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vid 22)us ouron ostowe omatra wnas an internal standard. These values were compared with published concentrations of other available fluoro-quinolones under similar dosing conditions.

Results: The mean age of the moxifloxacin 0.5% group was 67.89.7 years, whereas that of the gatifloxacin0.3ga

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2Pub% group was 69.98.7 years. The moxifloxacin AH concentration was 1.861.06 g/ml, and that oftifloxacin was 0.940.72 g/ml. This 2-fold difference was statistically significant (P 0.001).Conclusions: Aqueous humor antibiotic concentrations achieved at the time of cataract surgery after topicalplication can serve as an effective surrogate for what can be achieved with typical postoperative topical dosingg., 4 times daily). Both fourth-generation fluoroquinolones achieved a greater AH concentration after 4 timesily dosing relative to prior-generation fluoroquinolones. Moxifloxacin 0.5% ophthalmic solution achieved afold higher aqueous humor concentration than gatifloxacin 0.3% ophthalmic solution. The superior penetrationmoxifloxacin into the AHmay be attributed partially to its high degree of lipophilicity, greater solubility at neutral, and higher concentration in the commercial formulation. The enhanced penetration of moxifloxacin 0.5%hthalmic solution may provide better protection against ocular infections. Ophthalmology 2006;113:9559592006 by the American Academy of Ophthalmology.

e to the recent emergence of resistance ocular pathogens,rowing need for new ophthalmic antibiotics has arisen.1e optimal molecule should possess the characteristics oftter gram-positive coverage (especially against strepto-

cocci) than previous agents; efficacy against resistant organ-isms, such as resistant Staphylococci; efficacy against atyp-ical mycobacteria; and better penetration into the aqueoushumor (AH) with dosing 4 times daily (in general, prior-generation topical fluoroquinolones do not penetrate intoaqueous at therapeutic levels), and treated patients shoulddemonstrate a lower tendency to develop resistant organisms.Two fluoroquinolone antibiotics, moxifloxacin 0.5% ophthal-mic solution and gatifloxacin 0.3% solution, were developed toaddress increasing resistance concerns. Both medications areapproved for the treatment of bacterial conjunctivitis.

There are several considerations when assessing a post-operative antibiotic ocular surgical prophylaxis model. Hu-man subjects with healthy uninflamed ocular surfaces andeyes are preferred. The dosing regimen for the patientshould reflect a realistic topical frequency, with no routinesystemic dosing. Concentrations at the beginning of surgerymay provide a surrogate to assess achievable postoperativeconcentrations, provided that the dosing regimen is relevantto anticipated postoperative dosing.

ginally received: June 14, 2005.cepted: January 8, 2006. Manuscript no. 2005-530.m the Department of Ophthalmology, University of Texas Southwest-Medical Center, Dallas, Texas.

sented at: American Academy of Ophthalmology meeting, October4, New Orleans, Louisiana, and Association for Research in Vision and

hthalmology meeting, May 2005, Fort Lauderdale, Florida.e study was supported by a grant from Alcon Laboratories, Inc., Fortrth, Texas, and an unrestricted grant from Research to Prevent Blind-s, Inc., New York, New York.McCulley serves as a consultant for Alcon Laboratories, Inc. Ms

udle, Dr Aronowicz, and Dr Shine have no financial interest in theducts discussed in the article.rrespondence to James P. McCulley, MD, Department of Ophthalmol-, University of Texas Southwestern Medical School at Dallas, 5323

rry Hines Boulevard, Dallas, TX 75390-9057. E-mail: James.McCulley@Southwestern.edu.

955006 by the American Academy of Ophthalmology ISSN 0161-6420/06/$see front matterlished by Elsevier Inc. doi:10.1016/j.ophtha.2006.01.061enetration into the Aumor in Humans

