LABORATORY SCIENCES Comparative Efficacy of Topical Gatifloxacin With Ciprofloxacin, Amikacin, and Clarithromycin in the Treatment of Experimental Mycobacterium chelonae Keratitis Joon-Young Hyon, MD; Myung-Jin Joo, MD; Stacey Hose; Debasish Sinha, PhD; James D. Dick, PhD; Terrence P. O’Brien, MD Objective: To determine the comparative efficacy of topi- more significantly than the controls that were treated with cal gatifloxacin with ciprofloxacin, fortified amikacin, and a topical balanced salt solution (both PϽ.001). Therapy clarithromycin against Mycobacterium chelonae keratitis with 0.3% gatifloxacin was more effective than 0.3% cipro- in an animal model. floxacin alone (PϽ.001) and demonstrated synergy by enhancing the efficacy of the combination of fortified ami- Methods: Experimental M chelonae keratitis was in- kacin (50 mg/mL) and clarithromycin (10 mg/mL) duced via intrastromal inoculation in a rabbit model. (PϽ.001). Neither 0.3% ciprofloxacin nor the combina- Thirty-five rabbits were randomly divided into 5 groups tion of fortified amikacin (50 mg/mL) and clarithromy- and each group was treated hourly for 12 hours with topi- cin (10 mg/mL) demonstrated a significant difference in cal 0.9% balanced salt solution, 0.3% gatifloxacin, 0.3% activity against mycobacteria compared with the topical ciprofloxacin hydrochloride, a combination of topical for- balanced salt solution. tified amikacin sulfate (50 mg/mL) and clarithromycin (10 mg/mL), or a triple combination of topical 0.3% gati- Conclusion: These results suggest that topical 0.3% gati- floxacin, fortified amikacin sulfate (50 mg/mL), and cla- floxacin ophthalmic solution can be a new initial treat- rithromycin (10 mg/mL). Antibacterial efficacy of each ment agent against M chelonae keratitis. regimen was determined by quantitative bacteriologic analysis. Clinical Relevance: Topical gatifloxacin 0.3% may provide an initial alternative in thereapy of M chelonae Results: Treatment with 0.3% gatifloxacin or the triple keratitis. combination of 0.3% gatifloxacin, topical fortified ami- kacin sulfate (50 mg/mL), and clarithromycin (10 mg/ mL) reduced the number of mycobacterial organisms Arch Ophthalmol. 2004;122:1166-1169 NFECTIOUS KERATITIS DUE TO NON- crobial activity, has been reported to be tuberculous mycobacterial spe- 4-fold more active than ciprofloxacin cies is a rare, but devastating, against rapidly growing mycobacteria in complication after laser in situ vitro.14 Yet, to our knowledge, no in vivo keratomileusis (LASIK). Myco- data are available for results of treatment Ibacterium chelonae is reported as the most of nontuberculous mycobacterial infec- common species isolated of the nontuber- tions with gatifloxacin. Given its excel- culous mycobacteria causing keratitis fol- lent in vitro activity, gatifloxacin can be lowing LASIK.1-12 Combination therapy considered as a potential candidate for a with topical amikacin and ciprofloxacin or new therapeutic strategy against nontu- From the Ocular Microbiology with amikacin and clarithromycin has been berculous mycobacterial keratitis. The aim and Immunology Laboratory, the mainstay of medical therapy.2,3,7,8 De- of this study was to compare the efficacy Wilmer Eye Institute spite aggressive and protracted treat- of topical gatifloxacin with ciprofloxa- (Drs Hyon, Joo, Sinha, and ment, the clinical outcome of medical cin, an earlier generation fluoroquino- O’Brien and Ms Hose), therapy has been unsatisfactory in many lone, and combination therapy with ami- Department of Pathology cases. Ford et al13 reported that 55% of the kacin and clarithromycin in the rabbit (Dr Dick), The Johns Hopkins cases of keratitis due to nontuberculous model of M chelonae keratitis. University School of Medicine, Baltimore, Md. Dr O’Brien is a mycobacteria did not respond to medical nonsalaried ad hoc consultant therapy alone and ultimately required a METHODS for Alcon Laboratories Inc, surgical procedure. Allergan Inc, Pharmacia Corp, Gatifloxacin, 1 of 8-methoxy fluoro- A stock strain of M chelonae ATCC-35752 and Santen Inc. quinolones with broad-spectrum antimi- (American Type Culture Collection, Rock- (REPRINTED) ARCH OPHTHALMOL / VOL 122, AUG 2004 WWW.ARCHOPHTHALMOL.COM 1166 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 ville, Md) was selected as the test organism. This strain dem- onstrated via pilot laboratory testing to induce keratitis com- Quantitative Mycobacterial Culture Results in Experimental parable to human isolates. The suspension was diluted to 107 Mycobacterium chelonae Keratitis* organisms per milliliter in phosphate buffer solution. In vitro susceptibility testing determined that the mimimum inhibi- Bacterial Load, P †tory concentration (MIC) of amikacin was 