- Email: [email protected]
Aqueous penetration of moxifloxacin 0.5% ophthalmic solution and besifloxacin 0.6% ophthalmic suspension in cataract surgery patients
ARTICLE
Aqueous penetration of moxifloxacin 0.5% ophthalmic solution and besifloxacin 0.6% ophthalmic suspension in cataract surgery patients Junko Yoshida, MD, Alisa Kim, MD, Kimberly A. Pratzer, COT, ROUB, Walter J. Stark, MD
PURPOSE: To determine the aqueous humor concentrations of moxifloxacin and besifloxacin after routine preoperative topical dosing in patients having cataract surgery. SETTING: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. METHODS: In this prospective randomized parallel double-masked clinical trial, 1 drop of commercially available moxifloxacin 0.5% ophthalmic solution or besifloxacin 0.6% ophthalmic suspension was administered every 10 minutes for a total of 4 doses beginning 1 hour before routine cataract surgery. Aqueous humor was sampled via the paracentesis, and antibiotic concentrations were determined using validated high-performance liquid chromatography procedures. RESULTS: The study enrolled 50 patients. The aqueous concentration of the antibiotic agent was detectable in all 23 moxifloxacin samples and in 10 (40%) of the 25 besifloxacin samples (P<.0001, Pearson chi-square test). The mean aqueous concentration in the moxifloxacin samples was 50-fold higher than in the besifloxacin samples (1.6108 mg/mL versus 0.0319 mg/mL) when all samples were included (P<.0001, Wilcoxon test), while the moxifloxacin concentration was 38-fold higher than the besifloxacin concentration (1.6108 mg/mL versus 0.0422 mg/mL) in the samples with detectable antibiotic agent (P<.0001). CONCLUSIONS: After topical preoperative administration, moxifloxacin 0.5% ophthalmic solution had a 38-fold to 50-fold higher concentration in the aqueous humor than besifloxacin 0.6% ophthalmic suspension. Besifloxacin was undetectable in more than half the aqueous humor samples. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2010; 36:1499–1502 Q 2010 ASCRS and ESCRS
Endophthalmitis remains a serious complication after cataract surgery and can lead to severe visual loss or even loss of the eye. For this reason, researchers continue to evaluate methods of preventing endophthalmitis, including surgical techniques1–3 as well as the use of perioperative antibiotic agents.4–6 Endophthalmitis occurs from the influx of bacterial flora at the time of cataract surgery; therefore, antibiotic agents for conjunctivitis with good gram-positive and gram-negative coverage are considered suitable for prophylaxis of endophthalmitis, although no topical antibiotic agent has received U.S. Food and Drug Administration (FDA) approval for this purpose. In a 2007 American Society of Cataract and Refractive Surgery survey, 91% of cataract surgeons said they Q 2010 ASCRS and ESCRS Published by Elsevier Inc.
used perioperative topical antibiotic agents to prevent endophthalmitis, with 81% of them choosing a fourthgeneration fluoroquinolone.7,8 Moxifloxacin has been shown to have higher penetration into the aqueous humor than gatifloxacin in patients having cataract surgery.8–10 In May 2009, a new fourth-generation fluoroquinolone, besifloxacin ophthalmic suspension 0.6% (Besivance), received FDA approval for the treatment of conjunctivitis, joining other fluoroquinolones in the arsenal of ophthalmic antibacterial agents. Besivance is formulated with DuraSite polycarbophil suspension, which has mucoadhesive properties designed to increase the time the drug remains on the ocular surface to treat conjunctivitis. Because besifloxacin is the newest 0886-3350/$dsee front matter doi:10.1016/j.jcrs.2010.04.030
1499
1500
AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
fluoroquinolone to receive FDA approval for the treatment of bacterial conjunctivitis, physicians might consider that its effectiveness in endophthalmitis prophylaxis is similar to that of other fluoroquinolones. However, the aqueous humor penetration of besifloxacin has not been studied in humans. The current study was performed to compare the aqueous penetration of besifloxacin with that of moxifloxacin after routine preoperative topical dosing in patients having cataract surgery. PATIENTS AND METHODS In this prospective randomized parallel double-masked clinical trial, patients having cataract extraction were given perioperative topical moxifloxacin 0.5% solution (Vigamox) or besifloxacin 0.6% suspension. Institutional review board/ethics committee approval was obtained. Surgical methods were described in a preliminary report.11 On the day of surgery, patients were randomly assigned to receive 1 drop of moxifloxacin or besifloxacin every 10 minutes for a total of 4 doses, with the last dose given 30 G 2 minutes before the cataract incision was initiated. A 15-degree superblade was used to create a paracentesis. Immediately after, a 30-gauge cannula on a tuberculin syringe was used to collect the aqueous specimen through the paracentesis site. Once the specimen was acquired, it was transferred immediately to a polypropylene tube using sterile gloves and stored upright at 20 C or lower. Moxifloxacin and besifloxacin concentrations in the aqueous humor were determined by an independent laboratory using a validated high-performance liquid chromatography (HPLC)–tandem mass spectrometry method. Statistical analysis was performed using the Pearson chi-square test and the Wilcoxon rank sum test to detect differences between the 2 antibiotic treatment groups. The mean values are G SD.