P. McCulley, MD, FACS, D. Caudle, MS, J. D. Aro

Purpose: To compare the penetration and levels% ophthalmic solution and gatifloxacin 0.3% solutioplication with published levels of other available fluorDesign: Prospective, randomized, double-maskedParticipants: Forty-six patients undergoing cataracMethods: Patients scheduled for routine phacoemed either moxifloxacin 0.5% ophthalmic solution (n e 4 times daily the day before surgery plus 1 drop 1 hthe day of surgery. This regimen simulated a realistic pre obtained and analyzed by high-pressure liquid chrtions were calculated by peak comparison with a knoeous

icz, MD, W. E. Shine, PhD

e fourth-generation fluoroquinolones moxifloxacinthe aqueous humor (AH) in humans after topical

inolones under similar dosing conditions.al trial.traction.cation and intraocular lens implantation were pro-or gatifloxacin 0.3% ophthalmic solution (n 24) tobefore the surgical entry into the anterior chamberperative dosing schedule. Aqueous humor samplestography. Aqueous humor fluoroquinolone concen-concentration peak for ciprofloxacin that was used

The aim of this study was to compare the penetration ofmoxifloxacin 0.5% ophthalmic solution and gatifloxacin0.3tim1othgodo

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Ophthalmology Volume 113, Number 6, June 2006

95% ophthalmic solution into the AH in humans after 4es daily topical application (the day before surgery plus

drop 1 hour before surgery) with published levels wither fluoroquinolones using similar dosing protocols. The

al of this regimen was to simulate a real-life postoperativesing schedule.

tients and Methods

eoperative Fluoroquinolone Dosing

is was a prospective, randomized, double-masked clinical trial.titutional review board approval was obtained before initiationthe study. Moxifloxacin 0.5% ophthalmic solution or gatifloxa-

0.3% ophthalmic solution was administered 1 drop 4 timesly to the appropriate eye 1 day before planned routine phaco-ulsification in otherwise normal human eyes. The patients weresed 1 drop of the appropriate antibiotic to the randomized eye 1ur before obtaining an aqueous sample on the day of surgery.ueous samples were obtained without contamination from thelar surface. The samples were frozen immediately for futureh-pressure liquid chromatography analysis.

antitative Fluoroquinolone Procedure

e microliter of 75-mol/l ciprofloxacin was added as an internalndard to a 20-l aliquot of the patient sample, and high-pressureuid chromatography was performed. The Waters 515 pump wasipped with a U6K injector, Atlantis dC18 54.6150-mmumn, and a 2475 multiwavelength fluorescence detector thaterated at excitation and emission wavelengths of 293 nm and0 nm, respectively (Waters Corp., Milford, MA). The columnperature was set at 30 C. The high-pressure liquid chroma-raphy mobile phase was comprised of 43% aqueous acetoni-e, 10-mmol/l sodium dodecyl sulfate, 10-mmol/l tetrabutylammo-m acetate, and 25-mmol/l citric acid (adjusted to pH 3.5).2 Thecentration of the patient fluoroquinolone was calculated from thewn amount of the ciprofloxacin standard and the relative area of2 chromatographic peaks. This procedure was repeated as manyes as permitted by the original volume of the patient sample.

sults

ble 1 shows the patient demographic characteristics from thisdy. The mean age of the moxifloxacin 0.5% group was

Table 1. Patient Demographic Characteristics of GroupsReceiving Moxifloxacin 0.5% Ophthalmic Solution and

Gatifloxacin 0.3% Ophthalmic Solution

Characteristic Moxifloxacin Group Gatifloxacin Group

e (yrs) 67.89.7 69.98.7nderale 10 7emale 12 17nicityaucasian 20 21frican-American 1 3ispanic 1 06.89.7 years, whereas that of the gatifloxacin 0.3% group was

.98.7 years. There was not a significant difference between theroups based on age.Two representative chromatograms of moxifloxacin and gatifloxa-with a ciprofloxacin internal standard are shown in Figure 1. Meaneous concentrations ( standard deviation) were 1.861.06

/ml (n 22) for moxifloxacin 0.5% ophthalmic solution and40.72 g/ml (n 24) for gatifloxacin 0.3% ophthalmic solution.is 2-fold greater penetration into the AH for moxifloxacin wastistically significant (P 0.001). The penetration values from

current study relative to published minimum inhibitory con-tration (MIC) values1 for moxifloxacin and gatifloxacin arewn in Figures 2 and 3.

