Topical Fluoroquinolones for Eye and Ear

Am Fam Physician. 2000 Oct 15;62(8):1870-1876.

Topical fluoroquinolones are now available for use in the eye and ear. Their broad spectrum of activity includes the common eye and ear pathogens Staphylococcus aureus and Pseudomonas aeruginosa. For the treatment of acute otitis externa, these agents are as effective as previously available otic preparations. For the treatment of otitis media with tympanic membrane perforation, topical fluoroquinolones are effective and safe. These preparations are approved for use in children, and lack of ototoxicity permits prolonged administration when necessary. Topical fluoroquinolones are not appropriate for the treatment of uncomplicated conjunctivitis where narrower spectrum agents suffice; they represent a simplified regimen for the treatment of bacterial keratitis (corneal ulcers). When administered topically, fluoroquinolones are well tolerated and offer convenient dosing schedules. Currently, bacterial resistance appears limited.

Since fluoroquinolone antibiotics were introduced for systemic use in the 1980s, their indications and use have increased rapidly. Recently, topical formulations for the eye and ear have appeared, expanding the options for the treatment of certain bacterial infections.

Fluoroquinolones are formulated by adding fluorine and other groups to nalidixic acid. Their bactericidal and bacteriostatic properties result from inhibition of the enzyme DNA gyrase.1  The broad spectrum of fluoroquinolone activity (Table 1), especially activity against Staphylococcus aureus and Pseudomonas aeruginosa, has generated interest in the use of this class of agents for topical eye and ear treatment.

TABLE 1

Antibacterial Spectrum of Fluoroquinolones

Susceptible*

Escherichia coli

Klebsiella pneumoniae

Enterobacter species

Citrobacter species

Serratia marcescens

Shigella species

Salmonella species

Aeromonas species

Yersinia species

Proteus species

Providencia species

Pseudomonas aeruginosa †‡

Staphylococcus aureus †‡

Staphylococcus epidermidis

Haemophilus species †‡

Neisseria species

Moraxella aeromonas vibrius

Campylobacter species

Variable activity*

Streptococcus pyogenes

Hemolytic streptococci Groups B, C, F, G

Streptococcus pneumoniae †‡

Streptococcus faecalis

Inhibit*

Mycoplasma species

Chlamydia species

Legionella species

Resistant*

Anaerobic cocci

Clostridia species

Bacteroides species


*—Includes organisms resistant to penicillins, cephalosporins and aminoglycosides.

—Common ear pathogens.

—Common eye pathogens.

Adapted with permission from Neu HE. Microbiologic aspects of fluoroquinolones. Am J Ophthalmol 1991;112(suppl):18S.

TABLE 1   Antibacterial Spectrum of Fluoroquinolones

View Table

TABLE 1

Antibacterial Spectrum of Fluoroquinolones

Susceptible*

Escherichia coli

Klebsiella pneumoniae

Enterobacter species

Citrobacter species

Serratia marcescens

Shigella species

Salmonella species

Aeromonas species

Yersinia species

Proteus species

Providencia species

Pseudomonas aeruginosa †‡

Staphylococcus aureus †‡

Staphylococcus epidermidis

Haemophilus species †‡

Neisseria species

Moraxella aeromonas vibrius

Campylobacter species

Variable activity*

Streptococcus pyogenes

Hemolytic streptococci Groups B, C, F, G

Streptococcus pneumoniae †‡

Streptococcus faecalis

Inhibit*

Mycoplasma species

Chlamydia species

Legionella species

Resistant*

Anaerobic cocci

Clostridia species

Bacteroides species


*—Includes organisms resistant to penicillins, cephalosporins and aminoglycosides.

—Common ear pathogens.

—Common eye pathogens.

Adapted with permission from Neu HE. Microbiologic aspects of fluoroquinolones. Am J Ophthalmol 1991;112(suppl):18S.

The Ear

Bacterial ear infections, such as necrotizing (malignant) otitis externa and otitis media in ears with intact tympanic membranes, require systemic treatment. However, other forms of infection respond well to topical antibiotics. Two otic preparations of topical fluoroquinolones, ofloxacin 0.3 percent (Floxin otic) and ciprofloxacin 0.2 percent with hydrocortisone 1.0 percent (Cipro HC otic), have been introduced. Ofloxacin otic solution is approved for the treatment of otitis externa and otitis media with perforated or ventilated tympanic membrane. Ciprofloxacin otic suspension is approved for the treatment of otitis externa. Both preparations may be used in patients one year or older.2  Recommended treatment regimens are summarized in Table 2.