RESULTS There were 25 patients each in the moxifloxacin group and the besifloxacin group. The mean age of the patients was 74.26 years (range 51 to 89 years) and
Submitted: February 6, 2010. Final revision submitted: April 2, 2010. Accepted: April 2, 2010. From the Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. Supported in part from an unrestricted research grant from Alcon Laboratories to Johns Hopkins University School of Medicine, Baltimore. Christina Ohnsman, MD, provided editorial assistance. Corresponding author: Walter J Stark, MD, The Wilmer Eye Institute, Johns Hopkins University, Maumenee Building 327, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. E-mail: [email protected].
67.96 years (range 30 to 85 years), respectively. Two moxifloxacin samples were excluded; 1 had insufficient volume for processing, and the other was from a patient who had mistakenly received an extra dose of moxifloxacin. No patient had an adverse event. The aqueous concentration of antibiotic agent was detectable in all 23 moxifloxacin samples included in the analysis and in 10 (40%) of the 25 besifloxacin samples (P!.0001, Pearson chi-square test). The mean aqueous humor concentration on HPLC analysis was 1.6108 G 0.6835 mg/mL (range 0.7780 to 3.170 mg/mL) for moxifloxacin and 0.0319 G 0.0133 mg/mL (range 0.0250 to 0.0822 mg/mL) for besifloxacin. This 50-fold difference in measured aqueous humor antibiotic concentrations was statistically significant (P!.0001, Wilcoxon test). The value 0.025 mg/mL was used for samples in which the concentration was below the quantifiable limit (%0.025 mg/mL). In aqueous samples with detectable antibiotic agent, the moxifloxacin concentration was 38-fold higher than that of besifloxacin (1.6108 mg/mL versus 0.0422 mg/mL) (P!.0001, Wilcoxon test). DISCUSSION Endophthalmitis remains a persistent complication of cataract surgery. Its low incidence makes it difficult to design a prospective study of any type of chemoprophylaxis because of the prohibitively high number of cases needed for adequate statistical power, although the recent European Society of Cataract & Refractive Surgeons study4 showed that it is not impossible to do so. Despite a lack of such studies of topical perioperative antibiotic agents, almost all ophthalmologists use some form of topical antibiotic agent perioperatively.7 Cataract surgeons in the United States have widely accepted fourth-generation fluoroquinolones as the drugs of choice for perioperative use. As resistance has increased to older antibiotics, including fluoroquinolones, the fourth-generation drugs have been embraced for their improved coverage of gram-positive pathogens and their decreased likelihood of causing further resistance. This reduced propensity for causing resistance is because it is improbable that an organism will develop 2 simultaneous mutations, as would be required to acquire resistance to this class of antibiotic agents.12 Unfortunately, due to widespread systemic13 and agricultural use14,15 of earlier generation fluoroquinolones, increasing numbers of some bacterial species resistant to fourth-generation fluoroquinolones have been reported.16,17 This is true for both moxifloxacin and besifloxacin, regardless of whether a fluoroquinolone is used systemically or in ophthalmology topically (eg, moxifloxacin) or only in
J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
