Journal Reading

Infectious Keratitis: an Update on Epidemiology, Causative

Microorganisms, Risk Factors, and Antimicrobial Resistance

Darren Shu Jeng Ting, Charlotte Shan Ho, Rashmi Deshmukh, Dalia G Said,
Harminder S Dua

Dipresentasikan Oleh:

Bening Osia Suseno, S.Ked

Yolanda Qonita Salihat, S.Ked

KEPANITERAAN KLINIK BAGIAN ILMU PENYAKIT MATA

FAKULTAS KEDOKTERAN UNIVERSITAS RIAU
RUMAH SAKIT UMUM DAERAH ARIFIN ACHMAD PROVINSI RIAU
2022
 RESUME JURNAL

Nama Jurnal dan Edisi : The Scientific Journal of The Royal College of
Ophthalmologist Vol. 35, No. 4, 1084-1101
Judul Artikel : Infectious keratitis: an update on epidemiology,
causative microorganisms, risk factors, and
antimicrobial resistance
Tanggal/Bulan/Tahun : 7 Januari 2021
Latar Belakang : Kekeruhan kornea merupakan penyebab utama ke-
5 kebutaan secara global terhitung ~3,2% dari semua
kasus. World Health Organization (WHO)
melaporkan bahwa ~6 juta kasus kebutaan di dunia
berkaitan dengan kornea atau gangguan
penglihatan sedang/berat, termasuk 2 juta dari
mereka yang terkena trachoma. Selain itu, kekeruhan
kornea diperkirakan berperan pada 1,5-2,0 juta
kebutaan unilateral setiap tahun.
Beberapa gangguan yang menyebabkan gangguan
kornea seperti infeksi, trauma, peradangan,
degenerasi, atau defisiensi nutrisi dapat
menyebabkan kekeruhan kornea disertai gangguan
penglihatan. Diantara semuanya, keratitis telah
terbukti menjadi penyebab paling umum kebutaan
kornea di negara maju dan berkembang. Menurut
sebuah studi nasional, keratitis terbukti menjadi
penyebab paling umum dari semua kebutaan
kornea di Cina, terutama dikaitkan dengan
peningkatan risiko trauma, status sosial ekonomi
rendah dan buta huruf. Keratitis adalah kondisi mata
yang umum namun berpotensi mengancam
penglihatan, ditandai dengan nyeri mata akut,
penurunan penglihatan, ulserasi kornea, dan/atau
infiltrat stroma. Sebelumnya, keratitis disebut
sebagai “silent epidemic” di negara berkembang.
Namun baru-baru ini, ketua konsorsium telah
menyarankan keratitis sebagai "Neglected Tropical
Disease” (NTD), yang ditambahkan ke dalam daftar
NTDs oftalmologi (seperti trachoma, onchocerciasis
dan kusta). Proposal mengenai pencapaian status
NTD bertujuan untuk menarik upaya global dalam
mengatasi keratitis di negara-negara tropis yang
kekurangan sumber daya, memperbaiki beban
sosial, serta humanistik keratitis.
Keratitis dapat disebabkan oleh berbagai macam
patogen termasuk bakteri, jamur, protozoa dan virus.
Selain itu, infeksi polimikrobial telah terbukti
bertanggung jawab untuk ~2-15% dari semua kasus
keratitis. Karena permukaan okular dilengkapi
dengan mekanisme pertahanan bawaan dan adaptif
yang sangat diatur, maka keratitis jarang terjadi
tanpa adanya faktor predisposisi seperti pemakaian
kontak lensa, trauma, ocular surface diseases (OSD),
dan paska operasi kornea.
Keratitis tidak hanya menyebabkan gangguan
penglihatan, tetapi juga berdampak negatif pada
quality of life (QOL) pasien. Studi dari Uganda
melaporkan bahwa keratitis mempengaruhi QOL
terkait penglihatan (dikaitkan dengan kehilangan
penglihatan) dan QOL terkait kesehatan (dikaitkan
dengan nyeri pada fase akut). Dampak psikologis
pada pasien ini terkait dengan rasa takut kehilangan
mata dan stigma sosial yang melekat. Bahkan ketika
pemulihan visual selesai, individu yang terkena
keratitis menunjukkan skor QOL yang lebih rendah
daripada kontrol yang tidak terpengaruh. Keratitis
dapat mempengaruhi produktivitas ekonomi
penderita dan juga bertanggung jawab atas beban
ekonomi yang sangat besar bagi masyarakat.
Menurut sebuah laporan pada tahun 2010, US
menghabiskan sekitar 175 juta dolar untuk
pengobatan keratitis. Selanjutnya, komplikasi
keratitis seperti perforasi kornea dan jaringan parut
merupakan indikasi utama transplantasi kornea di
negara berkembang seperti India, Thailand dan Cina
sehingga menyebabkan terbatasnya donor kornea.
Terjadinya kekurangan sumber daya akibat
keratitis, kemungkinan besar menjadi beban
keratitis yang sebenarnya diremehkan akibat
kurangnya pengawasan dan pelaporan. Mengingat
beban global yang ditimbulkan keratitis, tinjauan
ini bertujuan untuk memberikan gambaran yang
terbaru dan komprehensif tentang epidemiologi,
 mikroorganisme penyebab, faktor risiko dan dampak
resistensi antimikroba dalam kaitannya dengan
keratitis.
Tujuan :
Memberikan gambaran yang terbaru dan
komprehensif tentang epidemiologi, mikroorganisme
penyebab, faktor risiko dan dampak resistensi
antimikroba dalam kaitannya dengan keratitis.
Metodologi : Studi literatur dengan mencari di PubMed (Januari
1980 - Mei 2020) untuk artikel yang relevan terkait
keratitis dengan menggunakan kata kunci seperti
“infeksi kornea”, “ulkus kornea”, “IK”, “keratitis
mikroba”, “insiden”, “prevalensi”, "epidemiologi",
"faktor risiko", "resistensi antibiotik" dan "resistensi
antimikroba". Tidak ada batasan bahasa yang
digunakan. Bibliografi artikel yang disertakan disaring
secara manual untuk mengidentifikasi studi lebih lanjut
yang relevan. Pencarian terakhir diperbarui pada 15
Juni 2020.
Sebuah aplikasi web yang dirancang untuk tinjauan
sistematis, Rayyan (Qatar), digunakan untuk membantu
menyusun studi potensial dan mempercepat
penyaringan awal abstrak dan judul. Judul dan abstrak
yang diperoleh dari pencarian disaring secara
independen oleh dua penulis (DSJT dan CSH) untuk
memasukkan studi yang memenuhi kriteria kelayakan.
Para penulis kemudian secara independen menilai versi
teks lengkap dari semua artikel yang dipilih dan
mengekstrak data ke dalam formulir pengumpulan data
standar untuk sintesis data. Data yang diekstraksi
termasuk penulis, tahun publikasi, negara, ukuran
sampel, faktor demografi, hasil kultur, faktor risiko dan
kerentanan antibiotik in vitro. Perbedaan diselesaikan
dengan konsensus kelompok dan ajudikasi independen
(HSD) jika konsensus tidak dapat dicapai. Ringkasan
pencarian literatur dirinci dalam diagram alir PRISMA.
Hasil dan Pembahasan : Jurnal ini memberikan gambaran yang terbaru dan
komprehensif tentang epidemiologi, mikroorganisme
penyebab, faktor risiko dan dampak resistensi
antimikroba dalam kaitannya dengan keratitis.

A. Epidemiologi
A1. Insiden
Sampai saat ini terdapat keterbatasan literatur yang
meneliti kejadian keratits dan sebagian besar studi yag
dilakukan telah lebih dari satu dekade. Berdasarkan
lokasi geografis, kejadian keratitis diperkirakan
berkisar 2,5-799 kasus per 100.000 penduduk-tahun,
terutama lebih umum di negara-negara berpenghasilan
rendah. Studi sebelumnya memperkirakan angka
kejadian keratitis 2,5-27,6 per 100.000 populasi-tahun
di US dan 2,6–40,3 per 100.000 penduduk-tahun di UK.
Penulis mengamati insiden yang terjadi di Nottingham,
UK relatif stabil sebesar 34,7 per 100.000 penduduk-
tahun, antara tahun 2007-2019. Studi baru yang
dilakukan di Australia juga menunjukkan insiden
keratitis yang rendah sebesar 6,6 per 100.000
penduduk-tahun selama periode 2005-2015. Namun,
perlu dicatat bahwa insiden yang dilaporkan dalam
dua penelitian ini kemungkinan diremehkan karena
jumlahnya didasarkan pada pasien keratitis yang
menjalani pengikisan kornea.
Sebaliknya, tingkat keratitis yang jauh lebih tinggi
telah dilaporkan di negara-negara yang kekurangan
sumber daya seperti India Selatan (113 per 100.000
penduduk-tahun) dan Nepal (799 per 100.000
penduduk-tahun). Hal ini disebabkan oleh
kebersihan lingkungan dan higienitas individu yang
lebih buruk, tingkat pendidikan yang lebih rendah,
industri pertanian, peningkatan risiko trauma
kornea terkait pekerjaan dan akses yang lebih buruk
ke fasilitas sanitasi dan pelayanan kesehatan.
A2. Usia
Keratitis telah terbukti mempengaruhi individu di
semua kelompok umur. Berdasarkan studi skala
besar (>500 pasien), keratitis paling banyak
ditemukan pada individu usia antara 30 dan 55 tahun,
terutama dikaitkan dengan faktor risiko penggunaan
kontak lensa dan trauma okular yang terkait dengan
kelompok usia kerja. Pasien yang terkena keratitis
terkait trauma akibat produk pertanian dan benda
asing biasanya berusia sekitar 45-55 tahun. Tenaga
kerja yang dipekerjakan di beberapa negara
berkembang terutama terdiri dari petani dan buruh
lebih rentan terhadap keratitis yang disebabkan
trauma. Pada penelitian lain melaporkan pasien yang
terkena keratitis terkait kontak lensa biasanya
berusia antara 25 dan 40 tahun.
Meskipun prevalensi keratitis umumnya rendah
pada usia ekstrim, namun keratitis dapat
berkontribusi utama pada anak di beberapa negara,
misalnya keratitis menjadi penyebab paling umum
kedua gangguan penglihatan pada anak-anak
berusia <15 tahun di Uganda.
Selain itu, beberapa penelitian menunjukkan
bahwa keratitis pada usia lanjut berkaitan dengan
hasil visual yang buruk (sekitar 40-75% dengan
ketajaman visual <6/60) dan tingkat komplikasi yang
lebih tinggi, seperti pelelehan kornea, perforasi, dan
kehilangan mata (yaitu eviserasi atau enukleasi). Ini
mungkin terkait dengan tingkat komorbiditas okular
yang lebih tinggi dan keterlambatan dalam
mengidentifikasi dan/atau mendiagnosis keratitis karena
pasien lanjut usia biasanya bergantung pada pasangan
atau keluarga ketika mencari perawatan medis dan
mereka mungkin menghubungkan kondisi mereka
dengan usia "normal" terkait perubahan tersebut.
A3. Jenis Kelamin
Mayoritas penelitian tidak mengamati predileksi
jenis kelamin keratitis. Namun, ketika terdapat
perbedaan gender atau dominasi, biasanya dikaitkan
dengan faktor risiko yang mendasari di berbagai
daerah. Misalnya, keratitis terkait kontak lensa
telah terbukti menunjukkan dominasi wanita 57-
69%, sedangkan keratitis terkait trauma dikaitkan
dengan dominasi laki-laki sebesar 74-78%, kejadian
ini berkorelasi dengan tingginya prevalensi laki-laki
(58-75%) dari keratitis di daerah yang mengalami
kekurangan sumber daya seperti Amerika Selatan,
Asia, dan Afrika. Menariknya, sebuah penelitian di
Nepal menemukan bahwa ada lebih banyak pasien
laki-laki daripada perempuan di semua kelompok
umur. Ini mungkin karena kombinasi dari tingkat
trauma yang lebih tinggi, jumlah pemakaian
kontak lensa yang lebih rendah, dan berkurangnya
kesempatan diantara perempuan untuk mengakses
layanan medis karena kebiasaan budaya.
A.4 Status Sosial Ekonomi dan Tingkat Pendidikan
Status sosial ekonomi yang rendah telah terbukti
meningkatkan risiko terjadinya keratitis, terutama
disebabkan oleh pendidikan rendah, higienitas yang
buruk, dan akses terbatas ke perawatan mata di
masyarakat pedesaan. Di Asia dan Afrika, diantara
mereka yang didiagnosis keratitis, ~ 45-71% pasien
dengan buta huruf dan 62-79% dari mereka tinggal
di daerah pedesaan dengan akses yang lebih buruk ke
fasilitas kesehatan. Selain itu, ditemukan bahwa
petani, penduduk pedesaan, dan buta huruf memiliki
risiko keratitis refrakter yang lebih tinggi dengan
hasil yang lebih buruk.
Beberapa studi melaporkan hampir setengah dari
pasien dengan keratitis mengalami perburukan
akibat pengobatan tradisional menggunakan ASI
atau tanaman langsung diberikan ke mata yang
dilakukan sendiri atau dukun desa, sehingga pasien
cenderung datang terlambat ke ahli perawatan
mata.

