Ciprofloxacin (EENT)

AHFS Class: Antibacterials (52:04.04)

View the associated AHFS monograph.

Brands: Ciloxan^® , Cipro^® HC Otic Drops , Ciprodex^®; also available generically.

Introduction

Fluoroquinolone antibacterial.^{1 2 5 6 8}

Uses

Bacterial Ophthalmic Infections

Ophthalmic ointment: Treatment of conjunctivitis caused by susceptible strains of Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, or viridans streptococci.¹¹⁹

Ophthalmic solution: Treatment of conjunctivitis caused by susceptible strains of S. aureus, S. epidermidis, S. pneumoniae, or H. influenzae.¹

Some clinicians suggest that quinolones be reserved principally for severe bacterial conjunctivitis because of potential development of quinolone resistance, and possibly, cost considerations.^{4 111 116}

Ophthalmic solution: Treatment of keratitis (corneal ulcer) caused by susceptible strains of Pseudomonas aeruginosa, Serratia marcescens, S. aureus , S. epidermidis, S. pneumoniae, or viridans streptococci.^{1 24 25 26 27 101 102 103 112}

Some clinicians suggest that single-agent topical fluoroquinolone therapy be considered for initial treatment in patients with equivocal gram stain results on diagnostic corneal smear, presence of >1 organism, contact lens associated keratitis (suspected to be caused by gram-negative bacteria), or in settings where culture and sensitivity tests are impossible or impractical.¹¹⁸

Bacterial Otic Infections

Ciprofloxacin-dexamethasone otic suspension: Treatment of acute otitis externa caused by susceptible strains of S. aureus or Ps. aeruginosa.¹²⁵

Ciprofloxacin-hydrocortisone otic suspension: Treatment of acute otitis externa caused by susceptible strains of S. aureus, Ps. aeruginosa, or Proteus mirabilis.¹²⁰

Ciprofloxacin-dexamethasone otic suspension: Treatment of acute otitis media caused by susceptible strains of S. aureus, S. pneumoniae, H. influenzae, Moraxella catarrhalis, or Ps. aeruginosa in patients with tympanostomy tubes.¹²⁵

Dosage and Administration

General

• Avoid contamination of container.^{1 116 119 120 125}

Administration

Apply topically to the eye as an ophthalmic ointment or solution.^{1 116 119}

Not for injection.^{1 119}

Remove contact lenses before administration of ophthalmic solution.¹

For treatment of bacterial keratitis, administer ophthalmic solution around the clock.^{25 115}

Administered as otic suspension in fixed combination with dexamethasone or hydrocortisone.^{120 125}

For otic use only.^{120 125} Not for ophthalmic use.^{120 125} Not for injection.^{120 125}

Discard unused portion after therapy is completed.^{120 125}

Prior to administration, warm container in hand for 1–2 minutes before use to avoid dizziness associated with instillation of cold solution into ear canal.^{120 125} Shake well before use.^{120 125}

To administer fixed combination otic suspensions of ciprofloxacin with dexamethasone or hydrocortisone for treatment of acute otitis externa, instill drops while patient lies with affected ear upward; maintain position for 30–60 seconds to facilitate penetration of drops into ear.^{120 125} Repeat for opposite ear if necessary.^{120 125}

To administer ciprofloxacin-dexamethasone otic suspension for treatment of acute otitis media in pediatric patients with tympanostomy tubes, instill drops while patient lies with affected ear upward.¹²⁵ Pump tragus 5 times by pushing inward to facilitate penetration of drops into middle ear; maintain position for 60 seconds.¹²⁵ Repeat for opposite ear if necessary.¹²⁵

Dosage

Available as ciprofloxacin hydrochloride; dosage expressed in terms of ciprofloxacin.^{1 108 119 120 125}

Ophthalmic Infections.

> Conjunctivitis (S. aureus, S. epidermidis, S. pneumoniae, H. influenzae, or viridans streptococci). Ophthalmic— Ointment: In children ≥2 years of age, apply approximately 1.27 cm (½ inch) ribbon into conjunctival sac of affected eye(s) 3 times daily for 2 days, then twice daily for next 5 days.¹¹⁹

> Conjunctivitis (S. aureus, S. epidermidis, S. pneumoniae, or H. influenzae). Ophthalmic— Solution: In children ≥1 year of age, 1 or 2 drops of 0.3% solution into conjunctival sac of affected eye(s) every 2 hours while awake for 2 days, then 1–2 drops every 4 hours while awake for next 5 days.^{1 3}

> Keratitis. Ophthalmic— Solution: In children ≥1 year of age, 2 drops of 0.3% solution into affected eye(s) every 15 minutes for 6 hours, followed by 2 drops every 30 minutes for remainder of first day.^{1 3 25} On the second day, instill 2 drops into affected eye(s) every hour, and on days 3–14, instill 2 drops every 4 hours.^{1 3} May continue longer than 14 days if corneal reepithelialization is not complete.^{1 3}

Otic Infections.

