote the production of inflammation cytokines and chemokines, increase polymorphonuclear (PMN) infiltration, however, also can cause an excessive immune response and lead to more severe corneal infection[1],[6],[41]. Neutrophils are important and active in innate immunity. Once being infected, neutrophils are the earliest infiltrating the cornea against fungi. Macrophage inflammatory protein-2 (MIP-2), intercellular cell adhesion molecule-1 (ICAM-1) and some cytokines can attract neutrophils to the inflammatory site in the cornea[1],[48]–[49]. A study also showed that γδ T cells may play a role in recruitment and activation of neutrophils[48]. γδ T cells are essential in innate immunity, they also take part in FK by secreting cytokines and chemokines. γδ T cells also involve in the repair in trauma by secretion of chemokines like CC chemotactic factor-3, 4, 5 (CCL-3, 4, 5)[48]. interleukin-1β, 6, 8 (IL-1β, 6, 8) are found in tears of patients with FK, suggesting that inflammatory cytokines are involved in FK[14],[49]. IL-6, IL-8 and MCP-1 play a significant role in inflammatory response against fungal infection[49]. IL-1β and TNF-α increase in the early period of Aspergillus and Fusarium keratitis[50]. Increase of IL-17 has been detected in tears of filamentous fungi infection.IL-17, produced by neutrophils, plays a critical role in the severity of autoimmune and inflammatory infection, resulting in protection against fungal infection. Activation of IL-17 receptors on epithelial cells increases the production of cytokines which mediate recruitment of neutrophils to infected site[44],[51]–[54]. Antifungal anctivity depends on CD18, not Dectin-1[55]. Matrix metalloproteinases-14 (MMP14) is upregulated in the early process of trauma forming. MMPs can mediate cellular adhesion and play an essential role in fungal infection [56]. IL-10 is considered to be a negative regulator of imflammation, inhibiting proinflammation cytokines. COX-2 also can regulate immunity. Th cells are essential in immune response. Th1 cells can improve the anti-fungal ability, however, Th2 cells stand in the opposite side. The balance between them may effect the outcome of the disease[57].

Humoral Immunity

HCEC-derived thymic stromal lymphopoietin production (TSLP) can promote humoral immunity and take part in adaptive immune response of FK[58].Vasoactive intestinal peptide (VIP), anti-inflammation neuropeptide, can decrease pro-inflammation cytokines, limit cellular immunity, inhibit the proliferation of macrophages and T cells, and contribute to healing in Pseudomonas aeruginosa keratitis[59]–[60]. Antimicrobial peptides (AMPs) are essential parts if innate and adaptive immunity and are considered to have wide multifunction. AMPs are chemotatic for some immune cells. AMPs provide protective effect in FK[61].

NEW TARGETS

Chitinase 3-like 1 (CHI3L1) is a multifunctional protein that plays a regulatory role in corneal innate immunity through mediating the production of chemokines AMPs, and anti-inflammatory factors. It has been implicated as a regulator of adaptive Th2 responses[62]. The role of miRNA in FK has not been classified. A recent study demonstrated that miRNAs play a regulatory role in trauma inflammation of cornea[63] (Figure 1).

Figure 1. The mechanism of FK.

Figure 1

Open in a new tab

THE PROGRESSIONS OF DIAGNOSIS OF FUNGAL KERATITIS

Conventional microbiological methods remain to be the “gold standard” for the diagnosis of FK. Culture results are highly specific but insensitive and time-consuming. And expertise is required to identify the fungal specis isolates precisely[17]–[18],[21]. Smear microscopy is a rapid and direct method. A recent study shows that the positive detection rate of smear is higher than that of culture[17]. In vivo confocal microscopy (IVCM) is a rapid method to diagnose FK and is non-invasive safe technique, becoming a kind of routine[19]–[20]. In addition, it has unique advantages that can monitor therapeutic response[19]–[20],[64]. Currently, IVCM is the only means allowing to detect the depth of infection, helping determine the time for appropriate surgical treatment. However, smaller microbes, like bacteria and virus, are invisible. So IVCM is useless in these cases. Moreover, experienced technicians are necessary to accurate results[64]. Conflict views about IVCM have been proposed. One study did not suggest stand-alone use of IVCM while using a positive part as the reference. On the contrary, another study held that it provided precise evidence with the conventional microbiology as the gold standard, especially in deep corneal infiltrate[21]. PCR is a rapid and sensitive diagnostic method, which has been widely used in the diagnosis of infectious keratitis[17],[21]. There is a disadvantage of PCR that the rate of false positive error is high because of the commensal comtaminants. Quantitation of microbes using quantitative PCR, and multiplexing of primer sets have been allowed in recent advances[65]. However, template deoxyribonucleic acid (DNA) extraction is needed. The process of DNA extraction is limited by the specimens. A direct PCR without template DNA extraction which used a special polymerase was developed to detect microbes[17]. A study used a improved DNA extraction method and fungal pathogens could be detected specifically within 8h[66].

TREATMENT OF FUNGAL KERATITIS

Medical Treatment

So far, only the polyenes and azoles have been used commonly in the treatment of FK[24]. Biofilms of microorganisms are critical for resistant to antimicrobials[67]. Appropriate antifungal agents for FK are urgently needed.

