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VITREOUS PENETRATION OF TOPICAL
MOXIFLOXACIN AND GATIFLOXACIN IN
HUMANS
PATRICK COSTELLO, MD,* SOPHIE J. BAKRI, MD,† PAUL M. BEER, MD,*RAVINDER J. SINGH, PHD,‡ NAOMI S. FALK, MD,*GEORGE B. PETERS, MD,* J. ANDRE MELENDEZ, PHD§ Purpose: To determine the vitreous penetration of the new fourth-generation topical
fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3%.
Methods: A prospective randomized clinical trial comprising 12 eyes of 12 patients
scheduled for pars plana vitrectomy between August 2003 and September 2003 wasperformed in a clinical practice. The patients were randomly assigned to receive topicalmoxifloxacin 0.5% (n ϭ 6) or gatifloxacin 0.3% (n ϭ 6). One half the patients in eachantibiotic group received 1 drop every 15 minutes for a total of 3 doses starting 1 hourbefore surgery, and the other one half self-administered the antibiotic drop 4 times daily for3 days before surgery and at 7 AM on the day of surgery. Undiluted vitreous samples wereobtained and analyzed using high-performance liquid chromatography.
Results: Either moxifloxacin 0.5% or gatifloxacin 0.3% was detected in the vitreous in all
12 patients in the study. There was no significant difference between the mean vitreousconcentration of moxifloxacin 0.5% given over 1 hour preoperatively (0.012 Ϯ 0.011 ␮g/mL)and that given in the 3-day regimen (0.011 Ϯ 0.008 ␮g/mL) (P ϭ 0.93). There was also nosignificant difference between the mean vitreous concentration of gatifloxacin 0.3% given over1 hour preoperatively (0.001 Ϯ 0.0003␮g/mL) and that given over 3 days (0.008 Ϯ 0.006 ␮g/mL) (P ϭ 0.11). Vitreous concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% in eacheye were all lower than the 90% minimum inhibitory concentration for the commonest bacterialisolates causing endophthalmitis. With both dosing regimens, the mean vitreous concentrationof moxifloxacin 0.5% was higher than that of gatifloxacin 0.3% administered at the sameregimen, but this was not statistically significant.
Conclusion:
Both topical moxifloxacin 0.5% and gatifloxacin 0.3% penetrated the vitreous in the uninflamed eye, but the vitreous concentrations attained were all lower thanthe 90% minimum inhibitory concentration for the commonest bacterial pathogens caus-ing acute postoperative endophthalmitis.
RETINA 25:1-1, 2005
Postsurgical infectious endophthalmitis is a devas- sociated with endophthalmitis occurring after cataract tating complication of intraocular surgery. Even extraction is 20/100.1 The causative agents introduced with early intervention, the median visual acuity as- to the eye during surgery usually originate on theocular surface, with Staphylococcus epidermidis and From *Lions Eye Institute, Albany Medical College, Albany, Staphylococcus aureus being the most common patho- New York; †Department of Ophthalmology, Mayo Clinic, Roch- gens implicated in bacterial endophthalmitis.2 Several ester, Minnesota; ‡Department of Laboratory Medicine and Pathol- prophylactic techniques have been studied for the ogy, Mayo Clinic, Rochester, Minnesota; and §Department ofImmunology and Microbiology, Albany Medical College, Albany, prevention of postoperative endophthalmitis, but only preoperative sterilization with povidone–iodine solu- Reprint requests: Paul M. Beer, MD, Lions Eye Institute, 35 Hackett Boulevard, Albany Medical College, Albany, NY 12208.
tion has been shown to be moderately important to Presented in part as a poster at the annual meeting of the clinical outcome.3 All other reported prophylactic in- American Academy of Ophthalmology; October 25, 2004; New terventions, including postoperative subconjunctival Orleans. None of the authors have any financial interest in any ofthe products mentioned in this article.
antibiotic injection, preoperative lash trimming, pre- Both topical moxifloxacin 0.5% and gatifloxacin 0.3% penetrated the vitreous in the uninflamed eye, but the vitreous concentrations attained
were all lower than the MIC
for the commonest bacterial pathogens causing acute postoperative endophthalmitis.
