Ciprofloxacin Hydrochloride

AHFS Class: Antibacterials (52:04.04)

ATC Class: J01MA02
VA Class: OP210
Molecular Formula: C₁₇H₁₈FN₃O₃•ClH•H₂O

View the associated Essentials monograph.

Introduction

Ciprofloxacin is a fluoroquinolone anti-infective agent.^{1 2 5 6 8}

Uses

Ciprofloxacin ophthalmic solution is used in the treatment of keratitis and conjunctivitis caused by susceptible bacteria.^{1 24 25 26 27 102 103 104 110 111 112} Ciprofloxacin ophthalmic ointment is used in the treatment of conjunctivitis caused by susceptible bacteria.¹¹⁹

Ciprofloxacin in fixed combination with hydrocortisone is applied to the ear canal for the treatment of acute otitis externa caused by susceptible bacteria.¹²⁰

Ciprofloxacin in fixed combination with dexamethasone is instilled into the ear for the treatment of acute otitis media caused by susceptible bacteria in pediatric patients with tympanostomy tubes.¹²⁵ Ciprofloxacin in fixed combination with dexamethasone also is applied to the ear canal for the treatment of acute otitis externa caused by susceptible bacteria.¹²⁵

Ophthalmic Infections

Keratitis

Ciprofloxacin ophthalmic solution is used in the treatment of keratitis (corneal ulcer) caused by susceptible Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, or viridans streptococci.^{1 24 25 26 27 101 102 103 112} Results of comparative studies in patients receiving a fluoroquinolone ophthalmic solution (e.g., ciprofloxacin, ofloxacin) for bacterial keratitis suggests that such therapy produces results comparable to those observed with more complex treatment regimens (e.g., a topical “fortified” aminoglycoside used in conjunction with a topical cephalosporin).^{24 25 26 27 111 115 116 118 127 128 129 130 131 132}

In a multicenter study, treatment with ciprofloxacin 0.3% ophthalmic solution in the recommended dosage resulted in clinical cure (i.e., complete reepithelization, no evidence of bacterial infection, absence of symptoms) in 76% of patients with bacterial keratitis; complete reepithelization with no evidence of bacterial infection occurred in 92% of patients.^{1 25} In this study, success of ciprofloxacin therapy did not depend on the severity (initial size) of the corneal ulcer, and such therapy also was effective in most patients with bacterial keratitis that did not respond to treatment with other ophthalmic anti-infectives.²⁵ Ciprofloxacin ophthalmic solution also has been used with variable success with other systemic and/or ophthalmic anti-infectives in the management of keratitis caused by opportunistic mycobacteria† (e.g., Mycobacterium gordonae, M. fortuitum, M. chelonae).^{28 29 121} Treatment with more than one anti-infective agent may be needed for the treatment of keratitis caused by such organisms.¹²⁷

Ciprofloxacin also has been used successfully as a 0.3% ophthalmic ointment† in patients with bacterial keratitis.¹¹⁷

Conjunctivitis

Ciprofloxacin ophthalmic solution is used in the treatment of conjunctivitis caused by susceptible Staphylococcus aureus , S. epidermidis, Streptococcus pneumoniae, or Haemophilus influenzae.¹

Ciprofloxacin ophthalmic ointment is used in the treatment of conjunctivitis caused by susceptible S. aureus, S. epidermidis, S. pneumoniae, viridans streptococci, or H. influenzae.¹¹⁹

Although most cases of acute bacterial conjunctivitis improve without anti-infective therapy, topical application of anti-infectives may shorten the infectious process.^{3 22 23 104 126} In addition, topical application of anti-infectives may reduce recurrence rate and morbidity associated with bacterial conjunctivitis.¹²⁶

Results from a placebo-controlled and a comparative study indicate that ciprofloxacin 0.3% ophthalmic solution is more effective than placebo (e.g., vehicle) and as effective as tobramycin 0.3% ophthalmic solution in patients with acute bacterial conjunctivitis caused by various gram-positive and -negative bacteria.¹⁰⁴ In these studies, topical application of ciprofloxacin 0.3% ophthalmic solution to the eye for 3–7 days was effective in reducing or eradicating all conjunctival pathogens in approximately 70–95%^{3 104 111} of patients with acute bacterial conjunctivitis but produced clinical cures less frequently.^{1 3}

