Microbial Keratitis ( Bacterial, Fungal, Viral and Protozoal ) in Adults
|Next review: 01/06/2024|
|Approved By: Improving Antimicrobial Prescribing Group|
|Copyright© Leeds Teaching Hospitals NHS Trust 2018|
This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
Guideline for Diagnosis and Management of Microbial Keratitis (Bacterial, Fungal, Viral and Protozoal) in Adults
Microbial Keratitis ( Bacterial, Fungal, Viral and Protozoal ) in Adults
Microbial keratitis (infection of the cornea with ulceration) should be suspected in any patient with risk factors (see box 1.) and a red eye.
History: patients may describe any of the following:
Identify any risk factor(s) (check Box 1):
Characteristic lesion is a corneal epithelial defect with associated infiltrate into the stroma.
Empirical antimicrobial therapy
Directed antimicrobial therapy
Microbial keratitis is inflammation of the cornea due to infection with bacteria, fungi, viruses or protozoa, but is rare in the absence of predisposing factors. It can be a sight threatening condition and delays in diagnosing and treating this condition have been associated with a 50% reduction in healing with good visual outcomes. If scarring occurs it can lead to visual loss (especially if central cornea affected) and untreated or severe keratitis can lead to corneal perforation with the potential to develop into an endophthalmitis and the possible loss of an eye. As this can occur within 24 hours if virulent organisms are present it is vital that there is prompt identification and treatment.1,2
In the last 10-12 years contact lens wear has become the major cause of keratitis in developed countries, with the risk being 80 times that compared to patients with no ocular risk factors. Overnight wear of soft contact lenses has a risk five times greater than daily wear soft lenses and twenty times greater than rigid lenses. Contact lens wear is the greatest risk factor for bacterial keratitis independent of other factors, including hygiene, and it has been reported that 65% of all new cases of keratitis in London were due to contact lens wear.3 Poor hygiene practices double the risk of bacterial keratitis and one study from Moorfields shows that some disposable lenses (Acuvue) may have a higher risk for bacterial keratitis.4
Geography and underlying causes determine the most likely causative organisms e.g. fungal keratitis is more common in tropical countries and Acanthameoba more common in contact lens wearers.
The introduction of refractive surgery, especially laser-assisted in-situ keratomileusis (LASIK), appears to have coincided with the appearance of keratitis caused by more unusual organisms, such as Nocardia and Mycobacterium spp.6 Numerous factors may account for the apparent changes in causative organisms but might include: culture techniques; use of single agent therapy (i.e. fluoroquinolones); increased use of topical corticosteroids (in refractive and cataract surgery); increased population of systemically immunodeficient patients; and an expansion in the use of soft contact lenses, especially extended-wear and cosmetic lenses.6
Local patterns of antimicrobial resistance can vary and treatment guidelines need to be amended accordingly.7 For example, in a US centre, Gentamicin resistance among staphylococci has remained low (<10%) while resistance to quinolones and Cefuroxime increased.
Microbial keratitis should be suspected in any contact lens wearer with a red eye.
History: patients may describe any of the following
It is important to identify the precipitating factor(s) in each case (see box 1).
The characteristic lesion of bacterial keratitis is a corneal epithelial defect (ulcer) with associated suppurative infiltrate into the stroma. (Although some pathogens cause characteristic changes to the cornea, examination findings alone are insufficient to make a microbiological diagnosis).
Clinical features suggestive of fungal keratitis:
The clinical presentation of fungal keratitis is insidious and slowly-progressive ulceration of the cornea with variable degrees of inflammation and pain. Hypopyon may be seen. Characteristic features include feathery edges to the ulcer, a dry grey elevated infiltrate and satellite lesions.14
Diagnosis of Acanthamoeba infection is difficult and it is important to have a high index of suspicion especially in contact lens wearers. As it is often initially diagnosed as herpes simplex, it is worth reviewing contact lens wearers who have been newly diagnosed with herpes simplex if they have significant pain and poor response to therapy.