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operative saline irrigation, preoperative topical antibi- vitrectomy between August 2003 and September 2003 otics, antibiotic-containing irrigating solutions, and were enrolled in the study. Excluded were female the use of intraoperative heparin, have received the patients of childbearing age and patients with known sensitivity to fluoroquinolones, use of antibiotics, or There is no clear consensus on preoperative pro- intraocular or laser surgery in the preceding month.
phylaxis with antibiotic therapy. Many ophthalmolo- Patients who had received surgery for glaucoma (tra- gists choose to use topical antibacterial prophylaxis in beculectomy or a tube), aphakic patients, and pseu- the preoperative period.4,5 The US Food and Drug dophakic patients with an open capsule were also Administration approval of the fourth-generation top- ical fluoroquinolones Zymar (gatifloxacin ophthalmic Twelve eyes of 12 patients were randomly assigned solution 0.3%) and Vigamox (moxifloxacin HCl oph- to 1 of 4 study groups (3 eyes per group). Patients in thalmic solution 0.5%) has made additional choices groups 1 and 2 were administered 1 drop of topical available in the treatment of ocular bacterial infec- gatifloxacin or moxifloxacin, respectively, every 15 tions. These drugs have been shown to be more effec- minutes for a total of 3 doses starting 1 hour before tive than their second- and third-generation predeces- surgery. Other preoperative drops were administered 5 sors in combating gram-positive bacteria, particularly minutes before and after the antibiotic drop to avoid isolate strains of S. aureus and coagulase-negative any dilution. Patients in groups 3 and 4 self-adminis- staphylococci that were resistant to ciprofloxacin and tered gatifloxacin and moxifloxacin, respectively, 4 times daily for 3 days before surgery and at 7 AM on Ocular penetration of fluoroquinolones has been the day of surgery. The patients taking drops at home studied in the aqueous and vitreous humor of humans for 3 days were contacted by telephone each day to be and animals in normal and inflamed eyes when ad- reminded to take the drops. All 6 of these patients ministered both topically and orally.7–10 In humans, reported 100% compliance with the preoperative an- topical ciprofloxacin 0.3% and topical ofloxacin 0.3% tibiotic regimen when presenting for surgery.
reached the 90% minimum inhibitory concentration At the time of surgery, a 1-mL syringe was attached (MIC ) for the commonest ocular pathogens in the to the aspiration port of an unprimed disposable vit- aqueous but not in the vitreous.7 Oral levofloxacin rectomy cutter. Before the infusion cannula was levels in the vitreous did not reach the MIC .8 Vit- turned on, 0.2 mL of vitreous was manually aspirated reous and aqueous concentrations of oral gatifloxacin from the syringe as the vitreous cutter engaged the vitreous gel. The vitreous sample was immediately Vitreous levels of oral moxifloxacin in inflamed and transferred into a plain red top vacutainer tube and normal rabbit eyes reached the MIC ,12 and aqueous frozen. The tubes were delivered on dry ice overnight levels of oral moxifloxacin, ciprofloxacin, and levo- to the Endocrine Laboratory at the Mayo Clinic floxacin13 have also been shown to attain the MIC .
The aqueous penetration of topical moxifloxacin 0.5% Concentrations of gatifloxacin and moxifloxacin and gatifloxacin 0.3% is higher than that of topical cip- were measured using high-performance liquid chro- rofloxacin 0.3%.14 One study15 showed that the levels of matography–tandem mass spectrometry method on topical moxifloxacin 0.5% exceeded the MIC the API 3000 Sciex triple-quadruple mass spectrom- aqueous but not the vitreous for the commonest bacterial eter (ABI-PE Sciex, Toronto, Ontario, Canada). The specific mass-to-charge ratio transitions for gatifloxa- The goals of this study were to determine whether cin and moxifloxacin were 376 and 402 to 384, re- topical moxifloxacin 0.5% and gatifloxacin 0.3% pen- spectively. The mobile phase was 40/60 (v/v) aceto- etrate the vitreous, whether the concentration of drug containing 0.05% formic acid. Acetonitrile was added mon pathogens causing endophthalmitis, and whether to each sample (1:1 parts) to precipitate proteins. The the duration of preoperative treatment affects the con- supernatants were dried under nitrogen and reconsti- centration in the vitreous at the time of surgery.
tuted in 100 ␮L of the mobile phase. Thirty microli-ters of the reconstituted extract was injected onto a reversed-phase 15 ϫ 0.46-cm MAX-RP column andanalyzed using a tandem mass spectrometer operating Approval was obtained from the Institutional Re- in the positive mode. The interassay coefficients of view Board of the Albany Memorial Hospital (Al- variation of the analysis were Ͻ20%.
bany, NY). After informed consent was obtained, 12 Statistical analysis was performed using an un- eyes of 12 patients undergoing elective pars plana paired two-tailed Student’s t-test.