B. Mikroorganisme Penyebab
Berbagai mikroorganisme termasuk bakteri,
jamur, protozoa (khususnya Acanthamoeba), dan
virus dapat menyebabkan keratitis. Baru-baru ini,
Ung et al telah memberikan ringkasan literatur yang
komprehensif tentang mikroorganisme penyebab
keratitis (hingga Juni 2018). Mengingat literatur yang
berkembang baru-baru ini, bagian ini bertujuan untuk
meringkas bukti berdasarkan studi besar keratitis (>
500 ukuran sampel) yang diterbitkan selama 2010-
2020.
B1. Bakteri
Keratitis bakteri merupakan jenis keratitis yang
paling umum di sebagian besar wilayah, termasuk
UK (91-93%), Amerika Utara (86-92%), Amerika
Selatan (79-88%), Timur Tengah (91,8%), dan
Australia (93-100%). Dalam hal strain bakteri
tertentu, Coagulase Negative Staphylococci (CoNS),
yang merupakan kelompok komensal okular umum,
terbukti menjadi organisme yang paling sering
diisolasi (24-46%) dari setengah studi yang
disertakan. Bakteri umum lainnya yang terlibat
dalam keratitis termasuk S.aureus (5-36%),
Streptococci ssp. (7–16%), Pseudomonas aeruginosa
(5–24%), Enterobacteriaceae spp. (15%),
Corynebacterium spp. (14%), dan Propionibacterium
spp (9%). Selama dekade terakhir, ada beberapa
penelitian di UK yang mendokumentasikan
peningkatan yang signifikan pada keratitis Moraxella,
yang sering dikaitkan dengan waktu penyembuhan
kornea yang lebih
lama. Menariknya, Nocardia keratitis, penyebab langka
keratitis, diidentifikasi sebagai mikroorganisme ketiga
yang paling umum (11% dari semua kasus) dalam
Steroids Corneal Ulcers Trial (SCUT), dan hasilnya
ditemukan dipengaruhi secara negatif oleh penggunaan
steroid topikal. Basil tahan asam seperti Non-
Tuberculous Mycobacteria (NTM) berfungsi sebagai
kelompok patogen penting lainnya yang mampu
menyebabkan keratitis. Keratitis NTM umumnya terkait
dengan bedah refraktif dan trauma, dan sering
membutuhkan pengobatan yang lama dan agresif untuk
penyembuhan total, sebagian besar dikaitkan dengan
kecenderungan mereka untuk membentuk biofilm.
B2. Jamur
Beberapa penelitian telah menunjukkan bahwa
Fusarium spp. (13–24%) dan Aspergillus spp. (8–
30%) adalah penyebab utama keratitis di Asia,
khususnya India dan Cina. Pada tahun 2018, Asian
Cornea Society Infectious Keratitis Study (ACSIKS)
melibatkan lebih dari 6000 pasien dari delapan
negara Asia dan menegaskan kembali dominasi
Fusarium spp. di Cina (26%) dan India (31%) terjadi
pada dua dekade lalu. Meskipun prevalensi keratitis
jamur di daerah beriklim sedang seperti UK, Eropa
dan Amerika Utara dilaporkan lebih rendah,
pertumbuhan jamur ragi seperti Candida spp. relatif
umum pada pasien dengan riwayat transplantasi
kornea atau OSD. Mengingat perkembangan dalam
teknik diagnostik, patogen langka, seperti Cryptococcus
curvatus, Arthrographis kalrae , Pythium spp ., dan
banyak lainnya semakin diidentifikasi dan dilaporkan
sebagai penyebab langka keratitis jamur.
B3. Protozoa
Acanthamoeba keratitis merupakan penyebab
penting lain dari keratitis, meskipun tidak umum seperti
keratitis bakteri atau jamur karena sering dikaitkan
dengan pengobatan yang berkepanjangan dan hasil
visual yang buruk. Diperkirakan bahwa
keratitis Acanthamoeba mempengaruhi 1-33 per juta
pemakai kontak lensa per tahun. Di UK, Carnt et
al, baru-baru ini mengkonfirmasi wabah
keratitis Acanthamoeba di Inggris Tenggara selama
2010-2016 dengan peningkatan sekitar tiga kali lipat
dibandingkan dekade sebelumnya.
Berdasarkan studi besar baru-baru ini,
Acanthamoeba keratitis menyumbang ~ 0–5% dari
semua keratitis. Sebagian besar Acanthamoeba
keratitis diamati pada pemakai kontak lensa (71-
91%). Namun, orang yang tidak menggunakan
kontak lensa juga dapat mengalami infeksi jika mata
terkena air, tanah atau debu yang terkontaminasi.
Salah satu penelitian di India melaporkan bahwa
hanya 4% dari Acanthamoeba keratitis dikaitkan
dengan penggunaan kontak lensa dan sisanya
dikaitkan dengan trauma dan atau paparan air yang
terkontaminasi. Selain itu, gambaran klinis
keratitis Acanthamoeba yang tidak terkait dengan
kontak lensa mungkin berbeda dari kasus terkait
penggunaan kontak lensa. Selain itu, Acanthamoeba
sclerokeratitis dapat bermanifestasi sebagai entitas
klinis yang jarang tetapi sulit diobati yang biasanya
dikaitkan dengan hasil klinis yang buruk.
Keratitis mikrosporidial merupakan jenis lain dari
keratitis parasit yang menyumbang ~0,4% kasus dari
semua keratitis. Hal ini terutama diamati di negara-
negara Asia dan dapat bermanifestasi sebagai
keratokonjungtivitis superfisial atau keratitis stroma.
Hal ini umumnya terkait dengan trauma mata,
paparan air/tanah yang terkontaminasi, dan
sindrom imunodefisiensi yang didapat.
B4. Virus
Keratitis virus paling sering dalam bentuk herpes
simpleks keratitis (HSK) dan herpes zoster keratitis
(HZK) merupakan penyebab umum keratitis. Namun,
karena kasus keratitis virus umumnya diobati
berdasarkan penampilan klinisnya yang khas
(misalnya ulkus kornea dendritik pada HSK) dan/
atau riwayat okular sebelumnya, sebagian besar
kasus tidak memerlukan pemeriksaan mikrobiologi
dan karenanya tidak ditemukan dalam banyak
penelitian keratitis. Meskipun demikian, penelitian
ACSIKS menunjukkan bahwa keratitis virus
merupakan penyebab paling umum (46%) keratitis di
Cina, terutama disebabkan oleh HSK (24%) dan HZK
(17%).
Berdasarkan hasil ini, kemungkinan keratitis virus
merupakan penyebab penting dan umum dari
keratitis di banyak daerah lain, meskipun penelitian
lebih lanjut diperlukan untuk menjelaskan hal ini.
Keratitis herpes sering dikaitkan dengan keratopati
neurotropik yang dapat mengakibatkan
penyembuhan kornea yang buruk, peningkatan risiko
keratitis lebih lanjut dan komplikasi kornea lainnya
seperti pelelehan dan perforasi.
B5. Infeksi Polimikroba
Keratitis polimikrobial (keratitis yang disebabkan
oleh dua atau lebih mikroorganisme penyebab) telah
dilaporkan pada sekitar 2–15% dari semua kasus
keratitis. Tergantung pada desain penelitian dan
definisi yang digunakan, keratitis polimikrobial
dapat mencakup dua atau lebih jenis organisme dari
kategori yang sama (misalnya bakteri-bakteri, jamur-
jamur) atau kategori yang berbeda (bakteri jamur,
jamur-protozoa). Keratitis polimikrobial sering
menimbulkan tantangan diagnostik dan terapeutik
yang signifikan, dan biasanya lebih buruk daripada
keratitis monomikrobial. Khoo dkk, mengamati
bahwa pasien yang terkena keratitis polimikrobial
(median penglihatan 6/60) memiliki hasil visual
yang jauh lebih buruk dibandingkan dengan mereka
yang terkena keratitis bakteri (median penglihatan
6/18) atau kultur negatif. Dalam studi komparatif
retrospektif lainnya, Lim et al. menunjukkan bahwa
terapi medis cukup untuk menyelesaikan semua kasus
keratitis monomikroba tetapi hanya 81% pada
keratitis polimikrobial.
B6. Variasi Musiman
Banyak penelitian telah menunjukkan bahwa
keratitis paling umum selama musim panas dengan
P. aeruginosa menjadi salah satu mikroba yang
paling sering diisolasi. Predileksi musiman keratitis
selama musim panas dikaitkan dengan kemungkinan
peningkatan penggunaan kontak lensa dan
keterlibatan dalam aktivitas air, sedangkan di India
kejadian keratitis jamur meningkat selama musim
berangin, terutama terkait dengan risiko trauma
sekunder yang lebih tinggi akibat kegiatan pertanian
dan serpihan pertanian yang tertiup angin ke mata.
Variasi musiman juga diamati di Acanthamoeba
keratitis, meskipun dengan hasil yang
bertentangan. Lin dkk. mengamati bahwa
Acanthamoeba keratitis terjadi lebih sering selama
musim panas di India Selatan, berpotensi terkait
dengan suhu yang lebih tinggi dan peningkatan
risiko trauma kornea selama musim berangin,
sedangkan Walkden et al, melaporkan peningkatan
Acanthamoeba keratitis selama musim dingin di
UK.

