Microbial keratitis is a common potentially sight-threatening condition and is considered an ocular emergency. Managing them brings forth multiple challenges to the ophthalmologist one of them being to primarily distinguish an infective from non-infective keratitis. Based on signs, symptoms, history, and laboratory investigations a treatment plan is laid out which is modified based on clinical response and antimicrobial sensitivity. However, if the response to treatment is inadequate or the microbial keratitis is resistant to treatment it becomes mandatory to assess the factors causing it and change the therapeutic strategy accordingly. The present article attempts to look at the different factors which cause resistant microbial keratitis and means to manage them.
Both local/ocular and systemic factors can contribute to the resistant nature of the ulcer and are listed in table 1. The need to address systemic concerns with the help of a physician along with the ocular factors cannot be overemphasized.
4.Choice of topicals
3. On Oral immunosuppressives
Table 1: Factors contributing to resistant microbial keratitis
1. Are you hitting the right target? : Diagnosis
Proper identification of the causative organism is crucial for successful management, clinical features do aid but a microbiological investigation is essential for a confirmatory diagnosis. Corneal scraping for stains, culture, and polymerase chain reaction (PCR) are needed to carry out the investigative procedures. A repeat scraping should be considered if the ulcer is not responding, the initial stains were inconclusive and no growth was noted in the culture media after 48 hours. It is also indicated when a sudden worsening is noted in an earlier well-responding ulcer to rule out a secondary infection.1 However if it’s a deep-seated infection with clinically uninvolved overlying tissue a corneal biopsy or confocal microscopy would help. Confocal microscopy produces real-time images; is especially useful in identifying deep-seated fungal filaments and acanthamoeba cysts but might not be able to identify the bacterial isolates as they are very small in size. However, a few reports of Nocardia being diagnosed with confocal have been published.4 In cases with endothelial plaques an anterior chamber tap can be attempted if confocal is inconclusive or unavailable. PCR is a highly sensitive and rapid technique that is used to amplify and detect small amounts of DNA sequences and is specifically indicated in smear and culture-negative cases.3
2. Is there just one or more targets ?: Superadded infection:
Occasionally a well-responding ulcer suddenly presents with increased symptoms of pain, discomfort, and increase in infiltrate or hypopyon, a secondary or superadded infection should be considered in such situations, and repeat microbiological tests would aid in verification.1
3. Are there any other contributing factors?
Factors like exposure, neurotrophy, dry eye, severe blepharitis, and blockage of nasolacrimal duct/ dacryocystitis, or inadvertent use of topical steroids may all contribute to the delayed/nonhealing of the ulcer and need to be appropriately managed.5
4.Are you hitting it with the right ammunition? : Choice of topical antimicrobials
The choice of topical antimicrobials should be ideally based on sensitivity but incases of bacterial keratitis since they are rapidly progressive, empirical therapy is recommended either in the form of a fluoroquinolone monotherapy or a combination of fortified antibiotics (cephazolin 5% and tobramycin/ gentamycin- 1.4%) till sensitivity reports are available. Subconjunctival antibiotics cause pain, redness, and failure to provide any added advantage to the topical application and therefore are no longer recommended. Oral antibiotics can be considered in cases of endophthalmitis or adjoining scleritis.1However with antifungals the choice is limited and Natamycin is the drug of choice for filamentous fungi. Amphotericin (0.15%) is particularly effective against yeasts and can be combined with topical natamycin for resistant cases. Penetration of natamycin is a concern especially with an overlying intact epithelium and therefore combining topical voriconazole in the treatment of deep-seated infiltrates has been indicated. A recent study showed no added advantage of intrastromal voriconazole to the topical application along with natamycin in treating recalcitrant fungal keratitis. Oral antifungals also have been found to have limited indications.6For acanthamoeba infections combining a biguanide with a diamidine or recently even voriconazole is recommended.7
5. Is the ammunition sufficient? : Adequate dosage
In addition to using the appropriate antimicrobials, the frequency with which it is used is also essential. In severe bacterial ulcers; a loading dose is recommended which necessitates the use of antimicrobials every 5-15 mins for the first 30-60 minutes, then every hourly initially and thereafter reduced based on the clinical response.1In fungal keratitis the antifungals are usually instilled every half to 1 hourly for the first few days and then gradually tapered. Fungal keratitis is slow to respond and the topicals usually need to continue for 1-2 weeks after the complete resolution, however, a bacterial infection resolves much faster and the topicals can be discontinued earlier.6 In cases with acanthamoeba, topicals are continued for almost 4-6 months post scarring of infiltrate.7 However, continued aggressive therapy can cause drug toxicity which by itself could result in delayed epithelisation and a stromal melt and therefore needs to be considered.