ophthalmology topically (eg, besifloxacin). In the first study of its kind, Marshall et al.A found that topical ophthalmic use of moxifloxacin did not contribute to resistant organisms in the eye or at distal sites. However, the reverse is not true: Systemic use of early-generation fluoroquinolones is contributing to the increase in resistant organisms in ophthalmic infections, including endophthalmitis. Achieving a higher drug concentration at the target site also helps reduce the development of drug resistance because the mutant prevention concentration is usually 10-fold higher than the minimum inhibitory concentration (MIC) for a given organism. Besifloxacin is in a suspension, which may reduce its penetration into the anterior chamber. However, the increased residence time may result in enhanced penetration in the conjunctiva. Moxifloxacin may confer an advantage in the anterior chamber by achieving a higher possible ratio between the aqueous fluoroquinolone concentration and MIC for microorganisms relevant to ocular infections. Further study is warranted. In this study, besifloxacin suspension had very low ocular penetration. Proksch et al.18 found that the concentration of besifloxacin was comparable to that of moxifloxacin in the anterior chamber of rabbits and monkeys. Our study indicates that these data may not be analogous to the clinical situation in human eyes. The ability of moxifloxacin to cross the lipid layers of the epithelial and endothelial cell membranes may be due to the bicyclic amine moiety at the C-7 position. In contrast, besifloxacin has a less lipophilic monocyclic amine structure at the same position. Furthermore, commercial besifloxacin is formulated with the DuraSite polycarbophil suspension, which has mucoadhesive properties to increase the residence time of the drug on the ocular surface. Although this may assist in the treatment of conjunctivitis, it may have contributed to substantially lower anterior chamber penetration of besifloxacin than of moxifloxacin in our study. Considering the above factors, it follows that to achieve effective endophthalmitis prophylaxis, an antibiotic agent must not only penetrate well into the anterior chamber, but must also exceed the MIC of potential pathogens introduced into the aqueous during cataract surgery. A previous study8 found a mean moxifloxacin aqueous concentration of 1.80 G 1.21 mg/mL and a mean gatifloxacin aqueous concentration of 0.48 G 0.34 mg/mL after preoperative topical dosing (P Z .00003), supporting the current study’s penetration data. Although these studies show that moxifloxacin has the advantage over other fourth-generation fluoroquinolones in terms of penetration, how the aqueous concentrations compare
1501
Figure 1. Moxifloxacin MIC50 values in relation to aqueous humor concentrations in the current study (MIC values from Bausch & LombB using all phenotypes of each species).
with the MICs of potential endophthalmitis pathogens is another important consideration. Recent MIC data for a variety of ocular isolates were reported by Bausch & Lomb in its FDA approval package.B Figures 1 and 2 compare the MIC50 data for moxifloxacin and besifloxacin, giving a perspective on the typical isolate encountered in clinical practice. The aqueous penetration of moxifloxacin has been found to be at least 2-fold higher than that of gatifloxacin. In this study, moxifloxacin achieved a 38-fold to 50-fold higher concentration in aqueous humor than besifloxacin. Sixty percent of patients receiving preoperative topical besifloxacin had no detectable antibiotic agent in the aqueous at the time the cataract incision was initiated. Although both besifloxacin and moxifloxacin are FDA approved for their intended use against conjunctival bacteria, our study indicates that besifloxacin suspension would be less effective in eradicating organisms that enter the anterior chamber during or after cataract surgery. Therefore, in terms of penetration and potency against bacterial species implicated in endophthalmitis, moxifloxacin provides advantages as a topical antibiotic agent for preoperative, and more important, for intraoperative and postoperative use.
Figure 2. Besifloxacin MIC50 values in relation to aqueous humor concentrations in the current study (MIC values from Bausch & LombB using all phenotypes of each species).
