Diagnostic and therapeutic advances Update emerging for fungal

Cheryl Guttman limits the concentration of amphotericin B Study provides insight on therapeutic selection for fungal keratitis that can be applied topically as well as its use FUNGAL keratitis is an important cause of subconjunctivally. In addition, both vision loss in developing countries, and while RESULTS of a study evaluating the in vitro “Unfortunately, traditional approaches for and amphotericin B are large molecules with its prevalence has been increasing over the susceptibility of 90 clinical fungal keratitis isolates treatment of fungal keratitis offer relatively poor only limited penetration into the cornea,” past few decades, the recent outbreak of suggest the management of these challenging efficacy. The data from this study support noted Dr Mannis, professor and chair, contact -associated Fusarium keratitis has infections may be improved by increased use of increased use of voriconazole, but ideally, its role Department of & Vision drawn attention to these serious infections voriconazole, according to the investigators who and the relationship between in vitro susceptibility Science, University of California, Davis. seen by ophthalmologists worldwide. reported their findings in a paper published in the and clinical outcomes will be more rigorously Results of a small case series suggested a Newer antifungal compounds have shown June, 2007 issue of Archives of Ophthalmology. investigated in the context of prospective clinical possible role for intracameral amphotericin promise for delivering better treatment, and The experience of recent increases in cases of studies.” B in the treatment of deep keratomycosis. In authors of a recent study evaluating the in fungal keratitis in the US provided the stimulus for All Fusarium spp were resistant to the highest addition, a newly available, systemically vitro susceptibility of clinical fungal keratitis the research project, said corresponding author, tested concentrations of itraconazole (8 mcg/mL) administered preparation of amphotericin in isolates in India suggest greater use of Tom Lietman MD, FI Proctor Foundation, and caspofungin acetate (16 mcg/mL). a liposomal formulation (AmBisome) has voriconazole (Vfend, Pfizer) in particular may University of California at San Francisco. “Itraconazole is used in India as a commercially been shown to have enhanced corneal afford better outcomes. Currently, fungal “Recognising that fungal infection is the leading available topical preparation and has been used bioavailability and less toxicity compared keratitis remains a perplexing diagnostic infectious cause of corneal ulcers in South India, orally to treat fungal keratitis in the US. The with conventional amphotericin B challenge and a difficult management we decided to take advantage of the expertise of susceptibility data indicate it does not have good (Fungizone) or amphotericin B lipid complex problem for ophthalmologists. our foreign colleagues in order to learn how to activity against Fusarium and should not be used,” (ABLC) and may offer a useful alternative in “Knowledge of the risk factors for fungal improve patient care at home,” he said. Dr Lietman said. the future for treating fungal keratitis. keratitis and its clinical characteristics are The study was conducted at the Aravind Eye The investigators noted that their study does not Other newer antifungal agents that have important to enable prompt diagnosis and Hospital, South India, by Prajna Lalitha MD, in adjust for possible bioavailability differences been used off-label to treat fungal keratitis appropriate care. Medical therapy remains conjunction with Dr Lietman, Brett Shapiro, MD, between the antifungals, which may also influence include voriconazole, which has broad- empiric, but understanding of the aetiology and other researchers from the University of clinical response. spectrum antifungal activity and has been of these infections and the differing California at San Francisco and University of Texas “Natamycin also had significantly lower MICs associated with success when used both susceptibility profiles of common pathogens Health Sciences Center, San Antonio. Fungal than amphotericin B against both Aspergillus spp. topically and orally for the treatment of to antifungal agents can help guide selection susceptibility to amphotericin B, natamycin, and Fusarium spp. in the concentration-adjusted infections caused by Candida and Aspergillus. of effective treatment,” Denise de Freitas itraconazole and the newer antifungals, analysis. However, both amphotericin B and Caspofungin (Cancidas Merck), an MD, Department of Ophthalmology, Federal caspofungin acetate, voriconazole, and natamycin penetrate poorly through the intact echinocandin compound, has a favourable University of Sao Paulo, Brazil, told posaconazole, was tested using a macrodilution corneal epithelium while voriconazole appears to safety profile and has been effective in EuroTimes. assay technique. The majority of the 90 fungal penetrate well,” Dr Lietman explained. treating corneal fungal infections caused by The principal risk factors for fungal isolates were accounted for by Aspergillus spp. Despite recent improvements in techniques for Candida and Aspergillus.There have also been keratitis are similar worldwide and include and Fusarium spp. fungal susceptibility testing, as of yet, few encouraging