ABSTRACT: Microbial keratitis is an acute infection of the cornea that can be caused by bacteria, fungi, viruses, or Acanthamoeba. Contamination of eye drops because of improper use or storage, ophthalmic use of steroids, contact lens wear, and certain systemic diseases, such as diabetes and HIV, are risk factors for developing microbial keratitis. Pharmacists can educate patients about the risk factors relevant to them and on proper use and storage of eye drops and contact lenses. Pharmacists should also be aware of the signs and symptoms of microbial keratitis so that patients can be referred for immediate medical attention. Many of the antimicrobials used for treating keratitis are not commercially available as eye drops and require compounding. Pharmacists may compound eye drops or assist prescribers and patients in finding a pharmacy licensed to compound ophthalmic products.

US Pharm. 2018;(43):27-30.

The 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 by bacteria, fungi, viruses, or Acanthamoeba. In the United States, about 30,000 cases of microbial keratitis 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 microbes present in the environment, the incidence of microbial keratitis is uncommon because of the protection offered by epithelial cells, resident immune cells, and tear-film antimicrobial substances.² Among these mechanisms, an intact layer of epithelial cells covering the cornea constitutes the strongest barrier to microbes.² Therefore, factors that may damage the epithelial barrier, such as improper or extended contact lens wear, corneal abrasion, trauma, or corneal surgery, are significant risk factors for microbial keratitis.² Systemic diseases such as diabetes mellitus or HIV can also be significant risk factors for microbial keratitis.³ 

Use of contaminated eye drops and extended use of ocular steroids—and the resultant corneal immunosuppression—are also significant risk factors.³ Patients who may be predisposed to risk factors for infectious keratitis should be educated about the early signs and symptoms of infection and urged to seek medical attention in a timely manner. Patients with keratitis typically present with a sudden onset of symptoms, which include ocular redness, acute ocular pain, blurred vision, photophobia, swelling of the eyelids, discharge, and reports of white spots in the field of vision.

DIAGNOSIS

The diagnosis of microbial keratitis includes obtaining a detailed patient history, performing slit lamp examination, and taking a corneal swab culture. A history of the type of corneal injury, predisposing risk factors, preexisting medical conditions. and characteristic appearance of the corneal ulcer can help establish a differential diagnosis for the type of microbial keratitis. For example, a history of improper contact lens use or a vegetation injury will be suggestive of Acanthamoeba or fungal keratitis, respectively, and a corneal ulcer with dendritic appearance is typical of herpes keratitis.^4-6

MANAGEMENT OF MICROBIAL KERATITIS

Bacterial Keratitis

Bacterial infection is the leading cause of microbial keratitis. The common pathogens causing bacterial keratitis are Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Moraxella, Klebsiella, Proteus, and Serratia.³ Treatment for bacterial keratitis typically involves the use of a fortified aminoglycoside in combination with a fortified cephalosporin or monotherapy with a fluoroquinolone (Table 1).^4,7,8 The fortified antibiotics must be compounded by a licensed compounding pharmacy accredited by the Pharmacy Compounding Accreditation Board and comply with the standards outlined in USP 797.⁹

For each medication that is prepared for ophthalmic use, the compounding pharmacy must confirm the dose and sterility, provide storage and “beyond-use” instructions, and indicate the vial lot number. The recommended fortified antibiotic combination for bacterial keratitis is gentamicin or tobramycin (9-14 mg/mL), together with cefazolin (50 mg/mL), to ensure coverage against both gram-positive and gram-negative bacteria.⁴ Aminoglycoside and cefazolin ophthalmic solutions need to be stored in a refrigerator. Cefazolin should be discarded if yellow discoloration develops or after 1 week, whichever comes first. The advantage of using fortified antibiotics is that they are effective against most pathogenic bacteria causing keratitis. However, a limiting factor is the expensive cost of compounding these antibiotics and the lack of awareness among ophthalmologists about pharmacies that are licensed to compound. Side effects of these antibiotics that patients should be counseled on include stinging upon instillation and possible toxicity to corneal epithelial cells.¹⁰