6. Are instructions being adhered to? : Compliance
The importance of patient compliance for the resolution of keratitis cannot be overemphasized.
7. Are you dealing with a recalcitrant target? : Refractory organism
Antimicrobial resistance, reduced awareness, diagnostic and therapeutic limitations all contribute in keratitis-related complications, especially in refractory infections. Current research focuses on treatment options or adjuncts beyond antimicrobials to prevent the need for a therapeutic penetrating keratoplasty (TPK) with a few of them being used as surgical adjuncts to prevent recurrences.
i) Photo Activated Chromophore for Keratitis-Corneal Cross-linking(PACK- CXL): PACK CXL now has significant clinical evidence to support its antimicrobial efficacy. The mechanism of action is multifactorial: inactivation of pathogens by direct damage to the bacterial DNA, reduction in inflammatory and immune cells, promoting wound healing by inducing apoptosis, and increasing the resistance to enzymatic degradation. Regulation of toll-like receptors and inflammatory cytokines in fungal keratitis by CXL has been recently reported.8,9
ii) Cryotherapy:Cryotherapy has been used as an adjunct in treating refractory acanthamoeba and pseudomonas keratitis and keratoscleritis.10,11 Recently it has also been used as a surgical adjunct to TPK in Pythium keratitis to reduce recurrence. Mechanism of cellular destruction during freeze phase includes ischaemic infarction, cellular dehydration, and accumulation of toxic concentrates inside the cell which further causes destabilization and rupture of cells. The thaw phase is even more crucial and allows for longer vascular stasis and longer exposure to toxic solutes. The depth of the freeze effect is directly related to the contact time. The best effect is reported when a freezing point is 1 mm larger than the probe, with freezing temperatures ranging from 50–60°C, and the freezing time ranged from 7 to 8 s. 12 Though the primary aim of treating infective keratitis is the resolution of infection, an option which results in minimal adverse effects or complications is always preferred. Histopathological reports done on rabbit corneas confirm corneal stromal elements regenerate after cryotherapy and can tolerate freezing as long as endothelium is not damaged.13,14
iii) Alcohol:Alcohol is a widely used antiseptic and disinfectant. It mainly acts on the cell membrane, alters its permeability and pH. It also decreases the viability of cells by causing cell lysis and inducing apoptosis. Based on its efficacy in reducing recurrence when used as an adjunct in the treatment of Pythium keratitis, the efficacy and safety profile of absolute topical ethanol were evaluated. Microbiologically it was found to inhibit the growth of Pythium at a concentration as low as 20% without causing any stromal necrosis. However the exact dose, strength, and duration of topical alcohol which will be most effective needs further work.15
iv) Argon laser:Argon laser causes thermal damage to the cells resulting in denaturation and coagulation of proteins. It has fungicidal properties and can be used as an adjunctin treating resistant fungal infections.16
v) Cold plasma:Plasma, the fourth state of matter is a partially ionized and overall neutral medium generated by the application of an electric field to a gas phase at low pressure. It is classified as hot and cold based on its energy and electronic density. Cold plasma acts by generating a wide range of reactive oxygen species (ROS) and reactive nitrogen species (RNS) to be effective against a wide spectrum of microorganisms like fungus, bacteria, acanthamoeba, and viruses.17 Reitberger et al studied the effects of cold plasma on the viability of limbal cells and its disinfective potential against common pathogens and concluded that cold plasma reduces or eliminates pathogens without impairing the epithelial cells.18
To summarise, managing a nonresponding ulcer entails a stepwise approach to look for a specific etiological factor and address it. With advances in research, newer modalities of treatment have shown to supplement or act as an alternative therapy for resistant microbial keratitis.