C. Faktor Risiko
Pada sebagian besar kasus keratitis, biasanya
terdapat faktor risiko lokal dan/atau sistemik. Faktor
risiko yang paling umum adalah penggunaan kontak
lensa, trauma okular, OSD (misalnya dry eye disease,
keratopati neurotropik, rosacea, dll.), penyakit
kelopak mata, operasi pasca-kornea (misalnya
keratoplasti, cross-linking kornea (CXL)), dan penyakit
sistemik (misalnya diabetes, imunosupresi), dan lain-
lain.
C1. Penggunaan Kontak Lensa
Penggunaan kontak lensa diakui sebagai salah satu
faktor risiko keratitis yang paling umum, terutama di
negara maju. Studi yang dilakukan di California Utara
melaporkan bahwa kejadian keratitis pada pemakai
kontak lensa lebih tinggi ~9,3 kali daripada yang
tidak menggunakan kontak lensa. Berdasarkan
penelitian besar (>200 pasien) yang diterbitkan
dalam literatur terbaru, penggunaan kontak lensa
pada keratitis terbukti menjadi faktor predisposisi
utama (29-64%) dari keratitis di negara maju seperti
Portugal, Prancis, Swedia, Amerika Serikat,
Singapura dan Australia. Sebaliknya, keratitis terkait
penggunaan kontak lensa jauh lebih jarang (0-18%)
di negara berkembang karena jumlah pemakai kontak
lensa yang lebih sedikit, menyoroti faktor risiko
perbedaan geografis berdasarkan mikroorganisme
penyebab keratitis antara negara berpenghasilan tinggi
dan berpenghasilan rendah.
Patogenesis keratitis terkait kontak lensa adalah
kompleks dan multifaktorial. Meskipun umumnya
keratitis terkait kontak lensa dipicu oleh trauma
superfisial sekunder, beberapa penelitian telah
membantah hipotesis ini karena ditunjukkan bahwa ada
atau tidak adanya trauma epitel tidak mempengaruhi
risiko atau tingkat keparahan keratitis. Mekanisme
keratitis terkait penggunan kontak lensa berkaitan
dengan berkurangnya pertukaran air mata selama
berkedip (yang mengarah pada potensi degradasi
komponen pelindung pada permukaan mata),
stagnasi air mata di bawah kontak lensa (terutama
kontak lensa lunak) yang mengakibatkan akumulasi
dan perlekatan mikroba ke kornea, berkurangnya
deskuamasi sel epitel korneal, dan perubahan
biokimia cairan air mata. Beberapa faktor
predisposisi keratitis terkait kontak lensa telah
diidentifikasi, termasuk jenis kontak lensa yang
digunakan (risiko lebih tinggi pada kontak lensa
lunak daripada kontak lensa permeabel gas),
kebersihan kotak kontak lensa dan kontak lensa yang
buruk, pemakaian semalaman, penggunaan kontak
lensa kadaluarsa, jenis larutan kontak lensa yang
digunakan, dan kontak lensa yang diresepkan/
dibagikan oleh non-oftalmologis atau non-optik.
Dalam hal etiologi yang mendasari keratitis
terkait kontak lensa paling sering dikaitkan dengan
P. aeruginosa dan Acanthamoeba spp.. Keratitis
pseudomonas adalah salah satu penyebab paling umum
dari keratitis, terutama di negara maju dimana terjadi
peningkatan prevalensi pengunaan kontak lensa. Yildiz
dkk dan Tong dkk mengamati bahwa P.
aeruginosa masing-masing berperan 63% dan 70%
dari keratitis terkait kontak lensa. Sementara
keratitis Acanthamoeba jarang terjadi, sebagian besar
kasus ini (71-91%) diamati pada pemakai kontak lensa.
Yu dkk mengamati bahwa lebih dari
90% keratitis Acanthamoeba dikaitkan dengan
penggunaan lensa. Studi Brasil dalam 32 tahun pada
lebih dari 6000 kasus keratitis, Cariello et
al. melaporkan bahwa pemakai kontak lensa memiliki
risiko 1,7 kali lebih tinggi mengembangkan kultur
Acanthamoeba positif daripada yang tidak
menggunakan kontak lensa. Menariknya, pemakaian
kontak lensa juga terbukti menjadi faktor risiko utama
untuk keratitis jamur dalam sebuah penelitian di AS.
C2. Trauma
Trauma merupakan faktor risiko umum lainnya
yang menyebabkan keratitis di negara maju dan
berkembang. Berdasarkan studi keratitis yang
dilaporkan dalam literatur, petani (54-70%) dan
pekerja berat (11-17%) merupakan pekerjaan utama
di Asia. Kelompok pekerja ini memiliki risiko tinggi
terkena keratitis akibat meningkatnya paparan kerja
terhadap bahan tanaman dan benda asing, yang
sering diperparah dengan kurangnya pelindung mata.
Keratitis jamur sejauh ini merupakan penyebab
paling umum (47-83%) dari keratitis terkait trauma,
terutama di daerah seperti Asia dan Afrika yang di
dominasi oleh komunitas pertanian. Paparan
pekerjaan terhadap bahan vegetatif, bahan organik dan
produk hewani, terutama pada laki-laki dalam
kelompok usia kerja, adalah penyebab utama di wilayah
ini. Risiko keratitis jamur semakin diperbesar oleh
iklim tropis yang kondusif untuk pertumbuhan jamur.
Cariello dkk. mengamati bahwa risiko berkembangnya
keratitis jamur yang terbukti dengan kultur meningkat
empat kali lipat jika pasien menderita trauma terkait
tanaman. Selain itu, beberapa penelitian menunjukkan
bahwa keratitis terkait trauma bernasib lebih buruk
daripada kasus non-trauma. Pan dkk. melakukan
penelitian 10 tahun di Cina dan mengungkapkan bahwa
pasien yang mengalami keratitis terkait trauma
memiliki risiko tinggi mengembangkan keratitis jamur
dan memerlukan intervensi bedah (89%), termasuk
keratoplasti terapeutik dan eviserasi/enukleasi.
Di sisi lain, mayoritas keratitis terkait trauma
yang dilaporkan di negara-negara Eropa disebabkan
oleh bakteri gram-positif, termasuk CoNS, S. aureus,
Streptococci, dan Corynebacterium. Bakteri tersebut
merupakan komensal permukaan mata yang umum,
yang memiliki kemampuan untuk mentolerir iklim
panas dan kering di zona beriklim sedang dan sub-
tropis. Trauma kornea akibat materi non-vegetatif
dengan konsekuensi infeksi oportunistik sekunder
akibat komensal permukaan okular dapat menjelaskan
tingginya tingkat infeksi gram-positif pada keratitis
terkait trauma di wilayah ini.
C3. Penyakit Permukaan Mata dan Kelopak Mata
OSD, meliputi Dry Eye Diseases (DED),
blefaritis, keratopati neurotropik, sindrom steven-
johnson, okular sikatrik pemfigoid dan keratopati
bulosa telah diidentifikasi sebagai salah satu faktor
risiko utama keratitis di negara maju dan
berkembang. Keratitis terkait OSD paling sering
disebabkan oleh bakteri gram-positif (sekitar 60-
80%). Secara khusus, CoNS dan S. aureus terbukti
menjadi penyebab utama keratitis terkait OSD.
DED adalah OSD paling umum yang ditandai
dengan hilangnya homeostasis lapisan air mata dengan
gejala okular, dimana ketidakstabilan lapisan air mata
dan hiperosmolaritas, peradangan dan kerusakan
permukaan mata, dan kelainan neurosensori
memainkan peran etiologis. Gangguan permukaan mata
dapat menyebabkan kerusakan epitel kornea,
pertahanan permukaan mata yang vital, dan peradangan
permukaan mata, akibatnya meningkatkan risiko
keratitis.
Blefaritis posterior atau Meibomian Gland
Diseases (MGD) adalah penyakit kelopak mata
yang umum yang sulit disembuhkan. Hal ini dapat
menyebabkan berbagai komplikasi permukaan mata,
termasuk evaporatif DED, keratitis marginal, dll.
Abnormalitas kelenjar Meibom (misalnya
penurunan kelenjar dan hiperkeratinisasi),
perubahan produk lipid yang disekresikan, dan
disregulasi populasi bakteri dan aktivitas lipase atau
esterase yang sesuai diyakini berkontribusi pada
inflamasi dan infeksi permukaan okular. Studi
Australia dalam 5 tahun, MGD terbukti menjadi
penyebab paling umum (79%) dari OSD yang
terlibat dalam keratitis. Selain itu, Nasolacrimal
Duct Obstruction (NLDO) juga dapat meningkatkan
risiko keratitis, terutama dikaitkan dengan stagnasi
air mata dan pengurangan pertukaran air mata, yang
mengakibatkan akumulasi mikroba dan debris
pada permukaan mata. Chidambaram dkk.,
menunjukkan bahwa NLDO dapat meningkatkan
risiko keratitis jamur dan bakteri, khususnya
keratitis S. pneumonia.
C4. Pasca Operasi Mata
Keratitis dapat terjadi paska beberapa tindakan
operasi mata, termasuk transplantasi kornea, operasi
refraktif, CXL, operasi pterigium, operasi katarak,
dan lain-lain. Transplantasi kornea berfungsi sebagai
operasi pemulihan penglihatan utama untuk berbagai
penyakit kornea, meskipun komplikasi paska operasi
seperti kegagalan cangkok dan keratitis dapat
berkembang.
Dalam studi retrospektif lebih dari 2000
transplantasi kornea, Dohse et al. melaporkan insiden
postkeratoplasty keratitis sebesar 4%, dengan jahitan
longgar dan lepas merupakan salah satu faktor
risiko yang paling umum (24%). Cariello dkk.
menunjukkan bahwa 22% dari kasus keratitis
dikaitkan dengan operasi mata sebelumnya,
khususnya cangkok kornea (56%).
Meskipun keratitis jarang berkembang setelah
operasi refraktif, sejumlah besar operasi refraktif yang
dilakukan secara global menjadikan ini entitas klinis
yang penting. Hal ini didukung oleh penelitian di Brazil
dimana operasi refraktif terbukti menjadi operasi kedua
yang paling umum terkait dengan keratitis. Keratitis
paska operasi refraksi paling sering disebabkan oleh
bakteri gram-positif dan NTM, meskipun infeksi jamur
dan Acanthamoeba juga dapat terjadi. Tingginya
tingkat keratitis bakteri gram-positif setelah jenis
operasi mata lainnya (misalnya operasi katarak, operasi
pterigium) juga diamati, kemungkinan besar sebagai
akibat dari infeksi oportunistik sekunder untuk
komensal permukaan mata.
C5. Penggunaan Steroid Topikal
Steroid umumnya digunakan dalam oftalmologi
sebagai agen imunosupresif/imunomodulator topikal
untuk mengelola berbagai penyakit inflamasi
permukaan intraokular dan okular, termasuk DED,
penyakit mata alergi, non-keratitis, cedera mata kimia,
konjungtivitis sikatrik, dll. Studi SCUT baru-baru ini
juga menunjukkan manfaat steroid topikal ajuvan
dalam meningkatkan hasil visual pada pasien dengan
keratitis bakteri berat dan sentral. Selain mengelola
OSD, steroid topikal juga sering digunakan sebagai
pengobatan topikal paska operasi setelah operasi
permukaan intraokular dan okular, termasuk
transplantasi kornea.
Namun, steroid topikal terkadang dapat bertindak
sebagai pedang bermata dua. Penelitian telah
menunjukkan bahwa steroid topikal dapat
meningkatkan risiko keratitis, terutama keratitis
jamur dan/atau keratitis polimikrobial. Dalam sebuah
studi dari 733 keratitis jamur, Keay et al.
melaporkan bahwa 13% kasus dikaitkan dengan
penggunaan steroid topikal kronis. Selain itu, sebuah
penelitian telah menunjukkan bahwa penggunaan
steroid topikal sebelumnya dapat berdampak negatif
pada hasil klinis keratitis dengan 73% berakhir
dengan hasil yang buruk (didefinisikan sebagai
penglihatan yang lebih buruk dari 6/60, penurunan
penglihatan selama pengobatan, atau perforasi).
Sementara steroid topikal berfungsi sebagai
pengobatan yang efektif untuk stroma HSK, terutama
keratitis terkait imunitas, namun penggunaannya
juga berpotensi memperburuk epitel HSK dan
berujung pada ulkus. Menariknya, sebuah penelitian
di India menunjukkan bahwa 41% dari kasus
keratitis Acanthamoeba dikaitkan dengan
penggunaan steroid topikal. Tingginya tingkat
penggunaan steroid sebelumnya mungkin terkait
dengan fakta bahwa Acanthamoeba keratitis sering
muncul dengan perubahan epitel kornea non-
spesifik dan kesalahan dalam pemberian terapi.
C6. Imunosupresi Sistemik
Imunosupresi sistemik, baik sekunder terhadap
penyakit atau agen imunosupresif, telah terbukti
meningkatkan risiko keratitis. Diabetes mellitus
berfungsi sebagai salah satu faktor risiko sistemik
yang paling penting untuk keratitis. Hiperglikemia
telah terbukti memfasilitasi pertumbuhan mikroba
dan mengubah mikrobiota permukaan mata,
termasuk peningkatan regulasi dan Acinetobacter
sp. serta mempengaruhi homeostasis, sensasi kornea
dan penyembuhan luka epitel kornea, sehingga
meningkatkan risiko keratitis. Pada pasien dengan
neuropati diabetik, pleksus saraf kornea sub-basal
sering terkena dan dapat menyebabkan keratopati
neuropatik dengan komplikasi seperti kornea
meleleh dan keratitis.
Beberapa penelitian besar telah menyoroti
hubungan antara diabetes dan keratitis (sekitar 8-
16%), terutama keratitis jamur dan bakteri. Zbiba
dkk. mengamati bahwa diabetes relatif umum pada
pasien dengan keratitis bakteri (15%) dan keratitis
jamur (16%) serta keratitis bakteri dan jamur
campuran (29%). Selain itu, keratitis virus juga
dilaporkan memiliki prevalensi tinggi di antara
pasien diabetes. Virus, khususnya HSV, ada di
mana-mana pada populasi umum, dengan perkiraan
prevalensi 1,5 per 1000 populasi. Kaiserman dkk.
menunjukkan bahwa pasien dengan diabetes
memiliki insiden yang lebih tinggi secara signifikan
dan tingkat kekambuhan penyakit herpes permukaan
mata bila dibandingkan dengan pasien non-diabetes.
Pan dkk. mengamati bahwa 17% pasien dengan
diabetes memiliki tingkat HSK yang jauh lebih
tinggi dibandingkan dengan keratitis bakteri atau
jamur. Studi lain menjelaskan bahwa didapatkan
semua pasien diabetes dengan keratitis virus, meskipun
ukuran sampelnya kecil. Heterogenitas dalam subtipe
mikroorganisme yang terkait dengan diabetes yang
diamati dalam penelitian yang berbeda kemungkinan
terkait dengan perbedaan faktor predisposisi okular dari
kohort yang diteliti karena lebih dari satu faktor risiko
sering muncul pada pasien dengan keratitis.
Selain diabetes, Jeng et al. mengamati sekitar
sepuluh kali lipat peningkatan risiko keratitis pada
individu yang terkena human immunodeficiency
viruses dibandingkan dengan individu yang sehat
(238,1 vs 27,6 per 100.000 populasi-tahun)
berkaitan dengan pentingnya kekebalan inang dalam
pertahanan permukaan mata. Menariknya, sebuah
penelitian menunjukkan bahwa 55% pasien dengan
HSK memiliki riwayat infeksi saluran pernapasan atas
sebelum infeksi atau rekurensi. Potensi ini dijelaskan
oleh mekanisme terkait dengan enzim sel inang yang
disebut heparanase, merupakan faktor yang diketahui
berkontribusi terhadap patogenesis beberapa virus,
termasuk HSV, respiratory syncytial virus, human
papilloma virus, dan lain-lain. Penyakit ginjal stadium
akhir, terutama yang terkait dengan diabetes, juga
terbukti menjadi faktor risiko keratitis.