The fluoroquinolones prescribed for management of bacterial keratitis are the second-generation fluoroquinolones ciprofloxacin (0.3% ophthalmic solution or ointment) and ofloxacin (0.3% ophthalmic solution) and the third-generation fluoroquinolone levofloxacin (1.5% ophthalmic solution).⁴ The ophthalmic solutions of fluoroquinolones are commercially available and FDA-approved for managing bacterial keratitis.⁴ Ciprofloxacin ointment may be useful as an adjunctive therapy for bedtime application in less severe cases. Fluoroquinolone ophthalmic solutions should be stored at room temperature. The fourth-generation fluoroquinolones gatifloxacin and moxifloxacin are not FDA-approved for treating keratitis but are frequently used as effective off-label treatment options. These newer fluoroquinolones are advantageous in their increased potency and decreased risk of developing bacterial resistance. The most frequent side effects of fluoroquinolone eye drops include transient discomfort and a burning sensation in the eye. Less frequent side effects include crystalline precipitates around the ulcer, especially with ciprofloxacin; lid margin crusting, foreign-body sensation; conjunctival hyperemia; and bad taste. Rare side effects include corneal staining, chemical keratitis, allergic reactions, facial or lid edema, photophobia, and nausea.^11-13

The advantage of using fluoroquinolones is that they are commercially available, have less epithelial toxicity, and are less expensive. Additionally, they allow patients to use only one medication, compared with two separate instillations as required for fortified antibiotics, and cause less patient discomfort upon instillation, which may result in better compliance.

If the causative agent is suspected to be methicillin-resistant S aureus, then the suggested treatment is vancomycin (15, 25, or 50 mg/mL).⁴ If Nocardia is the suspected agent, then sulfamethoxazole-trimethoprim (16 mg/mL + 80 mg/mL) should be given.⁴ Sulfamethoxazole-trimethoprim eye drops are commercially available, whereas vancomycin requires compounding.

Fungal Keratitis

The most common pathogens responsible for fungal keratitis are Fusarium, Aspergillus, Curvularia, Pencillium, and Candida.^5,14,15 The typical pathogenesis of fungal keratitis involves a history of corneal trauma from vegetation. The only FDA-approved treatment for fungal keratitis (Table 1) is natamycin, which is effective against Fusarium, Aspergillus, and Candida.^5,14,15 Natamycin is commercially available as a 5% ophthalmic suspension and can be stored either at room temperature or in the refrigerator. No definitive data are available on the frequency of adverse effects associated with natamycin. Side effects reported in post-marketing surveillance include allergic reaction, change in vision, chest pain, dyspnea, eye edema, eye hyperemia, foreign-body sensation, and paresthesia.¹⁶

Beside natamycin, amphotericin and voriconazole are the two other antifungals that are occasionally used off-label for the treatment of fungal keratitis. Amphotericin has good activity for Aspergillus and Candida, but has only limited activity against Fusarium.^5,14,15 Voriconazole offers the advantage of broad spectrum of activity against Candida, Aspergillus, and Fusarium. Unlike natamycin, amphotericin and voriconazole are not commercially available as eye drops and require compounding. Amphotericin is formulated as a 0.15%-0.5% ophthalmic solution from its IV formulation. The compounded liposomal solution can be kept refrigerated for 1 week after reconstitution and should be checked periodically for discoloration or precipitation. Voriconazole ophthalmic solution (1%) can be compounded by diluting the IV formulation with water for injection, and it should be stored in the refrigerator. Visual disturbance is the main side effect of voriconazole for ophthalmic use.¹⁷

Viral Keratitis

The main cause of viral keratitis is herpes simplex virus (HSV) type 1. The primary infection occurs in the oropharyngeal mucosa, but the virus can remain latent in trigeminal nerve ganglia for years. To cause keratitis, virus gets transported to the cornea in a retrograde fashion along sensory nerve axons.⁶ Trigger factors include stress, trauma, ultraviolet exposure, extreme temperatures, immunosuppression, and menstruation. The actively dividing virus infects the corneal epithelial cells, causing an ulcer that is dendritic in appearance. In a few cases, the infection can reach the deeper layers of corneal epithelium or anterior stroma, leading to herpetic stromal keratitis, or to the corneal endothelium, resulting in endothelial keratitis, also termed disciform keratitis because of its round, ground-glass like appearance.⁶