Natamycin, with a broad spectrum and stong anti-fungi activity, is safe and effective at a very low concentration[68]. Currently, natamycin is considered to be the most effective topical medical agent against Fusarium and Aspergillus[16],[27]–[28]. However, it has poor coverage against Candida species. Futhermore, natamycin can only be used topically resulting to limitation of deep stroma invasion[16]. It has been showed that voriconazole has a broad therapeutic window that covers not only filamentous fungi but also Candida. Therefore, it has been proposed as an alternative to natamycin. In cases refractory to topical natamycin, voriconazole was used as an adjunct to natamycin and showed good ocular penetration[16],[27],[69]–[70]. A study has shown that voriconazole was less effective in cases with infiltrates and hypopyon[71]. Natamycin is more effective than voriconazole in treatment of FK, especially Fusarium keratitis[72]–[75]. Natamycin has been proposed that it resulted in better visual acuity than outcome of voriconazole[76]. The susceptibility to natamycin was concerned with the size of ulcer and infiltrating. While there susceptibility to voriconazole was not associated with the outcome[77].

Amphotericin B is a drug choice for Aspergillus and Candida, while poor activity against Fusarium species[16],[78]. The side effect of amphotericin B is that it is toxic to human cells at a higher dose. Therefore, it is not a first line drug in treatment of FK while other better agents are at hands[16]. Instrastromal injection of amphotericin B may be an adjunct for deep severe FK[79]. Intracameral amphotericin (ICAMB) can be a safe agent in FK refractory to local conventional therapy to better outcome. But ICAMB is not benefit when given alone[80]–[81]. A study proposed that combining intravitreal amphorericin B and voriconzole could be a new choice in endophthalmitis caused by filamentous FK[82].

Fluconazole is known because of its low side effect and good intraocular penetration[16]. The 0.2% fluconazole is effective in FK combined with 5% natamycin[83]. Subconjunctival injection of fluconazole has been found efficacious in patients unresponsive to conventional antifungal medical treatment of Candida and alternaria keratitis[16],[84]. However, fluconazole has narrow coverage of filamentous fungi[16]. Oral ketoconazole combined with topical miconazole was effective in FK, but it did not add benefit to topical natamycin in deep FK[16],[85]. A study said that posaconazole might be effective in Paecilomyces and Fusarium keratitis refractory to conventional treatment[86]–[87].

The way of injection is essential to efficiency of drugs. Intracameral and intrastromal antifungal medication have been proved to be effective[88]–[89]. Intrastromal injection should be used to the severe and recalcitrant keratitis[90].

It has been proposed that liposomal formulation of voriconazole and itraconazole has better anti-fungal activity and is effective in treatment of FK[91]–[92]. Voriconazole aqueous drops have higher penetration and can be used topically in FK[93].

Terbinafine is a efficient anti-fungal agent used in fungal skin diseases. It also inhibits the growth of fungi in cornea. It has been proved that topical terbinafine was effective in filamentous keratomycosis[25]. Tacrolimus (FK506), a novel immunosuppressant, can inhibit the inflammation caused by fungi[30]. Caspofungin eye drops seem to be a possible alternative for treatment of FK. But it still needs more randomized controlled trails[24]. Topical micafungin, inhibiting β-[(]1[,]3)-glucan synthesis, appear to be effective for FK[29].

Corneal Collagen Cross Linking

CXL has been recently used as a promising and worthwhile treatment in refractory infectious keratitis, defined as PACK-CXL: photo activated chromophroe for keratitis[27],[32]–[33],[36],[94]. PACK-CXL can be a available adjuvant method in the management of FK unsensitive to medical treatment[35],[95]–[97]. CXL is a quick, efficient and less expensive means to eliminate pathogens which is non-pathogen-specific[34]. In deep stroma FK cases, CXL did not improve outcome and resulted in an increased risk of perforation[98]–[99]. Prospective studies are needed for further study of the anti-fungal function of PACK-CXL[100].

Therapeutic Surgical Intervention

Penetrating keratoplasty (PK) is the most commom therapeutic surgery[16]. It has been suggested that early suigical management of PK was required[101]. PK is an effective method in corneal infectious and non-infectious diseases resisitant to other treatment[102]. It is critical to remove the infected tissue through surgery to vision[103]. Lamellar keratoplasty (LK) and deep anterior lamellar keratoplasty (DALK) are selected for focal invasion or infection that did not invasive into deep layers of cornea[16]. A study demonstrated that DALK using the big bubble technique appear to be effective in FK resistant to medical treatment[104]. Acellular porcine corneal stromas (APCSs) grafts are safe and effective during LK in FK[105]. Higher rate of graft rejection, infection recurrence, secondary glaucoma in therapeutic corneal transplantation, but it remains to be an effective method for refractory FK[16],[106]. Amniotic membrane transplantation (AMT) is considered as an expedient to prevent PK secondary infection[16].

New Methods

A study used a novel combination of cryotherapy and anti-fungal agents to treat ulcer of FK and found that cryotherapy was effective in treating ulcer. Rose Bengal-mediated photodynamic therapy (PDT) can inhibit the growth of fungi. It may contribute to useful treatment for infectious keratitis[107]. With the role of VDR in innate immunity being discovered gradually, a new target of treatment can be explored for FK[31]. All-trans retinoic acids (ATRA) is proved to have anti-inflammatory and immunoregulatory effects[50]. However, it is difficult to put the new targets into use clinically. We still need to do more clinical trials.

CONCLUSION AND FUTURE PERSPECTIVE

Recent studies have revealed deeper understanding of the pathogenesis of FK. Current method of diagnosis and drugs are not effective enough, newer, more effective and promising means are urgent for better outcome. For instance, the immunotherapeutic modalities has attracted more and more attention. At the same time, clinical trials are needed to find new strategies that contribute to more effective control of the infection.

Acknowledgments

Foundations: Supported by the Natural Science Foundation of China (No.81300727); Research Fund of Jilin Provincial Science and Technology Department ( No. 20160101011JC)

Conflicts of Interest: Jie W, None; Zhang WS, None; Zhao J, None; Zhou HY, None.

