The risks of using intracameral antibiotics

ByJohn R. Wittpenn Jr., MD, FAAO

Discussions of endophthalmitis prophylaxis often begin with the assertion that the incidence of endophthalmitis after cataract surgery has risen in recent years, based on the study of Medicare claims data by West and colleagues that found a 37% increase in endophthalmitis over 8 years.¹ Although the West study was published in 2005, it is based on Medicare claims made from 1994 to 2001, a result of the delay involved in obtaining and analyzing the data. In fact, the incidence of endophthalmitis in the United States since 2001 is not known.

In addition, the West study data are not reflective of the current state of antibiotic prophylaxis. Many organisms that were increasingly resistant to earlier generation fluoroquinolones² are susceptible to available current generation topical ophthalmic fluoroquinolones.³

Additionally, many surgeons were transitioning from scleral tunnel to clear corneal incision techniques during the 1994 to 2001 period of study.^4,5 This temporal association between the transition to clear corneal incisions and the rise in endophthalmitis has led to the discussion of the possibility of a causative link.⁶ A retrospective case- controlled study found a threefold higher risk of post- cataract endophthalmitis with clear corneal incisions than with scleral tunnel incisions. ⁷ Also, a cadaveric eye study of clear corneal incisions showed that a decrease in IOP can result in poor wound apposition and an increased potential for fluid to flow through the wound and into the anterior chamber. ⁸

Studies suggest that adding intracameral antibiotics to a surgical regimen can lower the risk for endophthalmitis following cataract surgery.

Intracameral antibiotics and endophthalmitis

In a 3-year retrospective study by Garat and colleagues, the incidence of endophthalmitis was 0.42% in almost 6,000 surgeries in 2002 and 2003 without intracameral cefazolin.⁹ In 3,200 surgeries with intracameral cefazolin in 2004, the incidence was 0.031%.⁹

The large-scale multicenter study by members of the European Society of Cataract and Refractive Surgeons has recently brought the issue of intracameral antibiotic prophylaxis to the forefront.¹⁰ The study’s authors concluded that intracameral cefuroxime administered at the time of cataract surgery significantly reduces the risk of postoperative endophthalmitis.¹⁰

No comparable study of the current endophthalmitis rate exists in the United States, but the closest study, roughly comparable in terms of the numbers of patients included and the rate of endophthalmitis, is a retrospective multicenter study by Moshirfar and colleagues. ¹¹ In that study of 20,013 cataract surgeries, patients received preoperative and postoperative topical antibiotic prophylaxis with one of two current generation ophthalmic fluoroquinolones: 16,209 patients received gatifloxacin 0.3% with benzalkonium chloride (BAK) and 3,804 patients received moxifloxacin 0.5%.¹¹

Fourteen patients in the study developed endophthalmitis, for an overall rate of 0.07%, roughly comparable to the rate in the prospective European study with both topical and intracameral prophylaxis.

The difference in the rate of endophthalmitis between patients receiving gatifloxacin and patients receiving moxifloxacin was not statistically significant.¹¹ Despite data on earlier generation ophthalmic fluoroquinolones that indicated the penetration of topically applied ofloxacin was greater than that of ciprofloxacin,¹² both current generation ophthalmic fluoroquinolones penetrate well, and their minimum inhibitory concentrations (MICs) against common pathogens are lower than those of the earlier drugs (Figure 1).^13-15

Figure 1
Concentrations of fluoroquinolones

Both moxifloxacin and gatifloxacin penetrate well into the aqueous humor, and both have MICs against common pathogens that are lower than previous generation drugs.^12-15

In addition, a high intracorneal concentration of gatifloxacin (16 µg/mL) is achieved when the drug is administered preoperatively for 3 days.¹⁶ The concentration exceeds the MICs of several ocular pathogens, particularly staphylococcal species,¹⁷ indicating that topical administration of gatifloxacin results in a depot of drug in the cornea that is available to fight contamination by pathogens present at the end of surgery.

Evans and colleagues showed that, using either gatifloxacin or moxifloxacin as preoperative antibiotics, less than 1% of aqueous cultures taken at the completion of cataract surgery contained detectable contamination.¹⁸

In other words, although it appears that intracameral antibiotic prophylaxis eliminates immediate postoperative contamination through high concentrations of antibiotic in the aqueous, studies show that the contamination rate is low with the use of preoperative topical prophylaxis, and that topical administration provides a significant concentration of drug at the wound site, particularly when topical administration is continued at the end of surgery.