TABLE 2

Recommended Treatment Regimens for Ear Infections

Condition Drug Dosage Duration Cost†

Acute otitis externa

Ciprofloxacin-hydrocortisone (Cipro HC)

Adult: 3 drops, twice daily

7 to 10 days

$59.00 ‡/10 mL

Child: 3 drops, twice daily

Ofloxacin (Floxin)

Adult: 10 drops, twice daily

7 to 10 days

34.00 ‡/5 mL

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§ (Cortisporin)

Adult: 5 drops, three to four times daily

7 to 10 days

Brand: 42.00 (solution or suspension)/10 mL

Child: 4 drops, three to four times daily

Generic: 10.00 to 28.00/10 mL

Acute otitis media with tympanostomy tubes

Ofloxacin

Adult: 5 drops, twice daily

10 to 14 days

Same as above

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§

Adult: 5 drops, three to four times daily

10 to 14 days

Same as above

Child: 4 drops, three to four times daily

Chronic suppurative otitis media [corrected]

Ofloxacin

Adult: 10 drops, twice daily

14 to 21 days

Same as above

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§

Not recommended

Same as above


*—Adult = 12 years and older; child = one to 11 years.

†—Costs are given for one-bottle supply. Estimated cost to pharmacist based on average wholesale prices, rounded to nearest dollar amount in Red Book. Montvale, NJ: Medical Economics Data, 2000.

‡—Generic not available.

§—Examples: Cortisporin, Colymycin, Pediotic.

TABLE 2   Recommended Treatment Regimens for Ear Infections

View Table

TABLE 2

Recommended Treatment Regimens for Ear Infections

Condition Drug Dosage Duration Cost†

Acute otitis externa

Ciprofloxacin-hydrocortisone (Cipro HC)

Adult: 3 drops, twice daily

7 to 10 days

$59.00 ‡/10 mL

Child: 3 drops, twice daily

Ofloxacin (Floxin)

Adult: 10 drops, twice daily

7 to 10 days

34.00 ‡/5 mL

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§ (Cortisporin)

Adult: 5 drops, three to four times daily

7 to 10 days

Brand: 42.00 (solution or suspension)/10 mL

Child: 4 drops, three to four times daily

Generic: 10.00 to 28.00/10 mL

Acute otitis media with tympanostomy tubes

Ofloxacin

Adult: 5 drops, twice daily

10 to 14 days

Same as above

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§

Adult: 5 drops, three to four times daily

10 to 14 days

Same as above

Child: 4 drops, three to four times daily

Chronic suppurative otitis media [corrected]

Ofloxacin

Adult: 10 drops, twice daily

14 to 21 days

Same as above

Child: 5 drops, twice daily

Polymyxin B-neomycin-hydrocortisone§

Not recommended

Same as above


*—Adult = 12 years and older; child = one to 11 years.

†—Costs are given for one-bottle supply. Estimated cost to pharmacist based on average wholesale prices, rounded to nearest dollar amount in Red Book. Montvale, NJ: Medical Economics Data, 2000.

‡—Generic not available.

§—Examples: Cortisporin, Colymycin, Pediotic.

Otitis Externa

Acute diffuse otitis externa (swimmer's ear) is an inflammatory infection of the external ear canal. Clinical presentation usually consists of pain, tenderness, itching and otorrhea. Epithelial breakdown from trauma and repeated exposure to moisture can predispose patients to this condition.3 Complications of acute otitis externa include ear canal stenosis, tympanic membrane perforation, auricular cellulitis and progression to necrotizing otitis externa.4 P. aeruginosa is the pathogen responsible in 40 to 60 percent of cases of otitis externa, and S. aureus causes 15 to 30 percent of cases. Fungi account for 10 percent of these infections in most settings, but the incidence increases in areas of high humidity.35

A recent, large study4 of acute otitis externa treatment patterns among subspecialists and generalists revealed that a combination topical product containing polymyxin B, neomycin (an aminoglycoside) and 1 percent hydrocortisone (Cortisporin) is the most frequently prescribed treatment for this condition. The results also showed that a significant number of physicians inappropriately prescribe oral antibiotics that are not active against P. aeruginosa and S. aureus, the two most common pathogens in acute otitis externa.

