When new antimicrobials are introduced in the fields of internal medicine or general surgery, it typically takes several years for ophthalmic formulations of these antimicrobials to reach the market. By the time ophthalmic formulations are introduced, organisms may have already begun developing resistance to the drug.
When topical fourth-generation fluoroquinolones were introduced in 2003, the hope was that they would be effective for a long period of time because organisms would have a harder time developing resistance to these agents compared to earlier generations of the drugs. Double mutation of the bacterial DNA gyrase enzyme theoretically makes it more difficult for the emergence of drug resistance.
Treatment Patterns
Topical fourth-generation fluoroquinolones are typically used before and after surgery by ophthalmologists to prevent endophthalmitis. Most surgeons are postoperatively treating patients with a fourth-generation fluoroquinolone four times a day for seven days. Additionally, some surgeons treat patients preoperatively for two or three days.
Fourth-generation fluoroquinolones are often favored over third-generation fluoroquinolones because of their superior penetration through the cornea and more favorable minimum inhibitory concentration levels in aqueous compared with third-generation fluoroquinolones. Another benefit of the fourth-generation fluoroquinolones is that they provide broad-spectrum coverage against both gram-positive and gram-negative organisms.
However, because no prospective or retrospective published studies had examined the rate of postop endophthalmitis in patients treated with fourth-generation fluoroquinolones, my colleagues and I decided to retrospectively estimate the rate of acute postoperative endophthalmitis after uncomplicated cataract surgery in patients treated both before and after surgery with either moxifloxacin or gatifloxacin.1
From March 2003 through July 2005, the nine participating surgeons performed 20,013 uncomplicated cataract surgeries. Fourth-generation fluoroquinolones were administered pre- and postoperatively. Five of the participating centers used gatifloxacin, two centers used moxifloxacin, and two used either of these. Most (16,209, 81 percent) patients received gatifloxacin, while 3,804 (19 percent) received moxifloxacin.
Fourteen patients (10 women, four men) suffered acute postop endophthalmitis, for an overall rate of 0.07 percent. Their average age was 65.7 years, with a range of 37 to 85 years. Their visual acuity at presentation ranged from 20/50 to light perception. Nine of these patients had received gatifloxacin, and five had received moxifloxacin. The estimated rates of infection were 0.1 percent with moxifloxacin and 0.06 percent with gatifloxacin. The difference in the rate of postop endophthalmitis did not reach statistical significance. Patients’ average time from the day of cataract surgery to the day of diagnosis with endophthalmitis was 9.3 days, with a range of two to 32 days. The average time from cataract surgery to presentation with endophthalmitis was 11.22 days (range: two to 32 days) for the nine patients treated with gatifloxacin and 5.2 days (range: two to 12 days) for the five patients treated with moxifloxacin.
Of the 14 patients who suffered acute postoperative endophthalmitis, 12 underwent vitreous culturing. Ten patients were culture-positive. Five patients were positive for staphylococcus. Four of these patients had coagulase-negative staphylococcus, and one patient had methicillin-resistant Staphylococcus aureus. Four patients had streptococcus, and one patient had culture-proven Pseudomonas aeruginosa endophthalmitis.
We requested that special sensitivity testing be performed on the bacterial isolates in three cases. According to the laboratory testing results, the Streptococcus pneumoniae isolate from one patient was sensitive to both gatifloxacin and moxifloxacin with an MIC of 0.125 µg/mL. The second case was positive for methicillin-resistant Staphylococcus aureus, which was found to be resistant to both gatifloxacin and moxifloxacin, with an MIC higher than 8.00 µg/mL. The third case was positive for P. aeruginosa, which was sensitive to both gatifloxacin and moxifloxacin. The MIC for moxifloxacin was 0.5 µg/mL, and the MIC for gatifloxacin was 0.25 µg/mL.
Endophthalmitis Rates
Although endophthalmitis after routine cataract surgery is not common, it can have devastating consequences. Reported endophthalmitis rates range from 0.07 percent to 0.2 percent. As the cause of most cases of postoperative endophthalmitis is the patient’s own conjunctival flora, prophylactic measures are used to try to decrease the number of ocular bacteria before and after surgery.
Unfortunately, similar rates of endophthalmitis have been reported with the fourth-generation fluoroquinolones and with previous generations of fluoroquinolones.
In our study, the rate of endophthalmitis was 0.07 percent, which is not significantly different from the 0.05 percent rate published by John Miller, MD, and colleagues in a study conducted between 2000 and 2004.2
At our institution, we recently studied the occurrences of endophthalmitis during the past 16 years, and we found that the occurrence of endophthalmitis during the era of the third-generation fluoroquinolones was higher than with fourth-generation fluoroquinolones. This was in one center with the same group of surgeons and almost the same surgical staff. However, when evaluating the global incidence or occurrence of endophthalmitis, there is no change or difference between the rate of endophthalmitis with the third- and the fourth-generation fluoroquinolones.
Also, because organisms would have to go through two mutations to develop resistance to fourth-generation fluoroquinolones, the hope was that they would be effective for a long time. Unfortunately, it takes so long for ophthalmic formulations of drugs to become available that organisms may have already begun developing resistance to them before their introduction into ophthalmology. In fact, cases of resistance to the fourth-generation fluoroquinolones have already been reported.
