Antibiotic Controversies In Vitreoretinal Practice
Two serious issues have arisen surrounding the use of fluoroquinolones in retina.
PETER A. KARTH, MD, MBA · THEODORE LENG, MD, MS
Peter A. Karth, MD, MBA, is a clinical assistant professor of ophthalmology at the Byers Eye Institute at Stanford University, Palo Alto, CA. Theodore Leng, MD, MS is a clinical assistant professor of ophthalmology Byers. The authors report no financial relationships related to the material discussed in this article. Dr. Leng’s e-mail is email@example.com.
Antimicrobial medications are among of the most commonly used drugs and are critical tools in the clinician’s black bag. This holds true in ophthalmology as well. Antibiotics are the cornerstone in the treatment and prophylaxis of eye infections, and retina specialists use them every day.
In recent months, specific issues regarding the use of antibiotics have come to the forefront, specifically: (1) the possible link between fluoroquinolones and retinal detachments (Figure 1); and (2) the routine use of prophylactic antibiotics with intravitreal injections.
FLUOROQUINOLONES AND RETINAL DETACHMENTS
A study recently published in JAMA concluded a link might exist between oral fluoroquinolone use and retinal detachments.1 Because fluoroquinolones are among the more commonly prescribed classes of antibiotics in North America, this study received coverage in the wider medical press and even in the popular press.
In that study, Etminan et al found that the “use of [oral] fluoroquinolones was associated with a higher risk of developing a retinal detachment” by 4.5-fold vs controls.
The case-control study consisted of 4,384 patients with retinal detachments and 43,840 age-matched control patients without retinal detachments. Their primary result was that 3.3% of the retinal detachment group were taking oral fluoroquinolones, while only 0.6% of the controls were taking the medications.
This finding led the authors to conclude that those patients taking oral fluoroquinolones were at a greater risk for retinal detachments. They estimated that for every 2,500 people taking oral fluoroquinolones, one would have a retinal detachment that he or she might not have had otherwise.
Figure 1. A slit-lamp photograph of a patient with a retinal detachment.
CREDIT: NATIONAL EYE INSTITUTE
We can extrapolate that if 5% of Americans were taking this medication, we could expect 6,000 additional retinal detachments.
What Should We Do?
In light of these findings, retinal specialists, comprehensive ophthalmologists, and primary care providers can only wonder if we are actually putting our patients at risk of vision loss by prescribing these efficacious medications. Or should all patients taking these medications receive extra retinal screening? What should we do with the results of this study?
We should be clear on the study’s results and structure when evaluating whether we should use this information in clinical practice. All of the patients in the study group had retinal detachments, while the control group consisted of patients without detachments. The study reported differences in rates of oral fluoroquinolones use in these two groups, not the rate of retinal detachment.
We feel this distinction is important. The 4.5-fold increase in “risk of developing a retinal detachment” stated in Etminan et al’s abstract could perhaps be better worded as follows: those diagnosed with retinal detachment had a 4.5-fold greater probability of being current users of oral fluoroquinolones than controls.
A Closer Look
Fluoroquinolones upregulate matrix metal-loproteinase-2, which can result in collagen cleavage.2 Ponsioen et al hypothesized that collagen-rich vitreous might degrade in this manner, causing acute posterior vitreous detachment,3 which can lead to retinal tears and a rhegmatogenous retinal detachment.
We also know that these medications have excellent penetration into the eye.4 The authors cited an animal study showing that collagen synthesis decreased by 48% after three days of exposure to ciprofloxacin culture.5
One of the more puzzling aspects of the study results was that the authors found the only statistically significant difference in fluoroquinolone use between groups in the subgroup currently taking antibiotics. Those subgroups that had recently taken but had discontinued fluoroquinolones as little as one day before being diagnosed with a retinal detachment were not statistically different from the controls.
Figure 2. A devastating outcome after endophthalmitis, following an intravitreal injection for AMD.
CREDIT: RAJ R. RATHOD, MD, AND WILLIAM F. MIELER, MD
This is a surprising result. On the one hand, it seems unlikely that there should be any real difference in effect whether the drug was currently being taken vs having discontinued it one day earlier. On the other hand, animal studies have shown that fluoroquinolones are cleared from the vitreous within 12 hours after intravitreal injection.6
The Role of Time
Moreover, it takes time for a pathologic PVD to evolve into a retinal detachment. For example, we can hypothetically assume that there is at least a three-day interval (and probably much longer) from collagen degradation leading to a PVD, to a tear, a detachment, and finally the date of diagnosis.