Clinical features suggestive of Acanthamoeba keratitis:
(Since early Acanthamoeba keratitis can appear dendritic, never diagnose HSV keratitis in a contact lens wearer without attempting to culture Acanthamoeba keratitis.)
The first symptoms of herpes simplex infection are usually irritation, photophobia and tearing. As corneal anaesthesia usually occurs early in the course of the infection the symptoms may be minimal. The most characteristic lesion is the dendritic ulcer, which occurs in the corneal epithelium and has a typical branching, linear pattern with feathery edges and terminal bulbs. However HSV may form a geographic ulcer in which the edges of the ulcer loose their feathery quality and an ulcerative or vesicular blepharitis may also occur.
Herpes simplex causes epithelial keratitis, an inflammation of the epithelial cells of the cornea and as it usually resolves after 1-2 weeks the rational for treatment is to minimize stromal damage and scaring. Patients who are immune deficient are more likely to develop stromal keratitis (inflammation of the stromal layer). The rate of recurrence of ocular herpes for people with one episode is 10% at 1 year, 23% at 2 years and 50% at 10 years. The risk of recurrence of ocular herpes also increases with the number of previous episodes reported.15
Recommendation: An ophthalmologist should undertake Investigation and management of suspected microbial keratitis.
Recommendation: A corneal scrape should be performed by an appropriately trained person (according to Standard operating procedure – appendix 1), on corneal ulcers in which any of the following features are present:
[Evidence level C] 6
Recommendation: In cases of contact lens associated keratitis the contact lens and contact lens case should be sent for culture (the lens and contact lens fluid will be cultured). Advise patients the case will not be returned.
Recommendation: If the patient is not responding to treatment at 48 hours and no organism has been cultured, consider stopping topical antibiotics for 12-24 hours and then re-sampling1, this should be done in conjunction with a consultant ophthalmologist.
Recommendation: A corneal biopsy should be sent for culture if debridement is required or if there is no response to treatment.
Recommendation: All patients with keratitis should be started on a mydriatic with cycloplegic action.
Recommendation: For severe cases of microbial keratitis (as judged clinically) atropine 1% eye drops once a day should be used.
Recommendation: For milder cases of microbial keratitis (as judged clinically) cyclopentolate 1% twice daily eye drops may be used as an alternative. Once the anterior chamber reaction has settled, topical cycloplegia can be discontinued.
Recommendation: Topical debridement of the cornea (in conjunction with corneal scrape sampling) can be a useful adjunct to therapy as it removes necrotic tissue and enhance antibiotic penetration.
Recommendation: Good lid hygiene is important especially in cases of blepharitis, all patient should receive patient information leaflet. A BMJ-recommended blepharitis leaflet can be found at patient.co.uk (www.patient.co.uk/health/Blepharitis.htm)16
Recommendation: Initially all topical ocular corticosteroids should be stopped or significantly reduced.
Recommendation: Contact lenses should be temporarily stopped until treatment is complete (see below)
Recommendation: Contact lens wear may be resumed two weeks after completion of the course of treatment providing the patient is asymptomatic.
Recommendation: For patient comfort a preservative free lubricant e.g. Carmellose 1% eye drops three to four times a day (adjusted up or down as required to maintain comfort) should be used especially if there are any epithelial defects.
Debridement is a common practice as it is thought to aid healing by increasing antibiotic penetration.17 There is little documented evidence of clinical trials to support this.
|Empirical Antimicrobial Treatment|
The aim of treatment is to resolve corneal inflammation and infection and to restore the corneal integrity with minimal scarring and vascularisation thereby restoring visual function.1
Recommendation: Benzalkonium chloride - free products should be used if there is a history of toxicity or evidence of toxicity develops on therapy.12
Recommendation: Corneal scrapings should be taken before antimicrobial therapy is started (Therapy can be modified once culture or sensitivity results are known – see directed therapy section.)
