The Pharmacist’s Role in Managing

Microbial Keratitis
T he cornea is the outermost, central, dome-shaped
part of the eye, and its transparency is of utmost
importance for normal vision. Microbial keratitis is
an acute infection of the cornea that can be caused

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by bacteria, fungi, viruses, or Acanthamoeba. In the
United States, about 30,000 cases of microbial kera-
titis are reported annually, resulting in $175 million
in direct healthcare costs.1 Keratitis is a medical
emergency, and if not treated promptly, it can cause
permanent damage to the cornea, leading to scarring,
loss of transparency, and visual impairment.
Although the cornea is constantly exposed to the ABSTRACT: Microbial keratitis is an acute
microbes present in the environment, the incidence of infection of the cornea that can be caused by
microbial keratitis is uncommon because of the protec- bacteria, fungi, viruses, or Acanthamoeba.
tion offered by epithelial cells, resident immune cells, Contamination of eye drops because of
and tear-film antimicrobial substances.2 Among these improper use or storage, ophthalmic use of
mechanisms, an intact layer of epithelial cells covering steroids, contact lens wear, and certain
the cornea constitutes the strongest barrier to microbes.2 systemic diseases, such as diabetes and HIV,
Therefore, factors that may damage the epithelial bar- are risk factors for developing microbial
rier, such as improper or extended contact lens wear, keratitis. Pharmacists can educate patients
corneal abrasion, trauma, or corneal surgery, are sig- about the risk factors relevant to them and on
nificant risk factors for microbial keratitis.2 Systemic proper use and storage of eye drops and
diseases such as diabetes mellitus or HIV can also be contact lenses. Pharmacists should also be
significant risk factors for microbial keratitis.3 aware of the signs and symptoms of microbial
Use of contaminated eye drops and extended use of keratitis so that patients can be referred for
ocular steroids—and the resultant corneal immunosup- immediate medical attention. Many of the
pression—are also significant risk factors.3 Patients antimicrobials used for treating keratitis are
who may be predisposed to risk factors for infectious not commercially available as eye drops and
keratitis should be educated about the early signs and require compounding. Pharmacists may
symptoms of infection and urged to seek medical atten- compound eye drops or assist prescribers and
tion in a timely manner. Patients with keratitis typically patients in finding a pharmacy licensed to
present with a sudden onset of symptoms, which include compound ophthalmic products.
ocular redness, acute ocular pain, blurred vision, pho-
tophobia, swelling of the eyelids, discharge, and reports ination, and taking a corneal swab culture. A history
of white spots in the field of vision. of the type of corneal injury, predisposing risk factors,
preexisting medical conditions. and characteristic
DIAGNOSIS appearance of the corneal ulcer can help establish a
The diagnosis of microbial keratitis includes obtaining differential diagnosis for the type of microbial kera-
a detailed patient history, performing slit lamp exam- titis. For example, a history of improper contact lens
Lauren Dea, PharmD use or a vegetation injury will be suggestive of Acan-
PGY-1 Acute Care Resident thamoeba or fungal keratitis, respectively, and a
Kindred Hospital
corneal ulcer with dendritic appearance is typical of
La Mirada, California
herpes keratitis.4-6
Jelena Lewis, PharmD
Assistant Professor of Pharmacy Practice
Ajay Sharma, B Pharm, PhD MANAGEMENT OF MICROBIAL KERATITIS
Assistant Professor of Pharmacology
Chapman University School of Pharmacy Bacterial Keratitis
Irvine, California Bacterial infection is the leading cause of microbial
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U.S. Pharmacist • July 2018 • www.uspharmacist.com
 The Pharmacist’s Role in Managing Microbial Keratitis
keratitis. The common pathogens causing bacterial the expensive cost of compounding these antibiotics
keratitis are Pseudomonas aeruginosa, Staphylococcus and the lack of awareness among ophthalmologists
aureus, Staphylococcus epidermidis, Streptococcus about pharmacies that are licensed to compound. Side
pneumoniae, Moraxella, Klebsiella, Proteus, and Ser- effects of these antibiotics that patients should be
ratia.3 Treatment for bacterial keratitis typically involves counseled on include stinging upon instillation and
the use of a fortified aminoglycoside in combination possible toxicity to corneal epithelial cells.10
with a fortified cephalosporin or monotherapy with The fluoroquinolones prescribed for management