> Otitis Externa (S. aureus or Ps. aeruginosa). Otic— Ciprofloxacin-dexamethasone otic suspension: In children ≥6 months of age, 4 drops into canal of affected ear(s) twice daily for 7 days.¹²⁵

> Otitis Externa (S. aureus, Ps. aeruginosa, or P. mirabilis). Otic— Ciprofloxacin-hydrocortisone otic suspension: In children ≥1 year of age, 3 drops into canal of affected ear(s) twice daily for 7 days.¹²⁰

> Otitis Media (Acute). Otic— Ciprofloxacin-dexamethasone otic suspension: In children ≥6 months of age, 4 drops into affected ear(s) twice daily through tympanostomy tube for 7 days.¹²⁵

Ophthalmic Infections.

> Conjunctivitis (S. aureus, S. epidermidis, S. pneumoniae, H. influenzae, or viridans streptococci). Ophthalmic— Ointment: Apply approximately 1.27 cm (½ inch) ribbon into conjunctival sac of affected eye(s) 3 times daily for 2 days, then twice daily for next 5 days.¹¹⁹

> Conjunctivitis (S. aureus, S. epidermidis, S. pneumoniae, or H. influenzae). Ophthalmic— Solution: 1 or 2 drops of 0.3% solution into conjunctival sac of affected eye(s) every 2 hours while awake for 2 days, then 1–2 drops every 4 hours while awake for next 5 days.^{1 3}

> Keratitis. Ophthalmic— Solution: 2 drops of 0.3% solution into affected eye(s) every 15 minutes for 6 hours, followed by 2 drops every 30 minutes for remainder of first day.^{1 3} On the second day, instill 2 drops into affected eye(s) every hour, and on days 3–14, instill 2 drops every 4 hours.^{1 3} May continue longer than 14 days if corneal reepithelialization is not complete.^{1 3}

Otic Infections.

> Otitis Externa (S. aureus or Ps. aeruginosa). Otic— Ciprofloxacin-dexamethasone otic suspension: 4 drops into canal of affected ear(s) twice daily for 7 days.¹²⁵

> Otitis Externa (S. aureus, Ps. aeruginosa, or P. mirabilis). Otic— Ciprofloxacin-hydrocortisone otic suspension: 3 drops into canal of affected ear(s) twice daily for 7 days.¹²⁰

Cautions

Contraindications

• Known hypersensitivity to ciprofloxacin, other quinolones, or any ingredient in the formulation.^{1 119 120 125}

• Otic formulations contraindicated in patients with viral infections (i.e., herpes simplex, varicella) of external ear canal.^{120 125}

• Because commercially available ciprofloxacin-hydrocortisone fixed combination otic suspension is nonsterile, do not use if tympanic membrane is perforated.¹²⁰

Warnings/Precautions

Hypersensitivity. Serious, potentially fatal hypersensitivity reactions possible, occasionally after initial systemic dose.^{1 99 119 120 125} If allergic reaction occurs, discontinue ciprofloxacin and institute appropriate therapy if indicated.^{1 119 120 125}

Infectious Complications.. Possible overgrowth of nonsusceptible organisms (e.g., fungi) with prolonged use; if superinfection occurs, discontinue drug and institute other appropriate therapy.^{1 119 120 125}

Patient Monitoring. Ophthalmic: Careful monitoring, including slit-lamp biomicroscopy and fluorescein staining when appropriate, may be necessary.^{1 119}

Otic: If otic infection is not improved after 1 week of treatment, obtain cultures to guide further treatment.^{120 125} If otorrhea persists after full course of therapy with ciprofloxacin-dexamethasone otic suspension, or if ≥2 episodes of otorrhea occur within 6 months, further evaluate to exclude underlying condition (e.g., cholesteatoma, foreign body, tumor).¹²⁵

Ocular Effects. In patients with bacterial keratitis, white crystalline precipitate in superficial portion of corneal defect possible; onset generally is within 1–7 days after initiation of therapy (when solution is administered repeatedly at relatively short intervals) and resolution usually during later phase of continued therapy (when administration frequency is reduced).^{1 3} Precipitate does not appear to preclude continued use nor adversely affect visual outcome or clinical course of corneal ulcer.^{1 3 25 115 116 117}

Use of Fixed Combination. When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Pregnancy.