iscussion

e increasing number of ophthalmic surgical proceduresd the increase in resistance to older fluoroquinolones haveated a need for more effective therapeutic agents for thevention and treatment of ocular infections. It is estimatedt nearly 3 million cataract and 1.3 million laser-basedractive surgical procedures were performed in 2004 inUnited States.4 Recent reports suggest that the incidence

bacterial infections after cataract and refractive surgery ising.57 The increasing risk of surgical complications suchpostoperative endophthalmitis and keratitis accentuatesneed for potent new antibiotics for the prevention and

atment of these potentially sight-threatening ocular infec-ns. Recent guidelines from the Medicare National Surgi-

ure 1. Two representative chromatograms showing the internal stan-d, ciprofloxacin, and gatifloxacin and moxifloxacin peaks. The 2 chro-tograms are normalized to the ciprofloxacin peak.

capre

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against gram-positive organisms is especially beneficial be-cause these pathogens are estimated to contribute to up to94 15chtartoltoflovabe

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McCulley et al Fourth-Generation Fluoroquinolone Penetration into the Aqueousl Infection Prevention Project point out the benefits ofoperative and postoperative antibiotic therapy.8In recent years, surgeons have shown a greater prefer-

ce for clear corneal incisions over scleral tunnel proce-res.9 There are reports of a rise in postoperative endoph-lmitis cases after clear corneal incisions.5,7,10 This rise in

dophthalmitis rates may not be related to the placement ofincision but may be due to the fact that the wound is notays watertight. The surgeon may attempt to stop the

kage using stromal hydration. However, this assumest the intraocular pressure (IOP) will be maintained im-diately after surgery and that the hydrated wound will notdehydrated rapidly by the corneal endothelium.11 In fact,IOP after surgery may drop to below 5 mmHg.12 Stro-

l hydration may last for only a few minutes, and then thel of the wound is not maintained. McDonnell et al

nducted a study using optical coherence tomography toamine the effects of the clear corneal cataract incisionhnique on corneal wound leakage.11 These investigatorsnd that the wound tended to open and close with changesIOP. They concluded that transient reductions in IOProduce the potential for fluid to flow across the cornead to be imbibed into the AH. This provides an opportunity

contamination of the AH. In a retrospective study thatorted a very low endophthalmitis rate (0.0084% from

ly 1995 to July 2002) at our institution, it was hypothe-ed that contributing factors were preoperative antisepsis,operative and postoperative topical antibiotic prophy-is, maintenance of a sterile surgical environment, andurance at the conclusion of surgery of a watertightund, without stromal hydration.13The risk of sight-threatening postoperative infectionsderscores the need for effective prophylactic antibiotics.e ideal perioperative antibiotic should possess severalportant therapeutic attributes.14 The agent should have aad spectrum of antibacterial activity. High potency

0

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Obtained MPC (~10 x MIC) for all susceptible organisms

ure 2. Moxifloxacin gram-positive minimum inhibitory concentra-ns (MICs) in relation to the mean moxifloxacin aqueous humor con-tration achieved after 4-times-daily dosing the day before surgery plus 1e 1 hour before surgery.1,30,31 FQR fluoroquinolone resistant; FQS roquinolone susceptible; MPC mutant prevention concentration; S.phylococcus; Strep. Streptococcus.% of endophthalmitis cases. Favorable penetrationaracteristics are needed to deliver the antibiotic to theget ocular tissues. Finally, high degrees of safety anderability of the medication are key factors that contributethe successful healing of the cornea after surgery. Moxi-xacin 0.5% ophthalmic solution has been shown in ariety of in vivo and human studies to possess theseneficial characteristics.1,3,1623The current study results compare favorably with other

netration studies that utilized a 4-times-daily dosing,lse dosing, or a combination of the 2 dosing strategies.e dosing frequency utilized in the current study is rele-nt to both cataract and refractive surgical procedures. Aent clinical study by Kim et al showed AH concentrations1.80g/ml for moxifloxacin and 0.48g/ml for gatifloxaciner 1 drop of antibiotic every 10 minutes for 4 doses begin-g 1 hour before cataract surgery.24 This pulse dosing regi-n produced AH moxifloxacin concentrations that were com-

rable to our results of 1.86 g/ml (using 4-times-dailyministration the day before surgery and 1 additional dose 1ur before surgery). Katz et al reported AH moxifloxacinncentrations of 1.74g/ml with 4-times-daily dosing the dayfore surgery plus 1 drop every 15 minutes for 4 doses beforegery.25 Solomon et al showed a 2-fold higher AH concen-tion for moxifloxacin over gatifloxacin1.31 g/ml and3 g/ml, respectivelywith 4-times-daily dosing for 3