REFERENCE

  • 1.Hu J, Hu Y, Chen S, Dong C, Zhang J, Li Y, Yang J, Han X, Zhu X, Xu G. Role of activated macrophages in experimental Fusarium solani keratitis. Exp Eye Res. 2014;129:57–65. doi: 10.1016/j.exer.2014.10.014. [DOI] [PubMed] [Google Scholar]
  • 2.Karthikeyan RS, Leal SM, Jr, Prajna NV, Dharmalingam K, Geiser DM, Pearlman E, Lalitha P. Expression of innate and adaptive immune mediators in human corneal tissue infected with Aspergillus or fusarium. J Infect Dis. 2011;204(6):942–950. doi: 10.1093/infdis/jir426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Zhu CC, Zhao GQ, Lin J, Hu LT, Xu Q, Peng XD, Wang X, Qiu S. Dectin-1 agonist curdlan modulates innate immunity to Aspergillus fumigatus in human corneal epithelial cells. Int J Ophthalmol. 2015;8(4):690–696. doi: 10.3980/j.issn.2222-3959.2015.04.09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Xu Q, Zhao G, Lin J, Wang Q, Hu L, Jiang Z. Role of Dectin-1 in the innate immune response of rat corneal epithelial cells to Aspergillus fumigatus. BMC Ophthalmol. 2015;15:126. doi: 10.1186/s12886-015-0112-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Qu X, Che C, Gao A, Lin J, Wang N, Du X, Liu Y, Guo Y, Chen W, Zhao G. Association of Dectin-1 and DC-SIGN gene single nucleotide polymorphisms with fungal keratitis in the northern Han Chinese population. Mol Vis. 2015;21:391–402. [PMC free article] [PubMed] [Google Scholar]
  • 6.Huang W, Ling S, Jia X, Lin B, Huang X, Zhong J, Li W, Lin X, Sun Y, Yuan J. Tacrolimus (FK506) suppresses TREM-1 expression at an early but not at a late stage in a murine model of fungalkeratitis. PLoS One. 2014;9(12):e114386. doi: 10.1371/journal.pone.0114386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Wu J, Zhang Y, Xin Z, Wu X. The crosstalk between TLR2 and NOD2 in Aspergillus fumigatus keratitis. Mol Immunol. 2015;64(2):235–243. doi: 10.1016/j.molimm.2014.11.021. [DOI] [PubMed] [Google Scholar]
  • 8.Jiang N, Zhao G, Lin J, Hu L, Che C, Li C, Wang Q, Xu Q, Peng X. Indoleamine 2,3-dioxygenase is involved in the inflammation response of corneal epithelial cells to aspergillus fumigatus infections. PLoS One. 2015;10(9):e0137423. doi: 10.1371/journal.pone.0137423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Wu X, Zhao G, Lin J, Jiang N, Li C, Hu L, Peng X, Xu Q, Wang Q, Li H, Zhang Y. The production mechanism and immunosuppression effect of pulmonary surfactant protein D via toll like receptor 4 signaling pathway in human corneal epithelial cells during Aspergillus fumigatus infection. Int Immunopharmacol. 2015;29(2):433–439. doi: 10.1016/j.intimp.2015.10.018. [DOI] [PubMed] [Google Scholar]
  • 10.Li C, Zhao G, Che C, Lin J, Li N, Hu L, Jiang N, Liu Y. The role of LOX-1 in innate immunity to aspergillus fumigatus in corneal epithelial cells. Invest Ophthalmol Vis Sci. 2015;56(6):3593–3603. doi: 10.1167/iovs.14-15989. [DOI] [PubMed] [Google Scholar]
  • 11.Pandey RK, Yu FS, Kumar A. Targeting toll-like receptor signaling as a novel approach to prevent ocular infectious diseases. Indian J Med Res. 2013;138(5):609–619. [PMC free article] [PubMed] [Google Scholar]
  • 12.Che CY, Li C, Gao A, Lin J, Zhang LL, Xu Q, Wang Q, Zhao GQ. Dectin-1 expression at early period of Aspergillus fumigatus infection in rat's corneal epithelium. Int J Ophthalmol. 2013;6(1):30–33. doi: 10.3980/j.issn.2222-3959.2013.01.06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Gornik K, Moore P, Figueiredo M, Vandenplas M. Expression of Toll-like receptors 2, 3, 4, 6, 9, and MD-2 in the normal equine cornea, limbus, and conjunctiva. Vet Ophthalmol. 2011;14(2):80–85. doi: 10.1111/j.1463-5224.2010.00844.x. [DOI] [PubMed] [Google Scholar]
  • 14.Santacruz C, Linares M, Garfias Y, Loustaunau LM, Pavon L, Perez-Tapia SM, Jimenez-Martinez MC. Expression of IL-8, IL-6 and IL-1β in tears as a main characteristic of the immune response in human microbial keratitis. Int J Mol Sci. 2015;16(3):4850–4864. doi: 10.3390/ijms16034850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Leal SM, Jr, Pearlman E. The role of cytokines and pathogen recognition molecules in fungal keratitis-insights from human disease and animal models. Cytokine. 2012;58(1):107–111. doi: 10.1016/j.cyto.2011.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ansari Z, Miller D, Galor A. Current thoughts in fungal keratitis: diagnosis and treatment. Curr Fungal Infect Rep. 2013;7(3):209–218. doi: 10.1007/s12281-013-0150-110.1007/s12281-013-0150-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Zhao G, Zhai H, Yuan Q, Sun S, Liu T, Xie L. Rapid and sensitive diagnosis of fungal keratitis with direct PCR without template DNA extraction. Clin Microbiol Infect. 2014;20(10):O776–O782. doi: 10.1111/1469-0691.12571. [DOI] [PubMed] [Google Scholar]
