Trading Topical for Intracameral: A Clouded Mandate
By Blake K. Williamson, MD, MPH
Endophthalmitis is the most feared complication of cataract surgery. A variety of prophylactic measures have been developed for endophthalmitis, targeted against the various sources of infection. Recently, there has been a push by surgeons to use intracameral (IC) antibiotics at the end of phacoemulsification as a result of overwhelming data showing their efficacy in reducing endophthalmitis. These data are so strong, in fact, that many surgeons are abandoning the use of postoperative topical flouroquinolone drops, which have been considered the gold standard for years, along with preoperative povidone-iodine wash. Although I believe that the benefits of IC are undeniable, I think there are several risks to adopting a purely dropless regimen devoid of postoperative topical antibiotic prophylaxis.
A POOR CONSENSUS
A recent study1 examined various endophthalmitis prophylaxis regimens in use around the world and found that there is no global consensus regarding endophthalmitis prophylaxis with cataract surgery, as several studies have shown clinical benefits with different regimens. On one hand, two well-known studies, the ESCRS study2 and the Kaiser study,3 both showed a reduced incidence of postoperative endophthalmitis with routine prophylaxis using IC antibiotics. These studies included 14,000 patients and more than 16,000 patients, respectively. On the other hand, a recent study by Rudnisky et al4 involving 75,318 eyes undergoing cataract surgery in Canada over an 8-year period demonstrated that there was no difference in the rate of endophthalmitis with or without IC prophylaxis. The study did conclude, however, that the incidence of endophthalmitis was lower if a fluoroquinolone was used after surgery.
Additionally, a large study by Lloyd and Braga-Mele5 including 13,000 eyes undergoing cataract surgery at one institute in Canada over a 2-year period showed postoperative endophthalmitis rates of 0.04%, despite no use of IC antibiotics. This incidence compares favorably to the IC data published in the ESCRS and Kaiser studies, which showed incidences of postoperative endophthalmitis of 0.32% and 0.35%, respectively, for the control groups. Further, the Lloyd and Braga-Mele study also found that more patients developed endophthalmitis if they did not receive postoperative flouroquinolones.
Although the use of IC is on the rise in the United States, 98% of surgeons reportedly still use prophylactic topical antibiotics.6 Although clearly there is no consensus on the exact best prophylactic regimen for endophthalmitis, I believe the evidence is clear that both IC and topical antibiotics play a role in helping protect patients from this potentially catastrophic outcome.
HURDLES OF RIDING THE DROPLESS- ONLY TRAIN
Most cases of endophthalmitis result from the seeding of organisms into the anterior chamber at surgery or in the immediate postoperative period; therefore, it makes sense that the injection of a powerful antibiotic into the anterior chamber would reduce potential bacterial load. However, this is complicated by a number of practical problems.
First, there is no FDA-approved class of antibiotics for IC prophylaxis of endophthalmitis. Second, in the United States, there is no approved, uniform, commercially produced, single-use, sterile product available that could even be used. This leaves the cataract surgeon in the unenviable position of relying on either a compounding laboratory to produce an antibiotic for IC injection or having to use commercially available drops (such as moxifloxacin) and to divide and dilute it themselves under sterile conditions (or, more likely and worse yet, someone else on the surgery team with no supervision from the surgeon) on the day of surgery.
Third, we know that some clear corneal cataract wounds remain unstable in the week following surgery, and this can potentially lead to pathogens entering the eye several days later. We also know there is a high rate of aqueous humor turnover in the anterior chamber, and, with the pure IC approach, there would be little drug left in the anterior chamber after 24 hours. Fourth, even with injection into the vitreous cavity, it is important to note that moxifloxacin, the most commonly used antibiotic in the dropless approach, is highly lipophilic and has a very short half-life of less than 2 hours in the vitreous cavity.