Recommendation: All cases of keratitis should be commenced on empirical antibacterial therapy pending cultures results.
Recommendation: Initial empirical therapy for small ulcers (<1mm) contact lens related keratitis is: Ofloxacin 0.3% eye drops hourly day and night for 24 hours and then hourly by day only. (Levofloxacin 0.5% unit dose if preservative free required)
Recommendation: Initial empirical therapy for large ulcers (>1mm) or in patients with ocular surface disease is: Ofloxacin 0.3% eye drops hourly (Levofloxacin 0.5% unit dose if preservative free required) and Cefuroxime 5% eye drops hourly day and night for 24 hours and then hourly by day only. Review at 48 hours – (see duration section) and onward referral to the corneal service.
Recommendation: If the patient gives a clear history of anaphylaxis to penicillin or a clear history of allergy to cephalosporin then empirical regimen is Ofloxacin 0.3% eye drops hourly plus Gentamicin 1.5% eye drops (instead of Cefuroxime ) hourly for 24 hours and then hourly day time only and then review.
If a patient is developing an allergy or intolerance to the benzalkonium chloride preservative consider swapping to Levofloxacin 0.5% preservative free and Gentamicin 1.5% eye drops preservative free (if available). Cefuroxime 5% eye drops is already preservative free.
Recommendation: topical Gentamicin should be reserved for second line therapy and used in place of Cefuroxime when clinical response is suboptimal at 48 hours and cultures remain negative (or for cephalosporin allergic patients).
Recommendation: Intensive topical therapy with drops is recommended. Hourly at first and then if the patient is responding after 24 hours gradually reduced slowly over several days to four times a day.
Recommendation: Routine addition of antifungal treatment is NOT required prior to microbiology results unless there is a history of long term topical steroid use OR immunocompromise OR ocular contamination with vegetative matter AND multifocal corneal infiltrates are seen and considered likely to be fungal keratitis by a consultant ophthalmologist.
Recommendation: Empirical therapy for suspected fungal keratitis: amphotericin 0.15% eye drops applied hourly.
Intensive topical therapy can lead to high concentrations of drug levels in the cornea maximising the possibility that the minimum inhibitory concentration of infecting bacteria are exceeded. It is not recommended that after initial intensive therapy the frequency of instillation is reduced to less than four times a day as concerns that sub therapeutic levels may occur and resistance can develop.1 Ointments do not provide the same concentration of antimicrobial and are therefore not recommended.
The ideal initial antimicrobial regimen should be effective against the likely corneal pathogens, and have low rates of resistance, minimal toxicity to ocular tissues, easy/comfortable to administer and penetrate rapidly into the cornea.6
The Ofloxacin study group found that Ofloxacin was as effective as single agent therapy.19 However, with reports of resistance developing to Ofloxacin it is current practice to use a combination of antibiotics unless the ulcer is small and non sight-threatening.
Aminoglycosides are effective for pseudomonal and coliform infections and have activity against staphylococci; resistance to Gentamicin in these microbial groups is not prevalent. Unfortunately, with intense treatment with Gentamicin 1.5% eye drops there can be marked epithelial toxicity with pain, redness, punctuate staining and retardation of epithelial healing. Therefore cefuroxime 5% and Ofloxacin ).3% eye drops are used first line and Gentamicin 1.5% eye drops substituted for Ofloxacin if there is insufficient clinical response.18-20
No robust head to head trials of monotherapy verses dual therapy have been performed.