Many physicians erroneously believe that topical agents cannot be used in the ear when perforation of the tympanic membrane is noted or suspected.6,7 This belief persists despite evidence that topical antibiotics are the most effective treatment of uncomplicated otorrhea with known tympanic membrane peforation.710 This concern, however, is reinforced by package inserts that advise “care” when using topical aminoglycosides in the setting of tympanic membrane perforation. Care is advised because of potential ototoxicity of aminoglycosides.1,11 No case of ototoxicity has been attributed to the use of topical aminoglycosides in ears with intact tympanic membranes. In ears with perforated tympanic membranes, toxicity is rare and occurs almost exclusively following prolonged (more than 14 days) or repeated treatment.7,12 The risk of contact sensitization to topical neomycin may add to the concerns about treating acute otitis externa as well, although sensitization rarely occurs.13

In the past, some physicians circumvented concerns of toxicity and sensitization by using ophthalmic antibiotic solutions in the ear. Fluoroquinolones were often chosen because of their broad activity and lack of ototoxicity.3,4 The fluoroquinolone otic preparations represent a new treatment option for acute otitis externa within labeling guidelines. A randomized comparison5 of topical ofloxacin and polymyxin B-neomycin-hydrocortisone for the treatment of acute otitis externa in children and adults demonstrated equal efficacy.

A similar three-armed study6 that compared ciprofloxacin otic solution 0.2 percent, ciprofloxacin otic solution 0.2 percent with hydrocortisone 1.0 percent and polymyxin B-neomycin-hydrocortisone for the treatment of acute otitis externa also showed the medications to be equally effective. Time to end of pain was significantly shorter in patients treated with the ciprofloxacin-hydrocortisone combination or with polymyxin B-neomycin-hydrocortisone (3.8 days) than with ciprofloxacin alone (4.8 days). Outcome was otherwise the same in all groups. This study has been the only one to show benefit of a steroid-containing antibiotic when compared with the same agent without added steroid.

Otitis Media with Perforated Tympanic Membrane

The development of otitis media following the placement of a tympanostomy tube is common. Otorrhea is generally the presenting complaint. Pain and fever are uncommon. Acute otitis media with perforation occurs at least once in 21 to 50 percent of ears with patent tubes.1416 The chronic form of this condition, chronic suppurative otitis media without cholesteatoma, is defined as otorrhea lasting three months or more in an ear with a disrupted tympanic membrane; it develops in 3.6 percent of patients with a patent tympanostomy tube.8,15 These conditions also occur in ears with nonsurgical tympanic membrane perforation. Treatment is directed at resolution of symptoms and prevention of hearing loss.9

The microbiology of otitis media with otorrhea varies according to duration, patient age and season. The most common pathogens isolated from ears with acute otitis media and a perforated tympanic membrane in patients younger than three years are the same pathogens that cause otitis media in ears with an intact membrane: Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. This is especially true if the infection develops during the winter months. Acute otitis media with perforation occurring during summer months and in children older than six years is most commonly caused by P. aeruginosa or S. aureus.16,17 The most common pathogens isolated from ears with chronic suppurative otitis media are P. aeruginosa and S. aureus.8,1518

While chronic suppurative otitis media and acute otitis media with perforation represent forms of middle ear infection, topical treatment of these conditions has proved more effective than systemic therapy.79,17,18 The superior efficacy of topical treatment may result from improved delivery of a concentrated solution to the site of infection.6,15,18 High drug concentration has been documented in the middle ear of patients treated with topical antibiotic.19 Additionally, S. aureus and P. aeruginosa are thought to cause sufficient tissue destruction to impede delivery of systemically administered agents.8,9 Topical therapy generally causes fewer side effects than systemic treatment; furthermore, no oral agent active against P. aeruginosa is currently available in the United States for use in children.14,15

Ciprofloxacin and ofloxacin have been studied in the treatment of acute otitis media with perforation and chronic suppurative otitis media. In one study,14 topical ofloxacin was compared with oral amoxicillin-clavulanate (Augmentin) in the treatment of children with tympanostomy tubes and acute otitis media with perforation. Ofloxacin and amoxicillin-clavulanate were equally effective in patients in whom typical otitis media pathogens were cultured (S. pneumoniae, H. influenzae and M. catarrhalis). Ofloxacin was more effective than amoxicillin-clavulanate in eradicating P. aeruginosa and S. aureus infection (96 and 67 percent of cases, respectively). Side effects were more common in the amoxicillin-clavulanate group. Another study8 compared topical ciprofloxacin with topical tobramycin (Tobrex) and placebo in the treatment of chronic suppurative otitis media; rates of eradication were the same (66 percent) in the two antibiotic groups. Placebo was not effective.