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MOXIFLOXACIN AND GATIFLOXACIN VITREOUS PENETRATION ● COSTELLO ET AL
Table 1. Study Patient Characteristics and Vitreous Concentrations of Moxifloxacin 0.5% and Gatifloxacin 0.3% GAT, gatifloxacin 0.3%; ERM, epiretinal membrane; MOX, moxifloxacin 0.5%; VH, vitreous hemorrhage; RRD, rhegmatogenous retinal detachment; CRVO, central retinal vein occlusion undergoing retinal endovascular surgery.
(0.001 ␮g/mL), but this was not statistically signifi-cant (P ϭ 0.17). The mean vitreous concentration The indications for pars plana vitrectomy surgery in after 1 drop of moxifloxacin 0.5% administered 4 the 12 patients were epiretinal membrane (n ϭ 9), times per day for 3 days before surgery (0.011 ␮g/mL) vitreous hemorrhage (n ϭ 1), retinal detachment (n ϭ was higher than that of gatifloxacin 0.3% administered 1), and central retinal vein occlusion undergoing ret- at the same regimen (0.008 ␮g/mL), but this was not inal endovascular surgery. Eight patients were phakic, statistically significant (P ϭ 0.65). The sample size and four were pseudophakic (Table 1).
was not large enough to determine whether pseu- Either moxifloxacin 0.5% or gatifloxacin 0.3% was dophakic or phakic eyes had a higher vitreous pene- detected in the vitreous in all 12 patients in the study tration of drug at each time point. Vitreous concen- (Table 1). There was no significant difference between trations of moxifloxacin 0.5% and gatifloxacin 0.3% the mean vitreous concentration of moxifloxacin 0.5% given over 1 hour preoperatively (0.012 Ϯ 0.011 commonest bacterial pathogens causing endoph- g/mL) and that given with the 3-day regimen (0.011 Ϯ 0.008 ␮g/mL) (P ϭ 0.93). There was also nosignificant difference between the mean vitreous con- Discussion
centration of gatifloxacin 0.3% given over 1 hourpreoperatively (0.001 Ϯ 0.0003 ␮g/mL) and that Endophthalmitis is one of the most serious compli- given over 3 days (0.008 Ϯ 0.006 ␮g/mL) (P ϭ 0.11).
cations of intraocular surgery, and it is therefore im- The mean vitreous concentration of 1 drop of moxi- portant to investigate the role of potential new thera- floxacin 0.5% given every 15 minutes 3 times starting pies that may be used as an adjunct for its prophylaxis 1 hour before surgery (0.012 ␮g/mL) was higher than and treatment. There is currently no strong evidence to that of the same dosing regimen of gatifloxacin 0.3% suggest that the administration of preoperative topical Table 2. Mean Vitreous Concentrations of Topical Moxifloxacin 0.5% and Gatifloxacin 0.3% Compared With Their for the Commonest Bacterial Pathogens Causing Endophthalmitis Mean vitreous concentration Ϯ SD (␮g/mL)QID ϫ 3 d before surgery MIC , 90% minimum inhibitory concentration.
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antibiotics reduces the incidence of postoperative en- preoperatively (0.001 Ϯ 0.0003 ␮g/mL) and that dophthalmitis.3 Recently, topical fourth-generation given over 3 days (0.008 Ϯ 0.006 ␮g/mL) (P ϭ 0.11).
fluoroquinolones have become available. The MICs of Overall, moxifloxacin 0.5% reached intravitreal topical gatifloxacin 0.3% and moxifloxacin 0.5% have concentrations that were 2 to 10 times greater than been shown to be statistically lower than those of the second-generation fluoroquinolones for all gram-pos- most common causative organisms is two times lower itive bacteria tested.16 Both drugs have been shown to for moxifloxacin than for gatifloxacin. Even with these advantages, moxifloxacin levels were still six ganisms in the aqueous humor of rabbits.17 Topical ofloxacin used 3 days before surgery has been shown cin vitreous concentrations were 11 to 220 times be- to be more effective in eliminating bacteria from the conjunctiva than an application of ofloxacin 1 hour previous studies examining vitreous levels after topi- cal application of a fluoroquinolone, vitreous levels in An inoculum of bacteria entering the vitreous poses our patients were shown to be consistently below the a greater risk than the same inoculum of bacteria in the levels of both gatifloxacin and moxifloxacin.
