Many studies have identified that the most common cause of postsurgical endophthalmitis is a result of endogenous ocular surface flora's entering the eye during surgery.1,2 Thus, even though no randomized clinical trial has been performed to investigate the role of preoperative topical antibiotic prophylaxis, many ophthalmologists still sterilize the ocular surface in order to prevent this devastating intraocular infection.3
The theoretical premise behind the use of preoperative topical antibiotics is twofold. The first is to decrease or eradicate the surface organisms, thus preventing intraocular inoculation of these organisms during surgery. The second is to provide a bactericidal level of antibiotic in the anterior chamber before cataract surgery to ensure that any organisms that do enter the eye intraoperatively are killed.
The ideal topical antibiotic should be effective against the many pathogens found on the ocular surface, including the staphylococcal species that are becoming increasingly resistant to commonly used topical medications. The ideal drug should also adequately penetrate the anterior chamber and vitreous to allow for a bactericidal killing level intraoperatively. The levels of this antibiotic should be unaffected by the cataract surgery itself. Finally, it must be capable of preventing endophthalmitis postoperatively should a pathogen enter the eye during surgery. The newest fourth-generation fluoroquinolones, moxifloxacin and gatifloxacin, appear to fulfill the aforementioned criteria and are increasingly becoming the antibacterial drugs of choice in the ophthalmic community. Their wide spectrum of activity, superior ocular penetration with minimal toxicity, and mechanism of action that minimizes the problematic issue of bacterial resistance make them potentially powerful weapons in the battle against endophthalmitis. The following articles were reviewed:
1. Speaker MG, Milch FA, Shah MK, et al. Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology. 1991;98:639-650.
2. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122:1-17.
3. Liesegang TJ. Use of antimicrobials to prevent postoperative infection in patients with cataracts. Curr Opin Ophthalmol. 2001;12:68-74.
4. Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect. 2005;11:256-280.
5. Mino de Kaspar H, Koss MJ, He L, et al. Antibiotic susceptibility of preoperative normal conjunctival bacteria. Am J Ophthalmol. 2005;139:730-733.
6. Solomon R, Donnenfeld ED, Perry HD, et al. Penetration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the aqueous humor. Ophthalmology. 2005;112:466-469.
7. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49(suppl 2):79-83.
8. Hariprasad SM, Blinder KJ, Shah GK, et al. Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol. 2005;123:39-44.
9. Mather R, Stewart JM, Prabriputaloong T, et al. The effect of cataract surgery on ocular levels of topical moxifloxacin. Am J Ophthalmol. 2004;138:554-559.
10. Kowalski RP, Romanowski EG, Mah FS, et al. Topical prophylaxis with moxifloxacin prevents endophthalmitis in a rabbit model. Am J Ophthalmol. 2004;138:33-37.
MECHANISM OF ACTION AND SPECTRUM OF ACTIVITY
Quinolones are derived from the parent compound of nalidixic acid, originally designed for antimalarial research.4 Both moxifloxacin and gatifloxacin are classified as fourth-generation fluoroquinolones due to a fluorine substitution at the C-6 position of their chemical structure, a methoxy group at the C-8 position, as well as larger moieties at the
C-1 and C-7 positions. Their activity stems from the formation of complexes with two enzymes crucial in the supercoiling of DNA, DNA gyrase, and topoisomerase IV. The inability of bacteria to supercoil their DNA induces cellular apoptosis. This process results in a surprisingly wide spectrum of activity.
Both moxifloxacin and gatifloxacin have an enhanced spectrum of activity against gram-positives compared to the older fluoroquinolones due to additional chemical alterations to their structures. For example, many isolates of coagulase-negative Staphylococcus (which accounts for more than 70% of all cases of endophthalmitis in the Western world) are showing heightened resistance to topical ofloxacin and ciprofloxacin. Many studies have demonstrated that the resistance level of these strains to the newer fluoroquinolones is less than 5%. In addition, this class of medicine also has strong activity against gram-negatives and anaerobes, atypical mycobacteria, and Chlamydia species.
ACTIVITY ON OCULAR SURFACE FLORA
Results from in vitro studies have found that the newer fluoroquinolones have excellent activity against ocular flora. De Kaspar et al5 took baseline conjunctival cultures from 164 eyes of 164 patients prior to anterior segment intraocular surgery and found a total of 124 species of coagulase-negative Staphylococcus, 19 cultures of Staphylococcus aureus, as well as eight positive cultures for Group D Streptococcus species and 11 species of gram-negative rods. Antibiotic susceptibility of the isolates was determined using the Kirby-Bauer disk diffusion technique.
Of the 124 species of coagulase-negative Staphylococcus, less than 3% were resistant to either moxifloxacin or gatifloxacin, compared to an ofloxacin resistance rate of 25%. None of the other isolated bacteria was resistant to either of the newer fluoroquinolones, however all eight Streptococcus species were resistant to either ofloxacin or ciprofloxacin. There were also 43 isolates of multiresistant bacteria, defined as those organisms resistant to more than five tested antibiotics. Of those organisms, resistance to the two newer fluoroquinolones was less than 10%, whereas for the older ones the resistance rate exceeded 65%.