J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
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AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
REFERENCES 1. Herretes S, Stark WJ, Pirouzmanesh A, Reyes JMG, McDonnell PJ, Behrens A. Inflow of ocular surface fluid into the anterior chamber after phacoemulsification through sutureless corneal cataract wounds. Am J Ophthalmol 2005; 140:737–740 2. Taban M, Sarayba MA, Ignacio TS, Behrens A, McDonnell PJ. Ingress of India ink into the anterior chamber through sutureless clear corneal cataract wounds. Arch Ophthalmol 2005; 123:643–648 3. Taban M, Behrens A, Newcomb RL, Nobe MY, Saedi G, Sweet PM, McDonnell PJ. Acute endophthalmitis following cataract surgery; a systematic review of the literature. Arch Ophthalmol 2005; 123:613–620 4. ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg 2007; 33:978–988 5. Barry P, Gardner S, Seal D, Gettinby G, Lees F, Peterson M, Revie C. Clinical observations associated with proven and unproven cases in the ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; the ESCRS Endophthalmitis Study Group. J Cataract Refract Surg 2009; 35:1523–1531 6. DeCroos FC, Afshari NA. Perioperative antibiotics and anti-inflammatory agents in cataract surgery. Curr Opin Ophthalmol 2008; 19:22–26 7. Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, Packard RB, Packer M. Prophylaxis of postoperative endophthalmitis after cataract surgery; results of the 2007 ASCRS member survey; the ASCRS Cataract Clinical Committee. J Cataract Refract Surg 2007; 33:1801–1805 8. Kim DH, Stark WJ, O’Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology 2005; 112:1992–1996 9. McCulley JP, Caudle D, Aronowicz JD, Shine WE. Fourth-generation fluoroquinolone penetration into the aqueous humor in humans. Ophthalmology 2006; 113:955–959 10. Ong-Tone L. Aqueous humor penetration of gatifloxacin and moxifloxacin eyedrops given by different methods before cataract surgery. J Cataract Refract Surg 2007; 33:59–62 11. Kim DH, Stark WJ, O’Brien TP. Ocular penetration of moxifloxacin 0.5% and gatifloxacin 0.3% ophthalmic solutions into the aqueous humor following topical administration prior to routine cataract surgery. Curr Med Res Opin 2005; 21:93–94 12. Mah FS. Fourth-generation fluoroquinolones: new topical agents in the war on ocular bacterial infections. Curr Opin Ophthalmol 2004; 15:316–320 13. Bertino JS Jr. Impact of antibiotic resistance in the management of ocular infections: the role of current and future antibiotics. Clin
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Ophthalmol 2009; 3:507–521. Available at: http://www.ncbi.nlm. nih.gov/pmc/articles/PMC2754082/pdf/opth-3-507.pdf. Accessed May 16, 2010 Shea KM. Nontherapeutic use of antimicrobial agents in animal agriculture: implications for pediatrics; American Academy of Pediatrics technical report. Pediatrics 2004; 114:862–910. Available at: http://pediatrics.aappublications.org/cgi/reprint/ 114/3/862. Accessed May 16, 2010 Shea KM. Antibiotic resistance: what is the impact of agricultural uses of antibiotics on children’s health? Pediatrics 2003; 112:253–258. Available at: http://pediatrics.aappublications. org/cgi/reprint/112/1/S1/253. Accessed May 16, 2010 Major JC Jr, Engelbert M, Flynn HW Jr, Miller D, Smiddy WE, Davis JL. Staphylococcus aureus endophthalmitis: antibiotic susceptibilities, methicillin resistance, and clinical outcomes. Am J Ophthalmol 2010; 149:278–283 Yamada M, Yoshida J, Hatou S, Yoshida T, Minagawa Y. Mutations in the quinolone resistance determining region in Staphylococcus epidermidis recovered from conjunctiva and their association with susceptibility to various fluoroquinolones. Br J Ophthalmol 2008; 92:848–851 Proksch JW, Granvil CP, Siou-Mermet R, Comstock TL, Paterno MR, Ward KW. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharm Ther 2009; 25:335–344
OTHER CITED MATERIAL A. Marshall B, Cupp G, Foster K, McLean C, Cockrum P, Lichtenstein S, De Leon L, Heller W, Levy S, Stroman DW. ‘‘Moxifloxacin Treatment of Conjunctivitis: Microbial Effects Beyond the Eye,’’ poster presented at 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, September 2009 B. Bausch & Lomb, Inc. Dermatologic and Ophthalmic Drugs Advisory Committee Meeting Briefing Document. FDA Advisory Committee Recommends Approval of Bausch & Lomb Besifloxacin Anti-Infective Eye Drop. December 5, 2008. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/ 2008-4397b1-02-BauschLomb.pdf. Accessed May 16, 2010
J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
First author: Junko Yoshida, MD Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA
Aqueous penetration of moxifloxacin 0.5% ophthalmic solution and besifloxacin 0.6% ophthalmic suspension in cataract surgery patients Junko Yoshida, MD, Alisa Kim, MD, Kimberly A. Pratzer, COT, ROUB, Walter J. Stark, MD