Category C.^{1 119 120 125}

Lactation. Distributed into milk after systemic administration; it is not known whether distributed into milk after topical application to the eye or ear.^{1 119 120 125}

Caution advised if ophthalmic solution or ointment is used in nursing women.^{1 119}

Discontinue nursing or ciprofloxacin-steroid otic suspension preparations.^{120 125}

Pediatric Use. Ophthalmic ointment: Safety and efficacy not established in children <2 years of age.¹¹⁹

Ophthalmic solution: Safety and efficacy not established in children <1 year of age.¹

Ciprofloxacin-dexamethasone otic suspension: Safety and efficacy not established in children <6 months of age, but there are no known safety concerns or differences in disease process to preclude use in children <6 months of age.¹²⁵

Ciprofloxacin-hydrocortisone otic suspension: Safety and efficacy not established in children <2 years of age, but there are no known safety concerns or differences in disease process to preclude use in children ≥1 year of age.¹²⁰

Common Adverse Effects

Ophthalmic: local burning or discomfort, lid margin crusting, crystals/scales, foreign body sensation, itching, conjunctival hyperemia, bad taste, keratopathy.^{1 119}

Otic: otic discomfort/pain/pruritus.^{120 125}

Interactions

No formal drug interaction studies to date.^{1 119 125} Since systemic absorption may occur following ophthalmic or otic^{1 119 125} administration, consider possible drug interactions such as those reported with systemic administration.^{1 119 125}

Pharmacokinetics

Absorption

Ophthalmic ointment: Extent of systemic absorption not evaluated, but mean maximal plasma ciprofloxacin concentrations expected to be <2.5 ng/mL, based on studies using 0.3% ophthalmic solution.¹¹⁹

Ophthalmic solution: Mean plasma ciprofloxacin concentrations generally averaged <2.5 ng/mL after topical application to each eye (1 drop of 0.3% ophthalmic solution every 2 hours while awake for 2 days, then every 4 hours while awake for 5 days).¹

Ciprofloxacin-dexamethasone otic suspension: Following a single bilateral 4-drop otic dose in pediatric patients after tympanostomy tube insertion, measurable plasma ciprofloxacin or dexamethasone concentrations were observed after 6 hours in 2 or 5 of 9 patients, respectively.¹²⁵ Peak plasma ciprofloxacin and dexamethasone concentrations were attained within 15 minutes to 2 hours.¹²⁵

Ciprofloxacin-hydrocortisone otic suspension: Systemic exposure to ciprofloxacin expected to be below assay quantitation limits (0.05 mg/mL) and maximum plasma hydrocortisone concentration is predicted to be within range of endogenous hydrocortisone.¹²⁰

Distribution

Distribution into human ocular tissues and fluids following topical ophthalmic or systemic administration not fully characterized to date.^{8 17}

Distributed into milk after systemic administration; it is not known whether distributed into milk after topical application to the eye or ear.^{1 119 120 125}

Stability

Storage

Ointment. 2–25°C.¹¹⁹

Solution. 2–25°C.¹ Protect from light.^{1 108}

Suspension. Ciprofloxacin-dexamethasone otic suspension: 15–30°C.¹²⁵ Avoid freezing; protect from light.¹²⁵

Ciprofloxacin-hydrocortisone otic suspension: <25°C.¹²⁰ Avoid freezing; protect from light.¹²⁰

Actions and Spectrum

• Inhibits DNA synthesis via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV).^{1 3 7 31 36 43 44 50 51 52 53 99}

• Usually bactericidal.^{1 3 6 37 40 41 42 43 44 45 47}

• Active in vitro against most gram-negative aerobic bacteria and many gram-positive aerobic bacteria,^{1 3 5 8 30 31 32 40 42 46 54} including penicillinase-producing, nonpenicillinase-producing, and oxacillin-resistant staphylococci;^{1 3 5 8 30 31 40 42 46 59 60} generally less active against gram-positive than gram-negative bacteria^{30 31 42 46 67 68 69} and less active in vitro on a weight basis against streptococci than against staphylococci.^{3 5 6 8 40 42 64 65 66 67 68} Most strains of Ps. cepacia, some strains of Ps. maltophilia, and most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile, are resistant.^{1 3} Inactive against fungi and viruses.^{1 3 5 6 8}