aqueous.19 The incidence of endophthalmitis with cat- There are several limitations to this study. The total aract surgery is higher when there is rupture of the number of patients was small. Sources for human posterior capsule requiring anterior vitrectomy.19,20 error were identified before the study and included the The best prophylaxis for postoperative endophthalmi- aspiration, handling, and transfer of samples. Despite tis would be an antibiotic that reaches therapeutic running the samples in triplicate, errors in the high- levels in the vitreous humor. Penetration of an antibi- performance liquid chromatography assay are alsopossible. Although 100% compliance with drop ad- otic into the vitreous cavity is an important aspect of ministration was reported and patients were called its pharmacokinetic profile, and the goal of our study each day, this is another potential source for error. The was to quantify the vitreous levels of these new topical nursing staff in the preoperative holding area of the fourth-generation fluoroquinolones after administra- hospital was meticulous about spacing the drops 15 tion 4 times per day over 3 days versus once every 15 minutes apart in the patients taking drops 1 hour before surgery, but in this busy atmosphere, patients Although present in the vitreous in all eyes in the could have missed a drop or had drops spaced at study, neither antibiotic reached the MIC different frequencies. However, the most likely signif- bacteria implicated in endophthalmitis. Prophylactic icant factor in the varying drug concentrations found topical ofloxacin has been shown to reduce the num- in these patients relates to expected variations in phar- ber of conjunctival bacterial colonies in eyes where macokinetic data from one case to another. No pa- the drug is administered over 3 days versus the num- tients had any obvious corneal disease at the time of ber of colonies in eyes which receive the drug 3 times surgery, another factor which may affect absorption of over 1 hour before surgery. A reduction in bacterial colonies may decrease the incidence of endophthalmi- In summary, our study did not show a significant tis by limiting the size of bacterial inoculum entering difference for either gatifloxacin 0.3% or moxifloxa- the eye. Although administering the drop over 3 days cin 0.5% in reaching the human vitreous. Both drugs before surgery may not increase the vitreous concen- reached the vitreous at levels 6 to 220 times below the tration of the drug, lowering the conjunctival bacterial for the most common bacterial pathogens caus- load may be beneficial for endophthalmitis prophy- ing endophthalmitis. There was no significant differ- laxis. It is possible that administering the antibiotic ence in vitreous concentration of either drug when drops more frequently may result in vitreous concen- administered over 3 days before surgery versus 1 hour before surgery. It would be desirable for topical ad- We found a difference in the mean concentration of ministration of antibiotics to reach therapeutic levels gatifloxacin after 1 hour of topical application versus in the vitreous, but this goal has not been achieved 3 days of application. Patient 6 had a concentration with this new generation of fluoroquinolones, using severalfold greater than those of Patients 1 and 2. This the regimen described in this article.
may be related to the pseudophakic status of Patient 6:0.012 Ϯ 0.011 ␮g/mL versus 0.011 Ϯ 0.008 ␮g/mL with the 3-day regimen (P ϭ 0.93). There was also no References
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Norregaard JC, Thoning H, Bernth-Petersen P, et al. Risk of endophthalmitis after cataract extraction: results from the Bronner S, Jehi F, Peter JD, et al. Moxifloxacin efficacy and International Cataract Surgery Outcomes study. Br J Oph- vitreous penetration in a rabbit model of Staphylococcus JOBNAME: AUTHOR QUERIES PAGE: 1 SESS: 1 OUTPUT: Thu Oct 6 10:37:08 2005 /balt6/z7jϪretina/z7jϪretina/z7jϪorig/z7j3217Ϫ05a AUTHOR PLEASE ANSWER ALL QUERIES
AQ1: AUTHOR— Correct to insert “annual meeting of the AAO”? Was there a numerical designation for the meeting (e.g., 33rd, etc)? AQ2: AUTHOR— Please provide manufacturers with their locations for Zymar and Vigamox.
AQ3: AUTHOR— If vacutainer is a trade name, please provide manufacturer with its location.
AQ4: AUTHOR— Please confirm changes to sentence starting “This may be related to the

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