a fluoroquinolone (TABLE 1).4,7,8 The fortified antibi- of bacterial keratitis are the second-generation fluo-
otics must be compounded by a licensed compound- roquinolones ciprofloxacin (0.3% ophthalmic solution
ing pharmacy accredited by the Pharmacy Compound- or ointment) and ofloxacin (0.3% ophthalmic solution)
ing Accreditation Board and comply with the standards and the third-generation fluoroquinolone levofloxacin
outlined in USP 797.9 (1.5% ophthalmic solution).4 The ophthalmic solu-
For each medication that is prepared for ophthal- tions of fluoroquinolones are commercially available
mic use, the compounding pharmacy must confirm and FDA-approved for managing bacterial keratitis.4
the dose and sterility, provide storage and “beyond- Ciprofloxacin ointment may be useful as an adjunc-
use” instructions, and indicate the vial lot number. tive therapy for bedtime application in less severe
The recommended fortified antibiotic combination cases. Fluoroquinolone ophthalmic solutions should
for bacterial keratitis is gentamicin or tobramycin be stored at room temperature. The fourth-generation
(9-14 mg/mL), together with cefazolin (50 mg/mL), fluoroquinolones gatifloxacin and moxifloxacin are
to ensure coverage against both gram-positive and not FDA-approved for treating keratitis but are fre-
gram-negative bacteria.4 Aminoglycoside and cefazo- quently used as effective off-label treatment options.
lin ophthalmic solutions need to be stored in a refrig- These newer fluoroquinolones are advantageous in
erator. Cefazolin should be discarded if yellow dis- their increased potency and decreased risk of develop-
coloration develops or after 1 week, whichever comes ing bacterial resistance. The most frequent side effects
first. The advantage of using fortified antibiotics is of fluoroquinolone eye drops include transient dis-
that they are effective against most pathogenic bac- comfort and a burning sensation in the eye. Less
teria causing keratitis. However, a limiting factor is frequent side effects include crystalline precipitates
Table 1

First-Line Antimicrobials for Treatment of Microbial Keratitis

Bacterial Keratitis
0.9%-1.4% gentamicin/ 1 drop every 5-15 min for the first 30-60 min, followed by every 30 min-1 h
tobramycin + 5% cefazolina around the clock. Taper depending upon response
0.3% ciprofloxacin Day 1: 2 drops every 15 min for the first 6 h, then 2 drops every 30 min while awake.
Day 2: 2 drops hourly. Taper down from Day 3 to 2 drops every 4 h
0.3% ofloxacin Days 1-2: 1 to 2 drops every 30 min while awake and every 4-6 h after retiring.
Taper down from Day 3 to every h while awake
1.5% levofloxacin Day 1-3: 1 to 2 drops every 30 min to 2 h while awake and every 4-6 h after
retiring. Taper down from Day 4 to every 1-4 h while awake
Fungal Keratitis
5% natamycin 1 drop every 1-2 h while awake on Day 1, followed by 1 drop 6-8 times daily
Viral Keratitis
1% trifluridine 1 drop every 2 h for a maximum of 9 drops/day; after reepithelialization taper to 1 drop every 4 h
0.15% ganciclovir gel 1 drop every 3 h for a maximum of 5 drops/day; after reepithelialization taper to 1 drop 3 times daily
Acanthamoebab
0.02% chlorhexidine a
Days 1-2: 1 drop every h around the clock. Day 3: every h while awake, then taper to qid
0.02% polyhexamethylene Days 1-2: 1 drop every h around the clock. Day 3: every h while awake, then taper to qid
biguanidea
a
Requires compounding.
b
Not FDA approved.
Min: minute.
Source: References 4, 11-13, 16, 19, 20, 25.

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U.S. Pharmacist • July 2018 • www.uspharmacist.com
 The Pharmacist’s Role in Managing Microbial Keratitis
around the ulcer, especially with ciprofloxacin; lid ophthalmic solution (1%) can be compounded by
margin crusting, foreign-body sensation; conjunctival diluting the IV formulation with water for injection,
hyperemia; and bad taste. Rare side effects include and it should be stored in the refrigerator. Visual
corneal staining, chemical keratitis, allergic reactions, disturbance is the main side effect of voriconazole
facial or lid edema, photophobia, and nausea.11-13 for ophthalmic use.17
The advantage of using fluoroquinolones is that
they are commercially available, have less epithelial Viral Keratitis
toxicity, and are less expensive. Additionally, they The main cause of viral keratitis is herpes simplex
allow patients to use only one medication, compared virus (HSV) type 1. The primary infection occurs
with two separate instillations as required for fortified in the oropharyngeal mucosa, but the virus can
antibiotics, and cause less patient discomfort upon remain latent in trigeminal nerve ganglia for years.