A recent study by Kishore et al7 included roughly 2,000 eyes undergoing cataract surgery over a 15-month period. The study authors concluded that, after as little as 14 hours, “the dropless approach may not provide adequate prophylaxis against susceptible organisms through the period when the eye is at risk.” Given this, what surgeon wouldn't want a daily topical antibiotic in his or her own eye after cataract surgery to combat the rare (but real) possibility of delayed bacterial migration into the anterior chamber, which would then be devoid of antibiotic coverage with a pure IC approach? Not for my eye.
STILL A PERSONAL DECISION
It is doubtful that industry will take on the daunting expenditure of time and money needed to develop an FDA-approved antibiotic for single-use IC injection for postcataract-surgery prophylaxis of endophthalmitis. A Cochrane review on the subject8 concluded that “The practitioner should rely on current evidence to make informed decisions regarding prophylaxis choices in cataract surgery.” Translation: Do what you think is right and cross your fingers—not much help. Imagine that courtroom scenario: “Dr. Williamson, you put a needle in Mrs. Smith's eye and injected a drug that wasn't approved by the FDA for this indication, and now she's lost vision? Further, you didn't use any antibiotic drops postoperatively, which is the gold standard?” To which I'd reply, “Well, yes, but there are some great studies out of Europe and India showing that this works!” Who is to say how a jury may vote, but I don't want to find out.
It seems that the use of povidone-iodine sterilization and topical antibiotics will continue to be the mainstay for prophylaxis of endophthalmitis, while IC approaches will continue to garner widespread acceptance, as they should, given the data. The efficacy of IC use will continue to be compelling, especially in high-risk patients such as those with PCR, who have a 14-fold increased risk of endophthalmitis. However, I believe the routine use of IC in place of topical antibiotics in every case will remain problematic. We know that the most commonly isolated organisms in endophthalmitis are coagulase-negative staphylococci, which have a reported high resistance to moxifloxacin. So the plan is to inject moxifloxacin into 99.9% of patients who would never have gotten endophthalmitis anyway to protect the 0.1%? If this scenario plays out, the eventuality of super-resistant strains is concerning.
Personally, I have decided to adopt IC antibiotics, but it wasn't without considerable thought and research, and I certainly will not abandon topical prophylaxis; I will use both for the reasons provided above and will have ironclad informed consent from all patients receiving IC antibiotics.
Surgeons will have to decide for themselves whether they are willing to trust a compounder or to take on the task of producing a single-unit, sterile-use, antibiotic for off-label use in IC injection for every cataract patient. They must also consider the unintended consequences of exposing millions of cataract patients who would never have developed endophthalmitis to the additional potential complications of IC drug use, whether from inflammation, allergy to the drug itself, complications with the actual injection, potential problems with compounding or sterile production of the drug by the surgeon, etc. It could be a daunting task practically and medicolegally on a large scale.
I would love for this to be a call to arms for major medical institutions to demand a study to achieve the production of an FDA-approved product for IC injection. I fear that this reality may not come to pass any time soon, however, and therefore the potential for risks and benefits to the patient is something that each surgeon must weigh for him- or herself.
1. Grzybowski A, Schwartz SG, Matsuura K, et al. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns around the world. Curr Pharm Des. 2017;23(4):565-573.
2. ESCRS Endophthalmitis Study Group. Prophylaxis of post-operative endophthalmitis following cataract surgery: results of the ESCRS multicentre study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978-988.
3. Shorstein NH, Winthrop KL, Herrington LJ. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. J Cataract Refract Surg. 2013;39(1):8-14.
4. Rudnisky CJ, Wan D, Weis E. Prevention of endophthalmitis after cataract surgery. Ophthalmology. 2014;121(4):835-841.
5. Lloyd JC, Braga-Mele R. Incidence of postoperative endophthalmitis in a high-volume cataract surgicentre in Canada. Can J Ophthalmol. 2009;44:288-292.