Advice to Patients

• Importance of discontinuing drug and informing clinician at first sign of rash or other sign of hypersensitivity.^{1 99 116 119 120 125}

• Importance of learning and adhering to proper administration techniques to avoid contamination of the product.^{1 116 119 120 125}

• Importance of not wearing contact lenses in presence of signs and symptoms of ophthalmic bacterial infections.¹¹⁹

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.^{1 119 120 125}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 119 120 125}

• Importance of informing patients of other important precautionary information. (See Cautions.)^{1 119 120 125}

Preparations

Ciprofloxacin Hydrochloride

Routes	Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Ointment	0.3% (of ciprofloxacin)	Ciloxan®	Alcon
	Solution	0.3% (of ciprofloxacin)	Ciloxan® (with benzalkonium chloride)	Alcon
			Ciprofloxacin Ophthalmic Solution (with benzalkonium chloride)	Bausch & Lomb, Hi-Tech, Novex

Ciprofloxacin Hydrochloride Combinations

Routes	Forms	Strengths	Brand Names	Manufacturer
Otic	Suspension	0.2% (of ciprofloxacin) with Hydrocortisone 1%	Cipro® HC Otic Drops (with benzyl alcohol 0.9%)	Alcon
		0.3% (of ciprofloxacin) with Dexamethasone 0.1%	Ciprodex® (with benzalkonium chloride)	Alcon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. For the most current and up-to-date pricing information, please visit www.drugstore.com.

Ciloxan 0.3% Solution (ALCON VISION): 5/$61.99 or 15/$169.97

Cipro HC 0.2-1% Suspension (ALCON VISION): 10/$99.99 or 30/$279.98

Ciprodex 0.3-0.1% Suspension (ALCON VISION): 7/$102.06 or 22/$285.78

Ciprofloxacin HCl 0.3% Solution (FALCON PHARMACEUTICALS): 10/$59.99 or 30/$159.96

Ciprofloxacin HCl 0.3% Solution (FALCON PHARMACEUTICALS): 2/$19.99 or 7/$45.97

Ciprofloxacin HCl 0.3% Solution (FALCON PHARMACEUTICALS): 5/$29.99 or 15/$79.96

Selected Revisions July 2006, © Copyright, May 2004, American Society of Health-System Pharmacists, Inc. 7272 Wisconsin Avenue, Bethesda, MD 20814.

References

1. Alcon Laboratories. Ciloxan^® (ciprofloxacin hydrochloride) ophthalmic solution prescribing information. Fort Worth, TX; 1999 Dec.

2. Alcon Laboratories. Product information form for American hospital formulary service: Ciloxan^® (ciprofloxacin HCl) 0.3% as base sterile ophthalmic solution. Fort Worth, TX: 1991 Mar.

3. Alcon Laboratories. Ciloxan^® product monograph. Ciloxan^® (ciprofloxacin HCl) 0.3% as base sterile ophthalmic solution. Fort Worth, TX: 1991 Apr.

4. Anon. Ophthalmic ciprofloxacin. Med Lett Drugs Ther. 1991; 33:52-3.

5. Campoli-Richards DM, Monk JP, Price A et al. Ciprofloxacin: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1988; 35:373-447.

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

7. Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis. 2000; 31(Suppl 2):S24-8.

8. Vance-Bryan K, Guay DRP, Rotschafer JC. Clinical pharmacokinetics of ciprofloxacin. Clin Pharmacokinet. 1990; 19:434-61.

9. Reidy JJ, Hobden JA, Hill JM et al. The efficacy of topical ciprofloxacin and norfloxacin in the treatment of experimental pseudomonas keratitis. Cornea. 1991; 10:25-8.

10. McDermott ML, Tran TD, Cowden JW et al. Corneal stromal penetration of topical ciprofloxacin in humans. Ophthalmology. 1993; 100:197-200.

11. O’Brien TP, Sawusch MR, Dick JD et al. Topical ciprofloxacin treatment of pseudomonas keratitis in rabbits. Arch Ophthalmol. 1988; 106:1444-6.