  • 18.Lan L, Wang FY, Zeng G. Staining with methylthioninium chloride for the diagnosis of fungal keratitis. Exp Ther Med. 2013;6(5):1229–1232. doi: 10.3892/etm.2013.1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ledbetter EC, Norman ML, Starr JK. In vivo confocal microscopy for the detection of canine fungal keratitis and monitoring of therapeutic response. Vet Ophthalmol. 2015;19(3):220–229. doi: 10.1111/vop.12287. [DOI] [PubMed] [Google Scholar]
  • 20.van Diepeningen AD, Brankovics B, Iltes J, van der Lee TA, Waalwijk C. Diagnosis of fusarium infections: approaches to identification by the clinical mycology laboratory. Curr Fungal Infect Rep. 2015;9(3):135–143. doi: 10.1007/s12281-015-0225-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Thomas PA, Kaliamurthy J. Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect. 2013;19(3):210–220. doi: 10.1111/1469-0691.12126. [DOI] [PubMed] [Google Scholar]
  • 22.Diongue K, Sow AS, Nguer M, Seck MC, Ndiaye M, Badiane AS, Ndiaye JM, Ndoye NW, Diallo MA, Diop A, Ndiaye YD, Dieye B, Déme A, Ndiaye IM, Ndir O, Ndiaye D. Keratomycosis due to Fusarium oxysporum treated with the combination povidone iodine eye drops and oral fluconazole. J Mycol Med. 2015;25(4):e134–137. doi: 10.1016/j.mycmed.2015.10.006. [DOI] [PubMed] [Google Scholar]
  • 23.Wu H, Ong ZY, Liu S, Li Y, Wiradharma N, Yang YY, Ying JY. Synthetic β-sheet forming peptide amphiphiles for treatment of fungal keratitis. Biomaterials. 2015;43:44–49. doi: 10.1016/j.biomaterials.2014.11.052. [DOI] [PubMed] [Google Scholar]
  • 24.Neoh CF, Daniell M, Chen SC, Stewart K, Kong DC. Clinical utility of caspofungin eye drops in fungal keratitis. Int J Antimicrob Agents. 2014;44(2):96–104. doi: 10.1016/j.ijantimicag.2014.04.008. [DOI] [PubMed] [Google Scholar]
  • 25.Bourguet A, Guyonnet A, Donzel E, Guillot J, Pignon C, Chahory S. Keratomycosis in a pet rabbit (Oryctolagus cuniculus) treated with topical 1% terbinafine ointment. Vet Ophthalmol. 2015 doi: 10.1111/vop.12318. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 26.Rajaraman R. topical 5% natamycin with oral ketoconazole in filamentous fungal keratitis: a randomized controlled trial. Asia Pac J Ophthalmol (Phila) 2015;4(6):399. doi: 10.1097/APO.0000000000000161. [DOI] [PubMed] [Google Scholar]
  • 27.Solanki S, Rathi M, Khanduja S, Dhull CS, Sachdeva S, Phogat J. Recent trends: medical management of infectious keratitis. Oman J Ophthalmol. 2015;8(2):83–85. doi: 10.4103/0974-620X.159104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Qiu S, Zhao GQ, Lin J, Wang X, Hu LT, Du ZD, Wang Q, Zhu CC. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kamoshita M, Matsumoto Y, Nishimura K, Katono Y, Murata M, Ozawa Y, Shimmura S, Tsubota K. Wickerhamomyces anomalus fungal keratitis responds to topical treatment with antifungal micafungin. J Infect Chemother. 2015;21(2):141–143. doi: 10.1016/j.jiac.2014.08.019. [DOI] [PubMed] [Google Scholar]
  • 30.Zhong J, Huang W, Deng Q, Wu M, Jiang H, Lin X, Sun Y, Huang X, Yuan J. Inhibition of TREM-1 and Dectin-1 alleviates the severity of fungal keratitis by modulating innate immune responses. PLoS One. 2016;11(3):e0150114. doi: 10.1371/journal.pone.0150114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Cong L, Xia YP, Zhao GQ, Lin J, Xu Q, Hu LT, Qu JQ, Peng XD. Expression of vitamin D receptor and cathelicidin in human corneal epithelium cells during fusarium solani infection. Int J Ophthalmol. 2015;8(5):866–871. doi: 10.3980/j.issn.2222-3959.2015.05.03. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Tayapad JB, Viguilla AQ, Reyes JM. Collagen cross-linking and corneal infections. Curr Opin Ophthalmol. 2013;24(4):288–290. doi: 10.1097/ICU.0b013e32836229c5. [DOI] [PubMed] [Google Scholar]
  • 33.Papaioannou L, Miligkos M, Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea. 2016;35(1):62–71. doi: 10.1097/ICO.0000000000000644. [DOI] [PubMed] [Google Scholar]
  • 34.Hafezi F, Randleman JB. PACK-CXL: defining CXL for infectious keratitis. J Refract Surg. 2014;30(7):438–439. doi: 10.3928/1081597X-20140609-01. [DOI] [PubMed] [Google Scholar]
  • 35.Li Z, Jhanji V, Tao X, Yu H, Chen W, Mu G. Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol. 2013;97(5):669–671. doi: 10.1136/bjophthalmol-2012-302518. [DOI] [PubMed] [Google Scholar]
  • 36.Bilgihan K, Kalkanci A, Ozdemir HB, Yazar R, Karakurt F, Yuksel E, Otag F, Karabicak N, Arikan-Akdagli S. Evaluation of antifungal efficacy of 0.1% and 0.25% riboflavin with UVA: a comparative in vitro study. Curr Eye Res. 2016;41(8):1050–1056. doi: 10.3109/02713683.2015.1088956. [DOI] [PubMed] [Google Scholar]