instillation, which may result in better compliance. To cause keratitis, virus gets transported to the
If the causative agent is suspected to be methicil- cornea in a retrograde fashion along sensory nerve
lin-resistant S aureus, then the suggested treatment axons.6 Trigger factors include stress, trauma, ultra-
is vancomycin (15, 25, or 50 mg/mL).4 If Nocardia violet exposure, extreme temperatures, immuno-
is the suspected agent, then sulfamethoxazole-trim- suppression, and menstruation. The actively divid-
ethoprim (16 mg/mL + 80 mg/mL) should be given.4 ing virus infects the corneal epithelial cells, causing
Sulfamethoxazole-trimethoprim eye drops are com- an ulcer that is dendritic in appearance. In a few
mercially available, whereas vancomycin requires cases, the infection can reach the deeper layers of
compounding. corneal epithelium or anterior stroma, leading to
herpetic stromal keratitis, or to the corneal endo-
Fungal Keratitis thelium, resulting in endothelial keratitis, also termed
The most common pathogens responsible for fungal disciform keratitis because of its round, ground-glass
keratitis are Fusarium, Aspergillus, Curvularia, Pencil- like appearance.6
lium, and Candida.5,14,15 The typical pathogenesis of The FDA-approved drugs for epithelial keratitis
fungal keratitis involves a history of corneal trauma are 1% trifluridine solution and 0.15% ganciclovir
from vegetation. The only FDA-approved treatment gel (TABLE 1).6,18 Removal of corneal epithelium, a
for fungal keratitis (TABLE 1) is natamycin, which is process termed debridement, is required for the
effective against Fusarium, Aspergillus, and Can- effective corneal penetration of these antiviral drugs.
dida.5,14,15 Natamycin is commercially available as a Trifluridine should be kept refrigerated at 2°C to
5% ophthalmic suspension and can be stored either 8°C.19 Patients who show hypersensitivity to triflu-
at room temperature or in the refrigerator. No defin- ridine products should not use the ophthalmic
itive data are available on the frequency of adverse formulation. Side effects of this medication include
effects associated with natamycin. Side effects reported a transient burning sensation in the eye and palpe-
in post-marketing surveillance include allergic reaction, bral edema.19 Ganciclovir 0.15% gel may also be
change in vision, chest pain, dyspnea, eye edema, eye used to treat herpes simplex keratitis. Patients using
hyperemia, foreign-body sensation, and paresthesia.16 ganciclovir gel should be counseled on potential
Beside natamycin, amphotericin and voriconazole side effects in order of decreasing frequency includ-
are the two other antifungals that are occasionally ing blurred vision, eye irritation, conjunctival hyper-
used off-label for the treatment of fungal keratitis. emia, and punctate keratitis.20 Patients receiving
Amphotericin has good activity for Aspergillus and either trifluridine or ganciclovir should avoid wear-
Candida, but has only limited activity against Fusar- ing contact lenses during therapy or while signs
ium.5,14,15 Voriconazole offers the advantage of broad and symptoms of herpetic keratitis are present.
spectrum of activity against Candida, Aspergillus, Topical corticosteroids are contraindicated for
and Fusarium. Unlike natamycin, amphotericin and epithelial keratitis. 6 On the other hand, topical
voriconazole are not commercially available as eye corticosteroids along with antivirals are indicated
drops and require compounding. Amphotericin is to suppress inflammation in stromal and endothe-
formulated as a 0.15%-0.5% ophthalmic solution lial keratitis.6 For HSV stromal and endothelial
from its IV formulation. The compounded liposomal keratitis, oral antiviral famciclovir, an l-valyl ester
solution can be kept refrigerated for 1 week after prodrug of acyclovir, and valacyclovir, a diacety-
reconstitution and should be checked periodically lester prodrug of penciclovir, are preferred over the
for discoloration or precipitation. Voriconazole topical antiviral drugs.6
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U.S. Pharmacist • July 2018 • www.uspharmacist.com
 The Pharmacist’s Role in Managing Microbial Keratitis
Acanthamoeba storage of contact lenses is highly valuable since the
Acanthamoeba keratitis is a rare form of keratitis that majority of keratitis cases in the developed world
typically occurs in contact lens wearers, although cases are related to contact lens wear. The importance of
in noncontact lens wearers have also been reported.21 hand washing prior to handling contact lenses should
Typically, a few amoebae gain access to the lens case be emphasized. Contact lenses should not be used
via tap water or the air, and if the case is not cleaned while swimming, especially in fresh water such as
regularly, amoebae rapidly grow to high numbers. ponds or lakes. Advising patients not to wear contact
Wearers of soft contact lenses are at particular risk lenses longer than recommended by the manufacturer
because Acanthamoeba adheres well to the hydrophilic is also imperative. If experiencing eye pain, discom-
polymer of soft lenses.22 Furthermore, soft contact fort, blurry vision, or redness, patients should be
lenses are more difficult to clean compared with rigid instructed to call their physician, remove their con-
lenses.22 Overwearing of soft contact lenses beyond tact lenses, and bring the lenses to the appointment.
