Recent trends: Medical management of infectious keratitis.

This review article highlights the newer diagnostic modalities and approaches in the medical management of infectious keratitis. A Medline literature search conducted to March 2014 has been included. Recent studies or publications were selected from international indexed journals using suitable key words. Development of specular microscopy and polymerase chain reaction (PCR) has a promising role as diagnostic modalities in infectious keratitis, especially in refractory cases. Previously fortified antibiotics have been the mainstay of treatment for bacterial keratitis. Recently, the advent of fourth-generation fluoroquinolones monotherapy has shown promising results in the management of bacterial keratitis. Corneal collagen cross-linking is being considered in the refractory cases. Topical natamycin and amphotericin B should be considered as the first choice anti-fungal agents in suspected filamentous or yeast infection respectively. Voriconazole and newer routes of administration such as intrastromal and intracameral injection of conventional anti-fungal agents have demonstrated a positive clinical response. Ganciclovir is a newer anti-viral agent with promising results in herpes simplex keratitis. Thus, introduction of newer diagnostic modalities and collagen cross-linking along with fourth-generation fluoroquinolones and newer azoles have a promising role in the management of infectious keratitis.

Introduction

Until date, infectious keratitis poses a diagnostic dilemma due to the varied presentation and visual morbidity if adequate control measures are not instituted in time.

Although the conventional causes are categorized into a variety of pathogens such as bacteriae, fungi, viruses and protozoae, confusion in the etiological diagnosis superadded with the problem of increasing resistance to the older anti-microbials often leads to a delay in the initiation of appropriate treatment. This has led the researchers to develop newer diagnostic and treatment modalities. Over the past few years, ophthalmologists worldwide have witnessed changing trends in the diagnostic techniques such as polymerase chain reaction (PCR) and confocal microscopy, as well as treatment strategies such as usage of ultraviolet light and newer antimicrobials.[1]

All these medical advancements have widened the scope of improvement of refractory cases of infectious keratitis. It is, therefore, essential to update our knowledge regarding the diagnosis and management of infectious keratitis.

Diagnosis

Although a detailed history along with presenting clinical features usually suffice in identifying the causative agent but it is highly recommended to thoroughly investigate the type of causative organism by combining the conventional diagnostic techniques of smear and culture with the newer diagnostic tools like confocal microscopy, PCR or genetic fingerprinting by pulsed field gel electrophoresis[2] after taking the corneal scrapings from the base and the edge of the ulcer.

A non-invasive, high-resolution technique of in vivo confocal microscopy of the cornea can be considered a diagnostic aid to help in making a rapid and accurate diagnosis of acanthamoeba or fungal infection while the results from other modalities are still awaited.[3] It has its limitation in diagnosing bacteria and microsporidium, which are too minute to be resolved by this technique.[4]

Polymerase chain reaction is a highly sensitive and rapid technique to identify pathogens by extraction and amplification from small quantities of DNA[5] and it seems to be a good adjunct to the conventional diagnostic techniques in refractory cases especially fungal and acanthamoeba infections where delay in the diagnosis of the pathogen worsens the ocular outcome of treatment. Limited availability of this modality limits its usage in the present scenario.[6] PCR high-resolution melting analysis is a recently introduced diagnostic strategy based on real-time and discriminates among the various varieties of fungi.[7]

Treatment Protocols Based on Causative Organism

Bacterial keratitis

Antibiotics

Topical route: Broad spectrum antibiotics demonstrating adequate coverage against both Gram-positive and Gram-negative pathogens should be started as the first line of treatment. The usual protocol is to start a combination therapy of topical fortified antibiotics (cefazolin 5% and tobramycin or gentamicin 1.4%) therapy aggressively on half-hourly basis all through 24 h to enhance the therapeutic levels of drugs thereby bringing the infection under control. Frequency should be reduced based on the clinical response. There is no indication for the use of oral antibiotics unless scleritis or endophalmitis are suspected.[1]

Fourth generation fluoroquinolone monotherapy (eg: Gatifloxacin or moxifloxacin) is a good alternative to the conventional therapy and has demonstrated encouraging results, documented by meta-analysis and randomized controlled trials where both forms of treatment have shown comparable results in terms of efficacy and safety.[89]

Fluoroquinolones demonstrate added advantages over fortified antibiotics in terms of better stability, longer shelf life and epitheliotoxicity, with the added advantage of not requiring refrigeration.[1]

Among the fluoroquinolones, the fourth generation (gatifloxacin and moxifloxacin) demonstrate the superiority over older generations (ciprofloxacin, ofloxacin) in terms of better coverage against both Gram-positive and Gram-negative microbes with no resistance documented until date.[10] Moxifloxacin has got the highest aqueous humour penetration, followed by gatifloxacin, with ciprofloxacin having the least penetration into the aqueous humour.[11]

Although fluoroquinolones can be recommended as the first line of treatment with promising results, the response to treatment should be closely monitored and changed according to the clinical response and culture results. The topical therapy may further be modified according to the results of in vitro bacterial sensitivity.