  • 37.Zhao G, Li S, Zhao W, He K, Xi H, Li W, Zhou Q, Wang Y. Phage display against corneal epithelial cells produced bioactive peptides that inhibit Aspergillus adhesion to the corneas. PLoS One. 2012;7(3):e33578. doi: 10.1371/journal.pone.0033578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Maharana PK, Sharma N, Nagpal R, Jhanji V, Das S, Vajpayee RB. Recent advances in diagnosis and management of Mycotic Keratitis. Indian J Ophthalmol. 2016;64(5):346–357. doi: 10.4103/0301-4738.185592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Hu LT, Du ZD, Zhao GQ, Jiang N, Lin J, Wang Q, Xu Q, Cong L, Qiu S. Role of TREM-1 in response to Aspergillus fumigatus infection in corneal epithelial cells. Int Immunopharmacol. 2014;23(1):288–293. doi: 10.1016/j.intimp.2014.09.011. [DOI] [PubMed] [Google Scholar]
  • 40.Liu Y, Zhao G, Lin J, Li C, Li Q, Che C, Wang Q, Hu L. The role of Syk signaling in antifungal innate immunity of human corneal epithelial cells. BMC Ophthalmol. 2015;15:55. doi: 10.1186/s12886-015-0041-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Ravikumar S, Win MS, Chai LY. Optimizing outcomes in immunocompromised hosts: understanding the role of immunotherapy in invasive fungal diseases. Front Microbiol. 2015;6:1322. doi: 10.3389/fmicb.2015.01322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Guo H, Gao J, Wu X. Toll-like receptor 2 siRNA suppresses corneal inflammation and attenuates Aspergillus fumigatus keratitis in rats. Immunol Cell Biol. 2012;90(3):352–357. doi: 10.1038/icb.2011.49. [DOI] [PubMed] [Google Scholar]
  • 43.Xiaoyan Zhang, Xinyi Wu, Li Gao. Pretreatment with lipopolysaccharide modulates innate immunity in corneal fibroblasts challenged with Aspergillus fumigatus. Innate Immun. 2011;17(3):237–244. doi: 10.1177/1753425910365364. [DOI] [PubMed] [Google Scholar]
  • 44.Taylor PR, Roy S, Leal SM, Jr, Sun Y, Howell SJ, Cobb BA, Li X, Pearlman E. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2. Nat Immunol. 2014;15(2):143–151. doi: 10.1038/ni.2797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Che CY, Li XJ, Jia WY, Li N, Xu Q, Lin J, Wang Q, Jiang N, Hu LT, Zhao GQ. Early expression of surfactant proteins D in Fusarium solani infected rat cornea. Int J Ophthalmol. 2012;5(3):297–300. doi: 10.3980/j.issn.2222-3959.2012.03.09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Zhang Y, Wu J, Xin Z, Wu X. Aspergillus fumigatus triggers innate immune response via NOD1 signaling in human corneal epithelial cells. Exp Eye Res. 2014;127:170–178. doi: 10.1016/j.exer.2014.07.025. [DOI] [PubMed] [Google Scholar]
  • 47.Hu LT, Du ZD, Zhao GQ, Qiu S, Jiang N, Lin J, Wang Q, Xu Q. TREM-1 expression in rat corneal epithelium with Aspergillus fumigatus infection. Int J Ophthalmol. 2015;8(2):222–227. doi: 10.3980/j.issn.2222-3959.2015.02.02. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.He S, Zhang H, Liu S, Liu H, Chen G, Xie Y, Zhang J, Sun S, Li Z, Wang L. γδ T cells regulate the expression of cytokines but not the manifestation of fungal keratitis. Exp Eye Res. 2015;135:93–101. doi: 10.1016/j.exer.2015.03.022. [DOI] [PubMed] [Google Scholar]
  • 49.Kimura K, Orita T, Nomi N, Fujitsu Y, Nishida T, Sonoda KH. Identification of common secreted factors in human corneal fibroblasts exposed to LPS, poly(I:C), or zymosan. Exp Eye Res. 2012;96(1):157–162. doi: 10.1016/j.exer.2011.10.015. [DOI] [PubMed] [Google Scholar]
  • 50.Zhou HY, Zhong W, Zhang H, Bi MM, Wang S, Zhang WS. Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis. Int J Ophthalmol. 2015;8(4):826–832. doi: 10.3980/j.issn.2222-395.2015.04.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Karthikeyan RS, Vareechon C, Prajna NV, Dharmalingam K, Pearlman E, Lalitha P. Interleukin 17 expression in peripheral blood neutrophils from fungal keratitis patients and healthy cohorts in southern India. J Infect Dis. 2015;211(1):130–134. doi: 10.1093/infdis/jiu381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Taylor PR, Leal SM, Jr, Sun Y, Pearlman E. Aspergillus and Fusarium corneal infections are regulated by Th17 cells and IL-17-producing neutrophils. J Immunol. 2014;192(7):3319–3327. doi: 10.4049/jimmunol.1302235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Zhang H, Li H, Li Y, Zou Y, Dong X, Song W, Jia C, Li S, Xi H, Liu D, Wang Y. IL-17 plays a central role in initiating experimental Candida albicans infection in mouse corneas. Eur J Immunol. 2013;43(10):2671–2682. doi: 10.1002/eji.201242891. [DOI] [PubMed] [Google Scholar]
  • 54.Zou Y, Zhang H, Li H, Chen H, Song W, Wang Y. Strain-dependent production of interleukin-17/interferon-γ and matrix remodeling-associated genes in experimental Candida albicans keratitis. Mol Vis. 2012;18:1215–1225. Epub 2012 May 10. [PMC free article] [PubMed] [Google Scholar]