In clinical studies, treatment with ciprofloxacin ophthalmic ointment was associated with clinical cure in approximately 75% of patients with bacterial conjunctivitis and positive conjunctival cultures, and the presumed pathogens were eradicated by day 7 in approximately 80% of patients.¹¹⁹

Otic Infections

Otitis Externa

Ciprofloxacin hydrochloride and hydrocortisone otic suspension is applied to the ear canal for the treatment of acute bacterial otitis externa caused by susceptible strains of S. aureus, Ps. aeruginosa, or Proteus mirabilis.¹²⁰ Because commercially available ciprofloxacin and hydrocortisone otic suspension is nonsterile, it should not be used if the tympanic membrane is perforated.¹²⁰

Ciprofloxacin hydrochloride and dexamethasone otic suspension is applied to the external ear canal for the treatment of acute otitis externa caused by susceptible strains of S. aureus or Ps. aeruginosa. The commercially available formulation is a sterile suspension.¹²⁵

Although acute bacterial otitis externa localized in the external auditory canal may be effectively treated using topical anti-infectives (e.g., ciprofloxacin otic suspension, ofloxacin otic solution), malignant otitis externa is an invasive, potentially life-threatening infection, especially in immunocompromised patients such as those with diabetes mellitus or human immunodeficiency virus (HIV) infection, and requires prompt diagnosis and long-term treatment with parenteral anti-infectives (e.g., ceftazidime and/or ciprofloxacin).^{123 124}

Acute Otitis Media

Ciprofloxacin hydrochloride and dexamethasone otic suspension is applied to the ear canal and middle ear for the treatment of acute otitis media caused by susceptible strains of S. aureus, S. pneumoniae, H. influenzae, Moraxella catarrhalis, or Ps. aeruginosa in pediatric patients’ tympanostomy tubes.¹²⁵

Systemic Uses

For systemic uses of ciprofloxacin, see Ciprofloxacin 8:12.18.

Dosage and Administration

Administration

Ciprofloxacin hydrochloride is applied topically to the eye as an ophthalmic solution or ointment.^{1 116 119} Ciprofloxacin in fixed combination with hydrocortisone or dexamethasone is applied topically to the ear canal as a suspension.^{120 125} Care should be taken to avoid contamination of the container.^{116 119 120 125}

While intravitreal injection of extemporaneously prepared ciprofloxacin solutions has been studied in animals,^{12 105} commercially available ciprofloxacin hydrochloride ophthalmic solution is not for injection and should not be injected subconjunctivally or directly into the anterior chamber of the eye.¹ Otic suspensions containing ciprofloxacin are not for ophthalmic use or for injection.^{120 125}

Prior to administration, ciprofloxacin hydrochloride and hydrocortisone or dexamethasone otic suspension should be warmed by holding the bottle in the hand for 1–2 minutes since instillation of a cold solution into the ear canal could precipitate dizziness.^{120 125} In addition, the suspension should be shaken well prior to use.^{120 125}

Contact lenses should be removed prior to administration of ciprofloxacin ophthalmic solution.¹ In addition, patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.¹¹⁹

Dosage

Dosage of ciprofloxacin hydrochloride is expressed in terms of ciprofloxacin.^{1 108 119 120 125}

Ophthalmic Infections

Keratitis. For the treatment of bacterial keratitis, the manufacturer recommends that ciprofloxacin ophthalmic solution be administered around the clock.^{25 115} The dosage of ciprofloxacin recommended by the manufacturer for the treatment of this infection is 2 drops of a 0.3% solution in the affected eye(s) every 15 minutes for 6 hours, followed by 2 drops in the affected eye(s) every 30 minutes for the remainder of the first day of treatment.^{1 3 25} On the second day of therapy, 2 drops of the solution may be instilled in the affected eye(s) every hour, and on days 3–14, this dose may be instilled in the affected eye(s) every 4 hours.^{1 3} Treatment may be continued for longer than 14 days if corneal reepithelialization is not complete;^{1 3} in clinical trials in patients with bacterial keratitis, the duration of ciprofloxacin therapy reportedly averaged about 3 weeks.³

Conjunctivitis. For the treatment of bacterial conjunctivitis, the dosage of ciprofloxacin recommended by the manufacturer is 1 or 2 drops of a 0.3% solution in the affected eye(s) every 2 hours while awake for 2 days, then 1–2 drops every 4 hours while awake for the next 5 days.^{1 3}