The FDA-approved drugs for epithelial keratitis are 1% trifluridine solution and 0.15% ganciclovir gel (Table 1).^6,18 Removal of corneal epithelium, a process termed debridement, is required for the effective corneal penetration of these antiviral drugs. Trifluridine should be kept refrigerated at 2°C to 8°C.¹⁹ Patients who show hypersensitivity to trifluridine products should not use the ophthalmic formulation. Side effects of this medication include a transient burning sensation in the eye and palpebral edema.¹⁹ Ganciclovir 0.15% gel may also be used to treat herpes simplex keratitis. Patients using ganciclovir gel should be counseled on potential side effects in order of decreasing frequency including blurred vision, eye irritation, conjunctival hyperemia, and punctate keratitis.²⁰ Patients receiving either trifluridine or ganciclovir should avoid wearing contact lenses during therapy or while signs and symptoms of herpetic keratitis are present. Topical corticosteroids are contraindicated for epithelial keratitis.⁶ On the other hand, topical corticosteroids along with antivirals are indicated to suppress inflammation in stromal and endothelial keratitis.⁶ For HSV stromal and endothelial keratitis, oral antiviral famciclovir, an l-valyl ester prodrug of acyclovir, and valacyclovir, a diacetylester prodrug of penciclovir, are preferred over the topical antiviral drugs.⁶

Acanthamoeba

Acanthamoeba keratitis is a rare form of keratitis that typically occurs in contact lens wearers, although cases in noncontact lens wearers have also been reported.²¹ Typically, a few amoebae gain access to the lens case via tap water or the air, and if the case is not cleaned regularly, amoebae rapidly grow to high numbers. Wearers of soft contact lenses are at particular risk because Acanthamoeba adheres well to the hydrophilic polymer of soft lenses.²² Furthermore, soft contact lenses are more difficult to clean compared with rigid lenses.²² Overwearing of soft contact lenses beyond the recommended days of use is an additional problem. Pharmacists should emphasize the importance of proper, regular cleaning and air-drying of lens cases. Lens cases have to be replaced regularly. Contact lenses should be cleaned and stored using an appropriate contact lens cleaning solution. Swimming or showering while wearing contact lenses is not recommended.

Acanthamoeba keratitis is notoriously difficult to diagnose and treat.^23-25 Acanthamoeba exists as a trophozoite and cyst in soil and water, including chlorinated pool water, because pool chlorination does not kill this organism. Management of Acanthamoeba keratitis (Table 1) may involve biguanides, which are effective against both cyst and trophozoite forms.^23-25 The biguanides include chlorhexidine 0.02% topical eye drops and polyhexamethylene biguanide 0.02% topical eye drops.^23-25 Diamidines are another class of drugs that are used in management of Acanthamoeba keratitis, but they are active against the trophozoite form only.^23-25 Damidines include propamidine 0.1% topical eye drops and hexamidine 0.1% topical eye drops.^23-25 Flurbiprofen ophthalmic solution may also be used in the management of pain due to Acanthamoeba keratitis.

ROLE OF THE PHARMACIST

Pharmacists can play a significant role in educating patients who have predisposing risk factors for microbial keratitis. Educating patients who regularly use eye drops for chronic conditions (e.g., glaucoma) on proper use and storage of eye drops can help minimize the chances of contamination. Patients who use ocular steroids or contact lenses should be educated on the increased risk of keratitis. Pharmacists can also play a vital role in educating patients on the signs and symptoms of keratitis. The patient should understand that keratitis is a medical emergency and that seeking early medical intervention is critical for a better vision prognosis.

Patient education on the proper use, cleaning, and storage of contact lenses is highly valuable since the majority of keratitis cases in the developed world are related to contact lens wear. The importance of hand washing prior to handling contact lenses should be emphasized. Contact lenses should not be used while swimming, especially in fresh water such as ponds or lakes. Advising patients not to wear contact lenses longer than recommended by the manufacturer is also imperative. If experiencing eye pain, discomfort, blurry vision, or redness, patients should be instructed to call their physician, remove their contact lenses, and bring the lenses to the appointment. Contact lenses must be cleaned with contact lens disinfecting solution, not with water. The contact lens solution should never be topped off or transferred into a smaller bottle, and the bottle  should be kept closed at all times to prevent contamination. Once the lenses are taken out of the case, the case should be rinsed with contact lens solution and left to dry so it is ready for the next use. The American Optometric Association recommends that contact lens cases be replaced at least every 3 months.²⁶ Quitting smoking, avoiding overnight use of contact lenses, and avoiding decorative lenses also help decrease the risk of keratitis.²¹ Studies have shown that patients who use extended-wear lenses or who wear contacts while sleeping have a six- to-eight-fold increased risk of contact lens–related eye infections.^21,22 If a patient does develop microbial keratitis, the pharmacist should realize the importance of referral and emphasize that the patient seek medical attention as soon as possible.