the recommended days of use is an additional problem. Contact lenses must be cleaned with contact lens
Pharmacists should emphasize the importance of proper, disinfecting solution, not with water. The contact
regular cleaning and air-drying of lens cases. Lens cases lens solution should never be topped off or transferred
have to be replaced regularly. Contact lenses should into a smaller bottle, and the bottle should be kept
be cleaned and stored using an appropriate contact closed at all times to prevent contamination. Once
lens cleaning solution. Swimming or showering while the lenses are taken out of the case, the case should
wearing contact lenses is not recommended. be rinsed with contact lens solution and left to dry
Acanthamoeba keratitis is notoriously difficult to so it is ready for the next use. The American Opto-
diagnose and treat.23-25 Acanthamoeba exists as a metric Association recommends that contact lens
trophozoite and cyst in soil and water, including cases be replaced at least every 3 months.26 Quitting
chlorinated pool water, because pool chlorination smoking, avoiding overnight use of contact lenses,
does not kill this organism. Management of Acan- and avoiding decorative lenses also help decrease the
thamoeba keratitis (TABLE 1) may involve biguanides, risk of keratitis.21 Studies have shown that patients
which are effective against both cyst and trophozo- who use extended-wear lenses or who wear contacts
ite forms.23-25 The biguanides include chlorhexidine while sleeping have a six- to-eight-fold increased risk
0.02% topical eye drops and polyhexamethylene of contact lens–related eye infections.21,22 If a patient
biguanide 0.02% topical eye drops.23-25 Diamidines does develop microbial keratitis, the pharmacist
are another class of drugs that are used in manage- should realize the importance of referral and empha-
ment of Acanthamoeba keratitis, but they are active size that the patient seek medical attention as soon
against the trophozoite form only.23-25 Damidines as possible.
include propamidine 0.1% topical eye drops and Pharmacists can also play a role in helping the
hexamidine 0.1% topical eye drops.23-25 Flurbiprofen prescriber or patient find a pharmacy that is licensed
ophthalmic solution may also be used in the manage- to compound antibiotics for ocular administration.
ment of pain due to Acanthamoeba keratitis. The Professional Compounding Centers of America
website (www.pccarx.com/contact-us/find-a-com-
ROLE OF THE PHARMACIST pounder) is a resource that can be searched to find a
Pharmacists can play a significant role in educating compounding pharmacy by the state, city, or zip code.
patients who have predisposing risk factors for
microbial keratitis. Educating patients who regularly CONCLUSION
use eye drops for chronic conditions (e.g., glaucoma) Microbial keratitis is an acute corneal infection
on proper use and storage of eye drops can help caused by bacteria, fungi, viruses, or Acanthamoeba.
minimize the chances of contamination. Patients who It is a vision-threatening medical emergency. Phar-
use ocular steroids or contact lenses should be edu- macists need to be aware of the signs and symptoms
cated on the increased risk of keratitis. Pharmacists of keratitis for timely referral and should counsel
can also play a vital role in educating patients on the patient to seek quick medical attention. Quite a
the signs and symptoms of keratitis. The patient few drugs used in the management of microbial
should understand that keratitis is a medical emer- keratitis require compounding and pharmacists can
gency and that seeking early medical intervention is be vital in assisting both the prescriber and the patient
critical for a better vision prognosis. in finding a compounding pharmacy.
Patient education on the proper use, cleaning, and References available online at www.uspharmacist.com.

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U.S. Pharmacist • July 2018 • www.uspharmacist.com