Subconjunctival route is no longer advisable for routine management of corneal infections[12] as it is associated with various ocular side-effects such as pain, redness, patient apprehension, risk of globe perforation and failure to provide enhanced corneal levels of antibiotic compared with drops.

Steroids

The use of topical steroids in infectious keratitis was analyzed in the multicentric, randomized clinical trial steroids in corneal ulcer trial (SCUT). Topical steroids, when used as an adjunctive treatment under antibiotic cover, do not provide any added benefit as proved by a SCUT.[113]

Corneal collagen cross linking

It uses ultraviolet: A light activated riboflavin to strengthen the corneal tissue. This technique has been recently introduced as a treatment modality especially in the healing of refractory cases of infectious keratitis and has shown promising results. A meta-analysis conducted by Alio et al. has very well documented the role of collagen cross-linking (CXL) in infectious keratitis. They observed that the use of CXL hastened the epithelialisation, decreased the need for keratoplasty and reduced corneal melting.[14]

Fungal keratitis

Antifugal therapy

Natamycin 5% suspension is considered to be the first choice among anti-fungal agents in cases of filamentary fungal keratitis.[15] In cases refractory to the conventional natamycin therapy, Voriconazole (broad spectrum azole), available as topical 0.1% or 1% drops or tablet (200 mg) can be used as an alternative to treat filamentous fungi corneal infection with oral administration having shown good ocular penetration.[161718] The mycotic ulcer treatment trial (MUTT) has demonstrated the superiority of natamycin over voriconazole in terms of better visual acuity outcomes and a lower rate of perforation. MUTT was a randomized, multi-centric trial where 368 patients were randomly distributed for topical natamycin and voriconazole therapy. Patients in the natamycin group reported better visual outcomes and fewer rates of perforation thereby reducing the need for therapeutic keratoplasty.[15] Topical amphotericin-B 0.015% therapy should be instituted in cases where yeast infection is suspected.

The newer antifungal voriconazole when given through intrastromal injection achieves high tissue concentrations, but at the same time increases the risk of perforation.[19]

Addition of oral antifungal treatment (fluconazole, voriconazole or itraconazole tablets) is indicated whenever there is an evidence of deep corneal invasion, intraocular spread or spread to the limbus.

Acanthamoeba keratitis

The diagnosis requires a high index of suspicion. A typical history of contact lens usage or swimming is the risk factors which aid in its diagnosis. Treatment is aimed toward killing the resistant amoebic cysts as opposed to the sensitive trophozoites. Chlorhexidine (0.02% or 0.2%) and polyhexamethylene biguanide (0.02% and 0.6%) should be initiated as the empiric therapy[2021] against trophozoites and cysts. Since these drops are not available commercially, they need to be procured from tertiary care ophthalmic institutes on request. Prolonged use even after the clinical resolution of the infection is advocated to prevent the occurrence of relapses. Although dual therapy with a second agent such as hexamidine or brolene is common, there is no published trial data to support this strategy. Oral non-steroidal agents (e.g. Flurbiprofen 50 mg TDS) can help control pain and immunosuppressive agents should be considered if there is an associated scleritis.[22]

Viral keratitis

Antiviral therapy

Antivirals have been in use for the treatment of herpetic keratitis for over two decades. The drugs commonly employed are idoxuridine, iododesoxycytidine, vidarabine, trifluridine, acyclovir and ganciclovir. In a recent multicentric trial ganciclovir 0.15% gel was found equivalent to 3% Acyclovir for the treatment of viral keratitis. Thery also observed that local tolerance of ganciclovir was better than that with acyclovir, particularly with regard to blurring and stinging after installation.[23]

Progressive disease

Microbial keratitis with negative initial culture reports, not responding to the conventional treatment is a challenge for an ophthalmologist. Fungal and acanthaoemba infection further add to the seriousness of the disease process as they are usually compounded with difficulty in the diagnosis with a high rate of false negative culture results along with greater ocular morbidity. A typically unusual history should raise the suspicion against unusual pathogens (e.g. mycobacterium, nocardia), particularly if there has been laser refractive surgery or foreign travel. A repeat culture onto selective media like Lowenstein Jensen medium, Sabouraud Dextrose Agar and non-nutrient agar should be done to determine the aetiological agent. A corneal biopsy (for culture and histopathology) would be required in those cases where the infection is deep seated in the cornea. The diagnosis can further be confirmed on confocal microscopy examination or tissue for PCR examination.

Conclusion

Management of infectious keratitis has evolved over the past decades with the advent of newer and improved rapid diagnostic modalities such as PCR and Confocal microscopy. These can detect the causative microorganism more efficiently and rapidly than conventional culture techniques. Newer drugs with an increased efficacy and less resistance have led to a decrease in the rates of blinding complications. Variability in the individual responses should provide us with the urge to find better treatment options. Continuous ongoing research will definitely provide better options in the future.