Drug Criteria & Outcomes
Ocuflox for conjunctivitis, corneal ulcers
By Tony Willoughby, PharmD candidate
Medical University of South Carolina
Charleston
Indications
Ofloxacin (Ocuflox), by Allergan, is indicated for the treatment of conjunctivitis and corneal ulcers caused by susceptible strains of organisms. Susceptible gram-positive organisms for both conjunctivitis and corneal ulcers include: Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pneumoniae. Susceptible gram-negative organisms for conjunctivitis include: Enterobacter cloacae, Haemophilus influenzae, Proteus mirabilis, and Pseudomonas aeruginosa. For corneal ulcers, susceptible gram-negative organisms include P. aeruginosa and Serratia marcescens as well as the anaerobe Propionibacterium acnes.1-3
Pharmacology
Ofloxacin is a member of the fluoroquinolone class of antibiotics. It exerts its bactericidal activity by inhibiting DNA gyrase. DNA gyrase is an enzyme necessary for DNA repair and replication.4,5 It inhibits excessive positive supercoiling of DNA strands during the uncoiling process necessary for transcription.4,5 Thus, ofloxacin inhibits bacterial DNA repair and replication secondary to its inhibition of DNA gyrase.
Pharmacokinetics
Serum, urine, and tear concentrations of ofloxacin were evaluated in 30 healthy women who received 10½ days of ofloxacin 0.3% solution administered topically four times daily. Maximum serum concentrations were more than 1,000 times lower than for standard oral ofloxacin administration. Four hours after topical administration, mean tear concentrations were 9.2 mcg/g. The majority of ofloxacin was excreted in the urine unchanged.1
A total of 50 patients who were to undergo cataract extraction were enrolled in a study to compare drug concentrations achieved in aqueous humor after instillation of ofloxacin 0.3% vs. ciprofloxacin 0.3%.6 The patients were randomized into two groups of 25 patients each. Six hours prior to surgery, patients received either ofloxacin 0.3% or ciprofloxacin 0.3%, 2 drops instilled into the operative eye, every 30 minutes for 3 hours, followed by 2 drops every hour for 3 hours. The medication was administered by a nurse to ensure compliance. Samples were taken at the onset of surgery. The ofloxacin group had statistically significantly higher mean, maximum, and minimum concentrations (1.43 ( 0.26, 2.08, and 0.13 mcg/mL, respectively) when compared to the ciprofloxacin group (0.35 ( 0.07, 1.09, and 0.11 mcg/mL, respectively) (p < 0.0002).6
Another study evaluated drug penetration in 224 patients who were to undergo cataract surgery.7 The patients received 0.3% solutions of ofloxacin, ciprofloxacin, or norfloxacin. Patients received either 1 drop of study medication in the operative eye at 15:00, 17:00, and 19:00 the day before surgery, and then 1 drop each hour from 06:00 to 08:00 on day of surgery; or 1 drop of study medication in the operative eye every 15 minutes from 6 a.m. to 8 a.m. on day of surgery. Samples were taken at the beginning of surgery. Ofloxacin concentrations were found to be significantly higher when compared to ciprofloxacin and norfloxacin in both treatment groups (p < 0.05). The second administration sequence was found to be most effective. The mean concentrations measured were ciprofloxacin 379.8 ( 327.8 mg/L, norfloxacin 182.1 ( 118.1 mg/L, and ofloxacin 563.9 ( 372.1 mg/L. Both ciprofloxacin and ofloxacin obtained concentrations that are higher than the MIC90 for the most common occurring infectious organisms.7
Selected clinical trials
The efficacy of ofloxacin ophthalmic solution was evaluated in 146 patients with suspected bacterial keratitis.8 Patients were enrolled upon presentation at the Aravind Eye Hospital in Madurai, India. The population consisted of 97 males and 49 females, with a mean age of 47 years. At enrollment, cultures of the infected cornea were obtained for microbiological examination. After cultures were obtained, therapy was initiated with ofloxacin 0.3% solution, instilled in the affected eye every 30 minutes for two days. The dose was reduced to hourly administration for days three to five. The dose was further reduced to four times daily for days seven to nine, or until the ulcer was healed. Patients were hospitalized for at least the first seven days of therapy in order to ensure compliance. A total of 105 cultures were positive. The most common causative organisms were Streptococcus pneumoniae (42%), followed by P. aeruginosa (30%), and S. epidermidis (9%). Of the 105 culture-positive patients, 99 achieved clinical success by day 23, with an average time to endpoint of 13.8 + 1.6 days. The remaining six patients were discontinued from the study due to lack of efficacy. There were no adverse effects reported during the study. The authors concluded that ofloxacin 0.3% topical solution is effective in the treatment of bacterial keratitis.8 These data are currently available only in abstract form.