- Lin A, Rhee MK, Akpek EK, et al. Bacterial keratitis preferred practice pattern®. Ophthalmology 2019;126:1-55.
- Levey SB, Katz HR, Abrams DA, et al . The role of 593 cultures in the management of ulcerative keratitis. Cornea 1997;16:383–6.
- Kumar RL, Cruzat A, Hamrah P. Current state of in vivo confocal microscopy in management of microbial keratitis.Semin Ophthalmol. 2010;25:166-170.
- Liu HY, Hopping GC, Vaidyanathan U, Ronquillo YC, Hoopes PC, Moshirfar M. Polymerase Chain Reaction and Its Application in the Diagnosis of Infectious Keratitis.Med Hypothesis Discov Innov Ophthalmol. 2019;8(3):152-155.
- Bharathi MJ, Ramakrishnan R, Meenakshi R, et al . Analysis of the risk factors predisposing to fungal, bacterial & Acanthamoeba keratitis in south India.Indian J Med Res. 2009;130 :749-757.
- Prajna VN, Prajna L, Muthiah S. Fungal keratitis: The Aravind experience. Indian J Ophthalmol. 2017;65:912-9
- Maycock NJ, Jayaswal R. Update on Acanthamoeba Keratitis: Diagnosis, Treatment, and Outcomes.Cornea. 2016;35:713-720.
- Panda A; Krishna NS ; Kumar S. Photo-Activated Riboflavin Therapy of Refractory Corneal Ulcers. Cornea: 2012 ;31:1210-1213
- Jeyalatha Mani V, Parthasarathy D, Padmanabhan P, et al. Therapeutic Effect of Corneal Crosslinking on Fungal Keratitis: Efficacy of Corneal Collagen Crosslinking as an Adjuvant Therapy for Fungal Keratitis in a Tertiary Eye Hospital in South India .Ocul Immunol Inflamm. 2020;1-8.
- Eiferman RA. Cryotherapy of Pseudomonas keratitis and scleritis.Arch Ophthalmol. 1979;97:1637-1639.
- Binder PS. Cryotherapy for medically unresponsive acanthamoeba keratitis.Cornea. 1989;8 :106-114.
- Agarwal S, Iyer G, Srinivasan B,et al. Clinical profile of pythium keratitis: perioperative measures to reduce risk of recurrence.Br J Ophthalmol. 2018;102:153-157.
- Hanna C, Sherman JK: Survival of rabbit corneal cells after the formation and dissolution of intracellular ice. Cryobiology 8:46-72, 1971.
- Maumenee AE, Kornblueth W: Regeneration of corneal stromal cells. Am J Ophthalmol .32:1051, 1949
- Agarwal S, Srinivasan B, Janakiraman N, et al. Role of Topical Ethanol in the Treatment of Pythium insidiosum Keratitis-A Proof of Concept.Cornea. 2020;39 :1102-1107.
- Pellegrino F, Carrasco MA. Argon laser phototherapy in the treatment of refractory fungal keratitis. Cornea 2013;32:95–97.
- Park HJ, Kim SH, Ju HW, et al. Microplasma Jet Arrays as a Therapeutic Choice for Fungal Keratitis.Sci Rep. 2018;8:2422.
- Reitberger HH, Czugala M, Chow C, et al. Argon Cold Plasma-A Novel Tool to Treat Therapy-resistant Corneal Infections.Am J Ophthalmol. 2018;190:150-163.