12. Rootman DS, Savage P, Hasany SM et al. Toxicity and pharmacokinetics of intravitreally injected ciprofloxacin in rabbit eyes. Can J Ophthalmol. 1992; 27:277-82.

13. Behrens-Baumann W, Martell J. Ciprofloxacin concentration in the rabbit aqueous humor and vitreous following intravenous and subconjuctival administration. Infection. 1988; 16:54-7.

14. Skoutelis AT, Gartaganis SP, Chrysanthopoulos CJ et al. Aqueous humor penetration of ciprofloxacin in the human eye. Arch Ophthalmol. 1988; 106:404-5.

15. Bron A, Talon D, Cellier T et al. La ciprofloxacine: pénétration intra-camérulaire chez l’homme. Bull Soc Opht France. 1990; 40:805-11.

16. Sweeney G, Fern AI, Lindsay G et al. Penetration of ciprofloxacin into the aqueous humour of the uninflamed human eye after oral administration. Br Soc Antimicrob Chemother. 1990; 26:99-105.

17. Barza M. Use of quinolones for treatment of ear and eye infections. Eur J Clin Microbiol Infect Dis. 1991; 10:296-303.

18. El Baba FZ, Trousdale MD, Gauderman WJ et al. Intravitreal penetration of oral ciprofloxacin in humans. Ophthalmology. 1992; 99:483-6.

19. Gardner DK, Gabbe SG, Harter C. Simultaneous concentrations of ciprofloxacin in breast milk and in serum in mother and breast-fed infant. Clin Pharm. 1992; 11: 352-4.

20. Cover DL, Mueller BA. Ciprofloxacin penetration into human breast milk: a case report. DICP. 1990; 24:703-4.

21. Giamarellou H, Kanellas D, Kavouklis E et al. Comparative pharmacokinetics of ciprofloxacin, ofloxacin and pefloxacin in human aqueous humour. Eur J Clin Microbiol Infect Dis. 1993; 12:293-7.

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

23. McDonnell PJ, Green WR. Conjunctivitis. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practices of infectious diseases. 3rd ed. New York: Churchill Livingstone; 1990:975-82.

24. Steinert RF. Current therapy for bacterial keratitis and bacterial conjunctivitis. Am J Ophthalmol. 1991; 112:10-4S.

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

26. Cokingtin CD, Hyndiuk RA. Insights from experimental data on ciprofloxacin in the treatment of bacterial keratitis and ocular infections. Am J Ophthalmol. 1991; 112:25-8S.

27. Insler MS, Fish LA, Silbernagel J et al. Successful treatment of methicillin-resistant Staphylococcus aureus keratitis with topical ciprofloxacin. Ophthalmology. 1991; 98:1690-2.

28. Sossi N, Feldman RM, Feldman ST et al. Mycobacterium gordonae keratitis after penetrating keratoplasty. Arch Ophthalmol. 1991; 109:1064-5.

29. Hwang DG, Biswell R. Ciprofloxacin therapy of Mycobacterium chelonae keratitis. Am J Ophthalmol. 1993; 115:114-5.

30. Nix DE, Devito JM. Ciprofloxacin and norfloxacin, two fluoroquinolone antimicrobials. Clin Pharm. 1987; 6:105-17.

31. Wolfson JS, Hooper DC. The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother. 1985; 28:581-6.

32. Janknegt R. Fluorinated quinolones: a review of their mode of action, antimicrobial activity, pharmacokinetics and clinical efficacy. Pharm Weekbl [Sci]. 1986; 8:1-21.

33. Verbist L. Quinolones: pharmacology. Pharm Weekbl [Sci]. 1986; 8:22-5.

34. Neuman M. Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin Pharmacokinet. 1988; 14:96-121.

35. Jack DB. Recent advances in pharmaceutical chemistry: the 4-quinolone antibiotics. J Clin Hosp Pharm. 1986; 11:75-93.

36. Bergan T. Quinolones. In: Peterson PK, Verhoef J, eds. The antimicrobial agents annual/1. Amsterdam: Elsevier Science Publishers BV; 1986: 164-78.

37. Miles. Cipro^® tablets (ciprofloxacin HCl) product monograph. West Haven, CT: 1987.

38. Crumplin GC. Aspects of chemistry in the development of the 4-quinolone antibacterial agents. Rev Infect Dis. 1988; 10(Suppl 1):S2-9.

39. Miles Inc, West Haven, CT: Personal communication.

40. Kayser FH, Novak J. In vitro activity of ciprofloxacin against gram-positive bacteria: an overview. Am J Med. 1987; 82(Suppl 4A):33-9.

