Aspergillus flavus keratitis in Adana, Turkey

Slayt 1Macit Ilkit, MD
Faculty of Medicine, University of Çukurova, Adana, Turkey
Nijmegen, June 2014
• Three clinical forms:
(iii) orbital infections
• Keratitis, an infection of the cornea, may result in reduced vision or blindness
• Mainly in farmers and agriculture-based tropical countries (India, the Middle-East, North Africa)
Thomas and Kaliamurthy, 2013
• 16.5%- co-existing disease
• Over 1 million eyes go blind each year because of MK
Manikandan et al, 2013; www.gaffi.org
Filamentous MK-Causative fungi
• Environmentally widespread molds
• The genera of Aspergillus, Fusarium, Curvularia, Scedosporium, and Paecilomyces
• A. flavus (section Flavi) is one of the most common pathogen!
Thomas and Kaliamurthy, 2013; Manikandan et al, 2013
Background-Risk factors
• Ocular trauma, caused by vegetative material (soil, leaves, or tree branches)
• History of contact-lens wearing
• Widespread use of broad-spectrum antibiotics/steroids, prolonged
• The most common surgery worldwide is cataract surgery: but MK is less reported
Thomas and Kaliamurthy, 2013; Kredics et al, 2015
Background-Treatment
(iii) therapy-refractive nature
(iv) poor corneal penetration of medications
(v) limited availability/efficacy of available drugs
Thomas and Kaliamurthy, 2013; Manikandan et al, 2013; Kredics et al, 2015; www.gaffi.org
MK-Intractable problem
• Corneal collagen cross-linking
• Topical steroids along with antifungals (polyenes or triazoles) are commonly applied for treatment of MK.
Thomas and Kaliamurthy, 2013; Manikandan et al, 2013; Kredics et al, 2015; Erdem et al. (In preparation)
Drug of choice
• Natamycine (5% suspension; pimaricine) and AmB are the drug of choices in filamentous MK
• But not active against A. flavus keratitis!!
• New strategies are needed!
• Antifungal therapy for MK is 60-75% effective in saving sight
Oz et al, 2012;2016; Thomas and Kaliamurthy, 2013; Kredics et al, 2015
Aim
Çukurova University, Adana, Turkey
• 64 corneal scrapings/smears; corneal ulcer (7 cases)
• Culture-positive (6 cases, %)
• Fusarium spp.-2 cases
• The time between the clinical presentation and diagnosis by culture was 2 weeks (8-25 days)
Predisposing factors
History: Age, 23-56 years
No history of systemic comorbidities
Corneal ulcer
• ulcer with satellite lesions (2 cases)

• Ocular pain, photophobia, mild disturbance of visual acuity-left eye-5 d
• History: wearing soft contact lenses-5 years
• Ruled out use: (i) sleeping with lenses
(ii) using tap water to clean
• 20/400-left eye, irregular margin
• switch therapy: topical voriconazole (hourly) + systemic ketoconazole (twice a day)
• day 18: corneal collagen crosslinking with UV- A and riboflavin + intrastromal voriconazole
Case 1
• topical propamidine isethionate (Brolene 0.1% eye drop) and chlorhexidine
• 3-month: complete recovery
Case 2
• 28-year-old man
• redness, pain, and a white fleck in his left-eye for 20 d
• mild, but resistant, keratitis
• worker at an iron-steel factory, ocular trauma of splashed iron dust
• history of topical antibiotics, not resolved
• slit-lamp: well-defined corneal ulcer
• culture: A. flavus
• rapid response:
Case 3
• 56-year-old woman
• ocular trauma inflicted by an umbrella tip to the right eye 1-month previously
• pain, redness, low visual acuity (hand motion level)
• slit-lamp exam: corneal ulcer, satellite lesions, and hypopyon
Case 3
• clinical signs progressed; culture- A. flavus
• day 12: switch intrastromal voriconazole injection
• no controlled of infection
• day 24: penetrating keratoplasty
• 6-months follow-up: no infection recurred
• visual acuity: 20/200
• penetrating keratoplasty-left eye-2-years previously
• mixed bacterial + fungal infection?
• visual acuity: hand-motion level, corneal edema, infiltrate size increase, hypopyon
• empirical therapy: voriconazole (10 mg/ml) drop hourly initiated+vancomycin+amikacin (6 drops/day)
• Fungal culture: A. flavus
• corneal collagen crosslinking (using uv and riboflavin).
• day 10: 20/400
30°C 7 d
37°C 3 d
Fig. 2 Microscopic examination of a corneal scraping sample. Black arrows indicate fungal hyphae (Papanicolaou dye)
Phylogeny, taxonomy, and nomenclature
• The β-tubulin gene, calmodulin, and, a lesser degree, ITS
• A. flavus, A. oryzae, A. tamarii, A. nomius..
Tam et al, 2012 Gonçalves et al, 2013
AFST-EUCAST
Discussion
• We observed that A. flavus keratitis can be present with different underlying factors and clinical conditions.
• This study suggested that A. flavus keratitis may occur with a high prevalence (66.7%) in a subtropical climate in Adana, Turkey
Corneal collagen cross-linking
• MK patients which were poor/no responder to topical voriconazole treatment
• Adjunctive therapy using ‘CXL for the management of mycotic keratitis’ (In preparation)
• CXL treatment may be effective in patients with small and superficial mycotic ulcers
Corneal collagen cross-linking (CXL)
Discussion
• A. fumigatus (n=23, 11.5%)
Manikandan et al, 2013
• We recently tested 50 ocular fungal isolates, including three CBS A. flavus isolates;
Proteinase: 30%
Phospholipase: 42%
• Eye clinics-research laboratory
Thomas and Kaliamurthy, 2013; Kredics et al, 2015;
Treatment of MK
• Aspergillus spp. keratitis- that show resistance to topical natamycine and AMB
• Voriconazole- drug of choice
Is mycology lab. indeed important?
• Region-specific epidemiological details are important for prompt treatment and prevention;
(i) ophthalmologists
Kredics et al, 2015; www.gaffi.org Erdem et al, In press
Conclusion
• A combination of antifungal therapy and supportive surgical intervention may resolve infection caused by A. flavus in the cornea
• Our results warrants the role of early diagnosis and initiation of specific antifungal therapy to improve outcome
Acknowledgments