For the treatment of bacterial conjunctivitis, a ribbon of ciprofloxacin ophthalmic ointment approximately 1.27 cm (½ inch) in length should be placed in the lower conjunctival sac of the infected eye(s) 3 times daily for 2 days, then 2 times daily for the next 5 days.¹¹⁹

Otic Infections

Otitis Externa. For the treatment of acute bacterial otitis externa, 3 drops of ciprofloxacin hydrochloride and hydrocortisone otic suspension are instilled into the canal of the affected ear(s) twice daily for 7 days.¹²⁰ Adults and children 1 year of age or older should lie with the affected ear upward and the suspension should be instilled into the ear canal; this position should be maintained for 30–60 seconds to facilitate penetration of the drops into the ear.¹²⁰ This procedure should be repeated if necessary for the opposite ear.¹²⁰

For the treatment of acute bacterial otitis externa in adults and pediatric patients 6 months of age and older, 4 drops of ciprofloxacin hydrochloride and dexamethasone otic suspension are instilled into the canal of the affected ear(s) twice daily for 7 days.¹²⁵ The patient should lie with the affected ear upward and the suspension should be instilled into the ear canal; this position should be maintained for 60 seconds to facilitate penetration of the drops into the ear.¹²⁵ This procedure should be repeated if necessary for the opposite ear.¹²⁵

Acute Otitis Media. For the treatment of acute otitis media in pediatric patients 6 months of age and older, ciprofloxacin hydrochloride and dexamethasone otic suspension should be administered through the tympanostomy tube by having the patient lie with the affected ear upward and then instilling 4 drops of the suspension into the ear canal twice daily for 7 days.¹²⁵ The tragus of the ear then should be pressed gently in a pumping action 5 times to allow the suspension to pass through the tympanostomy tube into the middle ear.¹²⁵ Gently pulling the outer ear lobe upward and backward will allow the suspension to flow down into the ear canal.¹²⁵ The patient should remain on their side for at least 60 seconds.¹²⁵ If the other ear also is infected, these procedures should be repeated.¹²⁵

Cautions

Ciprofloxacin hydrochloride ophthalmic solution, ophthalmic ointment, and otic suspension generally are well tolerated following topical application.^{1 3 25 119 120 125} In most cases, adverse effects reported with topical ciprofloxacin therapy have been mild and have resolved without specific treatment.^{25 115 116}

Ocular Effects

Overall, the most frequent adverse effects of topical ciprofloxacin are transient ocular discomfort (e.g., burning, stinging) following instillation of the solution or ointment.^{1 3 25 119} Such effects have been reported in approximately 10% of patients in clinical studies receiving ciprofloxacin ophthalmic solution for various ophthalmic conditions.^{25 115} Ocular discomfort occurred in 2% of patients receiving ciprofloxacin ophthalmic ointment.¹¹⁹

In patients with bacterial keratitis, however, the principal reported ocular effect has been the development of a white granular or crystalline precipitate in the superficial portion of the corneal defect,^{1 3 25} being observed in approximately 17% of patients treated with ciprofloxacin ophthalmic solution for this infection in clinical studies.^{1 3 25} This corneal precipitate, identified as ciprofloxacin, generally appears during the early intensive phase of therapy for keratitis (e.g., within 1–7 days of initiating therapy) when the solution is administered repeatedly at relatively short intervals^{1 3} and usually resolves during the later phase of continued therapy when dosage (e.g., frequency of administration) of the drug is reduced.^{1 3 25} Presence of this precipitate does not appear to preclude continued therapy with ciprofloxacin nor to affect visual outcome or the clinical course of the corneal ulcer,^{1 3 25 115 116 117} and adjunctive therapy for its management is not necessary.²⁵ In one study in patients with bacterial keratitis, the precipitate was observed more frequently in geriatric patients (older than 60 years of age) than in younger patients, but the risk of development appeared to be unrelated to gender, stromal depth of the ulcer or infiltrate, organism cultured, or time to resolution of infection.²⁵ A white precipitate also was observed in approximately 13% of patients receiving ciprofloxacin ophthalmic ointment in clinical studies.¹¹⁹ Factors contributing to such ocular precipitation of ciprofloxacin, other than dosage (e.g., frequency of administration), remain to be elucidated.²⁵