Pharmacists can also play a role in helping the prescriber or patient find a pharmacy that is licensed to compound antibiotics for ocular administration. The Professional Compounding Centers of America website (www.pccarx.com/contact-us/find-a-compounder) is a resource that can be searched to find a compounding pharmacy by the state, city, or zip code.

CONCLUSION

Microbial keratitis is an acute corneal infection caused by bacteria, fungi, viruses, or Acanthamoeba. It is a vision-threatening medical emergency. Pharmacists need to be aware of the signs and symptoms of keratitis for timely referral and should counsel the patient to seek quick medical attention. Quite a few drugs used in the management of microbial keratitis require compounding and pharmacists can be vital in assisting both the prescriber and the patient in finding a compounding pharmacy.

REFERENCES

1. Pepose JS, Wilhelmus KR. Divergent approaches to the management of corneal ulcers. Am J Ophthalmol. 1992;114:630-632.
2. Sharma A, Taniguchi J. Emerging strategies for antimicrobial drug delivery to the ocular surface: implications for infectious keratitis. Ocul Surf. 2017;15:670-679.
3. Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea. 2008;27:22-27.
4. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred practice pattern guidelines, bacterial keratitis-limited revision. San Francisco, CA: American Academy of Ophthalmology; 2013.
5. Wu J, Zhang WS, Zhao J, Zhou HY. Review of clinical and basic approaches of fungal keratitis. Int J Ophthalmol. 2016;9:1676-1683.
6. American Academy of Ophthalmology. Herpes simplex virus keratits. A treatment guideline. San Francisco, CA: American Academy of Ophthalmology; 2014.
7. Wong RL, Gangwani RA, Yu LW, Lai JS. New treatments for bacterial keratitis. J Ophthalmol. 2012;831502.
8. McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. Br J Ophthalmol. 2014;98:1470-1477.
9. Bloch D, Fiscella RG, Labib S, Jensen MK. Compounding in ophthalmology: know the risks. Rev Ophthalmol. 2005:55-61.
10. Fraunfelder FW. Corneal toxicity from topical ocular and systemic medications. Cornea. 2006;25:1133-1138.
11. Ciloxan (ciprofloxacin ophthalmic solution) package insert. Fort Worth, TX: Alcon Laboratories, Inc; April 2018.
12. Ocuflox (ofloxacin ophthalmic solution) package insert. Irvine, CA: Allergan; April 2017.
13. Quixin (levofloxacin ophthalmic solution) package insert. Tampere, Finland: Santen Pharmaceuticals; February 2004.
14. Garg P, Roy A, Roy S. Update on fungal keratitis. Curr Opin Ophthalmol. 2016;27:333-339.
15. Lakhundi S, Siddiqui R, Khan NA. Pathogenesis of microbial keratitis. Microb Pathog. 2017;104:97-109.
16. Natacyn (natamycin ophthalmic suspension) package insert. Fort Worth, TX: Alcon Laboratories, Inc; April 2018.
17. Xiong WH, Brow RL, Reed B, et al. Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci. 2015;56:1367-1373.
18. Tsatsos M, MacGregor C, Athanasiadis I, et al. Herpes simplex virus keratitis: an update of the pathogenesis and current treatment with oral and topical antiviral agents. Clin Exp Ophthalmol. 2016;44:824-837.
19. Virtoptic (trifluridine ophthalmic solution) package insert. New York, New York,NY: Pfizer Inc. March 2018.
20. Zirgan (ganciclovir ophthalmic gel) package insert. Bridgewater, NJ: Bausch+Lomb, a division of Valeant Pharmaceuticals North America LLC; June 2016.
21. Stapleton F, Edwards K, Keay L, et al. Risk factors for moderate and severe microbial keratitis in daily wear contact lens users. Ophthalmology. 2012;119:1516-1521.
22. Stapleton F, Keay L, Edwards K, et al. The incidence of contact lens-related microbial keratitis in Australia. Ophthalmology. 2008;115:1655-1662.
23. Maycock NJ, Jayaswal R. Update on Acanthamoeba keratitis: diagnosis, treatment, and outcomes. Cornea. 2016;35:713-720.
24. Lorenzo-Morales J, Khan NA, Walochnik J. An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite. 2015;22:10.
25. Saidel M. Acanthamoeba keratitis treatment. American Academy of Ophthalmology. www.aao.org/current-insight/acanthamoeba-keratitis-treatment. Accessed June 21, 2018.
26. American Optometric Association. Contact lens care recommendations. www.aoa.org/patients-and-public/caring-for-your-vision/contact-lenses. Accessed June 21, 2018.

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