Update on management of fungal keratitis Tom Lietman, MD F I Proctor Foundation Department of Ophthalmology University of California San Francisco Disclosure Voriconazole donated by Pfizer Natamycin and Moxifloxacin donated by Alcon NIH-NEI U10 EY018573 NIH-NEI U10 EY022880 Research to Prevent Blindness That Man May See Acknowledgments World Blindness 1993 N. V. Prajna Lalitha Prajna M. Srinivasan Jeena Mascarenhas R. Vijayakumar Sumithra R.D. Ravindran Tiruvengada Krishnan Rabindranath Reddy Vaitilingam Jayanthi Kavita Dhakhwa Kamal Bahadur Khadka R.P. Kandel Nisha Acharya Jennifer Rose-Nussbaumer Stephen McLeod John P. Whitcher Jeremy Keenan Vicky Cevallos Chuck Leiter Travis Porco Kathryn Ray Kevin Hong Catie Oldenburg Kieran O Brien Michael E. Zegans Christine Toutain Ivan Schwab Anthony Aldave Cataract Trachoma Glaucoma Corneal Ulcers Vitamin A Deficiency Onchocerciasis Leprosy Thylefors et al, Bull WHO 1995 Whitcher et al, BJO 1997 1
World Blindness 2002 World Blindness 2010 Cataract Glaucoma AMD Corneal Ulcers Diabetic Retinopathy Childhood blindness Trachoma Onchocerciasis Resnikoff et al, Bull WHO 2004 Cataract Glaucoma AMD Corneal Ulcers Refractive error Childhood blindness Trachoma Diabetic Retinopathy Mariotti et al, BJO 2012 2
Bacterial vs Fungal Experts correct 66% (63 to 68%) Good news: p<0.001 Bad news: need to do better Metagenomic Deep Sequencing Google trends: Fusarium presumed infectious failed diagnostics clinical progression Thuy Doan, MD PhD 3
Corneal Ulcer RCTs with >50 Ulcers Comparison N Inclusion Criteria Results Ofloxacin versus cefazolin 52 248 Bacterial No significant difference and tobramycin Ofloxacin monotherapy versus fortified gentamicin 122 All microbial No significant difference and cefuroxime 54 Chlorhexidine versus 60 71 Fungal No significant difference natamycin Econazole versus 53 116 Fungal No significant difference natamycin Moxifloxacin versus ofloxacin or fortified 229 Bacterial No significant difference tobramycin/cephazolin 51 Povidone-iodine as adjunctive therapy versus standard 358 All microbial No significant difference therapy 61 PHMB versus chlorhexidine 55 56 Acanthamoeba No significant difference as monotherapy Natamycin versus 6 120 Fungal No significant difference voriconazole Corticosteroid versus placebo as adjunctive therapy with 500 Bacterial No significant difference moxifloxacin 50 Survey of Cornea Specialists Most preferred antifungal in an ideal world? voriconazole 79% Mycotic Ulcer Treatment Trial I Natamycin versus Voriconazole Loh et al, Cornea 2009 4
MUTT I Which topical agent, voriconazole or natamycin, is more effective in the treatment of filamentous fungal keratitis? MUTT I (N=323) NEI U10 EY018573., Archives of Ophthalmology 2013 3-month Acuity 2-lines better with Natamycin (P=0.006) 3-month Acuity Fusarium species 4-lines better with Natamycin (P<0.001) 5
Corneal Ulcer RCTs with >50 Ulcers Do NOT use voriconazole monotherapy for Fusarium species Comparison Authors N Etiology Results Ofloxacin versus cefazolin and tobramycin Ofloxacin versus gentamicin and cefuroxime Chlorhexidine versus natamycin Econazole versus natamycin Povidone-iodine as adjunctive therapy versus standard Moxifloxacin versus ofloxacin or tobramycin and cephazolin PHMB versus chlorhexidine Natamycin versus voriconazole Steroid versus placebo with moxifloxacin Natamycin versus voriconazole O Brien et al Archives 1995 Ofloxacin Study Group Ophthalmology 1997 Rahman et al BJO 1998 BJO 2003 Katz et al BJO 2004 Constantinou et al Ophthalmology 2007 Lim et al AJO 2008 Archives 2010 Srinivasan et al Archives 2011 Archives 2013 248 Bacterial No significant difference 122 All microbial No significant difference 71 Fungal No significant difference 116 Fungal No significant difference 358 All microbial No significant difference 229 Bacterial No significant difference 56 Acanthamoeba No significant difference 120 Fungal No significant difference 500 Bacterial No significant difference 323 Fungal? Corneal Ulcer RCTs with >50 Ulcers Comparison Authors N Etiology Results Ofloxacin versus cefazolin and tobramycin Ofloxacin versus gentamicin and cefuroxime Chlorhexidine versus natamycin Econazole versus natamycin Povidone-iodine as adjunctive therapy versus standard Moxifloxacin versus ofloxacin or tobramycin and cephazolin PHMB versus chlorhexidine Natamycin versus voriconazole Steroid versus placebo with moxifloxacin Natamycin versus voriconazole O Brien et al Archives 1995 Ofloxacin Study Group Ophthalmology 1997 Rahman et al BJO 1998 BJO 2003 Katz et al BJO 2004 Constantinou et al Ophthalmology 2007 Lim et al AJO 2008 Archives 2010 Srinivasan et al Archives 2011 Archives 2013 248 Bacterial No significant difference 122 All microbial No significant difference 71 Fungal No significant difference 116 Fungal No significant difference 358 All microbial No significant difference 229 Bacterial No significant difference 56 Acanthamoeba No significant difference 120 Fungal No significant difference 500 Bacterial No significant difference 323 Fungal Natamycin better 6
MUTT II Does adjunctive oral voriconazole help in severe fungal ulcers? NEI U10 EY018573 MUTT II (N=240) MUTT II (N=240) 7
MUTT II (N=240) Corneal cross-linking? New with fungal ulcers? experts are moderately expert natamycin better than voriconazole oral voriconazole not necessary metagenomic deep sequencing corneal cross-linking 8