ys before surgery and 1 dose every 15 minutes for 3 doses 1ur before surgery.26 These results suggest rapid penetrationmoxifloxacin to the AH and ocular tissues.Penetration studies with earlier-generation fluoroquino-es have often included pulse dosing after several days ofimes-daily dosing. Price et al, for example, utilized aay 4-times-daily regimen augmented by 4 doses in the

ur before sampling.27 A concentration of 1.14 g/ml was

0

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Gaps in MPC (~10 x MIC) coverage for susceptible organisims

ure 3. Gatifloxacin gram-positive minimum inhibitory concentrationsICs) in relation to the mean gatifloxacin aqueous humor concentrationieved after 4-times-daily dosing the day before surgery plus 1 dose 1r before surgery.1,30,31 FQR fluoroquinolone resistant; FQS fluo-uinolone susceptible; MPC mutant prevention concentration; S. phylococcus; Strep. Streptococcus.957

achieved in the AH with this pulse dosing protocol. So-lomon et al reported 0.15 g/ml of ciprofloxacin in theaqdaho2 dsuforly.theweClbincincomotoggretib

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Aqueous humor antibiotic concentrations achieved at thetime of cataract surgery after topical application wereshwidagetraad2-fthaflothodosigattityciamovagrecususo

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Ophthalmology Volume 113, Number 6, June 2006

95ueous of patients who had been dosed 4 times daily for 3ys, followed by 1 dose every 15 minutes for 3 doses 1ur before surgery.26 Bucci dosed patients 4 times daily forays before surgery (without pulse dosing on the day of

rgery) and reported concentrations of 0.28 and 0.07 g/mllevofloxacin 0.5% and ciprofloxacin 0.3%, respective-

28 Comparisons between our study results and those frompublished literature have some limitations because they

re conducted at different times under varying conditions.inical studies using either 4-times-daily dosing or a com-ation of 4-times-daily and pulse dosing with ciprofloxa-, ofloxacin, and levofloxacin produced AH antibiotic

ncentrations up to 27-fold lower than those observed withxifloxacin 0.5% ophthalmic solution in our study. Takenether, these results demonstrate that moxifloxacin hasater AH penetration than the other fluoroquinolone an-iotics.Studies have been conducted to examine the reasons for the

hanced penetration properties of moxifloxacin. Rusinko et alorted that moxifloxacin was the most soluble of the fluoro-

inolones studied (ciprofloxacin, gatifloxacin, levofloxacin,efloxacin, moxifloxacin, norfloxacin, and ofloxacin; Invest

hthalmol Vis Sci 35[suppl]:4907, 2004). If other factors areentially equivalent, then a higher aqueous solubility shouldld a higher bioconcentration in the tear film. Moxifloxacino was reported to be more lipophilic than these otheroroquinolones. A correlation between corneal penetrationd fluoroquinolone lipophilicity has been established.29en et al showed that the apparent corneal penetration

efficient of moxifloxacin was 3.6-fold greater and itspearance on the endothelial side 2 times faster than that oftifloxacin (Invest Ophthalmol Vis Sci 45:abstract 4910,04). Although the drug penetration was greater, the cor-al permeability to carboxyfluoroscein was 1.6-fold lowerer exposure to moxifloxacin 0.5% ophthalmic solutionmpared with gatifloxacin 0.3% ophthalmic solution. Thismonstrated that moxifloxacin maintained better cornealegrity. These results suggest that the superior cornealnetration of moxifloxacin is due to the inherent charac-istics of the moxifloxacin molecule, and not to changes tocorneal epithelial intercellular (gap) junctions.

