INFECTIOUS KERATITIS

Newer drugs and fortified versions of existing agents are often effective in treating difficult infectious keratitis cases, including many involving resistant organisms, according to presenters at the American Academy of Ophthalmology (AAO) annual meeting in New Orleans.

However, compliance with treatment regimens remains critical for success. Lack of compliance may lead to treatment failure more often than antibiotic resistance.

Organisms found resistant to antibiotics in other parts of the body often can be treated with those compounds on the cornea, said Eduardo C Alfonso MD, medical director of the ocular microbiology lab and chairman at Bascom Palmer Eye Institute, University of Miami, Florida, US. This is because organisms are deemed resistant to specific anti-infective compounds if the minimum inhibitory concentration, or MIC, required to control the organism exceeds the maximum safe serum concentration for systemic use. But with topical application, much higher concentrations can safely be reached in the eye than systemically.

“If we can increase concentration and increase dosing, we can overcome intermediate resistance. We see this over and over in our clinical practice using fortified antibiotics,” Dr Alfonso said.

This may also explain why some patients started empirically on a drug get better even though lab tests later find the organisms resistant to that drug.

However, increasing concentration is not effective against highly resistant organisms, said Francis S Mah MD, Scripps Clinic, La Jolla, California, US. He tested the effects of higher concentrations of antibiotics on various levels of resistance by infecting rabbit eyes with Staphylococcus aureus K950 from a keratitis patient.

In the lab, the organism proved sensitive to vancomycin with an MIC of 2.0 micrograms/mL, considered a safe serum concentration for the compound. But it was considered resistant to gatifloxacin, with MIC of 12 micrograms/mL; levofloxacin, with MIC of 32 micrograms/mL; and highly resistant to ciprofloxacin, with MIC of 256 micrograms/mL.

In the rabbit eyes, both gatifloxacin and levofloxacin were effective as rated by clinical outcomes scores and colony count data, Dr Mah said. But ciprofloxacin-treated eyes fared no better than untreated controls on colony counts, and were actually graded worse clinically. Therefore, there is a certain amount of resistance which can be overcome with the higher concentration and more frequent dosing of topical therapy, however, there is a limit to this clinical phenomena.

FDA trials of fortified topical antibiotics have found them effective despite being labelled resistant by the microbiology laboratories, Dr Mah noted. Indeed, for peripheral keratitis lesions up to 2.0mm, the AAO preferred practice patterns call for Gram staining and empirical therapy with topical fluoroquinalones and/or fortified antibiotics, such as cefazolin with tobramycin, every one to two hours. Larger, central or treatment-resistant lesions and those with clinical features suggesting fungal, amoebic or mycobacterial involvement should be cultured. Loading doses every five to 15 minutes for the first hour followed by applications every 15 minutes to one hour around the clock may be indicated.

In case of treatment failure, look first at compliance, Dr Mah said.

“Organism resistance is almost never a reason for failure in a keratitis trial. Compliance is almost always the
biggest reason medications don’t work
in clinical trials.”

The tolerance of the ocular surface to highly concentrated antibiotics also allows greater use of fluoroquinolones, the most toxic antibiotics ever developed, Dr Alfonso said.

“Fluoroquinolones are the mainstay, but corneal specialists make more use of fortified antibiotics.”

Fluoroquinolones are good for many Gram positive organisms. Cephalosporins are about 65 per cent effective, but sometimes vancomycin is needed, Dr Alfonso said.

Gram-negative organisms are mostly well covered by fluoroquinolones, but sometimes aminoglycosides are required. MRSA is not well covered by fluoroquinolones and may require vancomycin. Agents including oxazolidinones, and synercid are useful when certain bacteria appear, he said.

Mycobacteria can be more difficult to treat as they develop resistance under treatment, Dr Alfonso said. He recommended combinations, with amikasin and clarithromycin the drugs of choice, but azithromycin, quinolones and linezolid may also be used.

Future treatments

Dr Alfonso expects future antibiotics will include oxazolidinones, synercid, glycopeptide and more fluoroquinolones. He also sees greater use of genomics and lipidomics to target medications as drug resistance increases.

Options for fungal keratitis are fewer, with natamycin 5.0 per cent the only commercially available topical preparation. However, systemic antifungals are also useful, including amphotericin B, ketoconazole, fluconazole and voriconazole, which is highly effective against candida, Dr Alfonso said. Newer antifungals such as caspofungin and posaconazole should also be considered.

Genotyping helps target antifungal therapy, Dr Alfonso said. For example, Fusarium other than F solani respond well to voriconazole, but F solani may respond better to natamycin, with infections often proceeding to keratoplasty.

For acanthamoeba, a combination of cationic antiseptics and aromatic diamides is effective for early disease, Dr Alfonso said. Eliminating bacteria which the acanthamoeba organism feeds on with neomycin can be helpful. Clotrimazole and miconazole are available in topical preparations and ketoconazole and itraconazole can be added orally.

Microsporidia on the conjunctival and epithelial surfaces generally goes away spontaneously, requiring no treatment, Dr Alfonso said. However, stromal keratitis is difficult to treat and often progresses
to keratoplasty.

Eduardo Alfonso: ealfonso@med.miami.edu

Francis Mah:
Mah.Francis@Scrippshealth.org