41. Lagast H, Husson M, Klastersky J. Bactericidal activity of ciprofloxacin in serum and urine against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus faecalis. J Antimicrob Chemother. 1985; 16:341-7.

42. Eliopoulos GM, Gardella A, Moellering RC. In vitro activity of ciprofloxacin, a new carboxyquinoline antimicrobial agent. Antimicrob Agents Chemother. 1984; 25:331-5.

43. Smith JT. The mode of action of 4-quinolones and possible mechanisms of resistance. J Antimicrob Chemother. 1986; 18(Suppl D):21-9.

44. Hooper DC, Wolfson JS, Ng EY et al. Mechanisms of action of and resistance to ciprofloxacin. Am J Med. 1987; 82(Suppl 4A):12-20.

45. Reeves DS, Bywater MJ, Holt HA et al. In vitro studies with ciprofloxacin, a new 4-quinolone compound. J Antimicrob Chemother. 1984; 13:333-6.

46. Terp DK, Rybak MJ. Ciprofloxacin. Drug Intell Clin Pharm. 1987; 21:568-74.

47. Standiford HC, Drusano GL, Forrest A et al. Bactericidal activity of ciprofloxacin compared with that of cefotaxime in normal volunteers. Antimicrob Agents Chemother. 1987; 31:1177-82.

48. Thadepalli H, Bansal MB, Rao B et al. Ciprofloxacin: in vitro, experimental, and clinical evaluation. Rev Infect Dis. 1988; 10:505-15.

49. Diver JM, Wise R. Morphological and biochemical changes in Escherichia coli after exposure to ciprofloxacin. J Antimicrob Chemother. 1986; 18(Suppl D):31-41.

50. Domagala JM, Hanna LD, Heifetz CL et al. New structure-activity relationships of the quinolone antibacterials using the target enzyme: the development and application of a DNA gyrase assay. J Med Chem. 1986; 29:394-404.

51. Zweerink MM, Edison A. Inhibition of Micrococcus luteus DNA gyrase by norfloxacin and 10 other quinolone carboxylic acids. Antimicrob Agents Chemother. 1986; 29:598-601.

52. Hussy P, Maass G, Tummler B et al. Effect of 4-quinolones and novobiocin on calf thymus DNA polymerase α-primase complex, topoisomerases I and II, and growth of mammalian lymphoblasts. Antimicrob Agents Chemother. 1986; 29:1073-8.

53. Bearden DT, Danziger LH. Mechanism of Action of and resistance to quinolones. Pharmacotherapy. 2001; 21:224S-32S

54. Sanders CC. Ciprofloxacin: in vitro activity, mechanism of action, and resistance. Rev Infect Dis. 1988; 10:516-27.

59. Smith SM, Eng RH, Berman E. The effect of ciprofloxacin on methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 1986; 17:287-95.

60. Smith SM, Eng RH. Activity of ciprofloxacin against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1985; 688-91. (IDIS 200502)

61. King A, Shannon K, Phillips I. The in-vitro activity of ciprofloxacin compared with that of norfloxacin and nalidixic acid. J Antimicrob Chemother. 1984; 13:325-31.

62. Barry AL, Jones RN. In vitro activity of ciprofloxacin against gram-positive cocci. Am J Med. 1987; 82(Suppl 4A):27-32.

63. Chau PY, Leung YK, Ng WW. Comparative in vitro antibacterial activity of ofloxacin and ciprofloxacin against some selected gram-positive and gram-negative isolates. Infection. 1986; 14(Suppl 4):S237-9.

64. Mandell W, Neu HC. In vitro activity of CI-934, a new quinolone, compared with that of other quinolones and other antimicrobial agents. Antimicrob Agents Chemother. 1986; 29:852-7.

65. Chin NX, Brittain DC, Neu HC. In vitro activity of Ro 23-6240, a new fluorinated 4-quinolone. Antimicrob Agents Chemother. 1986; 29:675-80.

66. Fass RJ. In vitro activity of ciprofloxacin (Bay o 9867). Antimicrob Agents Chemother. 1983; 24:568-74.

67. Chin NX, Neu HC. Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother. 1984; 25:319-26.

68. King A, Phillips I. The comparative in-vitro activity of eight newer quinolones and nalidixic acid. J Antimicrob Chemother. 1986; 18(Suppl D):1-20.