Other adverse ocular effects have been reported in less than 10% of patients receiving topically applied ciprofloxacin solution in clinical studies and include lid margin crusting,^{1 3} crystals/scales on eyelashes,^{1 3 25} foreign body sensation,^{1 3 25} itching,^{1 3 25} and conjunctival hyperemia.^{1 3 25} Corneal staining,^{1 25} keratopathy/keratitis,^{1 25} sensitivity reactions,¹ lid edema,^{1 25} tearing,^{1 25} photophobia,^{1 25} decrease in vision,¹ and corneal infiltrates^{1 25} have been reported in less than 1% of patients.^{1 3 25}

Keratopathy occurred in 2% of patients receiving ciprofloxacin ophthalmic ointment.¹¹⁹ Allergic reaction,¹¹⁹ blurred vision,¹¹⁹ corneal staining,¹¹⁹ decreased visual acuity,¹¹⁹ dry eye,¹¹⁹ edema,¹¹⁹ epitheliopathy,¹¹⁹ ocular pain,¹¹⁹ foreign body sensation,¹¹⁹ hyperemia,¹¹⁹ irritation,¹¹⁹ keratoconjunctivitis,¹¹⁹ lid erythema,¹¹⁹ lid margin hyperemia,¹¹⁹ photophobia,¹¹⁹ pruritus,¹¹⁹ or tearing¹¹⁹ was reported in less than 1% of patients receiving ciprofloxacin ophthalmic ointment.¹¹⁹

Systemic Effects

Taste abnormality (e.g., bad taste in the mouth) following instillation of ciprofloxacin ophthalmic solution has been reported in 5% of patients in clinical studies receiving the drug for various ophthalmic conditions.²⁵ Taste abnormality¹¹⁹ or dermatitis¹¹⁹ has occurred in less than 1% of patients receiving ciprofloxacin ophthalmic ointment.¹¹⁹ Nausea has been reported in less than 1% of patients.^{1 119}

Since systemic absorption may occur following topical application of ciprofloxacin hydrochloride to the eye,^{1 3} the possibility of adverse systemic effects exists.^{1 115}

Headache¹²⁰ or pruritus¹²⁰ occurred in 1.2 or 0.4% of patients, respectively, receiving ciprofloxacin hydrochloride and hydrocortisone otic suspension; other events that occurred in patients receiving the combination included migraine headache,¹²⁰ hypoesthesia,¹²⁰ paresthesia,¹²⁰ fungal dermatitis,¹²⁰ cough,¹²⁰ rash,¹²⁰ urticaria,¹²⁰ and alopecia.¹²⁰ Otic discomfort, pain, or pruritus has been reported in patients receiving ciprofloxacin hydrochloride and dexamethasone otic suspension.¹²⁵

Ciprofloxacin, like most other quinolone antibacterials, causes arthropathy in immature animals of various species.^{5 6 36 100} In young beagles, ciprofloxacin given in a dosage of 100 mg/kg for 4 weeks caused degenerative articular changes in the knee joint; in a daily dosage of 30 mg/kg, effects on the joint were minimal, although some damage to weight-bearing joints was observed even at the lower dosage.¹⁰⁰ However, application of ciprofloxacin ophthalmic solution for 1 month to the eye(s) of young beagles did not cause articular changes in weight-bearing joints.¹

No evidence of cochlear toxicity was observed when ciprofloxacin and hydrocortisone otic suspension was administered intratympanically twice daily for 30 days in guinea pigs.¹²⁰

For additional information on adverse systemic effects of ciprofloxacin, see Cautions in Ciprofloxacin 8:12.18.

Precautions and Contraindications

The use of ciprofloxacin may result in overgrowth of nonsusceptible organisms, including fungi.^{1 119 120 125} If superinfection occurs, the drug should be discontinued and appropriate therapy instituted.¹

Careful monitoring, including slit lamp microscopy and fluorescein staining when appropriate, may be necessary in some patients receiving topical ophthalmic ciprofloxacin therapy.^{1 119}