PURPOSE: To determine the aqueous humor concentrations of moxifloxacin and besifloxacin after routine preoperative topical dosing in patients having cataract surgery. SETTING: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. METHODS: In this prospective randomized parallel double-masked clinical trial, 1 drop of commercially available moxifloxacin 0.5% ophthalmic solution or besifloxacin 0.6% ophthalmic suspension was administered every 10 minutes for a total of 4 doses beginning 1 hour before routine cataract surgery. Aqueous humor was sampled via the paracentesis, and antibiotic concentrations were determined using validated high-performance liquid chromatography procedures. RESULTS: The study enrolled 50 patients. The aqueous concentration of the antibiotic agent was detectable in all 23 moxifloxacin samples and in 10 (40%) of the 25 besifloxacin samples (P<.0001, Pearson chi-square test). The mean aqueous concentration in the moxifloxacin samples was 50-fold higher than in the besifloxacin samples (1.6108 mg/mL versus 0.0319 mg/mL) when all samples were included (P<.0001, Wilcoxon test), while the moxifloxacin concentration was 38-fold higher than the besifloxacin concentration (1.6108 mg/mL versus 0.0422 mg/mL) in the samples with detectable antibiotic agent (P<.0001). CONCLUSIONS: After topical preoperative administration, moxifloxacin 0.5% ophthalmic solution had a 38-fold to 50-fold higher concentration in the aqueous humor than besifloxacin 0.6% ophthalmic suspension. Besifloxacin was undetectable in more than half the aqueous humor samples. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2010; 36:1499–1502 Q 2010 ASCRS and ESCRS
Endophthalmitis remains a serious complication after cataract surgery and can lead to severe visual loss or even loss of the eye. For this reason, researchers continue to evaluate methods of preventing endophthalmitis, including surgical techniques1–3 as well as the use of perioperative antibiotic agents.4–6 Endophthalmitis occurs from the influx of bacterial flora at the time of cataract surgery; therefore, antibiotic agents for conjunctivitis with good gram-positive and gram-negative coverage are considered suitable for prophylaxis of endophthalmitis, although no topical antibiotic agent has received U.S. Food and Drug Administration (FDA) approval for this purpose. In a 2007 American Society of Cataract and Refractive Surgery survey, 91% of cataract surgeons said they Q 2010 ASCRS and ESCRS Published by Elsevier Inc.
used perioperative topical antibiotic agents to prevent endophthalmitis, with 81% of them choosing a fourthgeneration fluoroquinolone.7,8 Moxifloxacin has been shown to have higher penetration into the aqueous humor than gatifloxacin in patients having cataract surgery.8–10 In May 2009, a new fourth-generation fluoroquinolone, besifloxacin ophthalmic suspension 0.6% (Besivance), received FDA approval for the treatment of conjunctivitis, joining other fluoroquinolones in the arsenal of ophthalmic antibacterial agents. Besivance is formulated with DuraSite polycarbophil suspension, which has mucoadhesive properties designed to increase the time the drug remains on the ocular surface to treat conjunctivitis. Because besifloxacin is the newest 0886-3350/$dsee front matter doi:10.1016/j.jcrs.2010.04.030
1499
1500
AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
fluoroquinolone to receive FDA approval for the treatment of bacterial conjunctivitis, physicians might consider that its effectiveness in endophthalmitis prophylaxis is similar to that of other fluoroquinolones. However, the aqueous humor penetration of besifloxacin has not been studied in humans. The current study was performed to compare the aqueous penetration of besifloxacin with that of moxifloxacin after routine preoperative topical dosing in patients having cataract surgery. PATIENTS AND METHODS In this prospective randomized parallel double-masked clinical trial, patients having cataract extraction were given perioperative topical moxifloxacin 0.5% solution (Vigamox) or besifloxacin 0.6% suspension. Institutional review board/ethics committee approval was obtained. Surgical methods were described in a preliminary report.11 On the day of surgery, patients were randomly assigned to receive 1 drop of moxifloxacin or besifloxacin every 10 minutes for a total of 4 doses, with the last dose given 30 G 2 minutes before the cataract incision was initiated. A 15-degree superblade was used to create a paracentesis. Immediately after, a 30-gauge cannula on a tuberculin syringe was used to collect the aqueous specimen through the paracentesis site. Once the specimen was acquired, it was transferred immediately to a polypropylene tube using sterile gloves and stored upright at 20 C or lower. Moxifloxacin and besifloxacin concentrations in the aqueous humor were determined by an independent laboratory using a validated high-performance liquid chromatography (HPLC)–tandem mass spectrometry method. Statistical analysis was performed using the Pearson chi-square test and the Wilcoxon rank sum test to detect differences between the 2 antibiotic treatment groups. The mean values are G SD.