69. Barry AL, Jones RN, Thornsberry C et al. Antibacterial activities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid. Antimicrob Agents Chemother. 1984; 25:633-7.

70. Young LS, Berlin OG, Inderlied CB. Activity of ciprofloxacin and other fluorinated quinolones against mycobacteria. Am J Med. 1987; 82(Suppl 4A):23-6.

71. Gay JD, DeYoung DR, Roberts GD. In vitro activities of norfloxacin and ciprofloxacin against Mycobacterium tuberculosis, M. avium complex, M. chelonei, M. fortuitum, and M. kansasii. Antimicrob Agents Chemother. 1984; 26:94-6.

72. Fenlon CH, Cynamon MH. Comparative in vitro activities of ciprofloxacin and other 4-quinolones against Mycobacterium tuberculosis and Mycobacterium intracellulare. Antimicrob Agents Chemother. 1986; 29:386-8.

73. Aznar J, Caballero MC, Loxano MC et al. Activities of new quinoline derivatives against genital pathogens. Antimicrob Agents Chemother. 1985; 27:76-8.

74. Ridgway GL, Mumtaz G, Gabriel FG et al. The activity of ciprofloxacin and other 4-quinolones against Chlamydia trachomatis and mycoplasmas in vitro. Eur J Clin Microbiol. 1984; 3:344-6.

75. Heppleston C, Richmond S, Bailey J. Antichlamydial activity of quinolone carboxylic acids. J Antimicrob Chemother. 1985; 15:645-7.

76. Sanders CC, Sanders WE, Goering RV et al. Selection of multiple antibiotic resistance by quinolones, β-lactams, and aminoglycosides with special reference to cross-resistance between unrelated drug classes. Antimicrob Agents Chemother. 1984; 26:797-801.

77. Barry AL, Jones RN. Cross-resistance among cinoxacin, ciprofloxacin, DJ-6783, enoxacin, nalidixic acid, norfloxacin, and oxolinic acid after in vitro selection of resistant populations. Antimicrob Agents Chemother. 1984; 25:775-7.

78. Kaatz GW, Seo SM. Mechanism of ciprofloxacin resistance in Pseudomonas aeruginosa. J Infect Dis. 1988; 158:537-41.

79. Follath F, Bindschedler M, Wenk M et al. Use of ciprofloxacin in the treatment of Pseudomonas aeruginosa infections. Eur J Clin Microbiol. 1986; 5:236-40.

80. Scully BE, Parry MF, Neu HC et al. Oral ciprofloxacin therapy of infections due to Pseudomonas aeruginosa. Lancet. 1986; 1:819-22.

81. Greenberg RN, Kennedy DJ, Reilly PM et al. Treatment of bone, joint, and soft-tissue infections with oral ciprofloxacin. Antimicrob Agents Chemother. 1987; 31:151-5.

82. Piercy EA, Barbaro D, Luby JP et al. Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother. 1989; 33:128-30.

83. Smith SM, Eng RH, Tecson-Tumang F. Ciprofloxacin therapy for methicillin-resistant Staphylococcus aureus infections or colonizations. Antimicrob Agents Chemother. 1989; 33:181-4.

87. Tartaglione TA, Raffalovich AC, Poynor WJ et al. Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses. Antimicrob Agents Chemother. 1986; 29:62-6.

88. Gonzalez MA, Uribe F, Moisen SD et al. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother. 1984; 26:741-4.

89. Hoffler J, Dalhoff A, Gau W et al. Dose- and sex-independent disposition of ciprofloxacin. Eur J Clin Microbiol. 1984; 3:363-6.

90. Wingender W, Graege KH, Gau W et al. Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers. Eur J Clin Microbiol. 1984; 3:355-9.

91. Gasser TC, Ebert SC, Graversen PH et al. Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function. Antimicrob Agents Chemother. 1987; 31:709-12.

92. Hoffken G, Lode H, Prinzing C et al. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother. 1985; 27:375-9.

93. Bergan T, Engeset A, Olszewski W. Does serum protein binding inhibit tissue penetration of antibiotics? Rev Infect Dis. 1987; 9:713-8. (IDIS 232250)

94. Giamarellou H, Kolokythas E, Petrikkos G et al. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med. 1989; 87(Suppl 5A):49-51S.

95. Zeiler HJ, Petersen U, Ploschke HJ. Antibacterial activity of the metabolites of ciprofloxacin and its significance in the bioassay. Arzneimittelforschung. 1987; 37:131-4.