  • 55.Leal SM, Jr, Vareechon C, Cowden S, Cobb BA, Latgé JP, Momany M, Pearlman E. Fungal antioxidant pathways promote survival against neutrophils during infection. J Clin Invest. 2012;122(7):2482–2498. doi: 10.1172/JCI63239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Chen H, Zheng Z, Chen P, Wu XG, Zhao G. Inhibitory effect of extracellular polysaccharide EPS-II from Pseudoalteromonas on Candida adhesion to cornea in vitro. Biomed Environ Sci. 2012;25(2):210–215. doi: 10.3967/0895-3988.2012.02.013. [DOI] [PubMed] [Google Scholar]
  • 57.Li N, Che CY, Hu LT, Lin J, Wang Q, Zhao GQ. Effects of COX-2 inhibitor NS-398 on IL-10 expression in rat fungal keratitis. Int J Ophthalmol. 2011;4(2):165–169. doi: 10.3980/j.issn.2222-3959.2011.02.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Wang L, Wang L, Wu X. Aspergillus fumigatus promotes T helper type 2 responses through thymic stromal lymphopoietin production by human corneal epithelial cells. Clin Experiment Ophthalmol. 2016;44(6):492–501. doi: 10.1111/ceo.12706. [DOI] [PubMed] [Google Scholar]
  • 59.Jiang X, McClellan SA, Barrett RP, Berger EA, Zhang Y, Hazlett LD. VIP and growth factors in the infected cornea. Invest Ophthalmol Vis Sci. 2011;52(9):6154–6161. doi: 10.1167/iovs.10-6943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Jiang X, McClellan SA, Barrett RP, Zhang Y, Hazlett LD. Vasoactive intestinal peptide downregulates proinflammatory TLRs while upregulating anti-inflammatory TLRs in the infected cornea. J Immunol. 2012;189(1):269–278. doi: 10.4049/jimmunol.1200365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Kolar SS, Baidouri H, Hanlon S, McDermott AM. Protective role of murine β-defensins 3 and 4 and cathelin-related antimicrobial peptide in Fusarium solani keratitis. Infect Immun. 2013;81(8):2669–2677. doi: 10.1128/IAI.00179-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Gao N, Yu FS. Chitinase 3-Like 1 Promotes Candida albicans killing and preserves corneal structure and function by controlling host antifungal responses. Infect Immun. 2015;83(10):4154–4164. doi: 10.1128/IAI.00980-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Boomiraj H, Mohankumar V, Lalitha P, Devarajan B. Human corneal microRNA expression profile in fungal keratitis. Invest Ophthalmol Vis Sci. 2015;56(13):7939–7946. doi: 10.1167/iovs.15-17619. [DOI] [PubMed] [Google Scholar]
  • 64.Villani E, Baudouin C, Efron N, Hamrah P, Kojima T, Patel SV, Pflugfelder SC, Zhivov A, Dogru M. In vivo confocal microscopy of the ocular surface: from bench to bedside. Curr Eye Res. 2014;39(3):213–231. doi: 10.3109/02713683.2013.842592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Taravati P, Lam D, Van Gelder RN. Role of molecular diagnostics in ocular microbiology. Curr Ophthalmol Rep. 2013;1(4) doi: 10.1007/s40135-013-0025-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.He D, Hao J, Gao S, Wan X, Wang W, Shan Q, Wang L. Etiological analysis of fungal keratitis and rapid identification of predominant fungal pathogens. Mycopathologia. 2016;181(1–2):75–82. doi: 10.1007/s11046-015-9950-x. [DOI] [PubMed] [Google Scholar]
  • 67.Mukherjee PK, Chandra J, Yu C, Sun Y, Pearlman E, Ghannoum MA. Characterization of fusarium keratitis outbreak isolates: contribution of biofilms to antimicrobial resistance and pathogenesis. Invest Ophthalmol Vis Sci. 2012;53(8):4450–4457. doi: 10.1167/iovs.12-9848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Aparicio JF, Barreales EG, Payero TD, Vicente CM, de Pedro A, Santos-Aberturas J. Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation. Appl Microbiol Biotechnol. 2016;100(1):61–78. doi: 10.1007/s00253-015-7077-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Troke P, Obenga G, Gaujoux T, Goldschmidt P, Bienvenu AL, Cornet M, Grenouillet F, Pons D, Ranque S, Sitbon K, Chaumeil C, Borderie V, Lortholary O. The efficacy of voriconazole in 24 ocular Fusarium infections. Infection. 2013;41(1):15–20. doi: 10.1007/s15010-012-0273-2. [DOI] [PubMed] [Google Scholar]
  • 70.Spierer O, Dugar J, Miller D, O'Brien TP. Comparative antifungal susceptibility analysis of Candida albicans versus non-albicans Candida corneal isolates. Cornea. 2015;34(5):576–579. doi: 10.1097/ICO.0000000000000380. [DOI] [PubMed] [Google Scholar]
  • 71.Ramakrishnan T, Constantinou M, Jhanji V, Vajpayee RB. Factors affecting treatment outcomes with voriconazole in cases with fungal keratitis. Cornea. 2013;32(4):445–449. doi: 10.1097/ICO.0b013e318254a41b. [DOI] [PubMed] [Google Scholar]
  • 72.Rose-Nussbaumer J, Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, Oldenburg CE, O'Brien KS, Ray KJ, Porco TC, McLeod SD, Acharya NR, Keenan JD, Lietman TM, Mycotic Ulcer Treatment Trial Group Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole. Br J Ophthalmol. 2015 doi: 10.1136/bjophthalmol-2015-306828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Sharma S, Das S, Virdi A, Fernandes M, Sahu SK, Kumar Koday N, Ali MH, Garg P, Motukupally SR. Re-appraisal of topical 1% voriconazole and 5% natamycin in the treatment of fungal keratitis in a randomised trial. Br J Ophthalmol. 2015;99(9):1190–1195. doi: 10.1136/bjophthalmol-2014-306485. [DOI] [PubMed] [Google Scholar]
