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Infectious Keratitis

Fluoroquinolone-resistant bacteria a growing problem in the treatment of infectious keratitis

Roibeard O’hEineachain

Posted: Monday, June 1, 2020

A characteristic slit-lamp photo of a corneal ulcer. Courtesy of Allan Slomovic MSc, MD, FRCS(C)

A 16-year review of bacterial keratitis isolates tends to support the use of fortified vancomycin and tobramycin drops for ulcerative keratitis, reported Allan Slomovic MSc, MD, FRCS(C), at the 24th Winter Meeting of the ESCRS in Marrakech, Morocco.

The Canadian research showed that Gram-negative bacteria remain more susceptible to standard antibiotics than do Gram-positive bacteria. Significantly, susceptibility of all Gram-positive isolates to vancomycin was 100% for all 16 years of the study.

“High susceptibility to vancomycin reinforces the empirical use of fortified tobramycin and vancomycin in the initial management of severe bacterial keratitis and in cases unresponsive to fourthgeneration fluoroquinolones,” said Dr Slomovic, Professor of Ophthalmology, Department of Ophthalmology and Visual Sciences, University of Toronto, Toronto.

The study involved a total of 2,330 corneal scrapings taken from January 1, 2000, through December 31, 2015. Pathogens were recovered in 1,335 samples (57.3%), with bacterial keratitis accounting for 1,189 (86.0%) of the positive cultures. Other pathogens recovered included fungi in 9%, a third of which were yeasts, and Acanthamoeba in 2%. In addition, 9% had viral infections.

Gram-positive bacteria accounted for 75% of bacterial growths, with coagulasenegative staphylococcus being the most common, accounting for 59% of Grampositive bacteria isolates and 37% of all bacterial isolates. Gram-negative bacteria accounted for 25% of bacterial isolates with pseudomonas aeruginosa being the most common, accounting for 47% of Gram-negative and 11% of all isolates.

Dr Slomovic noted that they obtained multiple isolates in 11% of cases, which were bacterial in 92%, fungal in 5%, viral in 2% and Acanthamoeba in 1%. Risk factors for polymicrobial infections included trauma, decreased systemic immunity, and ocular surface disease.

“Multiple isolates accounted for approximately One-in-10 cases of infectious keratitis, so it is important to think about polymicrobial infection when the patient is not responding as expected,” he added.

GRAM-NEGATIVE MORE RESPONSIVE THAN GRAM-POSITIVE BACTERIA

The Gram-negative isolates were very susceptible to the five most commonly used antibiotics for the pathogens, with mean sensitivity rates of 96% for ciprofloxacin sensitive, 95% for gentamicin, 94% for tobramycin, 91% for ceftazidime and 95% for piperacillin/ tazobactam. Pseudomonas was sensitive in every case to ceftazidime, tobramycin and piperacillin/tazobactam. Serratia marcescens was sensitive in every case to ciprofloxacin, gentamicin and piperacillin/tazobactam.

However, the Gram-positive bacteria were less susceptible to standard antibiotics with mean sensitivities of 56% to erythromycin, 66% to cefazolin, 87%, trimethoprim/ sulfamethoxazole, but 100% for vancomycin. Staph aureus, the most common Gram-positive pathogen detected in the study had sensitivities of 75% to erythromycin, 96% to cefazolin and 100% to vancomycin. Methicillin resistant staph aureus (MRSA) accounted for 1% of isolates, and methicillin-resistant coagulase-negative Staphylococcus accounted for 39% of isolates.

“Similar to other reports we found that the susceptibility to tested antibiotics for Gram-negative bacteria to be excellent, above the 90% range. By contrast, and again similar to other reports, we found that the susceptibility to tested antibiotics for Gram-positive bacteria to be far less sensitive between 56% to 87%, except for vancomycin to which all tested isolates have been 100% sensitive for all 16 years of the study,” Dr Slomovic said.

Among the trends observed since 2010 were that corneal cultures rates have been decreasing significantly and there has also been a significant decrease in percentage of Gram-positive isolates, including streptococcus (p<0.0001) and staphylococcus (p<0.005).

“This is largely due to the introduction and effectiveness of fourth-generation fluoroquinolones. Many community ophthalmologists are treating these ulcers without obtaining cultures. At the University where the cultures are being performed, we are only seeing the more serious ulcers or the ones not responding to treatment of with fourth-generation fluoroquinolones,” Dr Slomovic said.

LOOMING CRISIS

There was also a significant increasing trend towards resistance to erythromycin. The other antibiotics evaluated did not show any significant trend in resistance patterns. However, Dr Slomovic noted that both Gram-positive and Gram-negative bacteria have become increasingly resistant to fluoroquinolones.

He emphasised that a crisis appears to be looming with regard to antibiotic-resistant bacteria, which currently account for 35,000 deaths a year and increased morbidity in 2.8 million. According to the United Nations, if current trends continue, the global death toll from antibiotic resistance will reach 10 million in 2050.

“It has been 15 years since the fourth-generation fluoroquinolones entered the market. Since that time there really have been no new ophthalmic antibiotics,” Dr Slomovic added.

Meanwhile the use of topical steroids in conjunction with topical fortified antibiotics is showing promise in the treatment of infectious keratitis. In the Steroids for Corneal Ulcers trial (SCUT), among patients with positive bacterial ulcers who received topical steroids 48 hours after commencing antibiotic therapy, all those treated with topical steroids, other than those with nocardia ulcers, had better visual acuity at 12 months (Srinivasan et al, Arch Ophthalmol 2012, 130(2):143-50.). It is recommended that topical steroids are added only after the offending organism has been identified, antibiotic sensitivities have been determined and there is evidence of improvement. Corneal cross-linking (CXL) is also showing promise in the treatment of infectious keratitis. Several investigators have reported on the efficacy of CXL in infectious keratitis and a new trial, SCUT II, investigating the use of topical steroids combined with CXL, is now under way, Dr Slomovic said.