RESULTS There were 25 patients each in the moxifloxacin group and the besifloxacin group. The mean age of the patients was 74.26 years (range 51 to 89 years) and
Submitted: February 6, 2010. Final revision submitted: April 2, 2010. Accepted: April 2, 2010. From the Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA. Supported in part from an unrestricted research grant from Alcon Laboratories to Johns Hopkins University School of Medicine, Baltimore. Christina Ohnsman, MD, provided editorial assistance. Corresponding author: Walter J Stark, MD, The Wilmer Eye Institute, Johns Hopkins University, Maumenee Building 327, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. E-mail: [email protected].
67.96 years (range 30 to 85 years), respectively. Two moxifloxacin samples were excluded; 1 had insufficient volume for processing, and the other was from a patient who had mistakenly received an extra dose of moxifloxacin. No patient had an adverse event. The aqueous concentration of antibiotic agent was detectable in all 23 moxifloxacin samples included in the analysis and in 10 (40%) of the 25 besifloxacin samples (P!.0001, Pearson chi-square test). The mean aqueous humor concentration on HPLC analysis was 1.6108 G 0.6835 mg/mL (range 0.7780 to 3.170 mg/mL) for moxifloxacin and 0.0319 G 0.0133 mg/mL (range 0.0250 to 0.0822 mg/mL) for besifloxacin. This 50-fold difference in measured aqueous humor antibiotic concentrations was statistically significant (P!.0001, Wilcoxon test). The value 0.025 mg/mL was used for samples in which the concentration was below the quantifiable limit (%0.025 mg/mL). In aqueous samples with detectable antibiotic agent, the moxifloxacin concentration was 38-fold higher than that of besifloxacin (1.6108 mg/mL versus 0.0422 mg/mL) (P!.0001, Wilcoxon test). DISCUSSION Endophthalmitis remains a persistent complication of cataract surgery. Its low incidence makes it difficult to design a prospective study of any type of chemoprophylaxis because of the prohibitively high number of cases needed for adequate statistical power, although the recent European Society of Cataract & Refractive Surgeons study4 showed that it is not impossible to do so. Despite a lack of such studies of topical perioperative antibiotic agents, almost all ophthalmologists use some form of topical antibiotic agent perioperatively.7 Cataract surgeons in the United States have widely accepted fourth-generation fluoroquinolones as the drugs of choice for perioperative use. As resistance has increased to older antibiotics, including fluoroquinolones, the fourth-generation drugs have been embraced for their improved coverage of gram-positive pathogens and their decreased likelihood of causing further resistance. This reduced propensity for causing resistance is because it is improbable that an organism will develop 2 simultaneous mutations, as would be required to acquire resistance to this class of antibiotic agents.12 Unfortunately, due to widespread systemic13 and agricultural use14,15 of earlier generation fluoroquinolones, increasing numbers of some bacterial species resistant to fourth-generation fluoroquinolones have been reported.16,17 This is true for both moxifloxacin and besifloxacin, regardless of whether a fluoroquinolone is used systemically or in ophthalmology topically (eg, moxifloxacin) or only in
J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
ophthalmology topically (eg, besifloxacin). In the first study of its kind, Marshall et al.A found that topical ophthalmic use of moxifloxacin did not contribute to resistant organisms in the eye or at distal sites. However, the reverse is not true: Systemic use of early-generation fluoroquinolones is contributing to the increase in resistant organisms in ophthalmic infections, including endophthalmitis. Achieving a higher drug concentration at the target site also helps reduce the development of drug resistance because the mutant prevention concentration is usually 10-fold higher than the minimum inhibitory concentration (MIC) for a given organism. Besifloxacin