D. Resistensi Antimikroba (AMR)

D.1 Ringkasan AMR
AMR telah diakui sebagai krisis kesehatan
masyarakat yang utama dalam dua dekade terakhir,
dengan banyak organisme menular yang
mengembangkan resistensi terhadap agen antimikroba
yang sebelumnya efektif. Perkembangan AMR
sebagian besar didorong oleh banyak faktor, termasuk
penggunaan berlebihan/penyalahgunaan agen
antimikroba di sektor pertanian karena tekanan
komersial, ketidakpastian dalam diagnosis (misalnya
infeksi bakteri vs. infeksi virus) yang mengarah pada
penggunaan antibiotik yang tidak tepat, insentif
keuangan untuk meresepkan antibiotik, dan
penggunaan antibiotik non-resep di kalangan
masyarakat umum, terutama di negara-negara
berpenghasilan rendah dan menengah. Dari sudut
pandang genetik, bakteri terutama mengembangkan
AMR melalui dua strategi, yaitu resistensi mutasi
genetik dan transfer gen horizontal.
D2. AMR dalam Konteks Keratitis
Terapi antibiotik topikal spektrum luas adalah
gold standard pengobatan untuk keratitis.
Bergantung pada tingkat keparahan penyakit dan
preferensi dokter, terapi antibiotik umumnya
diberikan dalam bentuk terapi ganda
menggunakan sefalosporin dan aminoglikosida
atau monoterapi menggunakan fluoroquinolone.
Karena pemberian antibiotik topikal intensif
diterapkan secara langsung dan sering selama
pengobatan keratitis, antibiotik konsentrasi tinggi
dapat dicapai secara efektif di lokasi target (yaitu
kornea yang terinfeksi), yang berpotensi mengurangi
risiko AMR pada infeksi mata. Faktor presdiposi
terjadinya AMR multifaktorial termasuk penggunaan
antibiotik yang tidak bijak pada infeksi mata dan
sistemik, dosis yang tidak tepat, dan representasi
dari prevalensi komunitas resistensi obat dengan
konsekuensi kolonisasi permukaan mata oleh
patogen yang resistan terhadap obat. Misalnya, dalam
uji coba SCUT, terdapat MIC 3,5 kali lipat lebih tinggi
untuk bakteri yang diisolasi dari pasien yang pernah
menjalani pengobatan sebelumnya dengan
fluorokuinolon dibandingkan dengan pasien yang
belum pernah menjalani pengobatan.
Secara keseluruhan, infeksi yang resisten terhadap
fluroukuinolon, resisten methicillin dan multidrug
resistant (MDR; yaitu resisten terhadap 3 atau lebih
antibiotik) semakin dilaporkan di keratitis. Faktor
geografis dan temporal berperan dalam variasi pola
AMR pada infeksi mata. Laporan dari India Selatan
menunjukkan bahwa MDR umumnya diamati di
antara S. pneumoniae (44%), S. epidermidis (14,8%), S.
aureus (14%), dan P. aeruginosa (6%). Namun,
gatifloksasin—fluorokuinolon generasi keempat efektif
melawan sebagian besar bakteri gram-negatif (~90%),
termasuk P. aeruginosa dan Acinetobacter spp .,
sehingga penggunaannya sebagai monoterapi pada
keratitis gram-negatif direkomendasikan dalam kasus
wilayah tersebut. Studi lain dari Cina Selatan juga
melaporkan peningkatan MDR di antara kokus gram-
positif dari 2010 hingga 2018, sementara kerentanan
terhadap fluoroquinolone dan aminoglikosida di antara
basil gram-negatif tetap stabil. Sebaliknya, sebuah
penelitian di India Utara melaporkan tingkat resistensi
yang tinggi dari P. aeruginosa terhadap ciprofloxacin
(57%), moksifloksasin (47%), dan aminoglikosida (52-
60%).
Tren peningkatan infeksi mata terkait MRSA juga
telah dilaporkan dalam beberapa penelitian dalam
dekade terakhir. Studi resistensi antibiotik diantara
mikroorganisme okular di AS mengamati bahwa
tingkat AMR yang tinggi, khususnya resistensi
methicillin, diamati diantara Staphylococci
spp. dan Streptococci spp. dan risikonya meningkat
seiring bertambahnya usia. Lebih mengkhawatirkan, ~
75% dari MRSA dan MR-CoNS adalah MDR. Studi
AS lainnya menunjukkan peningkatan tingkat keratitis
terkait MRSA serta resistensi terhadap
fluoroquinolones, yang mempertanyakan penggunaan
berkelanjutan mereka sebagai monoterapi
primer. Demikian pula, studi Meksiko 10 tahun
menunjukkan bahwa 21-79% dari S. aureus dan 48-
71% dari CoNS resisten terhadap oksasilin (atau
methicillin). P. aeruginosa dan infeksi gram-negatif
lainnya menunjukkan resistensi terhadap oksasilin
(masing-masing 86% dan 90%) dan vankomisin
(masing-masing 97% dan 70%), dengan tren
peningkatan resistensi terhadap ceftazidime yang
diamati dari waktu ke waktu. Studi lain yang dilakukan
di Taiwan juga menyoroti masalah yang muncul dari
resistensi methicillin, dengan MRSA terhitung 43%
dari semua keratitis gram-positif. Di sisi lain,
peningkatan resistensi vorikonazol diamati di Mycotic
Ulcer Treatment Trial (MUTT)-I untuk keratitis jamur,
dengan peningkatan 2,1 kali lipat dalam rata-rata MIC
per tahun setelah penyesuaian untuk organisme
penyebab.
Secara meyakinkan, laporan dari Inggris
menunjukkan bahwa bakteri gram-positif menunjukkan
kerentanan tinggi terhadap sefalosporin (87-100%),
tetapi kerentanan sedang terhadap fluorokuinolon (61-
81%). Namun, bakteri gram-negatif sangat rentan
terhadap aminoglikosida (97-100%) dan fluorokuinolon
(91-100%), menunjukkan bahwa rejimen antibiotik saat
ini (monoterapi fluorokuinolon atau terapi ganda
sefalosporin-aminoglikosida) dapat tetap aman sebagai
pengobatan lini pertama di Inggris. Dalam Studi
Nottingham mengenai keratitis dalam 12 tahun ini,
penulis mengamati tren peningkatan resistensi terhadap
penisilin dari waktu ke waktu pada isolat gram-positif
dan gram-negatif tetapi kerentanan yang umumnya baik
terhadap aminoglikosida dan fluorokuinolon
dipertahankan. Oleh karena itu, tidak diperlukan
perubahan rejimen antibiotik.
D3. Dampak Klinis
AMR merupakan tantangan global dengan dampak
besar pada morbiditas dan mortalitas. Diperkirakan 2
juta orang/tahun di Amerika Serikat terinfeksi
organisme resisten antimikroba, dengan biaya $20
miliar yang dikeluarkan untuk sistem perawatan
kesehatan. Sebuah laporan Inggris baru-baru ini juga
memperkirakan kerugian global sebesar $100 triliun
pada tahun 2050 terkait dengan AMR.
Dalam konteks keratitis, AMR ditemukan
berdampak negatif terhadap hasil klinis keratitis. Kaye
dkk. mengamati bahwa waktu penyembuhan keratitis
kornea diperpanjang dengan peningkatan konsentrasi
penghambatan minimum (MIC; yaitu resistensi
antibiotik) organisme penyebab, termasuk P.
aeruginosa, S. aureus dan Enterobacteriaceae spp .,
terhadap monoterapi fluorokuinolon. Selain itu, Lalitha
et al. menunjukkan bahwa tingkat MIC yang lebih
tinggi dikaitkan dengan peningkatan risiko perforasi
kornea yang signifikan pada keratitis jamur.
AMR terus meningkat secara mengkhawatirkan. Ada
kebutuhan mendesak untuk meningkatkan kesadaran
pemberi resep tentang penggunaan antimikroba yang
bijaksana, untuk memperketat kontrol antimikroba over
the counter (OTC) di banyak negara, dan untuk
 mengembangkan modalitas dan strategi terapi baru
untuk keratitis, termasuk CXL terapeutik dan peptida
pertahanan inang (atau sebelumnya dikenal sebagai
peptida antimikroba), yang menjanjikan sebagai kelas
baru antimikroba di masa depan.
Kesimpulan : Keratitis merupakan penyakit yang masih banyak
ditemukan di negara maju dan berkembang. Karena
kejadian keratitis cenderung diabaikan dalam studi
terbaru, studi prospektif yang dirancang dengan baik
termasuk semua jenis mikroorganisme (yaitu bakteri,
jamur, protozoa dan virus) diperlukan untuk benar-
benar memastikan kejadian dan dampak keratitis.
Pemahaman tentang faktor risiko utama keratitis di
berbagai daerah, terutama pemakaian kontak lensa,
trauma, OSD, dan paska operasi okular, akan
memfasilitasi intervensi kesehatan masyarakat yang
lebih efektif untuk memodifikasi dan mengurangi risiko
keratitis. Tingkat peningkatan Antimicrobial Resistance
(AMR) pada infeksi mata di beberapa negara, termasuk
AS, Cina, dan India, selama dekade terakhir menyoroti
perlunya penggunaan antimikroba yang bijaksana,
kontrol yang lebih ketat terhadap antimikroba OTC dan
pengembangan antimikroba baru dan strategi untuk
terapi.
Rangkuman dan hasil : 1. Kekeruhan kornea merupakan penyebab utama
pembelajaran ke-5 kebutaan secara global, dengan keratitis
menjadi penyebab utama.
2. Keratitis dapat disebabkan oleh berbagai macam
patogen, termasuk bakteri, jamur, virus, parasit
dan infeksi polimikrobial
3. Memakai lensa kontak, trauma dan penyakit
permukaan mata adalah tiga faktor risiko paling
umum dari keratitis.
4. Beberapa penelitian telah menyoroti tren yang
muncul dalam resistensi antimikroba pada infeksi
mata, terutama di AS, Cina dan India.
 Eye (2021) 35:1084–1101
https://doi.org/10.1038/s41433-020-01339-3

REVIEW ARTICLE

Infectious keratitis: an update on epidemiology, causative

microorganisms, risk factors, and antimicrobial resistance
1,2 2
Darren Shu Jeng Ting ●
Charlotte Shan Ho ●
Rashmi Deshmukh2 Dalia G. Said1,2 Harminder S. Dua
● ●
1,2

Received: 20 July 2020 / Revised: 22 October 2020 / Accepted: 24 November 2020 / Published online: 7 January 2021
© The Author(s) 2021. This article is published with open access, corrected publication 2021

Abstract
Corneal opacity is the 5th leading cause of blindness and visual impairment globally, affecting ~6 million of the world
population. In addition, it is responsible for 1.5–2.0 million new cases of monocular blindness per year, highlighting an
ongoing uncurbed burden on human health. Among all aetiologies such as infection, trauma, inflammation, degeneration and
nutritional deficiency, infectious keratitis (IK) represents the leading cause of corneal blindness in both developed and
developing countries, with an estimated incidence ranging from 2.5 to 799 per 100,000 population-year. IK can be caused by
a wide range of microorganisms, including bacteria, fungi, virus, parasites and polymicrobial infection. Subject to the
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geographical and temporal variations, bacteria and fungi have been shown to be the most common causative microorganisms
for corneal infection. Although viral and Acanthamoeba keratitis are less common, they represent important causes for
corneal blindness in the developed countries. Contact lens wear, trauma, ocular surface diseases, lid diseases, and post-ocular
surgery have been shown to be the major risk factors for IK. Broad-spectrum topical antimicrobial treatment is the current
mainstay of treatment for IK, though its effectiveness is being challenged by the emergence of antimicrobial resistance,
including multidrug resistance, in some parts of the world. In this review, we aim to provide an updated review on IK,
encompassing the epidemiology, causative microorganisms, major risk factors and the impact of antimicrobial resistance.