Time to presentation

In my opinion, intracameral antibiotics are effective for several hours at most. If infection occurs beyond that time, the efficacy of intracameral prophylaxis may be negligible.

In the Moshirfar study, the time to presentation of endophthalmitis averaged 9.6 days postoperatively, exceeding the time of administration of postoperative topical antibiotics, which was 7 days postoperative.¹¹ It is common practice to administer antibiotics for 7 days postoperatively with clear corneal surgery. No reference to the time of presentation of endophthalmitis was made in the ESCRS study,¹⁰ but time to presentation may be important in assessing the efficacy of prophylactic regimens.

Late-presenting infections are often referred to as indolent endophthalmitis; the implication is that the pathogens are in the eye, but the infection does not develop until days later. But in the Moshirfar study, it is unlikely that organisms survived a week of antibiotic application with the low MICs of the drugs used. ¹¹

In several cases in which endophthalmitis developed, the contamination or infection of the eye most likely occurred after day 7, when antibiotic application was stopped. Clear corneal incisions have been shown to gape 24 hours after surgery. McDonnell and colleagues showed that particles of india ink can travel from the surface of the eye into a clear corneal incision, and that this influx can cause endophthalmic inoculation after surgery.^19,20

In the Moshirfar study, five of the 14 cases of endophthalmitis occurred after the postoperative topical antibiotics were stopped.¹¹ Those five cases should not have been included in the analysis of the risk of endophthalmitis as related to the topical antibiotic used because the event occurred after that factor had been removed. If those cases are removed from the analysis, the rate of endophthalmitis with gatifloxacin becomes 0.031%, which is comparable to the rate in the ESCRS study with intracameral cefuroxime, and the rate for moxifloxacin becomes 0.105%, making the probability value for a difference between the two drugs P = .056, which is not clinically significant but shows a strong trend.

Figure 2
Efficacy against MRSA

Gatifloxacin with BAK provided lower MICs than gatifloxacin alone or moxifloxacin alone. Gatifloxacin without BAK and moxifloxacin without BAK were equally efficacious. ²²

Fighting increasing resistance

Resistance of endophthalmitis-causing organisms to even the newest generation of fluoroquinolones has been demonstrated. Major and colleagues found that, in isolates from 11 culture-proven cases of methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis, 45% of the strains were resistant to both gatifloxacin and moxifloxacin.²¹ In one case of MRSA in the Moshirfar study, MICs of more than 8 µg/mL to both gatifloxacin and moxifloxacin were found. That patient was taking moxifloxacin, and the time to presentation was 4 days, indicating the contamination most likely occurred after the time of surgery.

Blondeau and colleagues showed in an in vitro study that gatifloxacin with BAK was more effective against MRSA than moxifloxacin or either fluoroquinolone without BAK (Figure 2).²² The two drugs without BAK were equally efficacious. Commercially available gatifloxacin is preserved with 0.005% BAK.

Risk with intracameral administration

Data compiled from all of these studies suggest that until cataract surgical wounds are sealed permanently — and that may in fact be longer than 7 days — the primary battle in preventing endophthalmitis is on the surface of the eye. It remains unknown, however, if surgeons who adopt intracameral administration in an effort to increase safety are adding risks in addition to the risk of a wrong concentration or toxic anterior segment syndrome (TASS).

Resistance of endophthalmitis-causing organisms to even the newest generation of fluoroquinolones has been demonstrated.
— John R. Wittpenn Jr., MD, FAAO

In patients without risk factors, the risk of retinal thickening after cataract surgery exists. A large, masked, multicenter study compared the incidence of cystoid macular edema and the degree of retinal thickening after cataract surgery in 546 patients who received either topical steroid plus ketorolac 0.4% or topical steroid alone.²³ Ketorolac reduced the degree of retinal thickening significantly at all time points measured, but thickening remained present. Furthermore, retinal thickening of more than 10 µm affected not only contrast sensitivity but also visual acuity. These effects on vision were statistically significant for retinal thickening greater than 10 µm, but they are not large changes; without the benefit of a large series of patients, they may not be noticed. A concern exists that similar changes are unappreciated in reports of small series of patients with intracameral administration of antibiotics.

Conclusion

Available data do not support an increased benefit for intracameral prophylaxis vs. current perioperative prophylaxis with current generation fluoroquinolones. The duration of high antibiotic levels in the anterior chamber after intracameral administration is short, whereas the risk of contamination through unsealed clear corneal wounds lasts for many days. In addition, the risk of decreased visual function and increased rates of TASS with compounded preparations of intracameral antibiotics are unknown.

References

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