Ofloxacin 0.3% eye drops is a preserved eye drop and contains benzalkonium chloride. Frequent application of benzalkonium chloride is toxic to the cornea and in some patients can lead to ocular surface pathology. Benzalkonium chloride can disrupt the tear film, decreasing the tear film break up time and lead to corneal erosion.12 If a patient is allergic to benzalkonium chloride or is showing signs of toxicity a benzalkonium -free preparation of Levofloxacin 0.5% eye drops is available. Levofloxacin is the L-enantiomer of Ofloxacin and as it is more soluble than Ofloxacin , it is available as a 0.5% solution (compared to 0.3% Ofloxacin ). Little clinical evidence is available for the treatment of keratitis however it has been found to be non-inferior to Ofloxacin in the treatment of conjunctivitis.21
The positive cultures from corneal scrapes at LTHT have been audited over a four-year cycle from 2006 to 2009. Over that period, three patients with severe pseudomonal keratitis had a poor clinical response to Ofloxacin 0.3% eye drops and Cefuroxime 5% eye drops in combination, but responded well to Ofloxacin 0.3% eye drops and Gentamicin 1.5% eye drops in combination. As expected, these strains were resistant to Cefuroxime ; they were susceptible to both Ofloxacin and Gentamicin in vitro. Several isolates of staphylococci and streptococci were resistant to Ofloxacin , but sensitive to Cefuroxime . The Gram positive organisms were all cultured from patients with ocular surface disease.
Systemic antibiotics are not usual in the treatment of bacterial keratitis. However, oral doxycycline is a metalloproteinase inhibitor and its addition to a topical antimicrobial regimen has been advocated by some to prevent corneal perforation in large ulcers with corneal thinning as part of anti-inflammatory therapy for ocular surface disease (Dose 100mg 12-hourly).19 It is worth noting that this approach has not been shown to be beneficial in infective keratitis but has been described primarily for severe chemical ocular injuries.22 If it is used, duration should therefore be kept as short as possible in an attempt to reduce adverse effects and colonization with resistant bacteria. NB. Tetracyclines are becoming an increasingly important therapy for infections caused by multi-resistant bacteria such as meticillin resistant Staphylococcus aureus (MRSA).
Choice of empirical antifungal
Anti viral therapy
Aciclovir 3% eye ointment is licensed in the UK, is relatively cheap and even though there are few comparative studies on toxicity it is regarded as having a low toxicity therefore can be recommended as first line treatment.
TFT 1% eye drops is unlicensed in the UK and although widely used in the USA it has poor penetration if the cornea is intact and requires initial administration of every two hours. It is significantly more expensive than aciclovir and is therefore not recommended first line.
Ganciclovir 0.15% eye drops is also licensed for the treatment of HSV in the UK. It does not appear to be more effective than aciclovir but is better tolerated and associated with a lower incidence of visual disturbances,24 it is therefore recommended as second line.
There is some evidence that physical debridement plus topical antiviral therapy is more effective than debridement alone but as the quality of the evidence is low firm recommendations cannot be supported.15
Adding steroids to antivirals in the treatment of stromal keratitis significantly reduced the persistence or progression of stromal inflammation and shortened the duration of stromal keratitis (median duration 26 days with corticosteroid vs 72 days with placebo; difference 46 days 95% CI 14 days to 58 days). However, it is usual to delay the use of steroids until epithelial healing has occurred as topical steroids applied to a herpetic corneal ulcer can lead to the development of an amoeboid ulcer which can be slow to heal and difficult to treat. Steroids should never be used without antiviral cover and with very careful monitoring by an ophthalmologist.15
The addition of oral acyclovir to topical treatment has not been found to be more effective than topical treatment alone. However, long term oral treatment was found to decrease the incidence of recurrence after one year compared with placebo.15
Herpes Zoster should be treated aggressively with oral anti-viral drugs. (See treatment for herpes zoster)
Trifluothymide (unlicensed) 1% eye drops is used in patients who have not responded to aciclovir. Instilled every two hours up to a maximum of nine times a day for one week then reduced to five times a day. Treatment should be continued for several days after healing has occurred.
|Directed Antimicrobial Treatment (when microbiology results are known)|
Recommendation: When culture results are available, antimicrobial therapy should be modified to optimise treatment of the pathogen(s) identified and to minimise unnecessary adverse effects of therapy.