reports of the use of another presence of ocular surface disease, prior Voriconazole, the other triazoles, and microbiology laboratories perform this service echinocandin, micafungin (Mycamin), applied therapy with a topical corticosteroid or caspofungin acetate had the lowest (best) MIC90 reliably. However, clinicians may still consider topically or as a subconjunctival injection to antibacterial agent, ocular trauma (especially values against the Aspergillus spp. (0.125 to 0.5 submitting clinical specimens from fungal keratitis treat refractory corneal ulcers caused by involving exposure to organic material), and a mcg/mL), and voriconazole together with patients because the laboratories offer pathogen Candida and with the oral triazole history of wear. amphotericin B had the lowest MIC90 values identification, said Dr Lietman. posaconazole (Noxafil) in refractory Candida The most common causative pathogens against Fusarium spp. (4 mcg/mL for both). “This information may be used to guide and Aspergillus infections. for these infections include the yeast However, in a separate analysis where the absolute therapeutic selection and hopefully result in more Although there has been a trend toward Candida albicans or either of the filamentous MIC values were corrected to account for the effective antifungal treatment,” he explained. the increasing use of corticosteroids early in moulds, Fusarium spp. or Aspergillus spp., different concentrations of the antifungals that are the management of bacterial keratitis, their although the prevalence of these organisms used clinically, voriconazole had significantly better [email protected] role for managing inflammation in fungal as clinical isolates in fungal keratitis varies MICs than amphotericin B against Fusarium spp. keratitis is controversial. For yeast infections, geographically. Aspergillus spp. and Fusarium topical corticosteroids may be started after spp. are the most common isolates in fungal specific antifungal treatment has been keratitis cases in the eastern hemisphere, and The diagnosis of fungal keratitis can often spoke on behalf of Dr de Freitas at the 2007 initiated although it has been recommended Fusarium infections have also been common be made by direct microscopic evaluation of Joint Congress of the European Society of that their use be avoided entirely in eyes in the southern US. Historically, Candida has material obtained through corneal scraping Ophthalmology and the American Academy with filamentous fungal infection or at least predominated in northern states, although using simple methods, including KOH, Gram of Ophthalmology (SOE/AAO). delayed until after the antifungal therapy has the recent outbreak of Fusarium keratitis in or giemsa stains, calcofluor white, or Currently, a typical antifungal regimen for sterilised the field. In addition, it is important contact lens wearers has caused a shift in the modified GMS. Culture represents the treatment of keratitis caused by filamentous to taper the corticosteroid treatment to epidemiology. definitive mode of pathogen identification. fungi may involve hourly administration of avoid rebound inflammation that can occur The patient’s history together with clinical Using appropriate inoculation media, 97 per topical natamycin five per cent combined following abrupt discontinuation. appearance at the slit-lamp may suggest the cent of positive cultures will show evidence with oral ketoconazole 200mg bid. Surgical therapy plays a role in the diagnosis of fungal infection. Hallmark of fungal growth within one week. Subconjunctival voriconazole 10mg or management of fungal keratitis both as an features of infections caused by filamentous Histopathological examination of a specimen miconazole 10mg may be added in severe adjunct to medical therapy for initial fungi include a lesion with irregular feathery obtained by corneal biopsy may be unresponsive infections. For yeast infections, management and when medical therapy fails. margins, dry rough texture, and presence of performed if the diagnosis of fungal infection the regimen would include topical “Surgical debridement of the epithelium satellite lesions. In more advanced cases, is suspected but the culture is negative. amphotericin B 0.15 per cent every hour and base of the fungal ulcer is important in there may be anterior chamber inflammation, “Confocal microscopy represents a newer with oral itraconazole or fluconazole 100mg the management because it debulks the , endothelial plaque, ring infiltrate, non-invasive tool that is fully diagnostic of bid and subconjunctival fluconazole 1.0- organisms as well as necrotic material from Descemet’s folds, and keratitic precipitates. fungal keratitis but is not available to most 2.0mg if needed. the cornea to enhance drug penetration,” Dr Yeast infections are more likely to mimic ophthalmologists. PCR modalities are also “The polyenes natamycin and Mannis said. bacterial keratitis.They are characterised by being developed and appear very promising, amphotericin B have been the mainstays for more circumscribed lesions with an overlying although their specificity and sensitivity are treating these difficult infections for decades. [email protected] epithelial defect and have a slow progression. variable to date,” said Mark Mannis, MD, who Natamycin is well tolerated, whereas toxicity [email protected]

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