  • 74.FlorCruz NV, Evans I., Jr Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015;4:CD004241. doi: 10.1002/14651858.CD004241.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Prajna L, Srinivasan M, Raghavan A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Porco TC, Acharya NR, Lietman TM, Mycotic Ulcer Treatment Trial Group The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422–429. doi: 10.1001/jamaophthalmol.2013.1497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Mcdonald EM, Ram FS, Patel DV, Mcghee CN. Effectiveness of topical antifungal drugs in the management of fungal keratitis: a systematic review and meta-analysis of randomized controlled trials. Asia Pac J Ophthalmol (Phila) 2014;3(1):41–47. doi: 10.1097/APO.0b013e3182a618dd. [DOI] [PubMed] [Google Scholar]
  • 77.Sun CQ, Lalitha P, Prajna NV, Karpagam R, Geetha M, O'Brien KS, Oldenburg CE, Ray KJ, McLeod SD, Acharya NR, Lietman TM, Mycotic UlcerTreatment Trial Group Association between in vitro susceptibility to natamycin and voriconazole and clinical outcomes in fungal keratitis. Ophthalmology. 2014;121(8):1495–1500.e1. doi: 10.1016/j.ophtha.2014.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Kothari SG, Kothari RS. Successful treatment of fusarium keratitis after photo refractive keratectomy. Indian J Ophthalmol. 2014;62(5):661. doi: 10.4103/0301-4738.133526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Qu L, Li L, Xie H. Toxicity and pharmacokinetics of intrastromal injection of amphotericin B in a rabbit model. Curr Eye Res. 2014;39(4):340–347. doi: 10.3109/02713683.2013.847961. [DOI] [PubMed] [Google Scholar]
  • 80.Sharma B, Kataria P, Anand R, Gupta R, Kumar K, Kumar S, Gupta R. Efficacy profile of intracameral amphotericin B. the often forgotten step. Asia Pac J Ophthalmol (Phila) 2015;4(6):360–366. doi: 10.1097/APO.0000000000000107. [DOI] [PubMed] [Google Scholar]
  • 81.Sharma N, Sankaran P, Agarwal T, Arora T, Chawla B, Titiyal JS, Tandon R, Satapathy G, Vajpayee RB. Evaluation of intracameral amphotericin B in the management of fungal keratitis: randomized controlled trial. Ocul Immunol Inflamm. 2015:1–5. doi: 10.3109/09273948.2015.1057597. [DOI] [PubMed] [Google Scholar]
  • 82.Mithal K, Pathengay A, Bawdekar A, Jindal A, Vira D, Relhan N, Choudhury H, Gupta N, Gupta V, Koday NK, Flynn HW., Jr Filamentous fungal endophthalmitis: results of combination therapy with intravitreal amphotericin B and voriconazole. Clin Ophthalmol. 2015;9:649–655. doi: 10.2147/OPTH.S80387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Gong H, Gong X. Combined application of 5% natamycin and 0.2% fluconazole for the treatment of fungal keratitis. Eye Sci. 2013;28(2):84–87. [PubMed] [Google Scholar]
  • 84.Tsai SH, Lin YC, Hsu HC, Chen YM. Subconjunctival injection of fluconazole in the treatment of fungal alternaria keratitis. Ocul Immunol Inflamm. 2016;24(1):103–106. doi: 10.3109/09273948.2014.916308. [DOI] [PubMed] [Google Scholar]
  • 85.Rajaraman R, Bhat P, Vaidee V, Maskibail S, Raghavan A, Sivasubramaniam S, Namperumalsamy VP. Topical 5% natamycin with oral ketoconazole in filamentous fungal keratitis: a randomized controlled trial. Asia Pac J Ophthalmol (Phila) 2015;4(3):146–150. doi: 10.1097/APO.0000000000000035. [DOI] [PubMed] [Google Scholar]
  • 86.Arnoldner MA, Kheirkhah A, Jakobiec FA, Durand ML, Hamrah P. Successful treatment of Paecilomyces lilacinus keratitis with oral posaconazole. Cornea. 2014;33(7):747–749. doi: 10.1097/ICO.0000000000000143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Altun A, Kurna SA, Sengor T, Altun G, Olcaysu OO, Aki SF, Simsek MH. Effectiveness of posaconazole in recalcitrant fungal keratitis resistant to conventional antifungal drugs. Case Rep Ophthalmol Med. 2014;2014:701653. doi: 10.1155/2014/701653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Cavallini GM, Ducange P, Volante V, Benatti C. Successful treatment of Fusarium keratitis after photo refractive keratectomy. Indian J Ophthalmol. 2013;61(11):669–671. doi: 10.4103/0301-4738.120213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Lekhanont K, Nonpassopon M, Nimvorapun N, Santanirand P. Treatment with intrastromal and intracameral voriconazole in 2 eyes with Lasiodiplodia theobromae keratitis: case reports. Medicine (Baltimore) 2015;94(6):e541. doi: 10.1097/MD.0000000000000541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Mimouni M, Tam G, Paitan Y, Kidron D, Segev F. Safety and efficacy of intrastromal injection of 5% natamycin in experimental fusarium keratitis. J Ocul Pharmacol Ther. 2014;30(7):543–547. doi: 10.1089/jop.2014.0004. [DOI] [PubMed] [Google Scholar]