Corneal scrape results are usually available after 48 hours. Discuss the results with microbiology if required and consider altering treatment according to sensitivities.
Coliforms isolated (e.g. Escherichia coli, Serratia, Enterobacter…)
Recommendation: For large ulcers (>1mm) or OSD, stop the topical Cefuroxime 5% eye drops and commence topical Gentamicin 1.5% eye drops hourly in combination with topical Ofloxacin 0.3% eye drops, provided isolate is susceptible to both agents.
There is no direct evidence to support directed therapy for staphylococci. Meticillin-susceptible S. aureus (MSSA) is susceptible to Cefuroxime 5% eye drops but has variable susceptibility to Ofloxacin 0.3% eye drops, while MRSA is often resistant to both. Coagulase negative staphylococci are also often resistant to both these agents.
Moxifloxacin 0.5% eye drops have been found to be more potent than other fluoroquinolones against Mycobacterium chelonae and equivalent in activity for M. fortuitum. Although more clinical trials are required to confirm these results it may be useful in the treatment of mycobacterial keratitis25.
Recommendation: If a patient with Candida keratitis is responding poorly to topical amphotericin at 48 hours, consider changing to topical voriconazole 1% eye drop instilled hourly initially and titrated down according to response. This is an unlicensed product obtained from NHS specials units.
Recommendation: Treatment of keratitis due to a mould (usually Fusarium or Aspergillus): Topical natamycin 5% eye drops initially hourly for 48 hours and then reduce to 2 hourly for 72 hours, tapered according to response. (continue empirical amphotericin until natamycin is available, via pharmacy)
Recommendation: Treatment of severe fungal infections which extend into the sclera or anterior chamber, or lack of response to initial agent after 2-3 days: add chlorhexidine 0.2% eye drops initially hourly and decreased according to response to the initial agent and oral voriconazole 200mg 12-hourly for at least 2 weeks. (Voriconazole may be increased to 300mg 12-hourly if no response occurs) [Evidence level C]
Recommendation: If required due to disease progression,
Recommendation: If corneal infection progresses in spite of vigorous antifungal therapy, surgical intervention may be required, i.e. excision biopsy/penetrating keratoplasty10
Since the Cochrane review was published, for the first time a large randomised, prospective, blinded study has demonstrated that topical 5% natamycin eye drops resulted in significantly better clinical and microbiological outcomes in 162 patients with confirmed fungal keratitis compared to 161 patients receiving topical 1% voriconazole eye drops.30 This difference was largely driven by the success of natamycin in treating Fusarium infections versus voriconazole (p<0.001). This study demonstrated superiority of natamycin against mould infections, hence its inclusion as first line therapy for a confirmed mould keraritis. This study did not include any yeasts infections, so amphotericin remains recommended therapy for confirmed yeast keratitis. (Note evidence for natamycin already in)
Voriconazole has activity in vitro against a wide range of fungal pathogens including those likely to cause fungal keratitis in the UK31 and in vitro it is generally more active than other antifungals.31-33 Topical voriconazole penetrates the cornea and achieves therapeutic concentrations in the aqueous, whilst oral voriconazole achieves therapeutic concentrations in the vitreous for most organisms with the possible exception of Fusarium species.34 Outcomes from non-comparative, observational data in patients receiving topical voriconazole +/- oral or injections of voriconazole have recently been reported for 26 patients and only 13 of them responded, with 11 requiring penetrating keratoplasty and two enucleation.35 Although other groups have reported more encouraging results,34,36 these concerns plus the practical issues of obtaining, storing and funding voriconazole mean that it use should be confined to treatment failures with first line agents or very severe cases.
Although many centres use a combination of topical and oral therapy, particularly in severe infections, there is currently no evidence to support this. One study comparing topical itraconazole with topical and oral itraconazole and found no difference in responses, although it was a small study with no statistical analysis.28 Some authors have suggested that use of combination therapy may reduce the risk of development of resistance,8 but again there is no evidence to support this. In spite of this, the addition of oral voriconazole has been recommended for severe infections because the risk of losing the eye is so high.