A study comparing ofloxacin and ciprofloxacin in the treatment of bacterial keratitis was conducted in 217 culture-positive patients.9 Patients were randomized to receive either topical ofloxacin 0.3% ophthalmic solution (n = 112) or topical ciprofloxacin 0.3% ophthalmic solution (n = 105). Treatment regimens were not provided in the available literature. The ofloxacin group had an average time to resolution of infection of 13.8 + 0.7 days. The ciprofloxacin group had an average time to resolution of infection of 14.6 + 0.6 days. The overall response rate at the end of the study was 85% in the ofloxacin group and 77% in the ciprofloxacin group. The difference between groups did not reach statistical significance (p = 0.32). The ofloxacin group displayed a higher resolution rate in the sub-group of patients with larger ulcers (> 10mm3) when compared to the patients receiving ciprofloxacin. The resolution rate was 77% in the ofloxacin group and 65% in the ciprofloxacin group. This was not statistically significant (p = 0.27). A total of 22 patients did not complete the trial due to lack of efficacy, 12 in the ciprofloxacin group and 10 in the ofloxacin group. This difference was not statistically significant (p = 0.83). Adverse events including burning and stinging upon application were comparable between groups. Precipitates were seen in 25 patients in the ciprofloxacin group. The authors concluded that ofloxacin and ciprofloxacin 0.3% topical solutions appear to be equally effective in the treatment of bacterial keratitis.9 These data are currently available only in abstract form.
Adverse reactions
The majority of adverse events reported by patients receiving ofloxacin ophthalmic solution include transient burning or discomfort following instillation. Other local adverse events include stinging, chemical conjunctivitis/keratitis, periocular/facial edema, redness, itching, foreign body sensation, photophobia, blurred vision, dryness, tearing, and eye pain. There have been rare reports of systemic side effects, including dizziness and hypersensitivity.1
Pregnancy and lactation
Ofloxacin is classified as a pregnancy category C medication.1,2 This indication means that human studies are not available to provide conclusive evidence regarding the safety of the fetus. Furthermore, there are animal studies either providing positive evidence of fetal risk, or that are inconclusive, as well.10 Potential risk vs. benefit must be considered when deciding to use medications within this classification.11 In animal studies involving rats, ofloxacin given at a dose 810 mg/kg/day (equivalent to 9,000 times the standard ophthalmic dose in humans) showed decreased fetal body weight and minor fetal skeletal variations. Animal studies in rabbits receiving 160 mg/kg/day (equivalent to 1,800 times the standard ophthalmic dose in humans) displayed an increase in fetal mortality.1 Additional studies in rats given doses up to 360 mg/kg/day during the latter stages of gestation displayed no effect on late fetal development, labor, delivery, neonatal vitality, lactation, or fetal growth.1
A single oral dose of 200 mg given to nursing women resulted in concentrations of ofloxacin in breast milk that were comparable to those found in plasma. To date, studies have not been conducted to determine if ofloxacin, administered topically, is excreted in breast milk.1
Contraindications
Ofloxacin ophthalmic solution is contraindicated in patients who have a history of hypersensitivity to ofloxacin, to other quinolones, or to any excipients contained in this medication.1
Warnings
Ofloxacin ophthalmic solution should not be used as a subconjunctival injection, nor should it be directly instilled into the anterior chamber of the eye.1
Serious and sometimes fatal hypersensitivity reactions have been reported in patients receiving systemic quinolones, including ofloxacin. Some of the reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal, or facial edema), airway obstruction, dyspnea, urticaria, and itching. A rare occurrence of Stevens-Johnson syndrome, which progressed to toxic epidermal necrolysis, was reported in a patient receiving topical ophthalmic ofloxacin. If an allergic reaction is suspected, the drug should be discontinued immediately. Serious acute hypersensitivity reaction may require immediate emergency treatment. Oxygen and airway management including intubation should be administered as clinically indicated.1
Dosage and administration
The recommended dosage for ofloxacin in the treatment of bacterial conjunctivitis and bacterial corneal ulcers is as follows:1
• Days 1 and 2 — Instill 1-2 drops every 2-4 hours into affected eye(s).
• Days 3 through 7 — Instill 1-2 drops four times daily into affected eye(s).
For the treatment of bacterial corneal ulcers, the recommended regimen for ofloxacin is as follows:1
• Days 1 and 2 — Instill 1-2 drops into affected eye(s) every 30 minutes while awake. Awaken at approximately 4 and 6 hours after retiring and instill 1 to 2 drops.
• Days 3 through 7 to 9 — Instill 1-2 drops, hourly while awake into affected eye(s).
• Days 7 through 9 or treatment completion — Instill 1-2 drops, 4 times daily into affected eye(s).