  • 91.Leal AF, Leite MC, Medeiros CS, Cavalcanti IM, Wanderley AG, Magalhães NS, Neves RP. Antifungal activity of a liposomal itraconazole formulation in experimental Aspergillus flavus keratitis with endophthalmitis. Mycopathologia. 2015;179(3–4):225–229. doi: 10.1007/s11046-014-9837-2. [DOI] [PubMed] [Google Scholar]
  • 92.de Sá FA, Taveira SF, Gelfuso GM, Lima EM, Gratieri T. Liposomal voriconazole (VOR) formulation for improved ocular delivery. Colloids Surf B Biointerfaces. 2015;133:331–338. doi: 10.1016/j.colsurfb.2015.06.036. [DOI] [PubMed] [Google Scholar]
  • 93.Pahuja P, Kashyap H, Pawar P. Design and evaluation of HP-β-CD based voriconazole formulations for ocular drug delivery. Curr Drug Deliv. 2014;11(2):223–232. doi: 10.2174/1567201810666131224105205. [DOI] [PubMed] [Google Scholar]
  • 94.Chan E, Snibson GR, Sullivan L. Treatment of infectious keratitis with riboflavin and ultraviolet-A irradiation. J Cataract Refract Surg. 2014;40(11):1919–1925. doi: 10.1016/j.jcrs.2014.09.001. [DOI] [PubMed] [Google Scholar]
  • 95.Saglk A, Uçakhan OO, Kanpolat A. Ultraviolet A and riboflavin therapy as an adjunct in corneal ulcer refractory to medical treatment. Eye Contact Lens. 2013;39(6):413–415. doi: 10.1097/ICL.0b013e3182960fdf. [DOI] [PubMed] [Google Scholar]
  • 96.Said DG, Elalfy MS, Gatzioufas Z, El-Zakzouk ES, Hassan MA, Saif MY, Zaki AA, Dua HS, Hafezi F. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014;121(7):1377–1382. doi: 10.1016/j.ophtha.2014.01.011. [DOI] [PubMed] [Google Scholar]
  • 97.Skaat A, Zadok D, Goldich Y, Varssano D, Berger Y, Ezra-Nimni O, Avni I, Barequet IS. Riboflavin/UVA photochemical therapy for severe infectious keratitis. Eur J Ophthalmol. 2014;24(1):21–28. doi: 10.5301/ejo.5000330. [DOI] [PubMed] [Google Scholar]
  • 98.Richoz O, Moore J, Hafezi F, Moore T. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial. Am J Ophthalmol. 2015;160(3):616–617. doi: 10.1016/j.ajo.2015.06.014. [DOI] [PubMed] [Google Scholar]
  • 99.Uddaraju M, Mascarenhas J, Das MR, Radhakrishnan N, Keenan JD, Prajna L, Prajna VN. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial. Am J Ophthalmol. 2015;160(1):131–134.e5. doi: 10.1016/j.ajo.2015.03.024. [DOI] [PubMed] [Google Scholar]
  • 100.Tabibian D, Richoz O, Riat A, Schrenzel J, Hafezi F. Accelerated photoactivated chromophore for keratitis-corneal collagen cross-linking as a first-line and sole treatment in early fungal keratitis. J Refract Surg. 2014;30(12):855–857. doi: 10.3928/1081597X-20141113-06. [DOI] [PubMed] [Google Scholar]
  • 101.Wessel JM, Bachmann BO, Meiller R, Kruse FE. Fungal interface keratitis by Candida orthopsilosis following deep anterior lamellar keratoplasty. BMJ Case Rep. 2013;2013:pii:bcr2012008361. doi: 10.1136/bcr-2012-008361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Yalniz-Akkaya Z, Burcu A, Dogan E, Onat M, Ornek F. Therapeutic penetrating keratoplasty for infectious and non-infectious corneal ulcers. Int Ophthalmol. 2015;35(2):193–200. doi: 10.1007/s10792-014-9931-y. [DOI] [PubMed] [Google Scholar]
  • 103.Kepez Yildiz B, Hasanreisoglu M, Aktas Z, Aksu G, Kocak BC, Akata F. Fungal keratitis secondary to Scedosporium apiospermum infection and successful treatment with surgical and medical intervention. Int Ophthalmol. 2014;34(2):305–308. doi: 10.1007/s10792-013-9777-8. [DOI] [PubMed] [Google Scholar]
  • 104.Gao H, Song P, Echegaray JJ, Jia Y, Li S, Du M, Perez VL, Shi W. Big bubble deep anterior lamellar keratoplasty for management of deep fungal keratitis. J Ophthalmol. 2014;2014:209759. doi: 10.1155/2014/209759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Zhang MC, Liu X, Jin Y, Jiang DL, Wei XS, Xie HT. Lamellar keratoplasty treatment of fungal corneal ulcers with acellular porcine corneal stroma. Am J Transplant. 2015;15(4):1068–1075. doi: 10.1111/ajt.13096. [DOI] [PubMed] [Google Scholar]
  • 106.Barut Selver O, Egrilmez S, Palamar M, Arici M, Hilmioglu Polat S, Yagci A. Therapeutic corneal transplant for fungal keratitis refractory to medical therapy. Exp Clin Transplant. 2015;13(4):355–359. doi: 10.6002/ect.2014.0108. [DOI] [PubMed] [Google Scholar]
  • 107.Arboleda A, Miller D, Cabot F, Taneja M, Aguilar MC, Alawa K, Amescua G, Yoo SH, Parel JM. Assessment of rose bengal versus riboflavin photodynamic therapy for inhibition of fungal keratitis isolates. Am J Ophthalmol. 2014;158(1):64–70.e2. doi: 10.1016/j.ajo.2014.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from International Journal of Ophthalmology are provided here courtesy of Press of International Journal of Ophthalmology

RESOURCES