TREATMENT SELECTION

Because P. aeruginosa and S. aureus are common pathogens in otorrhea, they must be considered at the time of treatment selection. Currently, no narrow-spectrum agent is available for the coverage of these two microbes. For the treatment of acute diffuse otitis externa, polymyxin B-neomycin-hydrocortisone combinations and fluoroquinolones are equally effective, and neither treatment carries known risk. The twice-daily dosing schedule of topical fluoroquinolones may improve compliance. When selecting treatment for acute otitis media with perforation, topical fluoroquinolones represent a good first-line option, although not clearly better than traditional topical therapy. For chronic suppurative otitis media topical fluoroquinolones likely represent the best choice because treatment is long, and repeated therapy is common.18

SIDE EFFECTS OF OTIC TOPICAL FLUOROQUINOLONES

Side effects of topical otic fluoroquinolones are rare. Many studies have reported no adverse reactions.15,17,19 In one study,6 headache, ear pain and pruritus necessitated premature discontinuation of treatment in less than 1 percent of subjects. Another study8 reported a 35 percent incidence of candidal overgrowth in patients treated with ciprofloxacin. Other studies have looked for fungal overgrowth and found none.14 To date, topical use of fluoroquinolones has not been shown to result in ototoxicity.8,10,15

The Eye

Bacterial infections of the eye occur in many forms. Hyperacute bacterial conjunctivitis in adults (usually caused by Neisseria gonorrhoeae) and neonatal conjunctivitis must be treated systemically.20 However, other ocular infections respond best to topical therapy. Ciprofloxacin 0.3 percent (Ciloxan) and ofloxacin 0.3 percent (Ocuflox) ophthalmic solutions have been approved for the treatment of bacterial keratitis and bacterial conjunctivitis.2

Bacterial Conjunctivitis

Acute bacterial conjunctivitis is often a self-limited condition. Worldwide, S. aureus and H. influenzae are the most commonly cultured pathogens from eyes with this condition, but dramatic regional variation exists. Despite a generally benign course, this infection is routinely treated with topical antibiotics to speed recovery and to minimize the risk of progression to corneal perforation.20,21 Treatment with topical erythromycin (Ilotycin), aminoglycosides such as gentamicin (Garamycin) or tobramycin, or bacitracin is usually sufficient for this condition.21,22

A recent study23 evaluated the use of topical ciprofloxacin for the treatment of culture-proven bacterial conjunctivitis. An eradication rate of 93.6 percent was achieved in the groups treated with a three-day course of topical ciprofloxacin or tobramycin. An eradication rate of 59.5 percent was seen in the placebo group. The author of the report concluded that ciprofloxacin offers effective treatment of bacterial conjunctivitis. Other authors emphasize that the use of fluoroquinolones should be reserved for the treatment of severe or refractory conjunctivitis and for more serious eye infections.21,22

Bacterial Keratitis

Bacterial keratitis, or bacterial corneal ulcer, has stimulated much interest in the ophthalmic use of topical fluoroquinolones. This vision-threatening infection, which is generally managed by ophthalmologists, requires microbiologic assessment (Gram stain and culture) and immediate, aggressive treatment. Even minor cases of bacterial keratitis can cause significant impairment when the visual axis is affected, and progression can be rapid.

Bacterial keratitis results from opportunistic infection of disrupted ocular epithelium (trauma, contact lenses, eyelid and tear disorders).20 Pathogens vary regionally and according to degree of industrialization. In the United States, the most common pathogens are S. aureus and Staphylococcus epidermidis. Children are prone to infection with H. influenzae and S. pneumoniae. Corneal ulcers in persons who wear contact lenses (especially extended-wear contact lenses) are often caused by P. aeruginosa infection.21

The consequences of inadequate treatment of bacterial keratitis are grave. For this reason, standard treatment in the United States has been double antibiotic therapy until culture results are available.21,24 The antibiotics are delivered topically to maximize drug concentration at the site of infection and to minimize toxicity.22 Ophthalmologists and pharmacists have routinely mixed and diluted intravenous antibiotic preparations to generate “fortified” topical solutions for this purpose.21,22,2527 In the past, standard treatment called for topical administration of cefazolin (Ancef) or vancomycin (Vancocin) for gram-positive coverage and gentamicin or tobramycin for the treatment of gram-negative organisms.21,2527

Topical fluoroquinolones represent a new option for the treatment of bacterial keratitis. Fluoroquinolones are active against the organisms most commonly found in bacterial keratitis. Studies that compared topical fluoroquinolones with dual fortified solutions for the treatment of keratitis have shown these regimens to be equally effective.21,2427 Use of a single agent simplifies treatment and improves the potential for compliance. Additionally, the use of a commercial preparation eliminates the risk of contamination and dilution errors that are inherent in extemporaneous preparation.24,25

SIDE EFFECTS OF OPHTHALMIC FLUOROQUINOLONES

Side effects that are unique to the eye must be considered when using fluoroquinolone ophthalmic solutions. Accumulation of ciprofloxacin crystals on the surface of the corneal ulcer has been noted. In all studies, precipitate resolved following treatment and in no cases did it necessitate premature discontinuation of treatment.21,24,27 Ofloxacin has not precipitated on the cornea.21,25,26 Other ocular side effects of topical fluoroquinolones include chemosis, conjunctival hyperemia, tearing and foreign-body sensation. These symptoms are generally mild, self-limited and do not require discontinuation of therapy.21,24,27 In comparative studies, fluoroquinolones caused less local discomfort than fortified solutions.2527

Fluoroquinolones are an effective and simplified initial treatment of bacterial keratitis. Resistance patterns must be followed closely to ensure continued adequacy of this drug class as empiric coverage for this serious condition. Fluoroquinolones should not be used as first-line therapy for uncomplicated bacterial conjunctivitis.

Safety

The safety of fluoroquinolones, especially for use in children, has been a concern since the drug class was introduced. Early studies of systemic fluoroquinolone administration to immature animals demonstrated changes in articular cartilage.1,28 For this reason, use of fluoroquinolones in children has been limited.15,17,18 However, many authors question this safety concern and the applicability of animal models to humans.5,15,17,19,29 Systemic ciprofloxacin has been given on a compassionate basis to more than 1,000 children with cystic fibrosis and resistant infections. Close monitoring has revealed no joint abnormalities in these children.11,29 This information, combined with studies demonstrating trivial or no systemic absorption of topically applied fluoroquinolones,15,19,24 has led many authors to conclude that topical fluoroquinolones are safe to use in children.5,15,17,19,29

Resistance

Resistance to fluoroquinolones develops from single-step mutation of DNA gyrase. Plasmid-mediated resistance has not been observed.1,28,30 Resistance occurs when the concentration of antibiotic in infected tissue falls below the minimum inhibitory concentration. Because topical application establishes and maintains drug concentrations at the site of infection that are well above the minimum inhibitory concentration, many authors conclude that resistance is not likely to develop following topical use.18,30,31 While this theory is appealing, it has not yet been proved. As use of these agents increases, resistance patterns should be followed closely to ensure continued efficacy.

The Authors

NANCY E. MORDEN, M.D., is an assistant professor of family medicine and community health at the University of Massachusetts Medical School in Worcester and a faculty physician at Family Health Center of Worcester. Dr. Morden graduated from Harvard Medical School, Boston, Mass., and completed a residency in family medicine at the University of Minnesota, Duluth.

ETHAN M. BERKE, M.D., is an assistant professor of family medicine and community health at the University of Massachusetts Medical School in Worcester and a faculty physician at Family Health Center of Worcester. Dr. Berke graduated from Albany Medical College, Albany, N.Y., and completed a residency in family medicine at the University of Washington, Seattle.

The authors thank Andy Dzaugis, M.L.S, UMass Memorial Medical Center Library Services, for assistance with medical informatics.

Address correspondence to Nancy E. Morden, M.D., Family Health Center of Worcester, 26 Queen St., Worcester, MA 01610 (e-mail: NancyMorden@compuserve.com). Reprints are not available from the authors.

REFERENCES

1. Goodman LS, Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman’s The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:1057–60.

2. Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics, 1999.

3. Halpern MT, Palmer CS, Seidlin M. Treatment patterns for otitis externa. J Am Board Fam Pract. 1999;12:1–7.

4. Bojrab DI, Bruderly T, Abdurlazzak Y. Otitis externa. Otolaryngol Clin North Am. 1996;29:761–82.

5. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otitis externa in children and adults. Arch Otolaryngol Head Neck Surg. 1997;123:1193–200[Published erratum appears in Arch Otolaryngol Head Neck Surg 1998;124:711]

6. Diagnosis and treatment of acute otitis externa. An interdisciplinary update. Ann Otol Rhinol Laryngol. 1999;176(suppl):1–23.