6. Chang DF, Braga-Mele R, Henderson BA, Mamalis N, Vasavada A; ASCRS Cataract Clinical Committee. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2014 ASCRS member survey. J Cataract Refract Surg. 2015;41:1300-1305.
7. Kishore K, Brown JA, Satar JM, Hahn JM, Bond WI. Acute-onset postoperative endophthalmitis after cataract surgery and transzonular triamcinolone-moxifloxacin. J Cataract Refract Surg. 2018;44(12):1436-1440.
8. Gower EW, Lindsley K, Nanji AA, Leyngold I, McDonnell PJ. Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery. Cochrane Database Syst Rev. 2013;(7):CD006364.
Blake K. Williamson, MD, MPH
• Refractive, Cataract, and MIGS Surgeon, Williamson Eye Center, Baton Rouge, Louisiana
• firstname.lastname@example.org; Twitter @drblakewilly; Instagram @WilliamsonLASIK
• Financial disclosure: Alcon, Allergan, Bausch & Lomb, Carl Zeiss Meditec, Johnson & Johnson Vision
A Requisite for Optimal Outcomes
By John P. Berdahl, MD
Cataract surgery is one of the most commonly performed surgeries in the world and also one of the safest.1 However, as with any surgical procedure, complications can occur. Although rare, these complications can be serious and may cause irreversible vision loss.2
As the population ages and the rates of cataract surgery increase, surgeons must continue to strive to deliver the most optimal and safest outcomes possible. In my opinion, this entails the use of intraocular antibiotics.
RATIONALE FOR ADOPTION
Endophthalmitis is likely the most feared complication of cataract surgery. Fortunately, due to advances in surgical techniques and practices, its incidence is rare; surgeons may perform thousands of surgeries without a single occurrence. For that reason, some ophthalmologists do not consider endophthalmitis to be a real risk to their patients. However, on an epidemiologic scale, the risk of endophthalmitis is real, as is its sight-threatening potential.
Given the severity of the potential complications, I use IC antibiotics in all cataract surgery cases, unless contraindicated by allergy. This approach is supported by an overwhelming quantity of literature showing the effectiveness of IC antibiotics for endophthalmitis prophylaxis. Key findings from a few significant studies are summarized below.
ESCRS. In 2007, the ESCRS Endophthalmitis Study Group published a landmark study3 on the effects of antibiotic prophylaxis on the incidence of endophthalmitis after cataract surgery. The prospective, randomized clinical trial included nearly 14,000 patients from 24 centers in nine European countries. Investigators evaluated the effects of an IC injection of 1.0 mg cefuroxime at the close of surgery and of an intensive pulsed perioperative topical application of levofloxacin in a 2 X 2 factorial design.
A total of 29 patients presented with endophthalmitis, of whom 20 were classified as having proven infective endophthalmitis. The study authors concluded that the absence of an IC cefuroxime prophylactic regimen was associated with a 4.92-fold increase (95% CI, 1.87–12.9) in the risk for total postoperative endophthalmitis. Topical levofloxacin had no statistically significant effect. In a 2013 followup to the ESCRS study,4 investigators found zero cases of endophthalmitis out of 13,390 cataract surgeries performed using IC cefuroxime.
Kaiser. In 2013, investigators at Kaiser Permanente in California set out to evaluate postcataract-surgery rates of endophthalmitis in relation to changing practice patterns in antibiotic administration.5 They looked at three distinct time periods: (1) 2007, when patients primarily received postoperative antibiotic drops without IC injection; (2) 2008 and 2009, when, in addition to surgeons' usual postoperative topical drop regimen, patients received IC cefuroxime unless contraindicated; and (3) 2010 and 2011, when all patients received IC injection of cefuroxime, moxifloxacin, or vancomycin while topical antibiotics were used according to surgeon preference. The investigators also evaluated consecutive patients without posterior capsular rupture (PCR) from a subgroup of three surgeons who used IC antibiotics alone without topical antibiotics.