Ciprofloxacin, like other quinolones, can cause serious, potentially fatal hypersensitivity reactions, occasionally following the initial systemic dose.^{1 99 119 120 125} (See Cautions: Dermatologic and Sensitivity Reactions, in Ciprofloxacin 8:12.18.) Patients receiving ciprofloxacin should be advised of this possibility and instructed to discontinue the drug and contact their physician at the first sign of rash or any other sign of hypersensitivity.^{1 99 116 119 120} Topical ciprofloxacin hydrochloride is contraindicated in patients with a history of hypersensitivity to ciprofloxacin or any ingredient in the formulation.^{1 119 120 125} The manufacturers state that a history of hypersensitivity to other quinolones (e.g., gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin) also may contraindicate use of topical ciprofloxacin.^{1 119 120 125}

Ciprofloxacin and hydrocortisone otic suspension should not be used if the tympanic membrane is perforated.¹²⁰ Ciprofloxacin and hydrocortisone or dexamethasone otic suspension is contraindicated in patients with viral infections (i.e., varicella, herpes simplex) of the external ear canal.^{120 125}

Pediatric Precautions

Safety and efficacy of ciprofloxacin hydrochloride ophthalmic solution in children younger than 1 year of age have not been established.¹ Safety and efficacy of ciprofloxacin ophthalmic ointment and ciprofloxacin and hydrocortisone otic suspension in children younger than 2 years of age have not been established.^{119 120} Safety and efficacy of ciprofloxacin and dexamethasone otic suspension in pediatric patients 6 months of age and older have been established in adequate and well-controlled studies involving 937 patients.¹²⁵ While ciprofloxacin and hydrocortisone or dexamethasone otic suspension has not been evaluated in children younger than 2 years or 6 months of age, respectively, there are no known safety concerns or differences in the disease process in these children to preclude administration of the respective formulations in children 1 year of age or older or in those younger than 6 months of age, respectively.^{120 125}

Mutagenicity and Carcinogenicity

Ciprofloxacin was not mutagenic in vivo in the rat hepatocyte DNA repair assay or dominant lethal or micronucleus tests in mice.^{1 3 37 115} Ciprofloxacin was positive for mutagenicity in the mouse lymphoma cell forward mutation assay and in vitro in the rat hepatocyte DNA repair assay; however, the drug was not mutagenic in other in vitro studies, including the Ames microbial (Salmonella) mutagen test with metabolic activation, Escherichia coli DNA repair assay, Chinese hamster V-79 cell HGPRT test, Syrian hamster embryo cell transformation assay, Saccharomyces cerevisiae point mutation assay, and mitotic crossover and gene conversion assays.^{1 3 37 115}

No evidence of carcinogenic potential was seen in mice and rats receiving oral ciprofloxacin daily for up to 2 years.¹

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and mice receiving oral ciprofloxacin dosages up to 6 times the usual human oral dosage have not revealed evidence of harm to the fetus.^{1 37 119 120} In rabbits, oral ciprofloxacin dosages of 30 and 100 mg/kg caused adverse GI effects resulting in maternal weight loss and an increased incidence of abortion, but there was no evidence of teratogenicity at either dosage.^{1 37 119 120} IV ciprofloxacin given to rabbits in dosages up to 20 mg/kg has not resulted in maternal toxicity, embryotoxicity, or teratogenicity.^{1 37 119 120} There are no adequate and controlled studies to date using ophthalmic ciprofloxacin in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.^{1 119} There are no adequate and controlled studies using otic suspension preparations containing ciprofloxacin and a corticosteroid in pregnant women, and these preparations should be used with caution in pregnant women.^{120 125}

Fertility

Reproduction studies in rats and mice receiving oral ciprofloxacin dosages up to 6 times the usual human oral dosage have not revealed evidence of impaired fertility.^{1 37 119 120}

Lactation

It is not known whether ciprofloxacin is distributed into milk following topical application to the eye or ear; however, ciprofloxacin is distributed into milk following systemic administration (see Pharmacokinetics: Distribution, in Ciprofloxacin 8:12.18).^{1 119 120} The ophthalmic solution and ointment should be used with caution in nursing women.^{1 119} Because of the potential for serious adverse reactions to the drug in nursing infants, a decision should be made whether to discontinue nursing or the ciprofloxacin-corticosteroid otic suspension, taking into account the importance of the drug to the woman.^{120 125}

Drug Interactions

Specific drug interaction studies involving ciprofloxacin hydrochloride ophthalmic solution or ophthalmic ointment and other drugs have not been conducted to date.^{1 119} However, since systemic absorption may occur following topical application of ciprofloxacin hydrochloride to the eye, the manufacturer states that the possibility of drug interactions such as those reported with systemic administration of ciprofloxacin should be considered.^{1 119} (See Drug Interactions in Ciprofloxacin 8:12.18.)