OCULAR PENETRATION AND INTRAOCULAR CONCENTRATION
Solomon et al6 instructed 52 patients undergoing cataract surgery to administer one of three different topical fluoroquinolones four times a day for 3 days prior to surgery. A total of 14 patients used moxifloxacin 0.5%, 16 patients received gatifloxacin 0.3%, and 22 patients used ciprofloxacin 0.3% preoperatively. One hour before surgery, patients were asked to use their antibiotic every 15 minutes for a total of three doses. In the OR, before the initiation of surgery, approximately 0.1mL of aqueous fluid was aspirated using an air cannula needle attached to a tuberculin syringe. The concentration of fluoroquinolone in each sample was determined with reverse-phase, high-pressure, liquid chromatography.
The mean aqueous concentration of moxifloxacin reached 1.31 ±0.46mcg/mL (range, 0.68 to 2.92mcg/mL) whereas those of gatifloxacin and ciprofloxacin were 0.63 ±0.30mcg/mL (range, 0.23 to 1.18mcg/mL) and 0.15 ±0.11mcg/mL (range, 0.09 to 0.58mcg/mL), respectively. The mean aqueous concentrations of both moxifloxacin and gatifloxacin were well above each drug's documented ocular pathogen MIC50 of 0.03 to 0.13mcg/mL and 0.08 to 0.50mcg/mL, respectively.7 Only ciprofloxacin's mean concentration fell below its ocular pathogen MIC50 of 0.25 to 32mcg/mL (32mcg/mL reported for Streptococcus pneumoniae).
In a similar study, Hariprasad et al8 studied the aqueous and vitreous concentrations of moxifloxacin 0.5% in 20 patients undergoing vitrectomy for various reasons, who self-administered topical moxifloxacin either every 2 hours or every 6 hours for 3 days prior to surgery. On the operative day, in addition to maintaining their drop-frequency protocol, a drop of moxifloxacin was administered 15 minutes before the surgery. Aqueous samples were obtained with the collection of 0.1mL via a 30-gauge needle attached to a syringe through a paracentesis. Vitreous samples were collected with the assistance of a vitreous cutter attached to a syringe that obtained 0.2 to 0.3mL.
Samples were analyzed for moxifloxacin concentration via high-performance liquid chromatography. For both of the dosing regimens of the two previously mentioned studies,6,8 the aqueous concentration of moxifloxacin exceeded the MIC90 for important pathogens causing endophthalmitis. However, only the dosage administered every two hours produced vitreous concentrations that exceeded the MIC50 for pathogens such as Streptococcus epidermidis, S. aureus, S. pneumoniae, Bacillus cereus, and others.
EFFECT OF SURGERY ON drug's
INTRAOCULAR CONCENTRATION
Mather et al9 investigated the effects of cataract surgery in rabbits on intraocular levels of topical moxifloxacin given for surgical prophylaxis. Thirty-six eyes of 18 rabbits were included in the study whereby both eyes of all rabbits received three drops of moxifloxacin 0.5%, separated by 5 minutes, approximately 1 hour before surgery. Only one eye of each of the rabbits was operated on, with the other eye acting as a nonsurgical control. Surgery consisted of phacoemulsification with a 3-mm clear corneal incision with two nylon sutures to close the surgical wound. At the end of the surgery, both eyes received three drops of moxifloxacin, again, separated by 5 minutes. The rabbits were then split into three groups and euthanized at 30, 60, and 120 minutes postoperatively to compare the levels of moxifloxacin in surgical and nonsurgical eyes. Aqueous and vitreous concentrations were determined by high-pressure liquid chromatography.
Although the aqueous levels of moxifloxacin were higher in the nonsurgical versus the operated eyes, the concentrations in both were at least 200-fold higher than the MIC90 for fluoroquinolone susceptible staphylococcal species, and at least fourfold higher than the MIC90 for fluoroquinolone-resistant staphylococci. In this study, neither the surgical nor the nonsurgical eyes reached therapeutic vitreous concentrations of moxifloxacin against the most common fluoroquinolone-resistant organisms. However, both were almost equivalent to the MIC90 of sensitive staphylococcal species. By inference, these results demonstrate that cataract surgery may not influence the level of intraoperative antibiotic resulting from presurgical prophylaxis.
PROOF OF PRINCIPLE IN THE PREVENTION OF ENDOPHTHALMITIS
Kowalski et al10 have provided the first proof that newer topical fluoroquinolones may be able to prevent postoperative endophthalmitis in an animal model. Three regimens of topical prophylaxis were used in three groups of 20 rabbits that had anterior chambers challenged with injections of 50,000 colony-forming units of S. aureus in 0.025mL (an amount of pathogen known to reproducibly induce endophthalmitis in the study animals).