An important consideration regarding the penetration ofopical antibiotic is ability to achieve a concentration wellove the MIC for a given microorganism. The mutantvention concentration (MPC) is generally maximum con-tration of the drug/MIC 8 to 10.30 The MPC can also be

fined as the antibiotic concentration threshold that woulduire 2 simultaneous mutations.31 When comparing the AH

ncentrations achieved in the current study with MPCs de-ed from the MICs from the Mather et al study, moxifloxacinieved MPCs for fluoroquinolone-susceptible Staphylococ-

s aureus, fluoroquinolone-susceptible coagulase-negativephylococcus, Streptococcus pneumoniae, Streptococcusidens, Enterococci species, and Bacillus species (Fig 3). Ofse organisms, gatifloxacin did not attain MPCs for S. pneu-niae, S. veridens, Enterococci species, or Bacillus spe-s or the MIC for fluoroquinolone-resistant S. aureus.18own to be effective surrogates for what can be achievedth typical postoperative topical dosing (e.g., 4 timesily). When compared with published reports, the fourth-neration fluoroquinolones achieved greater AH concen-tions after dosing than prior-generation fluoroquinolones. Indition, moxifloxacin 0.5% ophthalmic solution achieved aold higher AH concentration than gatifloxacin 0.3% oph-lmic solution. Aqueous humor concentrations for moxi-xacin 0.5% ophthalmic solution were substantially abovese needed for common pathogens with clinically relevantsing (i.e., 4 times daily).32 The superior and clinicallynificant penetration of moxifloxacin into the AH may beributed to its high degree of lipophilicity, greater solubil-at neutral pH, and higher concentration in the commer-l formulation. This enhanced penetration provides AHxifloxacin concentrations at or above the MPCs for a

riety of pathogenic microorganisms and may provideater protection against ocular infection. The results of the

rrent study as well as other published studies providepport for the utility of moxifloxacin 0.5% ophthalmiclution for use in surgical prophylaxis.

ferences

. Mather R, Karenchak LM, Romanowski EQ, Kowalski RP.Fourth generation fluoroquinolones: new weapons in the ar-senal of ophthalmic antibiotics. Am J Ophthalmol 2002;133:4636.

. Liang H, Kays MB, Sowinski KM. Separation of levofloxacin,ciprofloxacin, gatifloxacin, moxifloxacin, trovafloxacin andcinoxacin by high-performance liquid chromatography: appli-cation to levofloxacin determination in human plasma. J Chro-matogr B Analyt Technol Biomed Life Sci 2002;772:5363.

. Mather R, Stewart JM, Prabriputaloong T, et al. The effect ofcataract surgery on ocular levels of topical moxifloxacin. Am JOphthalmol 2004;138:5549.

. Arnold PP. Cataract and refractive surgerythe other side ofthe pond. Available at: http://www.bbriefings.com/pdf/952/Arnold.pdf. Accessed January 18, 2005.

. Colleaux KM, Hamilton WK. Effect of prophylactic antibiot-ics and incision type on the incidence of endophthalmitis aftercataract surgery. Can J Ophthalmol 2000;35:3738.

. Karp CL, Tuli SS, Yoo SH, et al. Infectious keratitis afterLASIK. Ophthalmology 2003;110:50310.

. Nagaki Y, Hayasaka S, Kadoi C, et al. Bacterial endoph-thalmitis alter small-incision cataract surgery: effect of inci-sion placement and intraocular lens type. J Cataract RefractSurg 2003;29:206.

. Bratzler DW, Houck PM, Surgical Infection PreventionGuidelines Writers Workgroup. Antimicrobial prophylaxis forsurgery: an advisory statement from the National Surgical In-fection Prevention Project. Clin Infect Dis 2004;38:170615.

. Leaming DV. Practice styles and preferences of ASCRSmember: 2000 survey. J Cataract Refract Surg 2001;27:94855.

. Stonecipher KG, Parmley VC, Jensen H, Rowsey JJ. Infec-tious endophthalmitis following sutureless cataract surgery.Arch Ophthalmol 1991;109:15623.

. McDonnell PJ, Taban M, Sarayba M, et al. Dynamic mor-phology of clear corneal cataract incisions. Ophthalmology2003;110:23428.

12. Shingleton BJ, Wadhwani RA, ODonoghue MW, et al. Eval-uation of intraocular pressure in the immediate period afterphacoemulsification. J Cataract Refract Surg 2001;27:5247.

13. McCulley JP. Low acute endophthalmitis rate: possible expla-nations [letter]. J Cataract Refract Surg 2005;31:10745.

14. Mah FS. Fourth-generation fluoroquinolones: new topicalagents in the war on ocular bacterial infections. Curr OpinOphthalmol 2004;15:31620.

15. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum andsusceptibilities of microbiologic isolates in the Endophthalmi-tis Vitrectomy Study. Am J Ophthalmol 1996;122:117.

16. Alfonso E, Crider J. Ophthalmic infections and their anti-infective challenges. Surv Ophthalmol 2005;50(suppl):S16.

17. Abshire R, Cockrum P, Crider J, Schlech B. Topical antibac-terial therapy for mycobacterial keratitis: potential for surgicalprophylaxis and treatment. Clin Ther 2004;26:1916.

18. Aliprandis E, Ciralsky J, Lai H, et al. Comparative efficacy oftopical moxifloxacin versus ciprofloxacin and vancomycin inthe treatment of P. aeruginosa and ciprofloxacin-resistantMRSA keratitis in rabbits. Cornea 2005;24:2015.

19. Durrie DS, Trattler W. A comparison of therapeutic regimenscontaining moxifloxacin 0.5% ophthalmic solution and gati-floxacin 0.3% ophthalmic solution for surgical prophylaxis inpatients undergoing LASIK or LASEK. J Ocular Pharm Ther2005;21:23641.

20. Kim DH, Stark WJ, OBrien TP. Ocular penetration ofmoxifloxacin 0.5% and gatifloxacin 0.3% ophthalmic solu-tions into the aqueous humor following topical administra-tion prior to routine cataract surgery. Cur Med Res Opin2005;21:93 4.

21. Kovoor TA, Kim AS, McCulley JP, et al. Evaluation of thecorneal effects of topical ophthalmic fluoroquinolones us-ing in vivo confocal microscopy. Eye Contact Lens 2004;

22

levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitisisolates. Am J Ophthalmol 2003;136:5005.

23. Kowalski RP, Romanowski EG, Mah FS, et al. Topical pro-phylaxis with moxifloxacin prevents endophthalmitis in a rab-bit model. Am J Ophthalmol 2004;138:337.

24. Kim DH, Stark WJ, OBrien TP, Dick JD. Aqueous penetra-tion and biological activity of moxifloxacin 0.5% ophthalmicsolution and gatifloxacin 0.3% solution in cataract surgerypatients. Ophthalmology 2005;112:19926.

25. Katz HR, Masket S, Lane SS, et al. Absorption of topicalmoxifloxacin ophthalmic solution into human aqueous humor.Cornea 2005;24:9558.

26. Solomon R, Donnenfeld ED, Perry HD, et al. Penetration oftopically applied gatifloxacin 0.3%, moxifloxacin 0.5%, andciprofloxacin 0.3% into the aqueous humor. Ophthalmology2005;112:4669.

27. Price FW Jr, Dobbins K, Zeh W. Penetration of topicallyadministered ofloxacin and trimethoprim into aqueous humor.J Ocular Pharmacol Ther 2002;18:44553.

28. Bucci FA Jr. An in vivo study comparing the ocular absorp-tion of levofloxacin and ciprofloxacin prior to phacoemulsifi-cation. Am J Ophthalmol 2004;137:30812.

29. Liu W, Liu QF, Perkins R, et al. Pharmacokinetics of sparfloxa-cin in the serum and vitreous humor of rabbits: physicochemicalproperties that regulate penetration of quinolone antimicrobials.Antimicrob Agents Chemother 1998;42:141723.

30. Schentag JJ. Pharmacokinetic and pharmacodynamic predic-tors of antimicrobial efficacy: moxifloxacin and Streptococcuspneumoniae. J Chemother 2002;14(suppl):1321.

31. Metzler K, Hansen GM, Hedlin P, et al. Comparison ofminimal inhibitory and mutant prevention drug concentrationsof 4 fluoroquinolones against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus. Int J Anti-

32

McCulley et al Fourth-Generation Fluoroquinolone Penetration into the Aqueous30:90 4.. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxa-

cin and moxifloxacin: an in vitro susceptibility comparison tomicrob Agents 2004;24:1617.. Neu HC, Ellner PD. The inhibitory quotient. Bull N Y Acad

Med 1983;59:43042.959

Fourth-Generation Fluoroquinolone Penetration into the Aqueous Humor in HumansPatients and MethodsPreoperative Fluoroquinolone DosingQuantitative Fluoroquinolone Procedure

ResultsDiscussionReferences