Acute Toxicity

Limited information is available on the acute toxicity of ciprofloxacin in humans.³⁷ The oral LD₅₀ of the drug is greater than 5 g/kg in mice and rats and approximately 2.5 g/kg in rabbits.³⁷

There currently is no information available on overdosage of topical ciprofloxacin in humans,¹ but the manufacturer states that overdosage following oral ingestion of the commercially available ophthalmic solution is unlikely given the limited amount of ciprofloxacin hydrochloride present in the solution.¹¹⁵ In case of topical overdosage of ciprofloxacin hydrochloride ophthalmic solution, the manufacturer states that the eye(s) may be flushed with warm tap water.¹

Results of in vitro studies using rabbit corneal epithelial cell cultures indicate that a 0.3% solution of ciprofloxacin does not damage epithelial cells.¹⁰⁷ Ocular toxicity studies in rabbits suggest that intravitreal injection of ciprofloxacin 100 mcg does not result in permanent retinal damage;^{12 105} however, retinal toxicity has occurred following intravitreal injection of higher dosages.¹⁰⁵ In addition, corneal toxicity has been documented in rabbits following injection of at least 25 mcg of ciprofloxacin into the anterior chamber of the eye or intravitreal injection of 100 mcg of the drug.¹⁰⁵

Mechanism of Action

Ciprofloxacin usually is bactericidal in action.^{1 3 6 37 40 41 42 43 44 45 47} Like other fluoroquinolone anti-infectives, ciprofloxacin inhibits DNA synthesis in susceptible organisms via inhibition of type II DNA topoisomerases (DNA gyrase, topoisomerase IV).^{1 3 7 31 36 43 44 50 51 52 53 99} For further information on the mechanism of action of ciprofloxacin, see Mechanism of Action in Ciprofloxacin 8:12.18.

Spectrum

Ciprofloxacin is 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 (previously known as methicillin-resistant staphylococci);^{1 3 5 8 30 31 40 42 46 59 60} the drug generally is less active against gram-positive than gram-negative bacteria^{30 31 42 46 67 68 69} and is 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 Pseudomonas cepacia, some strains of Ps. maltophilia, and most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile, are resistant to the drug.^{1 3} Ciprofloxacin is inactive against fungi and viruses.^{1 3 5 6 8}

In vitro, ciprofloxacin concentrations of 1 mcg/mL or less inhibit most strains of the following ocular pathogens: Acinetobacter calcoaceticus,^{3 5 8 64 65 66 67 69} Chlamydia trachomatis,^{3 5 6 8 73 74 75} Citrobacter spp.,^{3 5 6 8 64 65 66 69} Enterobacter spp.,^{3 5 6 8 42 63 64 65 66 67 69} Escherichia coli,^{3 5 6 8 42 64 65 67 69} Haemophilus influenzae,^{3 5 6 8 32 63 64 65 68 69} Klebsiella pneumoniae,^{3 5 6 8 64 65 66 67 69} Mycobacterium tuberculosis,^{3 5 8 32 70 71 72} Neisseria spp.,^{3 5 6 8 32 61 64 65 67 69} Proteus spp.,^{3 5 6 8 32 42 63 64 65 66 67 69} Pseudomonas aeruginosa,^{3 5 6 8 32 42 61 63 64 65 66 67 68 69} Staphylococcus aureus,^{3 5 6 8 32 42 61 62 63 64 65 66 67} S. epidermidis,^{3 5 6 8 42 63 64 65 66 67} and Serratia marcescens.^{3 5 63 64 65 66 67 69} Susceptible strains of Streptococcus pneumoniae^{3 5 6 8 40 42 64 65 66 67 68} and viridans streptococci^{3 5 6 8 40 42 64 66} are inhibited by ciprofloxacin concentrations of 4 mcg/mL or less.