Introduction blindness annually, highlighting an ongoing unchecked

Corneal opacity represents the 5th leading cause of blind-
ness globally, accounting for ~3.2% of all cases [1]. The
recent World Health Organisation (WHO) report high-
lighted that ~6 million of the world population are affected
by cornea-related blindness or moderate/severe visual
impairment, including 2 million of those who are affected
by trachoma [1, 2]. In addition, corneal opacity is estimated
to be responsible for 1.5–2.0 million cases of unilateral
These authors contributed equally: Darren Shu Jeng Ting, Charlotte
Shan Ho
* Harminder S. Dua
profdua@gmail.com
1
Academic Ophthalmology, Division of Clinical Neuroscience,
School of Medicine, University of Nottingham, Nottingham, UK
2
Department of Ophthalmology, Queen’s Medical Centre,
Nottingham, UK
burden on human health [3, 4].
Any significant insult to the cornea such as infection,
trauma, inflammation, degeneration, or nutritional defi-
ciency can result in corneal opacity with visual impairment.
Among all, infectious keratitis (IK) has been shown to be
the most common cause for corneal blindness in both
developed and developing countries [5]. According to a
nationwide study, IK was shown to be the most common
cause of all corneal blindness in China, primarily attributed
to increased risk of trauma, low socioeconomic status and
illiteracy [6]. IK is a common yet potentially vision-
threatening ophthalmic condition, characterised by acute
ocular pain, decreased vision, corneal ulceration, and/or
stromal infiltrates [5]. Previously, it has been recognised as
a “silent epidemic” in the developing world [3], and
recently, a consortium-led proposal has suggested the des-
ignation of IK as a “neglected tropical disease (NTD)” [7],
adding on to the list of NTDs in ophthalmology (i.e. tra-
choma, onchocerciasis and leprosy). The proposal to attain
status of an NTD aims to draw concerted global effort to
tackle IK in under-resourced tropical countries, to amelio-
rate the societal and humanistic burden of IK.
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . .
IK can be caused by a wide variety of pathogens
including bacteria, fungi, protozoa and viruses. In addition,
polymicrobial infection has shown to be accountable for
~2–15% of all IK cases [8–11]. As the ocular surface is
equipped with highly regulated innate and adaptive defense
mechanisms [12], IK rarely occurs in the absence of pre-
disposing factors such as contact lens (CL) wear, trauma,
ocular surface diseases (OSDs), and post-corneal surgery,
which are some of the common risk factors implicated in
IK [13].
IK not only causes visual impairment, but also negatively
impacts on the quality of life (QOL) of the affected indi-
viduals. A study from Uganda reported that IK affected both
vision-related QOL (attributed to vision loss) and health-
related QOL (attributed to pain in the acute phase) [14]. The
psychological impact on these patients was related to the
fear of losing the eye and the social stigma attached. Even
when the visual recovery was complete, the individuals
affected by IK displayed a lower QOL score than the
unaffected controls [14]. Apart from the impact on the
individuals which can affect their economic productivity,
IK is also responsible for a huge economic burden on
society. According to a report in 2010, the US spent an
estimated 175 million dollars on the treatment of IK [15].
Furthermore, complications of IK such as corneal perfora-
tions and scarring form the major indications of corneal
transplants in developing countries such as India, Thailand
and China [13], placing additional burden on the limited
pool of donor corneas.
Considering that most parts of the world affected by IK
are under-resourced, it is highly likely that the actual burden
of IK is underestimated due to the lack of surveillance and
under-reporting. In view of the global burden of IK, this
review aims to provide an updated and comprehensive
overview of the epidemiology, causative microorganisms,
risk factors and the impact of antimicrobial resistance in
relation to IK.
Epidemiology
B.1. Incidence
To date, there are limited studies available in the literature
that examined the incidence of IK and the majority of stu-
dies were conducted more than a decade ago [5]. Depending
on the geographical location and study design, the incidence
of IK has been estimated to be in the range of 2.5–799 cases
per 100,000 population/year [16, 17], particularly more
prevalent in the low-income countries. Previous IK studies
reported an estimated incidence of 2.5–27.6 per 100,000
population-year in the US [16, 18] and 2.6–40.3 per
100,000 population-year in the UK [19, 20]. Our recent
1085
Nottingham IK Study concurred with the findings of these
older studies. We observed a relatively stable incidence of
34.7 per 100,000 population-year in Nottingham, UK,
between 2007 and 2019 [8], highlighting a persistent burden
of IK in the developed countries. Another recent study
conducted in Australia similarly demonstrated a low IK
incidence of 6.6 per 100,000 population-year during the
period of 2005–2015 [21]. However, it is noteworthy that
the incidence reported in these two studies is likely to be
underestimated as the numbers were based on IK patients
who underwent corneal scraping.
In contrast, a substantially higher rate of IK has been
reported in under-resourced countries such as South India
(113 per 100,000 population-year) [22] and Nepal (799 per
100,000 population-year) [17]. The higher incidence
observed in these regions was primarily attributable to the
poorer environmental and personal hygiene, lower level of
education, agricultural industry, increased risk to work-
related corneal trauma and poorer access to sanitation and
healthcare facility.
B.2. Age
The epidemiological patterns and risk factors have been
found to vary with demographic factors such as age, gender
and socioeconomic status. A tabulated summary of the
demographic factors and microbiological profiles of IK is
provided in Table 1 [8–10, 13, 21, 23–43].
IK has been shown to affect individuals across all age
groups. Based on large-scale studies (>500 patients), IK most
commonly affected people aged between 30 and 55 years
(Table 1) [8–10, 13, 21, 24, 25, 29, 31, 35, 37, 39, 42, 43],
primarily attributed to the underlying risk factors such as CL
wear and ocular trauma associated with the working age
group. Patients affected by trauma-related IK secondary to
agricultural products and foreign bodies are usually around
45–55 years old [18, 44]. The employed workforce of some
developing countries is mainly composed of farmers and
manual labourers, rendering them more susceptible to IK of
traumatic aetiology [13, 45]. On the other hand, patients
affected by CL-related IK are usually between 25 and 40
years old [18, 44, 46, 47].
Although prevalence of IK is generally low in the
extremes of age [18, 48–51], IK may serve as a major
contributor to childhood blindness in some countries. For
instance, IK was shown to be the second most common
cause of visual impairment in children aged <15 years in
Uganda [52]. Ophthalmia neonatorum, defined as con-
junctivitis occurring in newborns within 28 days of life, is
another important cause of childhood corneal blindness in
developing countries, particularly when it is affected by
Neisseria gonorrhoea where bilateral ocular involvement is
common [4].
Table 1 Summary of the demographic factors and microbiological profiles of infectious keratitis in the literature published between 2010 and 2020, categorised into six distinct regions. Only

1086
studies that reported more than 500 cases are included.
Year Authors Study period Region Total CS Age Female (%) Positive Organismsa Microbiological profilesb
(years) culture (%)
B (%) F (%) A (%)

UK and Europe
2013 Kaye et al. [23] 1995–2010 Liverpool, UK 2418 – – 35.7 100 0 0 CoNS (26.3); Enterobacteriaceae (15.3);
Streptococci (13.9)
2017 Tan et al. [9] 2004–2015 Manchester, UK 4229 45.9 – 32.6 90.6 7.1 2.3 CoNS (24.4); S. aureus (15.1);
Streptococci (13.3)
2018 Ting et al. [10] 2008–2017 Sunderland, UK 914 55.9 ± 52.1 46.1 91.0 4.2 4.8 CoNS (25.9); S. aureus (13.6);
21.0 Streptococci (12.1)
2019 Tavassoli et al. [24] 2006–2017 Bristol and Bath, UK 2614 47.7 ± 51.1 38.1 91.6 6.9 1.4 CoNS (36.0); Pseudomonas (15.8);
21.2 Streptococci (7.0)
2020 Ting et al. [8] 2007–2019 Nottingham, UK 1333 49.9 ± 49.6 37.7 92.8 3.0 4.2 Pseudomonas (23.6); S. aureus (15.9);
22.2 Streptococci (13.5)
North America
2017 Tam et al. [25] 2000–2015 Toronto, Canada 2330 41.6 ± 53 57.3 86.0 4.9 2.2 CoNS (37); P aeruginosa (10); Streptococcus
24.0 spp. (15)
2018 Peng et al. [26] 1996–2015 San Francisco, US 2203 – – 23.7 100 0 0 S. aureus (20.1); S. viridans (13.2);
Pseudomonas (10.9)
2019 Kowalski et al. [27]c 1993–2018 Pittsburgh, US 1387 – – 100 72.1 6.7 5.2 S. aureus (20.3); Pseudomonas (18.0);
Streptococci. (8.5)
2020 Asbell et al. [28]d 2009–2018 US 6091 – 46.8 100 100 0 0 S. aureus (35.9); CoNS (29); H.
influenza (13)
South America
2011 Cariello et al. [29] 1975–2007 Brazil 6804 42.1 ± 40 48.6 78.9 11.0 3.6 CoNS (41.2); S. aureus (33.1);
21.4 Pseudomonas (18.5)
2013 Marujo et al. [30] 2005–2009 Brazil 2049 45 45 71.6 80.3 7.0 6 Staphylococci (52.5); Corynebacterium
(14.3); Streptococci (10.1)
2015 Hernandez-Camarena 2002–2011 Mexico 1638 45 51.4 38.0 88 12 0 S. epidermis (27.4); Pseudomonas (12.1); S.
et al. [31] aureus (9.0)
2016 Yu et al. [32] 1975–2010 Brazil 859 – 42.1 40.3 100 0 0 CoNS (23.8); S. aureus (20.9);
Pseudomonas (14.2)
Asia
2011 Rautaraya et al. [33] 2006–2009 India 997 – 29.9 74.6 23.4 26.4 1.4 Aspergillus spp. (23.1); Fusarium spp. (19.2);
Staphylococci (5.4)
2012 Lin et al. [34] 2006–2009 India 5221 – – 58 35.7 63.0 1.3 Fusarium spp. (15.5); S. pneumoniae (7.3);
Pseudomonas (5.0)
2013 Kaliamurthy et al. [35] 2005–2012 India 2170 45.7 ± 41.3 77 37.2 22.7 1.0 S. epidermis (44.0); S. aureus (19.5); S.
16.6 pneumonia (11.6)
D. S. J. Ting et al.
Table 1 (continued)
Year Authors Study period Region Total CS Age Female (%) Positive Organismsa Microbiological profilesb
(years) culture (%)
B (%) F (%) A (%)

2015 Lalitha et al. [36] 2002–2012 India 23,897 – – 59 24.7 34.3 2.2 Fusarium spp. (14.5); Aspergillus spp. (8.8);
S. pneumoniae (7)
2015 Wang et al. [37] 2013–2014 China 1000 – 31.8 53.5 0 100 0 Aspergillus spp. (53.8); Fusarium spp. (19.3)
2016 Hsiao et al. [38] 2003–2012 Taiwan 2012 – – 49.3 81.1 16 1.1 Pseudomonas (24.4); CoNS (16.6);
Propionibacterium (9.1)
2017 Zhang et al. [39] 2006–2015 China 6220 45.3 ± 40.6 18.2 100 0 0 S. epidermis (29.3); P. aeruginosa (11);
22.1
2018 Khor et al. [13] 2012–2014 Asia 6626 46.0 39.2 70.7 38 32.7 – Fusarium spp. (18.3); Pseudomonas (10.7);
Aspergillus flavus (8.3)
2019 Acharya et al. [40] 2015–2017 India 1169 – – 100 100 0 0 CoNS (46.3); Pseudomonas spp. (16.2);
Streptococci (15.5)
2019 Lin et al. [41] 2010–2018 China 7229 – – 42.8 52.7 57.6 0 CoNS (28.6); Fusarium spp. (23.5);
Aspergillus spp. (12.2)
Africa and Middle East
2016 Politis et al. [42] 2002–2014 Israel 943 47.0 ± 47 47.9 91.8 8.2 0 CoNS (32.8); Pseudomonas (19.3); S.
25.2 pneumonia (13.0)
Australasia
2019 Cabrera-Aguas et al. 2012–2016 Sydney, Australia 1084 54 48 66 100 0 0 CoNS (45.8); Pseudomonas spp. (12.2); S.
[43] aureus (11.7)
2019 Green et al. [21] 2005–2015 Queensland, 3182 53 ± 22.6 47.6 73.6 93.1 6.3 0.6 CoNS (33.9); Pseudomonas spp. (17.7); S.
Australia aureus (11.2)
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . .

CS corneal scrapes, CoNS coagulase negative staphylococci.