Drug interactions
Drug interaction studies between ofloxacin ophthalmic solution and other medications have not been conducted. However, systemic ofloxacin therapy has been associated with the several drug interactions.1 Decreased absorption is exhibited when ofloxacin is given in combination with aluminum, magnesium, or calcium containing antacids.2,3 Coadministration of ofloxacin resulted in increased concentrations/toxicity with warfarin, cyclosporine,1-3 procainamide,2,3 theophylline,1-3 and caffeine.1
Drug-food interactions
To date, there are no drug-food interactions reported in the package labeling for the ophthalmic solution of ofloxacin.1 However, when given systemically, ofloxacin does display drug-food interactions. When ofloxacin is taken in combination with products that contain high amounts of calcium (e.g., milk, cheese), decreased absorption can be seen.2,3 Ofloxacin can inhibit the metabolism of caffeine, thereby increasing and prolonging caffeine concentrations.1-3
Dosage forms available
Ofloxacin ophthalmic solution is available as a sterile 0.3% solution in 1, 5, and 10 mL plastic dropper bottles.1
Sample status
Samples of ofloxacin ophthalmic solution would be acceptable.
Potential for medication errors
There is the potential to make medication errors when writing or interpreting orders for Ocuflox (ofloxacin ophthalmic solution). It is possible to confuse Ocuflox with Ocufen (flurbiprofen).12 Ocufen is also an ophthalmic preparation; it is indicated intraoperatively for the inhibition of miosis.2 In addition, ofloxacin ophthalmic solution might be confused with ciprofloxacin ophthalmic solution (Ciloxan), ciprofloxacin otic solution (Cipro HC Otic), or ofloxacin otic solution (Floxin). Patient harm may result if otic solutions are instilled in the eye.
Filtration requirements
There are no filtration requirements for ofloxacin ophthalmic solution noted in the reviewed literature.1-10
Discussion
Ofloxacin is a well-tolerated topical fluoroquinolone approved for the treatment of bacterial conjunctivitis and corneal ulceration.1 The fluoroquinolones have been shown to have excellent in-vitro efficacy against the most common causative organisms seen in conjunctivitis and corneal ulcers.13-14 However, there are no data to suggest that any one of the available topical antibiotics is clinically superior to another.11 Ofloxacin has been shown to be as effective as topically applied aminoglycosides.15-16 There are few head-to-head trials comparing fluoroquinolones in the treatment of ocular infections. The two studies reviewed in the pharmacokinetic section support that ofloxacin has superior corneal penetration compared to ciprofloxacin.6-7 However, the one head-to-head outcome trial reviewed did not demonstrate statistical significance for any of the endpoints.8
References
1. Ocuflox (0.3% ofloxacin ophthalmic solution) package insert. Irvine, CA: Allergan; 1996.
2. Burnham TH, ed. Drug Facts and Comparisons. St. Louis: Walter Kluwer Co.; 1998.
3. Lacy CF, Armstrong LL, Ingrim NB, Lance LL. Drug Information Handbook. 6th ed. Hudson, OH: Lexicomp; 1998.
4. Mandel GL, Petri WA. "Antimicrobial agents." In: Hardman JG, Limbird LE, Molinoff PB, Rudon RW, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th ed. New York City: McGraw-Hill, 1996.
5. Stryer L, ed. Biochemistry 4th ed. New York City: WH Freeman and Co., 1995.
6. Cekic O, Batman C, Totan Y, et al. Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical administration. Ophthalmic Surg Lasers 1999; 30:465-8.
7. Beck R, Keyserlingk JV, Fischer U, Guthoff R, Drewelow B. Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humor using different topical application modes. Graefe’s Arch Clin Exp Ophthalmol 1999; 237:89-92.
8. Srinivasan M, Stoecker JF, Sundar K, Jensen, G. Successful treatment of bacterial corneal ulceration with 0.3% ofloxacin ophthalmic solution. Invest Ophthalmol Vis Sci 1995 Mar 15; 36:4.
9. LU KL, Prajna NV, McDonnell PJ. Comparison of ofloxacin and ciprofloxacin in the therapy of bacterial keratitis. Invest Ophthalmol Vis Sci 1998 Mar 15; 39(4):S140.
10. Cardinole V. RedBook. Montvale, NJ: Medical Economics Co. Inc.; 2000.
11. Sifton DW, Westley GJ. Physicians’ Desk Reference. Montvale, NJ: Medical Economics Co.; 2000.
12. Billups NF, Billups SM. American Drug Index. St. Louis: Wolters Kluwer Co.; 2000.
13. Everett SL, Kowalski RP, Karenchak LM, Landsittel D, Day R, Gordon YJ. An in vitro comparison of the susceptibilities of bacterial isolates from patients with conjunctivitis and blepharitis to newer and established topical antibiotics. Cornea 1995 Jul; 14(4):382-7.
14. Jensen HG, Felix C, et al. In vitro antibiotic susceptibilities of ocular isolates in North and South America. Cornea 1998 Jan:17(1):79-87.
15. Ofloxacin study group. Topical ofloxacin compared with gentamicin in the treatment of external ocular infection. Br J Ophthalmol 1992; 76:714-8.
16. Ofloxacin study group. Ofloxacin vs. tobramycin for the treatment of external ocular infection. Arch Ophthalmol 1992; 110:1234-7.
17. Moreira LB, Lee RF, de Oliveiria C, Labree L, MeDonnel PJ. Effect of topical fluoroquinolones on corneal re-epithelization after excimer laser keratectomy. J Cataract Refract Surg 1997; 23:845-8.
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