Resistance to fluoroquinolones impacts retina cases

Reviewed by Stephen J. Kim, MD

Antibiotic resistance against fluoroquinolones is increasing, and that may adversely impact patients with retinal disorders.

The introduction of intravitreal injections (IVT) to treat retinal diseases has increased from about 1 million in 2007 to an expected 6 million in 2016 (up from only 4,000 in 2001).

“The number of injections has rapidly exceeded the number of cataract surgeries performed in the United States,” said Stephen Kim, MD, Vanderbilt Eye Institute, Vanderbilt University, Nashville, TN.

In 2009, the American Society of Retina Specialists surveyed its members and found that 90% used antibiotics at the time of intravitreal injections, and 40% use topical antibiotics before intravitreal injections.¹

“There is rationale to support this practice,” Dr. Kim explained. “Antibiotics reduce conjunctival flora. They achieve MIC₅₀ levels in the vitreous-at least the fourth-generation fluoroquinolones do.”

From years of observation in cataract surgery, “we know that the vitreous is more vulnerable to infection than the anterior chamber,” he added. The medicolegal implications at that time compelled retina specialists to use antibiotics when administering injections.

Different circumstances

Unlike cataract surgery, IVT treat chronic conditions and are often given repeatedly and sometimes indefinitely, Dr. Kim said. Further, the nasopharynx is exposed to antibiotic after a single-drop application and “many potential pathogens” colonize the nasopharynx of healthy individuals, he added. For example, Dr. Kim noted 30% of people are colonized with Staphylococcus aureus.

“This is the most common cause of nosocomial-acquired pneumonia,” Dr. Kim said. “You can get the sense that repeated, short-term, indefinite use of antibiotics in the setting of IVT could profoundly increase antibiotic resistance.”

It was that potential that drove the initiation of the Antibiotic Resistance of Conjunctiva and Nasopharynx Evaluation Study (ARCaNE study). This is a prospective, randomized, longitudinal study designed to determine changes in antibiotic resistance after repeated exposure of flora, conjunctival, and nasopharyngeal, after repeated antibiotic use in patients undergoing IVT for choroidal neovascularization (CNV).

Inclusion criteria included any person with CNV in one eye only and planned IVT (no specification about which drug to be injected). Among the exclusion criteria were previous IVT in either eye, chronic use of topical medications, contact lens wear, ocular surgery, or use of topical drugs in either eye in the 3 months prior to study enrollment.

ARCaNE findings

ARCaNE findings

Enrolled subjects (N = 24) were all assigned and mandated to receive 4 consecutive injections (on a monthly dosing regimen). Subjects were treated as needed for 1 year, and randomized to 1 of 4 antibiotics (azithromycin, gatifloxacin, moxifloxacin, and ofloxacin). Each subject used the antibiotic for 3 days after each intravitreal injection.

Bilateral conjunctival cultures were taken at baseline and after each injection of both the treated eye and the fellow control eye (the untreated eye). Nasopharyngeal cultures also were taken on the treatment side at baseline and following each injection after exposure to antibiotics.

The 4 mandatory injections translated to a minimum of 5 culture results per subject, but the patients could have as many as 13 cultures if they were treated monthly for the full year of the study.

“This is really critical as the study was prospective and longitudinal and was able to establish cause and effect,” Dr. Kim said.

“We didn't pick up any Streptococcus pneumoniae from the nasopharynx, but 8 of the 24 patients tested positive for S. aureus,” Dr. Kim said. “The baseline antibiotic resistance of these 8 S. aureus demonstrated substantial resistance to macrolides (erythromycin and azithromycin), but minimal resistance to other antibiotic groups.” (See above table.)

Resistant strain emerges

Resistant strain emerges

During the course of the study, Dr. Kim noted 1 patient showed conclusive and compelling evidence of emergence of a resistant strain in the nasopharynx.

Using pulse gel electrophoresis, the patient at baseline had one specific species of S. aureus cultured from the nasopharynx. Pulse gel electrophoresis involves taking DNA from the bacterial strain and subjecting it to restriction enzymes that cleave the DNA into different fragments to get a “fingerprint” that then identifies certain species.

“This strain was pansensitive to all 16 antibiotics,” Dr. Kim said. “The same strain was re-cultured on visit 1 and visit 2. In visit 3, we didn't pick up the strain.”

However, by visit 4, there was a “very clear emergence of a different strain of S. aureus,”² Dr. Kim added. This strain, unlike the baseline strain, showed resistance to moxifloxacin, and to “all the other fluoroquinolones and to several other antibiotics, including clindamycin.”

Dr. Kim said that at baseline, there was “surprisingly and alarmingly, already substantial levels of resistance to macrolides, third-generation fluoroquinolones, and fourth-generation fluoroquinolones.”

An analysis of the antibiotic susceptibility of all the coagulase-negative Staphylococci (CoNS), isolated from the conjunctiva from visits 1-4 (excluding baseline cultures), found the antibiotic susceptibility of 48 CoNS from treated eyes exposed to fluoroquinolones had a clear pattern of increasing resistance to the third- and fourth-generation fluoroquinolones compared to the fellow control eye.

In the 17 CoNS that were isolated from treated eyes exposed only to azithromycin, a different pattern emerged showing increasing resistance to macrolides and decreasing resistance to the fluoroquinolones.

Multidrug resistance

Multidrug resistance

Results from 77 Staphylococcus epidermidis cultured from fluoroquinolone-treated eyes during the study showed an increased resistance to fluoroquinolones, but also co-resistance,³ Dr. Kim said.

“Co-resistance was a common pattern, with increasing resistance to Bactrim, 27% in the treated eye vs. 10% in the control eyes,” Dr. Kim explained. “You see increased resistance to clindamycin, 18% vs. 6% in the control eyes. Also, increasing resistance to gentamicin, 8% vs. 1% in the control eyes, was observed. This co-resistance to antibiotics occurred despite no obvious cross-mechanism of action.”

Over the course of the study, up to 25% of control eyes were still pansensitive. However, in the eyes that were treated with antibiotics, only 3% remained pansensitive, and “an alarming amount of these strains were multi-resistant to 8, 9, or 10 antibiotics,” Dr. Kim said.

References:

1. Bhavsar AR, Googe JM, Stockdale CR, eta al. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009; 127:1581-3.

2. Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011;118(7):1358-63.

3. Dave SB, Toma HS, Kim SJ. Ophthalmic antibiotic use and multidrug-resistant staphylococcus epidermidis: a controlled, longitudinal study. Ophthalmology. 2011;118:2035-40.

Stephen Kim, MD

E: stephen.j.kim@vanderbilt.edu.

This article was adapted from a presentation that Dr. Kim presented at the 2016 American Academy of Ophthalmology meeting. He has no financial disclosures to declare relevant to this topic.