is in a suspension, which may reduce its penetration into the anterior chamber. However, the increased residence time may result in enhanced penetration in the conjunctiva. Moxifloxacin may confer an advantage in the anterior chamber by achieving a higher possible ratio between the aqueous fluoroquinolone concentration and MIC for microorganisms relevant to ocular infections. Further study is warranted. In this study, besifloxacin suspension had very low ocular penetration. Proksch et al.18 found that the concentration of besifloxacin was comparable to that of moxifloxacin in the anterior chamber of rabbits and monkeys. Our study indicates that these data may not be analogous to the clinical situation in human eyes. The ability of moxifloxacin to cross the lipid layers of the epithelial and endothelial cell membranes may be due to the bicyclic amine moiety at the C-7 position. In contrast, besifloxacin has a less lipophilic monocyclic amine structure at the same position. Furthermore, commercial besifloxacin is formulated with the DuraSite polycarbophil suspension, which has mucoadhesive properties to increase the residence time of the drug on the ocular surface. Although this may assist in the treatment of conjunctivitis, it may have contributed to substantially lower anterior chamber penetration of besifloxacin than of moxifloxacin in our study. Considering the above factors, it follows that to achieve effective endophthalmitis prophylaxis, an antibiotic agent must not only penetrate well into the anterior chamber, but must also exceed the MIC of potential pathogens introduced into the aqueous during cataract surgery. A previous study8 found a mean moxifloxacin aqueous concentration of 1.80 G 1.21 mg/mL and a mean gatifloxacin aqueous concentration of 0.48 G 0.34 mg/mL after preoperative topical dosing (P Z .00003), supporting the current study’s penetration data. Although these studies show that moxifloxacin has the advantage over other fourth-generation fluoroquinolones in terms of penetration, how the aqueous concentrations compare
1501
Figure 1. Moxifloxacin MIC50 values in relation to aqueous humor concentrations in the current study (MIC values from Bausch & LombB using all phenotypes of each species).
with the MICs of potential endophthalmitis pathogens is another important consideration. Recent MIC data for a variety of ocular isolates were reported by Bausch & Lomb in its FDA approval package.B Figures 1 and 2 compare the MIC50 data for moxifloxacin and besifloxacin, giving a perspective on the typical isolate encountered in clinical practice. The aqueous penetration of moxifloxacin has been found to be at least 2-fold higher than that of gatifloxacin. In this study, moxifloxacin achieved a 38-fold to 50-fold higher concentration in aqueous humor than besifloxacin. Sixty percent of patients receiving preoperative topical besifloxacin had no detectable antibiotic agent in the aqueous at the time the cataract incision was initiated. Although both besifloxacin and moxifloxacin are FDA approved for their intended use against conjunctival bacteria, our study indicates that besifloxacin suspension would be less effective in eradicating organisms that enter the anterior chamber during or after cataract surgery. Therefore, in terms of penetration and potency against bacterial species implicated in endophthalmitis, moxifloxacin provides advantages as a topical antibiotic agent for preoperative, and more important, for intraoperative and postoperative use.
Figure 2. Besifloxacin MIC50 values in relation to aqueous humor concentrations in the current study (MIC values from Bausch & LombB using all phenotypes of each species).
J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
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AQUEOUS PENETRATION OF MOXIFLOXACIN 0.5% AND BESIFLOXACIN 0.6% OPHTHALMIC SUSPENSION
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J CATARACT REFRACT SURG - VOL 36, SEPTEMBER 2010
First author: Junko Yoshida, MD Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA