The Lore of Levofloxacin

Richard Abbott

Chair of the event, Abbott is the Thomas W. Boyden Endowed Chair in Health Sciences and is Clinical Professor of Ophthalmology at the Beckman Vision Center, University of California, San Francisco, USA. He is former President of the American Academy of Ophthalmologists.

The speakers were:

Alexander Doga

Professor of Ophthalmology and Deputy Director, Scientific and Clinical work at the Svyatoslav Fyodorov Eye Microsurgery State Institution in Moscow, Russia, and Vice President, Russian Society of Ophthalmology.

 

Tat Keong Chan

Senior Consultant, Refractive Surgery and Cataract/Comprehensive Ophthalmology Services, and Chairman of the Infection Control Committee at the Singapore National Eye Centre, Singapore. Chan is an international council member of the International Society of Refractive Surgery and a past Executive Committee member of the Singapore Society of Ophthalmology.

 

Roberto Bellucci

Chief of the Ophthalmic Unit, Hospital and University of Verona, Italy, and Professor of Anterior Segment Surgery at the University of Verona and at the University of Lugano, Switzerland. Bellucci is President-Elect of the European Society of Cataract and Refractive Surgeons.

 

The symposium addressed the use of levofloxacin in laser refractive surgery; in perioperative prophylaxis for cataract surgery, including the combination of topical treatment with intracameral cefuroxime; and in the treatment of bacterial keratitits.

Infection Prevention in Photorefractive Surgery

Alexander Doga described the collective experience of the dozen branches of the Svyatoslav Fyodorov Eye Microsurgery State Institution. Since 1989, more than 150,000 photorefractive surgery procedures have been performed, including photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK) and Femto LASIK surgery. Doga characterized the antibacterial protocols used as “straight-forward”, noting that in cataract surgery, the institution follows ESCRS’s 2007 Guidelines on Prevention, Investigation and Management of Post-Operative Endophthalmitis (1). For photorefractive surgery this protocol is simplified to: preoperatively, levofloxacin eye drops applied at 1 hour and at 30 minutes before the operation along with 5% povidone-iodine application; postoperatively, levofloxacin is applied four times per day for five to seven days, and preservative-free artificial tears for a period of up to three months.

Turning to infectious keratitis (inflammation of the cornea), a potentially devastating complication of refractive of surgery, Doga distinguished between early (1-2 weeks after surgery) and late (3-4 weeks or later) events. The former, which are often caused by gram-positive bacteria, are characterized clinically by multifocal infiltrates, deep corneal opacity, anterior chamber aqueous reactions; they require paralimbal injection. The latter tend to involve atypical mycobacteria or fungi, with clinical manifestations that include elevated lesions with margins that have a feathery appearance; they are treated with ciliary injections.

Reviewing the literature on infectious complications following refractive surgery, Doga noted that 12 percent of cases involve Gram-negative bacteria. This includes Pseudomonas aeruginosa, one of the most serious causes of postoperative infectious keratitis following PRK and LASIK. Prophylaxis with levofloxacin guards against both Gram-positive and Gram-negative bacteria, and Doga explained that a single drop of this antibiotic is sufficient to maintain, for six hours, concentrations at the ocular surface that inhibit most microorganisms. A further advantage of levofloxacin is that it displays low toxicity for ocular tissues in a range of in vitro studies. Doga concluded that topical treatment with levofloxacin is sufficient for safe and effective photorefractive surgery procedures.

Targeting Zero Infection in Cataract Surgery

Roberto Bellucci commented that as cataract surgery now provides postoperative vision that is better than the pre-cataract vision, more patients require early surgery. This trend, he argued, is limited by a number of factors, including intraoperative complications, postoperative infection and postoperative inflammation. Of these, endophthalmitis, which can be a devastating complication, is the major issue. Most cases of endophthalmitis, inflammation of the internal coats of the eye, are caused by bacteria already present in the conjunctiva of the patient so it is essential to make the area as sterile as possible before surgery. Bellucci explained that he treats both eyes of the patient, “to reduce the possibility that bacteria will be transferred by eye-rubbing.”

Although up to 94 percent of cases of infection are caused by Gram-positive bacteria, it is the Gram-negative cases that are the most troubling. “Bacteria, especially gram-negative bacteria, can destroy everything inside the eye within hours,” said Tat Keong Chan in his opening remarks, “You have to aim for zero infections.” He noted that the spectrum of bacteria implicated in serious ocular infections varies geographically, so there are no uniform practices: eye drops, intracameral and subconjunctival antibiotics, and various combinations of these, are all in use at different locations worldwide. At the Singapore National Eye Centre, where more than 12,000 cataract operations are performed annually, the incidence of endophthalmitis stands at just 0.05 percent over the last 22 years. This rate is similar to the lowest reported rates in the world.

Bellucci described certain risk factors for postoperative endophthalmitis, including capsular rupture, old age and being male. Chan mentioned three further risk factors following cataract surgery that were identified in an ESCRS multicenter study (2), namely the failure to inject intracameral cefuroxime; the use of clear corneal incisions without sutures; and the use of silicone intraocular lenses. Despite the evidence for the first of these factors, there remains no consensus on intracameral cefuroxime use in many countries (3). Obstacles to the widespread use of intracameral cefuroxime include legal barriers and lack of availability of the commercial preparation. Indeed, Chan’s center does not use intracameral antibiotics, while Bellucci’s does. In contrast, topical povidone-iodine has been universally adopted and postoperative topical antibiotics such as levofloxacin are used extensively.

Intracameral antibiotics alone are certainly not sufficient for prophylaxis, Chan stated, as they provide very high levels of the antibiotic in the anterior chamber for only a matter of hours, while the risk of contamination from leaking clear corneal incisions may persist for days. Sutureless, poorly constructed clear corneal incisions are especially prone to leak, and corneal incisions generally are truly vulnerable: the force generated by rubbing the eye for 2 to 3 seconds induces sufficient force to cause leakage from two-thirds of sutureless incisions and from a quarter of sutured incisions (4).

Other than the divergence in intracameral antibiotic use, the regimen for prophylaxis practiced by the two experts is remarkably similar, with levofloxacin playing a central role. The procedure includes:

• Topical levofloxacin every four hours one or two days pre-op, and every 15 minutes starting one hour before surgery
• Meticulous draping (complete isolation of lashes)
• Topical povidone-iodine: 10% on periocular  skin; 5% on ocular surface, for at least three minutes
• Limbal or corneal incision under topical anesthesia
• Routine stromal hydration of incision
• Ensure hermetic “watertight” seal of incision at the end of surgery
• Continued topical levofloxacin and topical steroids starting immediately at the end of surgery, every two hours on the day of surgery and every four hours thereafter
• Topical levofloxacin administered intensively (not less than QID dosage) and stopped abruptly with no tapering
• Telephone call to all patients to ensure strict compliance of the dosing schedule

Looking at recent developments in cataract surgery, Bellucci expressed the hope that microincision cataract surgery (MICS) and femto lasers will reduce complications, that disposable instruments will reduce toxic anterior segment syndrome (TASS) and that preloaded IOLs will reduce contamination. However, both speakers underlined the key role of levofloxacin in prevention of endophthalmitis. It should be used, they say, because it very effectively kills bacteria on the surface of the eye, kills bacteria that get inside the eye, and is effective and safe.

Therapy of Bacterial Keratitis

Half a million cases of bacterial keratitis are reported annually worldwide. If untreated, these would result in progressive tissue destruction, corneal perforation and extension to adjacent structures, causing loss of vision. Indeed, in excess of one million people worldwide suffer from decreased vision as a result of complications of the condition. Richard Abbott’s presentation took as its starting point the clinical guidelines for bacterial keratitis that have been developed by the American Academy of Ophthalmology and the International Council of Ophthalmology.

These guidelines state that bacterial keratitis should be treated with topical antibiotic drops using a broad-spectrum agent. Initially, very high doses and frequency are used (a loading dose), with treatment modified after 48 hours, depending on the response and cultures. Topical steroids can be introduced in due course to control scar formation in the cornea. Abbott pointed out that the most effective antibiotic is one which balances high, sustained levels at the site of infection with minimal associated toxicity. A broad-spectrum antibiotic is required until etiology is confirmed and, he noted, fluoroquinolones are the only antibiotic class that is recommended for all causes of bacterial keratitis. Of these, the most effective later-generation fluoroquinolone antibiotic is levofloxacin: it kills a wide range of bacterial targets rapidly; it readily penetrates the cornea, where it reaches high concentration, and it has minimal tissue toxicity.

Bacterial resistance is a major concern and Abbott summarized actions aimed at preventing its development. These include:

• Using high concentrations
• Using a bactericidal drug
• Using a high dosing frequency
• Using a maximum time course (of two weeks)
• Never tapering the dose
• Limiting the duration of the dose

Conclusion

The panel agreed that levofloxacin is as close to the ideal antibiotic as you can get for the conditions discussed in the symposium. Levofloxacin has the following qualities:

• Effective against a wide range of ocular pathogens
• Low level of bacterial resistance
• Excellent tissue-penetration
• Excellent solubility profile
• Rapid onset of action
• Low toxicity
• Compatible with other drugs