The use of intracameral and intrastromal voriconazole has been anecdotally reported in the management of fungal keratitis and endophthalmitis, usually in patients resistant to topical and/or systemic therapy34,37 Various doses have been used, generally with favourable results,37,38 but reports were all case reports with no comparator.
Recommendation: Alternative to propamidine isothionate 0.1% is hexamidine 0.1% eye drops only if propamidine is unavailable.Same frequency as propamidine eye drops.
Recommendation: Alternative to chlorhexidine 0.02%, e.g. in allergic patient, is polyhexamethylene biguanide (PHMB) 0.02% and used as the same frequency as chlorhexidine.
Herpes simplex virus
If it is a stromal keratitis the addition of a corticosteroid under careful monitoring has been found to reduce inflammation. For recurrent infections long term prophylactic treatment with oral acyclovir may reduce recurrence.
For pregnant patients
|Duration of Treatment|
Confirmed fungal keratitis
|Switch to oral agent(s)|
|Target patient group:||Any patient with confirmed or suspected microbial keratitis|
|Target professional group(s):||Pharmacists
Secondary Care Doctors
- Ophthalmologists AAo. Preferred practice pattern guideline. Bacterial Keratitis. 2011.
- Bennett HG, Hay J, Kirkness CM, Seal DV, Devonshire P. Antimicrobial management of presumed microbial keratitis: guidelines for treatment of central and peripheral ulcers. Br J Ophthalmol. Feb 1998;82(2):137-145.
- Dart JK, Stapleton F, Minassian D. Contact lenses and other risk factors in microbial keratitis. Lancet. Sep 14 1991;338(8768):650-653.
- Radford CF, Minassian DC, Dark JK. Disposable contact lens use as a risk factor for microbial keratitis. British Journal of Ophthalmology. 1998;82:1272-1275.
- Tuft SJ, Matheson M. In vitro antibiotic resistance in bacterial keratitis in London. Br J Ophthalmol. Jul 2000;84(7):687-691.
- Barnes SD, Pavon-Langston D, Azar DT. Microbial keratitis. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 1. 7th ed. Philadelphia: Churchill Livingstone; 2010:1539-1553.
- Afshari NA, Ma JJ, Duncan SM, et al. Trends in resistance to ciprofloxacin, cefazolin, and gentamicin in the treatment of bacterial keratitis. J Ocul Pharmacol Ther. Apr 2008;24(2):217-223.
- Tuli SS. Fungal keratitis. Clin Ophthalmol. 2011;5:275-279.
- Tuft SJ, Tullo AB. Fungal keratitis in the United Kingdom 2003-2005. Eye (Lond). Jun 2009;23(6):1308-1313.
- Thomas PA, Kaliamurthy J. Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect. Mar 2013;19(3):210-220.
- Radford CF, Minassian DC, Dart JK. Acanthamoeba keratitis in England and Wales: incidence, outcome, and risk factors. Br J Ophthalmol. May 2002;86(5):536-542.
- Bartlett JD, Jaanus SD. Clinical ocular pharmacology. 5th ed: Butterworth Heinemann Elsevier; 2008.
- Wilhelmus KR, Mitchell BM, Dawson CR, et al. Slitlamp biomicroscopy and photographic image analysis of herpes simplex virus stromal keratitis. Arch Ophthalmol. Feb 2009;127(2):161-166.
- Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. Aug 2004;15(4):321-327.
- Barker NH. Ocular herpes simplex. Clinical evidence. 2008;2008.
- Turnbull AM, Mayfield MP. Blepharitis. BMJ. 2012;344:e3328.
- Allan BD, Dart JK. Strategies for the management of microbial keratitis. Br J Ophthalmol. Aug 1995;79(8):777-786.
- Daniell M. Overview: Initial antimicrobial therapy for microbial keratitis. Br J Ophthalmol. Sep 2003;87(9):1172-1174.