A total of 19 cases of endophthalmitis occurred in 16,264 cataract surgeries. The respective rates per 1,000 during the three time periods were: 3.13 (95% CI, 1.43–5.93) in 2007, 1.43 (95% CI, 0.66–2.72) in 2008 and 2009, and 0.14 (95% CI, 0.00–0.78) in 2010 and 2011. One case of endophthalmitis was observed in the 2,083 patients who received IC injection only (rate per 1,000: 0.49; 95% CI, 0.01–2.73). The rate of endophthalmitis in 2007 was 0.32%, which was similar to the 0.35% observed in the control group of the ESCRS study.
Aravind. In 2017, investigators published the results of a study6 including 617,453 cataract surgeries performed from January 2014 to May 2016 at 10 Aravind Eye Hospitals in India. Endophthalmitis rates before and after initiation of IC moxifloxacin were statistically compared for all eyes and separately for phacoemulsification and manual small-incision cataract surgery (M-SICS) eyes and for eyes with PCR.
Overall, 314,638 eyes received IC moxifloxacin and 302,815 eyes did not. There was a significant decline in the endophthalmitis rate with IC moxifloxacin, from 0.07% to 0.02%. For the 194,252 phaco eyes, the endophthalmitis rate was 0.07% without IC moxifloxacin prophylaxis, compared with 0.01% with IC moxifloxacin. For the 414,657 M-SICS eyes, the endophthalmitis rate was 0.07% without IC moxifloxacin and 0.02% with moxifloxacin. Approximately half of the 8,479 eyes with PCR received IC moxifloxacin and half did not. Without IC moxifloxacin, PCR increased the endophthalmitis rate nearly sevenfold, to 0.48%; in contrast, IC moxifloxacin reduced the endophthalmitis rate with PCR to 0.21%.
The investigators concluded that routine IC moxifloxacin prophylaxis reduced the overall rate of endophthalmitis by 3.5-fold (threefold for M-SICS and nearly sixfold for phacoemulsification), and they noted that IC antibiotics had a significant benefit for eyes with PCR.
Bowen. A recent meta-analysis by Bowen and colleagues7 pooled data from 17 studies published over the past 2 decades. Apart from the ESCRS randomized clinical trial, all were observational studies. When pooled, more than 900,000 eyes could be analyzed.
Key takeaways from the meta-analysis include: (1) in terms of volume of studies and volume of patients, IC cefuroxime has the greatest support in the literature and vancomycin the least; (2) of cefuroxime, moxifloxacin, and vancomycin, cefuroxime was the least effective agent, although it was more efficacious than topical drops; (3) moxifloxacin was more effective than cefuroxime and was associated with less toxicity; (4) most effective of the three agents was vancomycin, although it has been associated with hemorrhagic occlusive retinal vasculitis; and (5) topical medications did not appear to be of benefit.
Bowen et al concluded that “[IC] cefuroxime and moxifloxacin reduced endophthalmitis rates compared with controls, with minimal or no toxicity events at standard doses. Additionally [IC] antibiotics alone may be as effective as [IC] plus topical antibiotics.”
Despite mounting evidence that routine prophylaxis with IC antibiotics reduces the rate of endophthalmitis after cataract surgery, surgeons—particularly those in the United States—have been slow to adopt this approach. The reasons for this are multiple, but not always sound.
Resistance to change. Humans have a natural resistance to change. In 2008, Peter Barry, MD, FRCSC, chair of the 2007 ESCRS study, noted, “When our results came out, we were the subject of robust challenge and debates in many roundtables and numerous discussions.”8 More than a decade later, the controversies remain. However, as ophthalmologists have learned before (eg, phacoemulsification), doing something a certain way simply because that's how it's always been done is insufficient and a disservice to patients.
Some ophthalmologists may feel more comfortable with their standard regimen of administering preoperative povidone-iodine and postoperative topical antibiotics than with an IC approach. However, have you ever seen patients administer eye drops? Enough said.