In vitro, ciprofloxacin usually is more active than tobramycin against Pseudomonas aeruginosa, Staphylococcus, and Streptococcus and at least as active as tobramycin against Serratia.³ Ciprofloxacin also is more active than norfloxacin against susceptible bacteria in vitro,^{5 6 23 107} and the drug has shown greater activity than norfloxacin in some in vivo models of bacterial keratitis caused by Ps. aeruginosa.^{9 110} Ciprofloxacin has demonstrated in vivo activity against most strains of Staphylococcus aureus (including oxacillin-resistant strains), S. epidermidis, Streptococcus pneumoniae, viridans streptococci, Pseudomonas aeruginosa, and Serratia marcescens in a limited number of clinical studies in patients with ocular infections.^{1 3 25 27}

Resistance

Resistance to ciprofloxacin can be produced in vitro in some organisms, including some strains of Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis (formerly Streptococcus faecalis), by serial passage in the presence of increasing concentrations of the drug.^{5 6 8 31 32 40 42 44 61 67 76 77 78} Ciprofloxacin resistance resulting from spontaneous mutation occurs rarely in vitro (i.e., with a frequency of 10⁹ to 10⁷).^{3 5 6 8 31 32 44 67 76} However, resistant strains of Ps. aeruginosa^{5 6 8 30 32 79 80} and staphylococci^{5 6 8 81 82 83} have emerged occasionally during systemic therapy with the drug. Spontaneous resistance to ciprofloxacin is concentration dependent, generally occurring only when the MIC for the organism exceeds the concentration of the drug at the infection site by several (e.g., 4–8)-fold.^{6 116} Therefore, the potential for development of resistance to ciprofloxacin during ophthalmic administration is likely to be less than that associated with systemic drug administration because of the relatively high drug concentrations achieved in ocular tissue with administration of commercially available ciprofloxacin hydrochloride ophthalmic solution.⁶

For information on the mechanism(s) of resistance with quinolones, see Resistance in Ciprofloxacin 8:12.18 and Ofloxacin 8:12.18.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, ciprofloxacin was administered as the hydrochloride salt; dosages and concentrations of the drug are expressed in terms of ciprofloxacin.^{1 6 8 9 11}

Absorption

The extent of ocular and systemic absorption of ciprofloxacin following topical application to the eye has not been fully elucidated; however, serum concentrations achieved following such application to uninflamed eyes are minimal relative to those produced by usual oral or parenteral doses of the drug.^{1 3 115 116} Following topical application to the eye, ciprofloxacin is absorbed through the cornea into aqueous humor;^{6 8 9 11} absorption is enhanced in the presence of ocular inflammation and/or epithelial defects.^{10 11 114} Following topical application to the eye of 1 drop (50 mcL)¹¹ of a 0.3% solution of ciprofloxacin (150 mcg) every 15 minutes for 1 hour and then every hour for 10 hours in patients undergoing keratoplasty, concentrations of the drug in corneal stromal tissue harvested within 1 hour after the last dose of ciprofloxacin averaged 5.28 mcg/g (range: 1.4–10.6 mcg/g).¹⁰ In anesthetized rabbits with intact ocular epithelium, topical application to the eye of 1 drop of a 0.3% solution of ciprofloxacin every 30 minutes for 6 doses produced aqueous humor concentrations averaging approximately 4.8 and 3.1 mcg/mL 30 and 90 minutes, respectively, after the last dose; in rabbits with ocular epithelial defects, aqueous humor concentrations averaged 12.9 and 7 mcg/mL 30 and 90 minutes, respectively, after application of the last dose.¹¹ Following topical application to the eye of 1 drop of ciprofloxacin 0.75% every 15 minutes for 4 doses and then every 30 minutes for 3 hours in anesthetized rabbits, drug concentrations in aqueous humor 1 hour after the last dose averaged 30.5 mcg/mL.⁹ Following intravitreal injection of 100 mcg of ciprofloxacin in rabbits, peak drug concentrations in aqueous and vitreous humor at 1 hour were approximately 0.6 and 27.3 mcg/mL, respectively.¹²

Some systemic absorption of ciprofloxacin occurs following topical application of the drug to the eyes,^{1 3} although systemic effects resulting from such absorption have not been reported to date.^{4 115 116} Following topical application to the eyes in healthy adults of 1 drop of a 0.3% solution of ciprofloxacin every 2 hours while awake for 2 days, then every 4 hours while awake for 5 days, serum ciprofloxacin concentrations reportedly ranged from undetectable to 4.7 ng/mL²⁵ but generally averaged less than 2.5 ng/mL.^{1 3 115} In contrast, peak serum concentrations generally average 0.8–1.5 mcg/mL (800–1500 ng/mL) following administration of a single 250-mg oral dose of ciprofloxacin in healthy, fasting adults.^{8 87 88 89 90 91}