This interval means that the drug would need to be active and present three days before the date of diagnosis, resulting in a higher incidence of diagnosed retinal detachments in patients who had discontinued the medication between one and three days earlier, using our example.
However, the study results showed no such statistical significance, nor did they show even a trend toward significance in the “recent” fluoroquinolone users — the group that discontinued the drug one to seven days before the diagnosis of retinal detachment.
Although a mechanism by which fluoroquinolones can cause retinal detachment may exist, a case-control study cannot prove true causation or association — merely correlation.
In the study, the controls were age-matched but were not matched for other possible confounding variables. For instance, the incidence of cataract surgery and myopia was somewhat higher in the retinal detachment group vs the control group, which may begin to become significant when taken with other possibly present, but unreported and uncontrolled, confounding factors, such as trauma and lattice degeneration.
Additionally, we could argue that a subgroup with significantly more antibiotic use may be a sicker population and more prone to other risk factors for retinal detachments, such as falls. Etminan et al calculated that it would be statistically improbable that cofounders could negate their results.
In a poster presented at the 2013 annual meeting of the ASRS, Barkmeier et al closely reproduced the study design of the Etminan et al study in the Olmsted County/Mayo Clinic population.7
They found that retinal reattachment surgery rates among patients prescribed fluoroquinolones were not statistically different from controls. They concluded that oral fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment.
Other leading retinal specialists have also expressed doubts regarding true causation or an association between oral fluoro-quinolones and retinal detachments.8,9
Additionally, considering the small risk of retinal detachment in the general population (less than a 1% lifetime risk), even a proportionally large increase in this risk yields minimal overall risk.
Using Our Judgment
Of course, as clinicians, we should still do everything in our power to minimize the risk of adverse events to our patients. Considering that fluoroquinolones can be life-preserving drugs in cases of systemic or organ infection, we must practice good risk management. We must bear in mind that a retinal detachment is a treatable condition, while serious infections, in contrast, often have significant morbidity and even mortality.
Considering the small risk of detachment, even a large incease yields minimal risk.
Even if we take the conclusions of Etminan et al at face value, we must not trade away a life-saving antibiotic to reduce further an already very low risk of a treatable nonlethal condition. When consulting our medical colleagues, ophthalmologists should be very clear on these issues to allow for the best care for our patients’ overall health.
In this day and age, we often consider medicolegal issues. A Google search on fluoroquinolones and retinal detachments yields at least one or two attorneys offering to “inform you of your rights” if you have been taking a fluoroquinolone antibiotic and have suffered a retinal detachment.
As prescribers, we must weigh all of the risks and benefits and give our patients the best recommendations in light of their entire bodies, not only their eyes. No one could quarrel with additional admonishments to patients directing them to seek prompt evaluation if they see new flashes or floaters.
This is good advice whether or not they are taking oral fluoroquinolones and whether or not these medications do indeed increase the risk of retinal detachments.
PROPHYLACTIC ANTIBIOTICS WITH INTRAVITREAL INJECTIONS
With the revolution in pharmacologic treatment of many of the most common retinal diseases, intravitreal injections are now among the most commonly employed tools used by retinal specialists.
In 2010, Medicare patients alone received more than 1 million intravitreal injections, vaulting this procedure to near the top of the list of most frequently performed medical procedures.10 With such a high volume, even small increases in the rates of negative side effects become important issues for retinal specialists and for public health.
Infectious endophthalmitis (Figure 2) is the most feared and devastating complication of intravitreal injections. The large trials validating the use of intravitreal medications, such as ANCHOR,11 MARINA,12 and RIDE/RISE,13 showed stabilization of vision with a modest gain of about 10 ETDRS letters on average, which is what we tell our patients they may expect.
Endophthalmitis quite often causes a permanent severe decline in vision, with an average loss of 25 ETDRS letters in one study14 of postinjection endophthalmitis, and with severe permanent vision loss in 22% of eyes in another study.15
Proceed With Caution
At first glance, it seems like good medicine: Use an effective, well-tolerated topical antibiotic to reduce the risk of a rare but severe infection. We have learned to do this with cataract surgery, so why not give our injection patients this extra protection?