a
Breakdown of organisms; B = Bacteria, F = Fungi, A = Acanthamoeba.
b
The three most common microorganisms isolated in the study.
c
Included all types of ocular infection.
d
Included all types of ocular infection but restricted to bacterial infection only.
1087
1088
In addition, some studies have demonstrated that elderly
patients affected by IK were associated with poor visual
outcome (around 40–75% with visual acuity of <6/60) and
higher rate of complications such as corneal melting, per-
foration and loss of eye (i.e. evisceration or enucleation)
[11, 53, 54]. This might be related to the higher rate of
ocular co-morbidities and the delay in presentation and/or
diagnosis of IK as elderly patients are usually dependent on
spouse or family when seeking medical care and they may
relate their condition to “normal” age-related changes
[55, 56].
B.3. Gender
The majority of studies did not observe any gender pre-
dilection in IK (Table 1). However, when gender difference
or predominance exists, it is usually attributed to the
underlying risk factors in different regions. For instance,
CL-related IK has been shown to exhibit a female pre-
dominance of 57–69% [18, 44, 46, 57], whereas trauma-
related IK is associated with a male predominance of
74–78% [18, 44, 46], correlating with a high male pre-
valence (58–75%) of IK in the under-resourced regions
such as South America [29, 32], Asia [13, 45, 49, 58], and
Africa [51, 59, 60]. Interestingly, a study in Nepal [49]
found that there are significantly more male than female
patients across all the age groups. This might be due to a
combination of higher rate of trauma, lower number of CL
wear, and reduced opportunities among the females to
access medical services due to cultural customs.
B.4. Socioeconomic status and level of education
Low socioeconomic status has been shown to increase the
risk of developing IK, primarily attributed to poor education,
lack of ocular protection and personal hygiene, and limited
access to eye care in rural communities [6, 13, 45, 51, 61]. In
Asia and Africa, amongst those who were diagnosed with
IK, ~45–71% of the patients were illiterate and 62–79% of
them resided in rural areas with a poorer access to healthcare
facilities [51, 60, 62]. In addition, it was found that farmers,
rural residents and illiterates were at a higher risk of
refractory IK with poorer outcomes [51].
In some countries such as Nigeria and Malawi, residents
in rural communities were shown to be more likely to self-
medicate or approach village healers for traditional eye
medicine [59, 63]. Although it would be unfair to conclude
that all therapies performed by traditional healers are
inimical, common beliefs or practises of applying breast
milk or plant products directly to the eye may actually
worsen their keratitis [63]. In addition, patients who had
prior use of traditional eye medicine tended to present later
to the eye care professionals, resulting in delayed treatment
D. S. J. Ting et al.
and poorer visual outcome [63]. Another study conducted in
Nepal reported almost half of the patients with keratitis did
not use any medication, self-medicated or treated with
undocumented medicine [61].
Causative microorganisms
A wide range of microorganisms, including bacteria, fungi,
protozoa (particularly Acanthamoeba), and viruses, are
capable of causing IK. Recently, Ung et al [5]. have pro-
vided a comprehensive summary of the literature concern-
ing the causative microorganisms of IK (up to June 2018).
In view of the recent growing literature, this section aimed
to summarise the evidence based on large IK studies
(>500 sample size) published during 2010–2020 (Table 1)
[8–10, 13, 21, 23–43].
C.1. Bacteria
Bacteria are commonly categorised into Gram-positive and
Gram-negative bacteria based on the difference in the
compositions of bacterial cell envelope. In addition to the
universal structure of inner/cytoplasmic membrane, Gram-
positive bacteria possess a thick outer cell wall, which is
composed of layers of peptidoglycan interspersed with tei-
choic acids and lipotechoic acids, whereas Gram-negative
bacteria consist of a thin middle-layer peptidoglycan and an
additional outer membrane primarily made of lipopoly-
saccharide, which has been shown to play an important role
in the pathogenesis of infection (including IK) and the
contribution to host inflammatory responses [64, 65].
Bacterial keratitis represents the most common type of
IK in most regions, including the UK (91–93%) [8–10, 24],
North America (86–92%) [25], South America (79–88%)
[29–31], Middle East (91.8%) [42], and Australasia
(93–100%) [21, 43]. In terms of specific bacterial strains,
coagulase negative staphylococci (CoNS), which are a
group of common ocular commensal [66], were shown to be
the most commonly isolated organisms (24–46%) in about
half of the included studies [9, 10, 21, 23–25, 29, 31,
32, 35, 39–43]. Other common bacteria implicated in IK
included S. aureus (5–36%), Streptococci spp. (7–16%),
Pseudomonas aeruginosa (5–24%), Enterobacteriaceae
spp. (15%), Corynebacterium spp. (14%), and Propioni-
bacterium spp. (9%; see Table 1). Over the past decade,
there were several studies in the UK documenting a sig-
nificant increase in Moraxella keratitis, which are often
associated with longer corneal healing time [8–10]. Inter-
estingly, Nocardia keratitis, a rare cause of IK, was iden-
tified as the third most common microorganism (11% of all
cases) in the Steroids for Corneal Ulcers Trial (SCUT), and
the outcome was found to be negatively influenced by the
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . .
use of topical steroids [67, 68]. Acid-fast bacilli such as
non-tuberculous mycobacteria (NTM) serve as another
important group of pathogens that are capable of causing IK
[69]. NTM keratitis is commonly associated with refractive
surgery and trauma, and it often requires prolonged and
aggressive treatment for complete eradication, largely
attributed to their propensity to form biofilms [69, 70].
C.2. Fungi
Fungi can be broadly divided into two categories, namely
filamentous and yeast or yeast-like fungi. Filamentous fungi
such as Fusarium spp. and Aspergillus spp. normally thrives
in tropical climates whereas yeast-like fungi such as Candida
spp. were more commonly observed in temperate regions
[71]. Several studies have demonstrated that Fusarium spp.
(13–24%) and Aspergillus spp. (8–30%) were the main
causes of IK in Asia, particularly India and China (Table 1)
[13, 33, 34, 36, 37, 41]. In 2018, the Asian Cornea Society
Infectious Keratitis Study (ACSIKS) included more than
6000 patients from eight Asian countries and re-confirmed
the dominance of Fusarium spp. keratitis within China
(26%) and India (31%) established two decades ago [72–74].
Although the prevalence of fungal keratitis in temperate
regions such as the UK, Europe and North America was
reportedly lower, the growth of yeast-like fungi such as
Candida spp. is relatively common in patients with history of
corneal transplantation or OSDs [44]. In view of the recent
improvement in the diagnostic techniques, rare pathogens
such as Cryptococcus curvatus, Arthrographis kalrae,
Pythium spp., and many others are increasingly being iden-
tified and reported as rare causes of fungal keratitis [75–77].
C.3. Protozoa
Acanthamoeba is a free-living protozoan that is found ubi-
quitously in the environment such as water, soil, air and dust
[78]. Although not as common as bacterial or fungal keratitis,
Acanthamoeba keratitis serves as another important cause of
IK as it is often associated with prolonged treatment course
and poor visual outcome [78]. It was estimated that Acan-
thamoeba keratitis affects 1–33 per million CL wearers per
year [78]. In the UK, Carnt et al [79]. recently confirmed an
outbreak of Acanthamoeba keratitis in the South East England
during 2010–2016, with an approximately threefold increase
compared to the preceding decade.
Based on recent large studies, Acanthamoeba keratitis
accounts for ~0–5% of all IK (Table 1). Most of the
Acanthamoeba keratitis were observed in CL wearer
(71–91%) [32, 60, 80]. However, non-CL wearers can also
develop this infection if their eyes are exposed to con-
taminated water, soil or dust, [81, 82]. One of the Indian
studies reported that only 4% of Acanthamoeba keratitis
1089
cases were associated with CL wear and the remainder were
associated with trauma and/or exposure to contaminated
water [82]. In addition, the clinical features of non-CL
related Acanthamoeba keratitis may differ from CL-related
cases [82]. Moreover, Acanthamoeba sclerokeratitis may
manifest as a rare but difficult-to-treat clinical entity that is
usually associated with poor clinical outcomes [83].
Microsporidial keratitis represents another type of para-
sitic IK that accounts for ~0.4% cases of all IK [84]. It is
mainly observed in Asian countries and may manifest as
superficial keratoconjunctivitis or stromal keratitis. It is
commonly associated with ocular trauma, exposure to
contaminated water/soil, and potentially acquired immuno-
deficiency syndrome [84, 85].
C.4. Viruses
Viral keratitis, most commonly in the form of herpes sim-
plex keratitis (HSK) and herpes zoster keratitis (HZK),
represents a common cause of IK [86, 87]. However, as
viral keratitis cases are commonly treated based on their
typical clinical appearance (e.g. dendritic corneal ulcer in
HSK) and/or previous ocular history, the majority of cases
did not require any microbiological investigation and hence
were not captured in many IK studies. Nonetheless, the
ACSIKS study demonstrated that viral keratitis represented
the most common cause (46%) of IK in China, primarily
attributed to HSK (24%) and HZK (17%) [13]. Another two
studies, conducted in Egypt and China, respectively,
observed that 15–21% of IK were caused by herpetic ker-
atitis [51, 58]. Based on these results, it is likely that viral
keratitis represents an important and common cause of IK in
many other regions, though further studies are required to
elucidate this. Herpetic keratitis is often associated with
neurotrophic keratopathy, which can result in poor corneal
healing, increased risk of further IK and other corneal
complications such as melting and perforation [86, 88].
C.5. Polymicrobial infection
Polymicrobial keratitis (IK caused by two or more causative
microorganisms) has been reported in around 2–15% of all IK
cases [8–11, 21]. Depending on the study design and the
definition used, polymicrobial keratitis may include two or
more types of organisms from the same category (e.g. bac-
teria-bacteria, fungus-fungus) or different categories (bacteria-
fungus, fungus-protozoan). Polymicrobial keratitis often
poses significant diagnostic and therapeutic challenges, and
usually fares worse than monomicrobial keratitis [11, 75, 89].
Khoo et al [11]. observed that patients affected by poly-
microbial keratitis (median of 6/60 vision) had a significantly
worse visual outcome as compared to those affected by
bacterial keratitis (median of 6/18 vision) or culture negative
1090
IK (median of 6/9 vision). In another retrospective com-
parative study, Lim et al [89]. demonstrated that medical
therapy was sufficient to resolve all monomicrobial IK cases
but only 81% of polymicrobial IK. In view of the relatively
common occurrence of polymicrobial keratitis and variably
low culture yield of current microbiological investigation,
clinicians should always maintain a low threshold of repeating
corneal scraping if patients are not responding to either anti-
bacterial or antifungal therapy, even in the presence of posi-
tive culture results.
C.6. Seasonal variations
Pathogens are tremendously adaptive to climate and sea-
sonality. Many studies have shown that IK was most pre-
valent during the summer season, with P. aeruginosa being
one of the most frequently isolated microbes [34, 90, 91]. P.
aeruginosa is a well-recognised organisms associated with
environmental water as in swimming pools [92] and CL
[44, 46, 48, 93, 94]. The seasonal predilection of IK during
summer is attributed to the likely increased use of CL wear
and engagement in water activities. On the other hand,
several studies have shown that the incidence of fungal
keratitis in India peaked during the windy and harvest
seasons, primarily related to a higher risk of trauma sec-
ondary to agricultural activities and agricultural debris
being blown in the eyes by the wind [34, 62].
Seasonal variation was similarly observed in Acantha-
moeba keratitis, though with conflicting results. Lin et al
[34]. observed that Acanthamoeba keratitis occurred more
commonly during summer in South India, potentially rela-
ted to the higher temperature and increased risk of corneal
trauma during windy seasons, whereas Walkden et al [91].
reported an increase in Acanthamoeba keratitis during the
winter in the UK.
Major risk factors
In the majority of IK cases, local and/or systemic risk factors
are usually present. The most common risk factors include CL
wear, ocular trauma, OSDs (e.g. dry eye diseases (DEDs),
neurotrophic keratopathy, rosacea, etc.), lid diseases, post-
corneal surgery (e.g. keratoplasty, corneal cross-linking
(CXL)), and systemic diseases (e.g. diabetes, immunosup-
pression), amongst others. A tabulated summary of large IK
studies reporting the risk factors of IK is provided in Table 2
[11, 13, 18, 29, 32, 35, 44–46, 48–51, 58–62, 93–101].
D.1. Contact lens (CL) wear
CL wear has been recognised as one of the most common risk
factors of IK, particularly in developed countries. A study
D. S. J. Ting et al.
conducted in Northern California reported that the incidence
of IK among CL wearers was ~9.3 times higher than the non-
CL wearers (130.4 vs. 14.0 per 100,000 person-years) [18].
Based on the large studies (>200 patients) published in the
recent literature, CL wear was shown to be the main predis-
posing factor (29–64%) of IK in developed countries like
Portugal [48], France [93], Sweden [95], the US [18, 44, 97],
Singapore[46] and Australia [11]. On the contrary, CL-related
IK was considerably less common (0–18%) in developing
countries due to less number of CL wearers [13, 35, 50,
59, 60], highlighting the geographical disparity in the risk
factors as well as the causative microorganisms of IK between
high income and low-income countries (Table 2).
The pathogenesis of CL-related IK is complex and
multifactorial. Although it is commonly believed that CL-
related IK is triggered by superficial injury secondary to CL
wear, several studies had refuted this hypothesis as it was
shown that the presence or absence of epithelial injury did
not influence the risk or severity of IK [65]. Plausible
mechanisms of CL-related IK include reduction of tear
exchange during blinking (which leads to potential degra-
dation of protective components at ocular surface), tear
stagnation under CL (particularly soft CL) resulting in
accumulation and adherence of microbes to the cornea,
reduced corneal epithelial cell desquamation, and alteration
of tear fluid biochemistry [65]. In addition, multiple pre-
disposing factors of CL-related IK have been identified,
including the types of CL used (higher risk in soft CL than
rigid gas permeable CL), poor CL and CL case hygiene,
overnight wear, use of expired CL, types of CL solution
used, and CL being prescribed/dispensed by non-
ophthalmologists or non-opticians [93, 102–106]. Reports
of IK secondary to the use of cosmetic lens and orthoker-
atology lens have also been highlighted [107, 108].
In terms of underlying aetiologies, CL-related keratitis is
most commonly associated with P. aeruginosa and Acan-
thamoeba spp., which are both free-living microorganisms
that are ubiquitously present in the environment, including
water and CL solutions [47]. As noted above, Pseudomonas
keratitis is one of the most common causes of IK, especially
in the developed countries where there is increased pre-
valence of CL wear. Yildiz et al [102]. and Tong et al [46].
observed that P. aeruginosa was responsible for 63% and
70% of the CL-related IK, respectively. While Acantha-
moeba keratitis is uncommon, most of these cases
(71–91%) were observed in CL wearers [32, 60, 80]. Yu
et al [32]. observed that more than 90% of the Acantha-
moeba keratitis were associated with CL use. In a 32-year
Brazilian study of over 6000 IK cases, Cariello et al [29].
reported that CL wearers had a 1.7 times higher risk of
developing Acanthamoeba-positive culture than non-CL
wearers. Interestingly, CL wear was also shown to be a
major risk factor for fungal keratitis in a US study [44].
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . . 1091

Table 2 Summary of risk factors and associated organisms of infectious keratitis in the literature published between 2010 and 2020, categorised
into six distinct regions. Only studies that reported more than 200 cases are included.
Year Authors Study period Region Patients Age, years Female, % Risk factors (%)
(Mean ± SD)