7. Marais J, Rutka JA. Ototoxicity and topical eardrops. Clin Otolaryngol. 1998;23:360–7.

8. Fradis M, Brodsky A, Ben-David J, Srugo I, Larboni J, Podoshin L. Chronic otitis media treated topically with ciprofloxacin or tobramycin. Arch Otolaryngol Head Neck Surg. 1997;123:1057–60.

9. Wright CG, Meyerhoff WL. Ototopical agents: efficacy or toxicity in humans. Ann Otol Rhinol Laryngol. 1988;97(suppl):30–2.

10. Kato M, Akahane K, Shimoda K. Lack of chondrotoxicity of ofloxacin otic solution on the auditory ossicle cartilages of juvenile guinea pigs. J Antimicrob Chemother. 1997;39:269–71.

11. Dohar JE, Alper CM, Rose EA, Doyle WJ, Casselbrant ML, Kenna MA, et al. Treatment of chronic suppurative otitis media with topical ciprofloxacin. Ann Otol Rhinol Laryngol. 1998;107:865–71.

12. Wong DL, Rutka JA. Do aminoglycoside otic preparations cause ototoxicity in the presence of tympanic membrane perforations?. Otolaryngol Head Neck Surg. 1997;116:404–10.

13. Leyden JJ, Kligman AM. Contact dermatitis to neomycin sulfate. JAMA. 1979;242:1276–8.

14. Goldblatt EL, Dohar J, Nozza RJ, Nielsen RW, Goldberg T, Sidman JD, et al. Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr Otorhinolaryngol. 1998;46:91–101.

15. Force RW, Hart MC, Plummer SA, Powell DA, Nahata MC. Topical ciprofloxacin for otorrhea after tympanostomy tube placement. Arch Otolaryngol Head Neck Surg. 1995;121:880–4.

16. Mandel EM, Casselbrant ML, Kurs-Lasky M. Acute otorrhea: bacteriology of a common complication of tympanostomy tubes. Ann Otol Rhinol Laryngol. 1994;103:713–8.

17. Wintermeyer SM, Hart MC, Nahata MC. Efficacy of ototopical ciprofloxacin in pediatric patients with otorrhea. Otolaryngol Head Neck Surg. 1997;116:450–3.

18. Agro AS, Garner ET, Wright JW 3d, Caballeros de Escobar I, Villeda B, Seidlin M. Clinical trial of ototopical ofloxacin for treatment of chronic suppurative otitis media. Clin Ther. 1998;20:744–59.

19. Ohyama M, Furuta S, Ueno K, Katsuda K, Nobori T, Kiyota R, et al. Ofloxacin otic solution in patients with otitis media: an analysis of drug concentrations. Arch Otolaryngol Head Neck Surg. 1999;125:337–40.

20. Limberg MB. A review of bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol. 1991;112:2S–9S.

21. Hammond RW, Edmondson W. Treatment of ocular bacterial infections: an update. J Am Optom Assoc. 1997;68:178–87.

22. Steinert RF. Current therapy for bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol. 1991;112:10S–14S.

23. Leibowitz HM. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis. Am J Ophthalmol. 1991;112:29S–33S.

24. Leibowitz HM. Clinical evaluation of ciprofloxacin 0.3% ophthalmic solution for treatment of bacterial keratitis. Am J Ophthalmol. 1991;112:34S–47S.

25. O'Brien TP, Maguire MG, Fink NE, Alfonso E, McDonnell P. Efficacy of ofloxacin vs. cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group. Arch Ophthalmol. 1995;113:1257–65.

26. Ofloxacin monotherapy for the primary treatment of microbial keratitis: a double-masked, randomized controlled trial with conventional dual therapy. The Ofloxacin Study Group. Ophthalmology. 1997;104:1902–9.

27. Hyndiuk RA, Eiferman RA, Caldwell DR, Rosenwasser GO, Santos CI, Katz HR, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycincefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group Ophthalmology. 1996;103:1854–62discussion 1862–3.

28. Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med. 1991;324:384–94.

29. Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 1991;19:289–96.

30. Cokingtin CD, Hyndiuk RA. Insights from experimental data on ciprofloxacin in the treatment of bacterial keratitis and ocular infections. Am J Ophthalmol. 1991;112:25S–28S.

31. Neu HC. Microbiologic aspects of fluoroquinolones. Am J Ophthalmol. 1991;112:15S–24S.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey.


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