In the full-prophylaxis group, 10 rabbits received one drop of moxifloxacin 0.5% every 15 minutes, 1 hour before intraocular injection, for a total of five drops. An additional drop was given immediately after the injection, and four more drops were administered during a 24-hour period.
In the prechallenge-prophylaxis group, 10 rabbits received moxifloxacin every 15 minutes for 1 hour prior to injection, with no additional drug given afterward. In the postchallenge-prophylaxis group, moxifloxacin was only applied immediately after injection in 10 animals and four more times in 24 hours, with no medicine given to any of the rabbits in advance.
In each group, 10 control rabbits (30 in total) endured the same prophylaxis and injection protocol, except saline was substituted for moxifloxacin. All eyes were graded clinically for signs of endophthalmitis at 4, 11, 18, and 22 hours postchallenge. Then, the animals were sacrificed, and samples from their anterior chambers and vitreous were cultured. None of the anterior chamber or vitreous cultures of the
30 rabbits receiving any type of moxifloxacin prophylaxis resulted in bacterial recovery compared with positive cultures from five, three, and six rabbit anterior-chamber cultures in the full-, prechallenge-, and postchallenge-prophylaxis control groups, respectively. Vitreous cultures were positive in three, one, and three of the aforementioned control groups, respectively. Clinical gradings for signs of endophthalmitis showed that rabbits in the full-prophylaxis group had no signs of infection and that postchallenge prophylaxis produced slightly fewer signs than prechallenge prophylaxis.
The investigators concluded that topical prophylaxis with moxifloxacin produces a sufficient bactericidal effect in the eyes of rabbits to prevent endophthalmitis when inoculated with a bacterial load comparable to one that might result if pathogens entered the eye during cataract surgery.
BOTTOM LINE
Fourth-generation fluoroquinolones are readily being accepted in the ophthalmic community as the topical medication of choice in surgical prophylaxis against endophthalmitis. Both moxifloxacin and gatifloxacin are effective in killing ocular surface flora, including gram-positive bacteria resistant to older fluoroquinolones. The newer fluoroquinolones also have excellent intraocular penetration and achieve adequate intraocular bactericidal levels, which were maintained even after cataract surgery in one animal study. Lastly, in vivo, the agents have been proven to eliminate anterior chamber bacterial inoculates similar to those that may occur during cataract surgery, and thus they may combat endophthalmitis postoperatively.
Reviewer
Dr. Sanghera states that he holds no financial interest in any product or company mentioned herein. He may be reached at (416) 666-7115; sanghera@rogers.com.
Panel Members
Y. Ralph Chu, MD, is Medical Director, Chu Vision Institute in Edina, Minnesota. He states that he holds no financial interest in any product or company mentioned herein. Dr. Chu may be reached at (952) 835-1235; yrchu@chuvision.com.
Nina Goyal, MD, is a resident in ophthalmology at the Rush University Medical Center in Chicago. She states that she holds no financial interest in any product or company mentioned herein. Dr. Goyal may be reached at (312) 942-5315;
ninagoyal@yahoo.com.
Wei Jiang, MD, is a resident in ophthalmology at the Jules Stein Eye Institute in Los Angeles. She states that she holds no financial interest in any product or company mentioned herein. Dr. Jiang may be reached at (310) 825-5000; wjiang70@yahoo.com.
Baseer Khan, MD, is a senior resident in ophthalmology in the Department of Ophthalmology at the University of Toronto. He states that he holds no financial interest in any product or company mentioned herein. Dr. Khan may be reached at (415) 258-8211; bob.khan@utoronto.ca.
Patty Lin, MD, MBA, is a resident in ophthalmology at the Jules Stein Eye Institute in Los Angeles. She states that she holds no financial interest in any product or company mentioned herein. Dr. Lin may be reached at (310) 825-5000; lin@jsei.ucla.edu.
Gregory J. McCormick, MD, is a resident in ophthalmology at the University of Rochester Eye Institute in New York. He states that he holds no financial interest in any product or company mentioned herein. Dr. McCormick may be reached at (585) 256-2569; mccormick_greg@hotmail.com.
Jay S. Pepose, MD, PhD, is Professor of Clinical Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis. He states that he holds no financial interest in any product or company mentioned herein. Dr. Pepose may be reached at (636) 728-0111; jpepose@peposevision.com.
Renée Solomon, MD, is an ophthalmology fellow at Ophthalmic Consultants of Long Island in New York. She states that she holds no financial interest in any product or company mentioned herein. Dr. Solomon may be reached at rensight@yahoo.com.
Dr. Swartz states that she holds no financial interest in any product or company mentioned herein. She may be reached at (615) 321-8881;
drswartz@wangvisioninstitute.com.
Dr. Wang states that he holds no financial interest in any product or company mentioned herein. He may be reached at (615) 321-8881; drwang@wangvisioninstitute.com.
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