Of course, it is not this simple. First, is the use of prophylactic topical antibiotics giving our patient any benefit? Second, are they possibly causing harm? Third, what are the current medicolegal issues surrounding this topic?
It is well recognized that thorough preparation of the eye with povidone-iodine is needed before injection.16 Iodine is an extremely effective agent, with near total bactericidal effectiveness by disrupting bacterial and viral cell walls. The mechanism of action of fluoroquinolones is to inhibit DNA topoisomerase/DNA gyrase.
The kill time of povidone-iodine is 15 to 120 seconds after contact.17 Topical moxifloxacin, however, failed to kill any Staphylococcus aureus isolates and killed only 20% of coagulase-negative Staphylococcal isolates at 60 minutes after application in one study.18 It can even have a kill time as long as four hours.19
These and other studies20,21 have shown that the application of topical fluoroquinolones, directly before or after the injection, in addition to povidone-iodine prep, provides no additional antibacterial activity and is most likely not a beneficial tactic.
Some retinal specialists prescribe a course of several days of topical antibiotics after injections. Concerns about fostering antibiotic resistance from peri- and postprocedural antibiotics have arisen. Many studies have shown that conjunctival bacterial resistance to fluoroquinolones as much as doubled (from 32% to 63%) in patients who received postinjection antibiotics.22-26
Taking this one step further, if the patient’s own eye flora is the source of most postprocedural endophthalmitis and the use of postinjection antibiotics leads to increased resistance, then the use of antibiotics would lead to more resistant organisms in cases of endophthalmitis.
No Real Benefits
This indeed has been shown: Schimel et al studied bacterial isolates from cases of endophthalmitis and found a tenfold increase over 10 years in resistance to topical fluoroquinolones and an additional doubling of resistance over a one-year period as intravitreal injections increased in use.27
Furthermore, if one were to hope to employ postinjection topical antibiotics for intraocular prophylaxis, rather than only acting at the conjunctiva, Costello et al showed that vitreous penetration of topical fluoroquinolones is quite poor.28
Many studies have shown that the use of peri- or postinjection topical antibiotics does not reduce rates of endophthalmitis. Cheung et al reviewed 15,895 injections in 2,465 patients and found that the use of topical antibiotics did not reduce the incidence of endophthalmitis.29 Another report, by the DRCR.net, examining this issue in their clinical trials showed that eliminating topical antibiotics did not increase infection rates.30
The medicolegal issues regarding discontinuance of antibiotics with intravitreal injection seem to be minimal, if not nonexistent. From 2006 to 2011, the Ophthalmic Mutual Insurance Company did not receive any claims on this issue while covering nearly 25% of practicing ophthalmologists.10 Many of the recent large randomized clinical trials we use to guide clinical practice have not included topical antibiotics in their injection protocols.
A Final Consideration Regarding Cost
Due to the sheer number of intravitreal injections, we must have an eye toward cost. Savings of $100 per year per patient (often the cost of prophylactic topical fluoroquinolones) or more can add up to tens of millions of dollars of savings for the healthcare system.
Overall, it seems the evidence supporting the discontinuance of peri-injection antibiotics is mounting, leading retinal specialists to call for their decreased use.31 We expect retinal specialists to use less of these medications going forward. RP
1. Etminan M, Forooghian F, Brophy JM, Bird ST, Maberley D. Oral fluoroquinolones and the risk of retinal detachment. JAMA. 2012;307:1414-1419.
2. Tsai W-C, Hsu C-C, Chen CPC, et al. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen. J Orthop Res. 2011;29:67-73.
3. Ponsioen TL, Hooymans JMM, Los LI. Remodelling of the human vitreous and vitreoretinal interface: a dynamic process. Prog Retin Eye Res. 2010;29:580- 595.
4. Keren G, Alhalel A, Bartov E, et al. The intravitreal penetration of orally administered ciprofloxacin in humans. Invest Ophthalmol Vis Sci. 1991;32:2388- 2392.
5. Williams RJ, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon, and capsular fibroblast metabolism. Am J Sports Med. 2000;28:364-369.
6. Iyer MN, He F, Wensel TG, Mieler WF, Benz MS, Holz ER. Intravitreal clearance of moxifloxacin. Trans Am Ophthalmol Soc. 2005;103:76-83.