Safety concerns. The reluctance to adopt IC antibiotics stems largely from the commercial unavailability of a single, sterile, FDA-approved unit dose for cataract surgery. However, designing a clinical trial large enough to show a reduction in a relatively rare condition is cost-prohibitive. A 2013 Cochrane review stated, “It is unlikely that additional clinical trials will be conducted to evaluate currently available prophylaxis. Practitioners should rely on current evidence to make informed decisions regarding prophylaxis choices.”9 As outlined above, the evidence in support of the use of IC antibiotics is overwhelming.
Financial disincentive. The lack of reimbursement for IC antibiotics is another major barrier to adoption. There is currently no mechanism to pay for the intraoperative use of a medication to prevent postoperative drops, even though it could save the system millions of dollars. IC moxifloxacin is more cost-effective than topical administration based on the cost of the drug and the money saved by preventing endophthalmitis. A 3-mL bottle of moxifloxacin is $153.30. One 3-mL bottle of moxifloxacin can be split up 20 times for IC injection, making the cost per patient $7.67. For those who would like a commercial option from a 503B compounding pharmacy, moxifloxacin is available for $15 (www.imprimisrx.com). Additionally, many 503A compounding pharmacies will prepare patient-specific formulations (www.ocularscience.com).
As with any surgical approach, there are hurdles to overcome. Initially, when I was injecting antibiotics into the vitreous, I was concerned about disturbing the vitreous, especially in high myopes. But now that I inject a combination antibiotic, steroid, and NSAID into the anterior chamber and subconjunctivally, those concerns have been alleviated. Further, I ensure the highest quality by using IC antibiotics supplied by a 503B compounding pharmacy.
As both surgeon and patient expectations of cataract surgery continue to increase, we cannot discount the significance of a potential complication such as endophthalmitis, regardless of its incidence in our ORs. The best outcomes mandate the best practices, which is why I utilize IC antibiotics.
1. Gollogly HE, Hodge DO, St Sauver JL, Erie JC. Increasing incidence of cataract surgery: population-based study. J Cataract Refract Surg. 2013;39:1383-1389.
2. Braga-Mele R, Chang DF, Henderson BA, Mamalis N, Talley-Rostov A; for the ASCRS Clinical Cataract Committee. Intracameral antibiotics: safety, efficacy, and preparation. J Cataract Refract Surg. 2014;40:2134-2142.
3. ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicentre study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978-988.
4. Beselga D, Campos A, Castro M, et al. Postcataract surgery endophthalmitis after introduction of the ESCRS protocol: a 5-year study. Eur J Ophthalmol. 2014;24(4):516-519.
5. Shorstein NH, Winthrop KL, Herrington LJ. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. J Cataract Refract Surg. 2013;39(1):8-14.
6. Haripriya A, Chang DF, Ravindran RD. Endophthalmitis reduction with intracameral moxifloxican prophylaxis: analysis of 600,000 surgeries. Ophthalmology. 2017;124(6):768-775.
7. Bowen RC, Zhou AX, Bondalapati S, et al. Comparative analysis of the safety and efficacy of intracameral cefuroxime, moxifloxacin and vancomycin at the end of cataract surgery: a meta-analysis. Br J Ophthalmol. 2018;102(9):1268-1276.
8. Barry P. Lessons from the ESCRS study on endophthalmitis prophylaxis. Cataract & Refractive Surgery Today. September 2008. https://crstodayeurope.com/articles/2008-sep/0908_12-php/. Accessed November 1, 2018.
9. Gower EW, Lindsley K, Nanji AA, Leyngold I, McDonnell PJ. Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery. Cochrane Database Syst Rev. 2013;(7):CD006364.
John P. Berdahl, MD
• Vance Thompson Vision, Sioux Falls, South Dakota
• Member, Glaucoma Today Editorial Advisory Board
• Financial disclosure: Alcon, Allergan, Bausch + Lomb, Imprimis, Novartis