96. Tanimura H, Tominaga S, Rai F et al. Transfer of ciprofloxacin to bile and determination of biliary metabolites in humans. Arzneimittelforschung. 1986; 26:1417-20.

97. Parry MF, Smego DA, Digiovanni MA. Hepatobiliary kinetics and excretion of ciprofloxacin. Antimicrob Agents Chemother. 1988; 32:982-5.

98. Drusano GL. An overview of the pharmacology of intravenously administered ciprofloxacin. Am J Med. 1987; 82(Suppl 4A):339-45.

99. Bayer. Cipro^® I.V. (ciprofloxacin) for intravenous infusion prescribing information. West Haven, CT; 2002 Jun.

100. Christ W, Lehnert T, Ulbrich B. Specific toxicologic aspects of the quinolones. Rev Infect Dis. 1988; 10(Suppl 1):S141-6.

101. Snyder ME, Katz HR. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol. 1992; 114:336-8.

102. Eiferman RA, Forgey DR, Snyder J. The successful treatment of bacterial corneal ulcers with ciprofloxacin. Invest Ophthalmol Vis Sci. 1991; (Suppl 32):1171.

103. Abrams DA, Sarfarazi FA, Parks DJ et al. Topical ciprofloxacin versus conventional antibiotic therapy in the treatment of ulcerative keratitis. Invest Ophthalmol Vis Sci. 1991; (Suppl 32):1171.

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

105. Stevens SX, Fouraker BD, Jensen HG. Intraocular safety of ciprofloxacin. Arch Ophthalmol. 1991; 109:1737-43.

107. Cutarelli PE, Lass JH, Lazarus HM et al. Topical fluoroquinolones: antimicrobial activity and in vitro corneal epithelial toxicity. Curr Eye Res. 1991; 10:557-63. Abstract.

108. The United States pharmacopeia, 22nd rev, and The national formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1990(Suppl 5):2596-7, (Suppl 7):3031.

110. Hobden JA, Reidy JJ, O’Callaghan RJ et al. Quinolones in collagen shields to treat aminoglycoside-resistant pseudomonal keratitis. Invest Ophthalmol Vis Sci. 1990; 31: 2241-3.

111. Yolton DP. New antibacterial drugs for topical ophthalmic use. Optom Clin. 1992; 2:59-72.

112. Parks DJ, Abrams DA, Sarfarazi FA et al. Comparison of topical ciprofloxacin to conventional antibiotic therapy in the treatment of ulcerative keratitis. Am J Ophthalmol. 1993; 115:471-7.

114. Lesar TS, Fiscella RG. Antimicrobial drug delivery to the eye. Drug Intell Clin Pharm. 1985; 19:642-54.

115. Alcon Laboratories, Fort Worth, TX: Personal communication.

116. Reviewers’ comments (personal observations).

117. Wilhelmus KR, Hyndiuk RA, Caldwell DR et al. 0.3% ciprofloxacin ophthalmic ointment in the treatment of bacterial keratitis. Arch Ophthalmol. 1993; 111:1210-8.

118. O’Brien TP, Maguire MG, Fink NE et al et al. 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.

119. Alcon Laboratories. Ciloxan^® (ciprofloxacin hydrochloride) ophthalmic ointment prescribing information. Fort Worth, TX; 2000 Sep.

120. Alcon Laboratories. Cipro^® HC Otic (ciprofloxacin hydrochloride and hydrocortisone) otic suspension prescribing information; undated. From Alcon website (http://www.alconlabs.com.) Accessed 2006 Apr 3.

121. Hu FR, Luh KT. Topical ciprofloxacin for treating nontuberculous mycobacterial keratitis. Ophthalmology. 1998; 105:269-72.

122. Alcon Laboratories, Fort Worth, TX: Personal communication.

123. Johnson MP, Ramphal R. Malignant external otitis: report on therapy with ceftazidime and review of therapy and prognosis. Clin Infect Dis. 1990; 12:173-80.

124. Hern JD, Ghufoor K, Jayaraj SM et al. ENT manifestations of Pseudomonas aeruginosa infection in HIV and AIDS. Int J Clin Pract. 1998; 52:141-4.

125. Alcon Laboratories. Ciprodex^® (ciprofloxacin hydrochloride and dexamethasone) otic suspension prescribing information. Fort Worth, TX; 2003 Jul 17.