As early as 2006, Vincent A. Deramo, MD, and colleagues reported acute endophthalmitis after cataract surgery despite the prophylactic use of fourth-generation fluoroquionolones.3 In this report, the researchers studied the use of gatifloxacin and moxifloxacin and bacterial sensitivity in 42 patients who developed acute postop endophthalmitis within six weeks after cataract surgery. Thirty-one of these patients were perioperatively treated with gatifloxacin or moxifloxacin, and 24 eyes were continuously receiving one of these antibiotics at the time of diagnosis. Nineteen eyes had a positive bacterial culture; 14 gram-positive organisms underwent sensitivity testing. The study results showed sensitivities to ciprofloxacin (50 percent), ofloxacin (44 percent), levofloxacin (46 percent), gatifloxacin (38 percent), and moxifloxacin (38 percent). Five organisms were resistant to moxifloxacin and gatifloxacin with an MIC of 8 µg/mL.
One possible explanation for the rapid development of resistance is that organisms had already undergone one mutation before the fourth-generation fluoroquinolones were introduced into ophthalmology. After developing one mutation, developing the second mutation would not be very difficult.
Another possibility is that these organisms don’t necessarily need to go through a second mutation to develop resistance. They could have developed a completely different mechanism, such as quick efflux of the drug from the bacterial wall.
Response to Increasing Resistance
I believe that the real issue is the delay in developing an ophthalmic formulation of these agents. Ideally, drugs should be introduced to ophthalmology at the same time they are introduced to general surgery because organisms begin developing resistance to medications as soon as their use becomes widespread.
In fact, infectious disease specialists and general surgeons have already shifted their paradigm away from the fourth-generation fluoroquinolones and are now using other new classifications of antimicrobials. However, ophthalmic formulations of these drugs are probably five to 10 years away. Another issue is that organisms are becoming much more resistant. Methicillin-resistant Staphylococcus aureus is just the tip of the iceberg. Other surgical subspecialties are reporting cases of vancomycin-resistant enterococci (VRE). We have only had a few cases of VRE reported in the ophthalmic field.
Organisms are definitely becoming much more resistant, and, at the same time, we are dealing with a new mutation in organisms. To deal with these organisms, we need new classes of antimicrobials with new mechanisms of action. While these new classes are already available in other specialties, they are not available for ophthalmology yet.
Optimal Use of Current Drugs
The results of our study highlighted several issues. Some cases of endophthalmitis occurred more than 72 hours after surgery, which has resulted in some surgeons questioning whether antimicrobials should be used for longer periods of time, such as q.i.d. for a week after surgery and then b.i.d. for another two weeks. However, I am not a great advocate of tapered regimens for antibiotics. I believe that patients should be on antibiotics at the same dosage for a certain amount of time, and then they need to stop. There is no need to taper these medications the way we do anti-inflammatories. However, while it cannot be scientifically concluded from our study results, it may be better to have patients take antibiotics four times a day for two weeks after surgery.
Some surgeons currently tell patients to take fourth-generation fluoroquinolones after surgery q.i.d. until the bottle is empty, which may take two to four weeks. Their reasoning is that the organisms may re-emerge later on and not during the early stages of recuperation post-cataract surgery. While we cannot infer that conclusion from our study, we certainly cannot reject their logic of longer use of antibiotics during the postoperative phase.
Another interesting finding from our study is that moxifloxacin and gatifloxacin had very similar efficiency. I was not surprised to see that moxifloxacin did not have superiority over gatifloxacin; however, I was surprised that we didn’t see a leading advantage of fourth-generation fluoroquinolones compared to third-generation fluoroquinolones.
The Future
We once thought that antimicrobials had a longevity of a decade before a new one was needed. Unfortunately, this turnaround is going to be much shorter in the future. In 10 years, I wouldn’t be surprised to see an armamentarium of different classes of antimicrobials, different indications for them, and much shorter commercial longevity. The next generation of ophthalmologists may need to use two different classes of antimicrobials with two different mechanisms of action in order to have better coverage of the gram-positives, which are becoming extremely resistant, and of the gram-negatives.
Additionally, because we are performing more intraocular procedures than in the past, even if the rate of endophthalmitis stays the same, the number of endophthalmitis cases will increase.
The catalysts for the development of new antimicrobials are the organisms themselves. Organisms are becoming more resistant, and this is the force behind the development of new classes of antimicrobials. However, there are many limiting factors to their development, such as the extensive financial resources required for research, the time it takes to develop a new agent, and the time it takes for government approval.
The fourth-generation fluoroquinolones should have been here several years before their market approval. The fact that it takes drugs much longer to reach the ophthalmology market shortens the longevity of their commercial efficacy. The life expectancy of being the leading antimicrobial on the market is decreasing because the organisms are becoming much more resilient.
Dr. Moshirfar is the director of the John A. Moran Eye Center’s Cornea and Refractive Surgery Program in Salt Lake City. He is professor of ophthalmology and visual sciences at the University of Utah School of Medicine.
1. Moshirfar M, Feiz V, Vitale AT, Wegelin JA, et al. Endophthalmitis after uncomplicated cataract surgery with the use of fourth-generation fluoroquinolones: A retrospective observational case series. Ophthalmology 2007;114:686-691.
2. Miller JJ, Scott IU, Flynn HW Jr., et al. Acute-onset endophthalmitis after cataract surgery (2000-2004): Incidence, clinical settings, and visual acuity outcomes after treatment. Am J Ophthalmol 2005;139: 983-987.
3. Deramo VA, Lai JC, Fastenberg DM, Udell IJ. Acute endophthalmitis in eyes treated prophylactically with gatifloxacin and moxifloxacin. Am J Ophthalmol 2006;142:721-725
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