UK and Europe
2013 Dethorey et al. [93] 2005–2011 France 268 45 50.4 CL (48.1), OSD (33.7), POS (17.5)
2018 Ferreira et al. [48] 2007–2015 Portugal 235 50.0 ± 20.7 55.1 CL (28.9), trauma (28.9), DM (13)
2020 Sagerfors et al. [95] 2004–2014 Sweden 398 49.5 57 CL (45.5), OSD (9.8), corneal transplant (9.5)
North America
2010 Jeng et al. [18] 1998–1999 US 302 42.8 57.3 CL (55), OSD (19.2), trauma (11.9)
2011 Keay et al. [44] 2001–2007 US 733 47.9 46.8 CL (36.6), OSD (28.5), trauma (24.6)
2013 French et al. [96]# 2010 US 2124 39.2 53.5 Scleral ectasia (4.8), CL (4.8), corneal
abrasion (3.1)
2015 Truong et al. [97] 2009–2014 US 318 42.9 40.3 CL (41), OSD (28), trauma (17), topical steroid (4)
South America
2011 Cariello et al. [29] 1975–2007 Brazil 16742 42.1 ± 21.4 40 POS (22.4), CL (12.8), trauma (16.4), topical
steroid (6.6)
2016 Yu et al. [32] 1975–2010 Brazil 859 – 42.1 Topical medication (30.6), Trauma (24), POS
(24), CL (13)
Asia
2011 Kumar et al. [62] 2003–2005 India 200 – 39 Trauma (78.5), OSD (12)
2011 Ganguly et al. [49] 2006–2007 Nepal 1880 – 40.7 Trauma (58), topical steroid (12), OSD (6), CL (5)
2012 Dhakhwa et al. [98] 2007 Nepal 414 – 42.8 Farmers (75.4), trauma (33.3), topical steroid (4.1)
2012 Hussain et al. [99] 2007–2009 Pakistan 228 42.8 ± 21.9 35.1 Trauma (31.5), POS (8.8), topical steroid (6.6)
2012 Deorukhkar et al. 2004–2009 India 852 – 31.7 Trauma (60.2), FB (15.6), POS (9.5)
[100]
2013 Kaliamurthy et al. 2005–2012 India 2170 45.7 ± 16.6 41.3 Trauma (64.0), traditional eye medicine (16.9)
[35]
2015 Sitoula et al. [101] 2011 Nepal 1644 44 ± 16 42 Trauma (60), dacryocystitis (5)
2016 Pan et al. [58] 2003–2012 China 578 52.4 25.4 Trauma (54.7), URTI (11.9), DM (8)
2018 Khor et al. [13] 2012–2014 Asia 6563 46.0 39.2 Trauma (34.7), CL (10.7), POS (6.8), OSD (4.2)
2018 Chidambaram et al. 2012–2013 India 252 50 36 Trauma (71.8), traditional eye medicine (19.0)
[45] topical steroid (9.9), DM (6.7)
2018 Al-Ghafri et al. [50] 2013–2016 Oman 304 52.2 ± 23.2 56.2 Blepharitis (54.3), trachoma (26.0), Other lid
diseases (18.1), CL (17.1), Climate droplet
keratopathy (15.5)
2018 Gautam et al. [61] 2016 Nepal 259 44.9 54.4 Trauma vegetative material (48), topical
steroid (9)
2019 Tong et al. [46] 2012–2016 Singapore 377 33.6 ± 17.2 53.5 CL (64.3), OSD (10), trauma (3.9)
2020 Khor et al. [94] 2010–2016 Malaysia 221 39.5 41.2 Trauma (49.3), CL (23.1), OSD (5.9)
Africa and Middle East
2013 Oladigbolu et al. 1995–2005 Nigeria 228 – 43.4 Trauma (51.3), traditional eye medication (17.1),
[59] topical steroid (5.7)
2014 Mandour et al. [51] 2010–2013 Egypt 340 – 41.2 Trauma (50), POS (14.7), topical steroid (11.8)
2018 Zbiba et al. [60] 2011–2016 Tunisia 230 – 40 OSD (58.7), Trauma (51.3), DM (16), topical
steroid (10.9), CL (9.5)
Australasia
2020 Khoo et al. [11] 2012–2016 Australia 979 54.7 ± 21.5 48.3 CL (63), topical steroid (24), OSD (18)
CL contact lens wear, POS previous ocular surgery, OSD ocular surface diseases, FB foreign bodies, DM diabetes, URTI upper respiratory tract
infection.
#
The data were based on patients presented to general emergency department; therefore, risk factors might not be accurately documented.
1092
D.2. Trauma
Trauma serves as another common risk factor for IK in both
developed and developing countries. Based on the IK stu-
dies reported in the literature, farmers (54–70%) and manual
labour workers (11–17%) constituted the main occupations
in Asia [13, 45, 49, 51, 58, 59, 109]. These groups of
workers were at a high risk of developing IK due to the
increased occupational exposure to plant materials and
foreign bodies, which was frequently compounded by the
lack of eye protection [45, 51, 58, 98, 109].
Fungal keratitis is by far the most common cause
(47–83%) of trauma-related IK, especially in regions such
as Asia and Africa which are dominated by agricultural
communities [45, 51, 58, 60, 94]. Occupational exposures
to vegetative matter, organic materials and animal products,
predominantly in males in the working age group, are the
main causes in these regions. The risk of fungal keratitis is
further magnified by tropical climates, which are conducive
to fungal growth [51, 60]. Cariello et al [29]. observed that
the risk of developing culture-proven fungal keratitis was
increased by four times if the patients suffered from plant-
related trauma. In addition, some studies demonstrated that
trauma-related IK fared worse than non-traumatic cases
[46, 58]. Pan et al [58]. conducted a 10-year study in China
and revealed that patients who presented with trauma-
related IK were at a high risk of developing fungal keratitis
and requiring surgical interventions (89%), including ther-
apeutic keratoplasty and evisceration/enucleation.
On the other hand, the majority of trauma-related IK
reported in European countries were caused by Gram-
positive bacteria, including CoNS, S. aureus, Streptococci,
and Corynebacterium [48, 95]. These are common ocular
surface commensals, which have the ability to tolerate hot
and dry climates in temperate and sub-tropical zones
[51, 110, 111]. Corneal trauma resulting from non-
vegetative matter with consequent secondary opportunistic
infection with ocular surface commensals could explain the
high rate of Gram-positive infection in trauma-related IK in
this region.
D.3. Ocular surface and eyelid diseases
Ocular surface diseases (OSDs), encompassing DEDs, ble-
pharitis, neurotrophic keratopathy, Steven–Johnson syn-
drome, ocular cicatricial pemphigoid and bullous
keratopathy, have been identified as one of the main risk
factors for IK in both developed and developing countries
[18, 44, 49, 60, 97, 112]. OSD-related IK is most commonly
caused by Gram-positive bacteria (around 60–80%)
[11, 60, 95, 112], which constitute the main group of ocular
surface commensals. In particular, CoNS and S. aureus were
shown to be the main culprits in OSD-related IK [95, 112].
D. S. J. Ting et al.
DED is the most common OSD that is characterised by
“a loss of tear film homeostasis with ocular symptoms, in
which tear film instability and hyperosmolarity, ocular
surface inflammation and damage, and neurosensory
abnormalities play etiological roles” [113]. The dysregu-
lated ocular surface health can lead to breakdown of the
corneal epithelium, a vital ocular surface defence, and
ocular surface inflammation, consequently increasing the
risk of IK [60, 114].
Posterior blepharitis or meibomian gland disease (MGD)
is a common eyelid disease, which is difficult to cure. It can
lead to an array of ocular surface complications, including
evaporative DED, marginal keratitis and IK, amongst others
[115]. Meibomian gland abnormalities (e.g. gland dropout
and hyperkeratinisation), alteration of the secreted lipid
products, and the dysregulation of bacterial populations and
their corresponding lipase or esterase activity are believed
to contribute to the ocular surface inflammation and infec-
tion. In a 5-year Australian study, MGD was shown to be
the most common cause (79%) of OSD implicated in IK
[112]. In addition, nasolacrimal duct obstruction (NLDO)
can also increase the risk of IK, primarily attributed to tear
stagnation and reduction of tear exchange, resulting in the
accumulation of microbes and debris on the ocular surface
with increased risk of IK. Chidambaram et al [45]. showed
that NLDO could increase the risk of fungal and bacterial
IK, particularly S. pneumonia keratitis.
D.5. Post-ocular surgery
IK may occur following various ocular surgeries, including
corneal transplant, refractive surgery, CXL, pterygium
surgery, cataract surgery, and others [29, 51, 116, 117].
Corneal transplant serves as the main sight-restoring sur-
gery for a wide range of corneal diseases, though post-
operative complications such as graft failure and IK may
develop. In a retrospective study of over 2000 corneal
transplants, Dohse et al [116]. reported an incidence of post-
keratoplasty IK of 4%, with loose and broken sutures being
reported as one of the most common risk factors (24%)
[116]. Cariello et al [29]. demonstrated that 22% of the IK
cases were associated with prior ocular surgery, particularly
corneal graft (56%). In addition, the paradigm shift of
penetrating keratoplasty to lamellar keratoplasty has created
a new array of host-graft interface complications such as
interface infectious keratitis (IIK), which often causes
diagnostic and therapeutic challenges due to the deep-seated
location of the infection [118, 119]. We have recently
highlighted a clinically challenging case of post-endothelial
keratoplasty interface fungal keratitis, which required
in vivo confocal microscopy for confirmatory diagnosis in
the absence of positive culture results [118]. Fortunately the
interface infection resolved quickly after the discontinuation
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . .
of topical steroids and initiation of appropriate antifungal
treatment.
Although IK rarely develops after refractive surgery, the
significant amount of refractive surgeries performed glob-
ally render this an important clinical entity [120]. This was
supported by a Brazilian study where refractive surgery was
shown to be the second commonest surgery associated with
IK [29]. Post-refractive surgery IK is most commonly
caused by Gram-positive bacteria and NTM, though fungal
and Acanthamoeba infection may also occur [120]. The
high rate of Gram-positive bacterial IK following other
types of ocular surgeries (e.g. cataract surgery, pterygium
surgery) were also observed, most likely as a result of
opportunistic infection secondary to ocular surface com-
mensals [51, 93, 95].
In the recent years, CXL has emerged as a therapeutic
modality for managing corneal ectactic conditions
[121, 122] and moderate-to-severe IK [123–125]. However,
the intraoperative removal of corneal epithelium and post-
operative insertion of bandage CL (which is the current
standard practice in most institutes) can increase the risk of
IK following CXL, particularly in patients with OSD such
as vernal or atopic keratoconjunctivitis [117, 126, 127].
Post-CXL IK may be further complicated by the reactiva-
tion of herpetic keratitis [126] and manifestation of acute
hydrops [127] and corneal melt/perforation [117].
D.6. Use of topical steroids
Steroids are commonly used in ophthalmology as a topical
immunosuppressive/immunomodulatory agent to manage a
wide range of intraocular and ocular surface inflammatory
diseases, including DED, allergic eye disease, non-IK,
chemical eye injury, cicatricial conjunctivitis and many
others [128, 129]. The recent SCUT study also demon-
strated the benefit of adjuvant topical steroids in improving
the visual outcome in patients with severe and central
bacterial keratitis [67]. In addition to managing OSDs,
topical steroids are also frequently used as postoperative
topical treatment following intraocular and ocular surface
surgeries, including corneal transplantation [130].
However, topical steroids can sometimes act as a double-
edge sword. Studies have shown that topical steroids can
increase the risk of IK, particularly fungal keratitis and/or
polymicrobial keratitis [11, 44, 118]. In a study of 733
fungal keratitis, Keay et al [44]. reported that 13% of the
cases were associated with chronic use of topical steroids.
In addition, a study has shown that previous use of topical
steroid could negatively impact on the clinical outcome of
IK, with 73% ending with poor outcome (defined as worse
than 6/60 vision, decreased vision during treatment, or
perforation) [11]. While topical steroids serve as an effec-
tive treatment for stromal HSK, which is primarily an
1093
immune-related keratitis [131], its use can potentially
exacerbate epithelial HSK and culminate in geographic
ulcer [132]. Interestingly, an Indian study showed that 41%
of the Acanthamoeba keratitis cases were associated with
the use of topical steroid [45]. The high rate of prior steroid
use might be related to the fact that Acanthamoeba keratitis
often presents with non-specific corneal epithelial changes
and is mismanaged as viral keratitis [104].
D.7. Systemic immunosuppression
Systemic immunosuppression, either secondary to diseases
or immunosuppressive agents, has been shown to increase
the risk of IK. Diabetes mellitus serves as one of the most
important systemic risk factors for IK. Hyperglycaemia has
been shown to facilitate microbial growth and alter the
microbiota of ocular surface, including an upregulation of
Pseudomonas spp. and Acinetobacter spp. [133], as well as
affect the homeostasis, corneal sensation and wound healing
of the corneal epithelium, thereby increasing the risk of IK
[134]. Sub-basal corneal nerve plexus of patients with dia-
betic neuropathy is often affected and can lead to neuro-
pathic keratopathy with complications such as corneal melt
and IK [135].
Several large studies have highlighted the association
between diabetes and IK (around 8–16%), particularly
fungal and bacterial keratitis [45, 58, 60, 136, 137]. Zbiba
et al [60]. observed that diabetes was relatively common in
patients with bacterial keratitis (15%) and fungal keratitis
(16%) as well as mixed bacterial and fungal keratitis (29%).
In addition, viral keratitis was also reported to have a high
prevalence amongst patients with diabetes [138]. Viruses,
particularly HSV, are omnipresent in the general popula-
tion, with an estimated prevalence of 1.5 per 1000 popu-
lation [139]. Kaiserman et al [140]. demonstrated that
patients with diabetes had a significantly higher incidence
and recurrence rate of ocular surface herpetic eye diseases
when compared to non-diabetic patients. Pan et al [58].
observed that 17% patients with diabetes had a substantially
higher rate of HSK as compared to bacterial or fungal
keratitis. Another study described that all patients with
diabetes presented with IK were of viral origin, though the
sample size was small [51]. The heterogeneity in the sub-
types of microorganisms associated with diabetes observed
in different studies was likely related to the disparity in the
ocular predisposing factors of the studied cohort since more
than one risk factor is often present in patients with IK [11].
Apart from diabetes, Jeng et al [18]. observed an
approximately tenfold increased risk of IK in individuals
affected by human immunodeficiency viruses compared to
healthy individuals (238.1 vs. 27.6 per 100,000 population-
year), highlighting the importance of host immunity in
ocular surface defence. Intriguingly, a study demonstrated
1094
that 55% of the patients with HSK had a history of upper
respiratory tract infection prior to the infection or recurrence
[58]. This could be potentially explained by the mechanism
linked to a host cell enzyme called heparanase [141], which
is a known contributing factor to the pathogenesis of several
viruses, including HSV, respiratory syncytial virus, human
papilloma virus, and others. End-stage renal disease, parti-
cularly associated with diabetes, was also shown to be a risk
factor for IK [142].
Antimicrobial resistance (AMR)
E.1. Overview
AMR has been recognised as a major public health crisis in
the past two decades, with many infectious organisms
developing resistance against previously effective anti-
microbial agents [143]. The development of AMR is largely
driven by a multitude of factors, including the overuse/
abuse of antimicrobial agents in agricultural sectors due to
commercial pressure, uncertainty in diagnosis (e.g. bacterial
infection vs. viral infection) leading to inappropriate use of
antibiotics, financial incentives for prescribing antibiotic,
and use of non-prescription antibiotics among the general
public, particularly in low- and middle-income countries
[143, 144]. From the genetic point of view, bacteria pri-
marily develop AMR through two strategies, namely
genetic mutational resistance and horizontal gene transfer.
The genetic and mechanistic basis of AMR can be referred
to a recent excellent review provided by Munita and Arias
[144].
E.2. AMR in the context of IK
Broad-spectrum topical antibiotic therapy is the gold stan-
dard treatment for IK. Depending on the disease severity
and clinicians’ preference, antibiotic therapy is commonly
administered in the form of dual therapy using cephalos-
porin and aminoglycoside or monotherapy using fluor-
oquinolone [145]. As intensive topical antibiotics are
applied directly and frequently during the treatment of IK,
high concentration of antibiotics can be effectively achieved
at the target site (i.e. the infected cornea), which could
potentially reduce the risk of AMR in ocular infections.
However, a few recent IK studies have highlighted the
emergence of AMR in ocular infections, particularly in the
US [28], China [41] and India [40]. The driving force is
likely to be multifactorial, including the injudicious wide-
spread use of antibiotics in both ocular and systemic
infections [146], incorrect dosing regimen [147], and
representations of the community prevalence of drug
resistance, with consequent colonisation of ocular surface
D. S. J. Ting et al.
by drug resistant pathogens [148]. For instance, in the
SCUT trial, there was a 3.5-fold higher MIC for bacteria
isolated from patients who had previous treatment with
fluoroquinolones compared to treatment naive patients
[149].
A tabulated summary of the literature concerning the
in vitro antibiotic susceptibility and resistance of IK-related
bacteria is provided in Table 3 [8, 9, 21, 24–26, 28,
31, 35, 38, 40–43, 150]. Overall, fluoroquinolone-resistant,
methicillin-resistant and multidrug resistant (MDR; i.e.
resistant to 3 or more antibiotics) infections are being
increasingly reported in IK [28, 31, 35, 40, 41, 150].
Geographical and temporal factors play a role in the var-
iation of AMR pattern in ocular infections. Reports from
Southern India demonstrated that MDR was commonly
observed among S. pneumoniae (44%), S. epidermidis
(14.8%), S. aureus (14%), and P. aeruginosa (6%). How-
ever, gatifloxacin—a fourth-generation fluoroquinolone—
was effective against the majority of Gram-negative bacteria
(~90%), including P. aeruginosa and Acinetobacter spp.,
thus its use as a monotherapy in Gram-negative IK was
recommended in that region [35]. Another study from
Southern China similarly reported an increase in MDR
among Gram-positive cocci from 2010 to 2018, while
susceptibility to fluoroquinolone and aminoglycoside
among Gram-negative bacilli remained stable [41]. In
contrast, a Northern India study reported a high rate of
resistance of P. aeruginosa against ciprofloxacin (57%),
moxifloxacin (47%), and aminoglycoside (52–60%) [40],
highlighting the geographical disparity in the AMR pattern
and the importance of region-specific interrogation of the
AMR profile in ocular infections.
An increasing trend of MRSA-related ocular infection
has also been reported in several studies in the past decade
[28, 31, 41]. The Antibiotic Resistance Among Ocular
Microorganisms study in the US observed that a high rate of
AMR, specifically methicillin resistance, was observed
among Staphylococci spp. and Streptococci spp. and the
risk increased with age [28]. More worryingly, ~75% of the
MRSA and MR-CoNS were MDR. Another US study
demonstrated an increased rate of MRSA-related IK as well
as resistance against fluoroquinolones, which questioned
their ongoing use as primary monotherapy [26]. Similarly, a
10-year Mexico study showed that 21–79% of the S. aureus
and 48–71% of the CoNS were resistant to oxacillin (or
methicillin). P. aeruginosa and other Gram-negative
infections displayed resistance against oxacillin (86% and
90%, respectively) and vancomycin (97% and 70%,
respectively), with an increasing trend of resistance to cef-
tazidime observed over time [31]. Another study conducted
in Taiwan also highlighted the emerging issue of methicillin
resistance, with MRSA accounting for 43% of all Gram-
positive IK [38]. On the other hand, an increase in
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . . 1095