16 µg/mL (suscep- Treatment Group CFUs؋10−3 Values tible) by broth microdilution technique using National Com- 0.9% BBS (n = 7) 5383 (4263) NA mittee for Clinical Laboratory Standards’ guidelines. The reports 0.3% Gatifloxacin (n = 7) 3.89 (9.65) Ͻ.001 from other separate laboratories have shown that the MIC of 0.3% Ciprofloxacin hydrochloride (n = 7) 1156.44 (926.95) .21 gatifloxacin was 0.12 µg/mL or less,14 the MIC of ciprofloxa- Amikacin sulfate (50 mg/mL) and 1505.45 (1413.02) .51 cin was 0.25 µg/mL,14 and the MIC of clarithromycin was 0.125 clarithromycin (10 mg/mL) (n = 7) µg/mL15 for this carefully selected test strain. Amikacin sulfate (50 mg/mL), clarithromycin 1.11 (1.10) Ͻ.001 Topical fortified amikacin (50 mg/mL) was prepared by (10 mg/mL), and 0.3% gatifloxacin (n = 7) the Johns Hopkins institutional research pharmacy from par- enteral formulations according to routine procedures. Topical Abbreviations: BSS, topical balanced salt solution; CFUs, colony-forming clarithromycin (10 mg/mL) was prepared by the research phar- units; NA, not applicable. *Data are given as mean (SD). macy by reconstituting an oral suspension powder with sterile †The P value was determined using the 1-way analysis of variance test with water followed by dilution with artificial tears as described by multiple comparisons compared with the BSS treatment group using Ford et al.13 Topical 0.3% ciprofloxacin (Ciloxan; Alcon Labo- logarithm-transformed data. ratories Inc, Fort Worth, Tex) was used as a commercial prepa- ration. Topical 0.3% gatifloxacin was provided by Allergan Inc, Irvine, Calif, for the animal experiment. RESULTS Thirty-five adult male New Zealand white rabbits, weigh- ing 3.0 to 4.0 kg, were randomly divided into 5 groups. Insti- By 4 days mycobacterial keratitis developed after inocu- tutional guidelines regarding animal experimentation were fol- lation in all 35 rabbits. Corneal infiltrates appeared as fo- lowed and all animals were treated according to the Association cal, fluffy white deposits with fine radiating projections, of Vision Research in Ophthalmology Statement for the Use of similar to observed and reported clinical signs in culture- Animals in Ophthalmic and Vision Research. Anesthesia was proven cases of mycobacterial keratitis in humans. induced with intramuscular injection of 30 mg/kg of ket- The quantitative culture results are summarized in amine hydrochloride (Ketaject; Phoenix Pharmaceutical Inc, St Joseph, Mo) and 5 mg/kg of xylazine hydrochloride (Xyla- the Table. The 0.3% gatifloxacin and triple combina- ject; Phoenix Pharmaceutical Inc). Topical anesthesia was tion therapy with 0.3% gatifloxacin, 50 mg/mL of forti- achieved with administration of 1 drop of 0.5% proparacaine fied amikacin sulfate, and 10 mg/mL of clarithromycin hydrochloride to the rabbit eyes. Through a 30-gauge needle, significantly reduced the number of M chelonae com- a 100-µg suspension of M chelonae containing 106 organisms pared with the control of 0.9% balanced salt solution (both was inoculated into the midstroma of the right cornea. Imme- PϽ.001). Gatifloxacin therapy demonstrated greater an- diately after the inoculation, 0.5 mL of dexamethasone so- timycobacterial activity than ciprofloxacin therapy dium phosphate (4 mg/mL) was injected subconjunctivally to Ͻ 16 (P .001). Triple combination therapy with gatifloxa- each rabbit. cin, amikacin, and clarithromycin resulted in a more fa- After the intrastromal inoculation, infection was allowed vorable result in reduction of bacterial colonies than to proceed for 5 days before initiation of antibiotic therapy. From the fifth day after the inoculation, topical antibiotics were ap- monotherapy with 0.3% gatifloxacin, but there was no plied to the affected right eyes hourly for 12 hours and each group statistical significance. There was no significant differ- was treated with one of the following regimens: (1) 3 mg/mL of ence observed between control eyes and eyes treated with gatifloxacin; (2) 3 mg/mL of ciprofloxacin; (3) a combination ciprofloxacin or with combination therapy using 50 of 50 mg/mL of fortified amikacin and 10 mg/mL of clarithro- mg/mL of amikacin sulfate and 10 mg/mL of clarithro- mycin; (4) a triple combination of topical 3 mg/mL of gati- mycin (Figure). floxacin, 50 mg/mL of fortified amikacin and 10 mg/mL of clarithromycin; or (5) 0.9% balanced salt solution as a con- trol. The rabbits were randomly allocated to each treatment COMMENT group prior to intrastromal inoculation. Nontuberculous mycobacterial keratitis represents a per- One hour after the final instillation of the antibiotic drops, the animals were killed with an overdose of barbiturate (Beutha- sistent challenge in diagnosis and treatment because of