7. Barkmeier A, et al. Oral fluoroquinolones and the incidence of rhegmatogenous retinal detachment and symptomatic retinal breaks: a population-based study. Poster presented at: Annual meeting the American Society of Retina Specialists; Toronto, Canada; August 24-28, 2013.
8. Han DP, Szabo A. Flashes, floaters, and oral fluoroquinolones: is retinal detachment a worry? JAMA Ophthalmol. 2013;131:91-93.
9. Albini TA, Karakousis PC, Abbey AM, Bartlett JG, Flynn HW Jr. Association between oral fluoroquinolones and retinal detachment. Am J Ophthalmol. 2012;154:919-921.
10. Wykoff C, Flynn HW. Are topical antibiotics helpful as prophylaxis for intravit-real injections? Retin Today. 2012;May:72-74.
11. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355:1432-44.
12. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355:1419-1431.
13. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.
14. Lyall DA, Tey A, Foot B, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26:1517-1526.
15. Simunovic MP, Rush RB, Hunyor AP, Chang AA. Endophthalmitis following intravitreal injection versus endophthalmitis following cataract surgery: clinical features, causative organisms and post-treatment outcomes. Br J Ophthalmol. 2012;96:862-866.
16. American Academy of Ophthalmology. Clinical statements. November 2008. Available at: one.aao.org/CE/PracticeGuidelines/ClinicalStatements_Content. aspx?cid=404813e9-b3dc-4d6d-a2c5-d1f1e78a926b#section4. Accessed September 1, 2013.
17. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982;15:635- 639.
18. Hyon JY, Eser I, O’Brien TP. Kill rates of preserved and preservative-free topical 8-methoxy fluoroquinolones against various strains of Staphylococcus. J Cataract Refract Surg. 2009;35:1609-1613.
19. Kowalski RP, Kowalski BR, Romanowski EG, Mah FS, Thompson PP, Gordon YJ. The in vitro impact of moxifloxacin and gatifloxacin concentration (0.5% vs 0.3%) and the addition of benzalkonium chloride on antibacterial efficacy. Am J Ophthalmol. 2006;142:730-735.
20. Halachmi-Eyal O, Lang Y, Keness Y, Miron D. Preoperative topical moxifloxacin 0.5% and povidone-iodine 5.0% versus povidone-iodine 5.0% alone to reduce bacterial colonization in the conjunctival sac. J Cataract Refract Surg. 2009;35:2109-2114.
21. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology. 2009;116:1498-1501.
22. Milder E, Vander J, Shah C, Garg S. Changes in antibiotic resistance patterns of conjunctival flora due to repeated use of topical antibiotics after intravitreal injection. Ophthalmology. 2012;119:1420-1424.
23. Dave SB, Toma HS, Kim SJ. Ophthalmic antibiotic use and multidrug-resistant staphylococcus epidermidis: a controlled, longitudinal study. Ophthalmology. 2011;118:2035-2040.
24. Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of ocular surface flora with repeated use of a topical antibiotic after intravitreal injection. JAMA Ophthalmol. 2013;131:456-61.
25. Kim SJ, Toma HS, Midha, Cherney EF, Recchia FM, Doherty TJ. Antibiotic resistance of conjunctiva and nasopharynx evaluation study: A prospective study of patients undergoing intravitreal injections. Ophthalmology. 2010;117:2372- 2378.
26. Kim SJ, Toma KS. Ophthalmic antibiotics and antimicrobial resistance. A randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011;118:1358-1363.
27. Schimel AM, Miller D, Flynn HW. Evolving fluoroquinolone resistance among coagulase-negative Staphylococcus isolates causing endophthalmitis. Arch Ophthalmol. 2012;130:1617-1618.
28. Costello P, Bakri SJ, Beer PM, et al. Vitreous penetration of topical moxifloxacin and gatifloxacin in humans. Retina. 2006;26:191-195.
29. Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119:1609-1614.
30. Bhavsar AR, Googe JM Jr, Stockdale CR, et al; Diabetic Retinopathy Clinical Research Network. 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;127:1581-1583.
31. Chen RW, Rachitskaya A, Scott IU, Flynn HW Jr. Is the use of topical antibiotics for intravitreal injections the standard of care or are we better off without antibiotics? JAMA Ophthalmol. 2013;131:840-842.