Antibiotics After Intraocular Injection Linked to Resistance

Kate Johnson

September 12, 2011

September 12, 2011 — Antibiotic eye drops, which are commonly prescribed after intraocular injections for choroidal neovascularization, have been linked to resistant strains of ocular flora as well as multiple-drug resistance, according to a study published in the September issue of the Archives of Ophthalmology.

"Our findings indicate the need for more judicious use of ophthalmic antibiotics after intraocular injection to reduce the potential emergence and spread of antimicrobial resistance," write Stephen Kim, MD, and Hassanain Toma, MD, from the Vanderbilt University School of Medicine in Nashville, Tennessee.

"Intraocular injections are the fastest-growing procedure in ophthalmology," with endophthalmitis being "the most devastating risk" of the injections, Dr. Kim told Medscape Medical News.

"About 1 in 2000 patients develops this infection, and when that happens, it's terrible. It can lead to a lot of morbidity, and you can lose the eye sometimes," he explained.

As a consequence, many eye care physicians use antibiotics "as a security blanket," but their benefit is theoretical, he said. "We don't have good studies that show that antibiotics reduce the rate of infections, and now there's very good evidence that they help promote resistance."

His longitudinal, randomized controlled study included 24 patients undergoing unilateral intraocular injection for choroidal neovascularization between February 1 and November 30, 2009.

The average age of the group was 75 years, and most (83%) needed the treatment because of age-related macular degeneration.

As part of the study protocol, all participants received 4 monthly intraocular injections and were randomly assigned to receive 1 of 4 antibiotic eye drops (ofloxacin 0.3%, gatifloxacin 0.3%, moxifloxacin hydrochloride 0.5%, or azithromycin 1%) on the day of and for 4 days after each injection.

Before each injection, conjunctival cultures were taken of both the treated and untreated eyes.

If patients needed more than 4 injections, they continued as needed throughout the year of follow-up, with preinjection cultures and postinjection antibiotic drops also continued as assigned.

If cultures from either treated or untreated eyes were positive for bacteria, the strain was identified, with further testing for the presence or absence of catalase and coagulase/agglutination, and specifically coagulate-negative staphylococci (CNS).

All positive cultures were tested for susceptibility to 16 different antibiotics: a combination of amoxicillin and clavulanate potassium, cefazolin sodium, cefoxitin sodium, erythromycin, azithromycin, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, a combination of trimethoprim and sulfamethoxazole, rifampin, gentamicin sulfate, doxycycline hyclate, linezolid, clindamycin hydrochloride, and vancomycin hydrochloride.

A total of 181 bacteria were isolated from control eyes, and 106 from treated eyes, during the study. Of these bacteria, the majority were CNS (73% of cultures from both treated and untreated eyes), primarily Staphylococcus epidermis (61% of control cultures and 67% of treated cultures).

Although resistance to both newer- and older-generation fluoroquinolones ranged from 20% to 59% in untreated CNS cultures, it was significantly higher in antibiotic-treated cultures, and particularly those treated with fluoroquinolones.

Specifically, in untreated eyes, resistance to ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin was 59%, 56%, 20%, and 26%, respectively, whereas in fluoroquinolone-treated eyes, it was 82%, 79%, 42%, and 65%, respectively.

"All CNS isolates resistant to gatifloxacin or moxifloxacin were also resistant to ofloxacin and levofloxacin, indicating high levels of cross-resistance between newer- and older-generation fluoroquinolone antibiotics," write the authors. "This high level of cross-resistance explains the increasing rate of levofloxacin resistance observed in this study despite absence of exposure."

In addition, increased resistance to macrolides was seen in CNS cultures from macrolide-treated eyes (95%) compared with cultures from control eyes (55% for erythromycin and 59% for azithromycin).

Interestingly, compared with untreated CNS cultures, macrolide-treated cultures actually showed decreased resistance to older- and new-generation fluoroquinolones (P = .03 and P < .001, respectively).

Multiple-drug resistance was also more common in antibiotic-treated CNS specimens compared with control CNS specimens. Resistance to at least 3 antibiotics was seen in 82% of antibiotic-treated specimens compared with 65% of control specimens (P = .01), and resistance to at least 5 antibiotics was seen in 68% of antibiotic-treated specimens compared with 48% of control specimens (P = .009).

"To our knowledge, this is the first controlled longitudinal study to directly establish ophthalmic antibiotic use with emergence of resistance and to determine its relationship with different classes of antibiotics," write the authors.

"I'm hopeful this paper will allow us to reach consensus in our field," said Dr. Kim, who said there is a growing trend toward abandoning antibiotics for this indication.

"I think we're going to see a growing number of eye care specialists stop using antibiotics entirely. I haven't gotten there yet, but I've seriously considered it, and what I have done is compromised. I used to be a big fluoroquinolone user, and I've stopped using those entirely and moved to older combination antibiotics."

Asked to comment on the findings, 2 spokespeople for the American Academy of Ophthalmology said they do not use antibiotics after intraocular injection.

"This is an interesting report, but it is unlikely to have a significant effect on clinical practice," commented George A. Williams, MD, chair of the Department of Ophthalmology at Oakland University William Beaumont School of Medicine in Royal Oak, Michigan.

As the authors noted, the study was small, and "the translation from in vitro resistance to clinical resistance is uncertain," said Dr. Williams.

In addition, a similar study published last month in the American Journal of Ophthalmology did not show increased resistance to fluoroquinolones, he told Medscape Medical News.

"There is increasing clinical experience suggesting that there is no clinical benefit to the use of postinjection antibiotics.... I no longer use antibiotics following intravitreal injection.... Therefore, I believe the burden of proof now lies with the advocates of postinjection topical antibiotic prophylaxis," he said.

The study's findings are "concerning, but at the same time expected," commented Abdhish R. Bhavsar, MD, director of clinical research at the Retina Center of Minnesota in Minneapolis.

"I have advocated not using topical antibiotics for many years," he told Medscape Medical News. "A growing number of us are not using topical antibiotics before or after intravitreal injections."

A low rate of endophthalmitis can be achieved "with a more minimalist approach that does not require antibiotics," he added. "I have recently presented my experience in over 10,000 consecutive intravitreal injections with only 1 case of endophthalmitis."

The study was supported in part by an unrestricted grant from Research to Prevent Blindness to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences. Dr. Kim is a paid consultant for Ophthotech, New York City. Dr. Bhavsar has received research funds from DRCR, Genentech, and Allergan, and has also consulted for Genentech and Allergan. Dr. Williams has disclosed no relevant financial relationships.

Arch Ophthalmol. 2011;129:1180-1188. Abstract