Table 3 A summary of the in vitro antimicrobial susceptibility and resistance of the causative microorganisms of infectious keratitis.
Year Authors Study period Region No. Antibiotic susceptibility (%)a
of cases
CEP AMG FQ

UK and Europe
2017 Tan et al. [9] 2004–2015 UK 4229 86 (P); 61 (N); 88 (P); 97 (N) 83 (P); 91 (N)
2019 Tavassoli et al. [24] 2006–2017 UK 2614 – 100 (P); 97.0-100 (N) 91-100 (P); 97-100 (N)
2020 Ting et al. [8] 2007–2019 UK 1333 100 (P); 81 (N) 95 (P); 98-99 (N) 90-100 (P); 98-100 (N)
North America
2017 Tam et al. [25] 2000–2015 Canada 2330 – 96 (P) 96 (P)
2018 Peng et al. [26] 1996–2015 US 2203 – 50-100 (N) 85-100 (P); 80-100 (N)
2020 Asbell et al. [28] 2009–2018 US 6091 – 97 (MSSA); 62 (MRSA); 94 89-90 (MSSA); 26-29
(MS-CoNS); 71 (MR- (MRSA); 88-89 (MS-CoNS);
CoNS); 97 (N) 43-49 (MR-CoNS); 93-
100 (N)
South America
2013 Vola et al. [150] 2000–2009 Brazil 566 – 93 (MSSA); 70 (MRSA) 96 (MSSA); 62 (MRSA)
2015 Hernandez- 2002–2011 Mexico 1638 18-90 (P); 10- 42-80 (P); 69-98 (N) 54-100 (P); 87-100 (N)
Camarena et al. 92 (N)
[31]
Asia
2013 Kaliamurthy et al. 2005–2012 India 2170 – 31-95 (P); 90-93 (N) 70.4-98 (P); 74-90 (N)
[35]
2016 Hsiao et al. [38] 2003–2012 Taiwan 2012 – 85-88 (N) 89 (P); 94 (N)
2019 Acharya et al. [40] 2015–2017 India 1169 – 73 (P); 89 (N) 69 (P); 69 (N)
2019 Lin et al. [41] 2010–2018 China 7229 84-91 (P); 68- – 63-75 (P); 46-75 (N)
75 (N)
Africa and Middle East
2016 Politis et al. [42] 2002–2014 Jerusalem 943 – 92-94 (P) 97-100% (P)
Australasia
2019 Cabrera-Aguas 2012–2016 Australia 1084 – 86-97 (P); 100 (N) 86-95 (P); 99 (N)
et al. [43]
2019 Green et al. [21] 2005–2015 Australia 3182 – 92 (P); 96 (N) 94 (P); 99 (N)
MSSA Methicillin-sensitive Staphylococcus aureus, MRSA Methicillin-resistant S. aureus, MS-CoNS Methicillin-sensitive coagulase negative
staphylococci, MR-CoNS Methicillin-resistant coagulase negative staphylococci.
a
Antibiotic susceptibility is reported for Gram-positive bacteria (P) and Gram-negative bacteria (N) against three common classes of antibiotics,
namely cephalosporin (CEP), aminoglycoside (AMG) and fluoroquinolone (FQ).

voriconazole resistance was observed in the Mycotic Ulcer
Treatment Trial (MUTT)-I for fungal keratitis, with a 2.1-
fold increase in the mean MIC per year after adjustment for
causative organism [151].
Reassuringly, reports from the UK showed that Gram-
positive bacteria exhibited a high susceptibility to cepha-
losporin (87–100%), but a moderate susceptibility to
fluoroquinolone (61–81%). However, Gram-negative bac-
teria were highly susceptible to both aminoglycoside
(97–100%) and fluoroquinolone (91–100%) [8, 9, 24],
suggesting that current antibiotic regimen (fluoroquinolone
monotherapy or cephalosporin-aminoglycoside dual ther-
apy) could safely remain as the first-line treatment in the
UK. In our recent 12-year Nottingham IK Study, we
observed an increasing trend of resistance against penicillin
over time in both Gram-positive and Gram-negative isolates
but a generally good susceptibility to aminoglycosides and
fluoroquinolones was maintained; therefore, no change of
antibiotic regimen was required [8].
E.3. Clinical impact
AMR represents a global challenge with a huge impact on
morbidity and mortality. It was estimated that 2 million
people/year in USA are infected with antimicrobial resistant
organisms, with a $20 billion cost incurred on the healthcare
system. A recent UK report also predicted a global loss of
$100 trillion by 2050 related to AMR [152].
1096
Within the context of IK, AMR was found to negatively
affect the clinical outcome of IK. Kaye et al [153]. observed
that the corneal healing time of IK was prolonged with the
increase of minimum inhibitory concentration (MIC; i.e.
antibiotic resistance) of the causative organisms, including
P. aeruginosa, S. aureus and Enterobacteriaceae spp.,
against fluoroquinolone monotherapy. In addition, Lalitha
et al [154]. demonstrated that higher level of MIC was
associated with a significantly increase risk of corneal per-
foration in fungal keratitis.
AMR is continuing to increase in an alarming way. There
is a pressing need to increase the awareness amongst pre-
scribers on judicious use of antimicrobials, to tighten the
control of ‘over the counter (OTC)” antimicrobials in many
countries, and to develop novel therapeutic modalities and
strategies for IK, including therapeutic CXL and host
defence peptides (or previously known as antimicrobial
peptides), which hold great promises as a new class of
antimicrobials in the future [123, 155–157].
Conclusions
IK represents a persistent burden on human health in both
developed and developing countries. As the incidence of IK
is likely to be underestimated in the recent studies, well-
designed prospective studies including all types of micro-
organisms (i.e. bacteria, fungi, protozoa and viruses) are
required to truly ascertain the incidence and impact of IK.
Understanding of the major risk factors for IK in different
regions, particularly CL wear, trauma, OSD, and post-
ocular surgery, will facilitate a more effective public health
intervention to modify and reduce the risk of IK. The
increase rate of AMR in ocular infection in several coun-
tries, including the US, China, and India, over the past
decade highlights the need for judicious use of anti-
microbials, tighter control of OTC antimicrobials and
development of new antimicrobials and strategies for ther-
apy. Improvement in the diagnostic yield of microbiological
investigations of IK with emerging technologies such as
next-generation sequencing and artificial intelligence-
assisted platforms could also provide a better guidance on
the appropriate use of antimicrobial therapy in the future,
ultimately reducing the risk of AMR [158, 159].
Methods of literature review
Two authors (DSJT and CSH) searched the PubMed (Jan-
uary 1980–May 2020) for relevant articles related to IK.
Keywords such as “corneal infection”, “corneal ulcer”,
“IK”, “microbial keratitis”, “incidence”, “prevalence”,
D. S. J. Ting et al.
Fig. 1 The PRISMA flow chart detailing the process and results of
literature search for articles related to infectious keratitis.
“epidemiology”, “risk factors”, “antibiotic resistance” and
“antimicrobial resistance” were used. There was no
restriction to the language used. Bibliographies of included
articles were manually screened to identify further relevant
studies. The final search was updated on 15 June 2020.
A web application designed for systematic reviews,
Rayyan (Qatar), was used to help collate the potential stu-
dies and expedite the initial screening of abstracts and titles
[160]. The titles and abstracts obtained from the searches
were independently screened by two authors (DSJT and
CSH) to include studies that fulfilled the eligibility criteria.
The authors then independently assessed the full-text ver-
sion of all selected articles and extracted data onto a stan-
dardised data collection form for data synthesis. The
extracted data included the authors, year of publication,
country, sample size, demographic factors, culture results,
risk factors and in vitro antibiotic susceptibility. Dis-
crepancies were resolved by group consensus and inde-
pendent adjudication (HSD) if consensus could not be
reached. The summary of literature search is detailed in the
PRISMA flow chart (Fig. 1).
Summary
● Corneal opacity represents the 5th leading cause of
blindness globally, with infectious keratitis (IK) being
the main culprit.
● IK can be caused by a wide variety of pathogens,
including bacteria, fungi, viruses, parasites and poly-
microbial infection.
● Contact lens wear, trauma and ocular surface diseases
are the three most common risk factors of IK.
● Several studies have highlighted the emerging trends in
antimicrobial resistance in ocular infections, particularly
in the US, China and India.
Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and. . .
Funding DSJT acknowledges support from the Medical Research
Council/Fight for Sight (FFS) Clinical Research Fellowship (MR/
T001674/1) and the FFS/John Lee, Royal College of Ophthalmologists
Primer Fellowship (24CO4).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
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