- Morlet N, Daniell M. Microbial keratitis: what's the preferred initial therapy? View 2: Empirical fluoroquinolone therapy is sufficient initial treatment. Br J Ophthalmol. Sep 2003;87(9):1169-1172.
- Mills R. Microbial keratitis: what's the preferred initial therapy? View 1: corneal scraping and combination antibiotic therapy is indicated. The British journal of ophthalmology. Sep 2003;87(9):1167-1169.
- Keating GM. Levofloxacin 0.5% ophthalmic solution: a review of its use in the treatment of external ocular infections and in intraocular surgery. Drugs. Jun 18 2009;69(9):1267-1286.
- Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea. May 2000;19(3):274-277.
- Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane database of systematic reviews (Online). 2010(12):CD002898.
- Croxtall JD. Ganciclovir ophthalmic gel 0.15%: in acute herpetic keratitis (dendritic ulcers). Drugs. Mar 26 2011;71(5):603-610.
- Abshire R, Cockrum P, Crider J, Schlech B. Topical antibacterial therapy for mycobacterial keratitis: potential for surgical prophylaxis and treatment. Clinical therapeutics. Feb 2004;26(2):191-196.
- Prajna NV, John RK, Nirmalan PK, Lalitha P, Srinivasan M. A randomised clinical trial comparing 2% econazole and 5% natamycin for the treatment of fungal keratitis. Br J Ophthalmol. Oct 2003;87(10):1235-1237.
- Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Archives of ophthalmology. Jun 2010;128(6):672-678.
- Agarwal PK, Roy P, Das A, Banerjee A, Maity PK, Banerjee AR. Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study. Indian journal of ophthalmology. Sep 2001;49(3):173-176.
- FlorCruz NV, Peczon IV, Evans JR. Medical interventions for fungal keratitis. Cochrane database of systematic reviews (Online). 2012;2:CD004241.
- Prajna NV, Krishnan T, Mascarenhas J, et al. The Mycotic Ulcer Treatment Trial: A Randomized Trial Comparing Natamycin vs Voriconazole. Arch Ophthalmol. Dec 10 2012:1-8.
- Lalitha P, Shapiro BL, Srinivasan M, et al. Antimicrobial susceptibility of Fusarium, Aspergillus, and other filamentous fungi isolated from keratitis. Arch Ophthalmol. Jun 2007;125(6):789-793.
- Galarreta DJ, Tuft SJ, Ramsay A, Dart JK. Fungal keratitis in London: microbiological and clinical evaluation. Cornea. Oct 2007;26(9):1082-1086.
- Marangon FB, Miller D, Giaconi JA, Alfonso EC. In vitro investigation of voriconazole susceptibility for keratitis and endophthalmitis fungal pathogens. Am J Ophthalmol. May 2004;137(5):820-825.
- Hariprasad SM, Mieler WF, Lin TK, Sponsel WE, Graybill JR. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. Jul 2008;92(7):871-878.
- Ramakrishnan T, Constantinou M, Jhanji V, Vajpayee RB. Factors affecting treatment outcomes with voriconazole in cases with fungal keratitis. Cornea. Apr 2013;32(4):445-449.
- Al-Badriyeh D, Neoh CF, Stewart K, Kong DC. Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis. Clin Ophthalmol. 2010;4:391-405.
- Prakash G, Sharma N, Goel M, Titiyal JS, Vajpayee RB. Evaluation of intrastromal injection of voriconazole as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J Ophthalmol. Jul 2008;146(1):56-59.
- Shen YC, Wang CY, Tsai HY, Lee HN. Intracameral voriconazole injection in the treatment of fungal endophthalmitis resulting from keratitis. Am J Ophthalmol. Jun 2010;149(6):916-921.
- Hammersmith KM. Diagnosis and management of Acanthamoeba keratitis. Curr Opin Ophthalmol. Aug 2006;17(4):327-331.
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