The extent of systemic absorption of ciprofloxacin following topical administration of the ophthalmic ointment has not been fully evaluated.¹¹⁹ Based on studies using ciprofloxacin 0.3% ophthalmic solution, the maximum plasma ciprofloxacin concentration following application of the ophthalmic ointment is expected to average less than 2.5 ng/mL.¹¹⁹

Plasma ciprofloxacin concentration following administration of 3 drops of ciprofloxacin and hydrocortisone otic suspension is expected to be lower than the limit of detection of the assay (50 ng/mL).¹²⁰

Following administration of 4 drops of ciprofloxacin and dexamethasone otic suspension into each ear canal in pediatric patients with tympanostomy tubes, plasma ciprofloxacin concentrations averaged 1.39 ng/mL.¹²⁵

Distribution

Distribution of ciprofloxacin into human ocular tissues and fluids following topical ophthalmic or systemic administration has not been fully characterized to date.^{8 17} Limited data in animals with experimentally induced ocular infection and in patients with intact corneal epithelium suggest that the drug penetrates into the cornea and other ocular tissues (e.g., aqueous humor) following topical application of a 0.3% solution of ciprofloxacin and is present in these tissues at concentrations exceeding the MIC of most corneal and conjunctival pathogens; the presence of ocular epithelial defects would likely result in enhanced penetration of the drug into ocular tissues.^{6 9 10 11 114}

Ciprofloxacin is widely distributed into body tissues and fluids following oral or IV administration.^{5 6 30 32 34 37} (See Pharmacokinetics: Distribution, in Ciprofloxacin 8:12.18.) Current information on the distribution of ciprofloxacin into ocular tissues and fluids following systemic administration of the drug is based principally on studies in patients with uninflamed and/or uninfected eyes; distribution is likely to be greater in the presence of inflammation or infection because of disruption of the blood/ocular barrier.^{17 114 115 116} Following oral or IV administration of ciprofloxacin in patients undergoing cataract extraction, peak drug concentrations in aqueous humor generally have averaged 3–33% of concurrent serum concentrations.^{8 14 15 16 17 21} Following single-dose oral or IV administration of ciprofloxacin in patients undergoing ocular surgery, concentrations in vitreous humor averaged about 20% of concurrent serum concentrations.^{17 18} Following IV administration of a single 12-mg dose of the drug in rabbits, ciprofloxacin concentrations in aqueous or vitreous humor averaged approximately 10 or approximately 1–5%, respectively, of concurrent serum concentrations.¹³

Ciprofloxacin is 16–43% bound to serum proteins in vitro.^{5 30 32 34 37 45 92 93}

Ciprofloxacin crosses the placenta and is distributed into amniotic fluid in humans;⁹⁴ the drug also is distributed into milk.^{19 20 94} (See Pharmacokinetics: Distribution, in Ciprofloxacin 8:12.18.)

Elimination

The metabolic fate and elimination characteristics of ciprofloxacin following topical application to the eye have not been elucidated.¹¹⁵ In a study in rabbits, the half-life of ciprofloxacin in aqueous humor was 1–2 hours.¹¹ The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3–5 hours.^{5 34 37 46 90}

Systemically absorbed ciprofloxacin is eliminated by renal and nonrenal mechanisms.^{5 30 34 37} The drug is partially metabolized in the liver to at least 4 metabolites;^{5 30 34 37} these metabolites have microbiologic activity that is less than that of ciprofloxacin^{32 34 37 96} but may be similar to or greater than that of other quinolones.^{95 96} Ciprofloxacin and its metabolites are excreted in urine^{5 30 32 34 35 46} and feces.^{5 34 37} Unchanged ciprofloxacin is excreted in urine by both glomerular filtration and tubular secretion.^{5 30 32 34 35 46} Most, but not all, unchanged ciprofloxacin in feces appears to result from biliary excretion.^{97 98}

Chemistry and Stability

Chemistry

Ciprofloxacin is a fluoroquinolone anti-infective agent.^{1 2 3 5 6 8} Like other commercially available fluoroquinolones, ciprofloxacin contains a fluorine at position 6 of the quinolone nucleus.^{5 30 31 32 33 34 35 36 37 38} Like some other fluoroquinolones (gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin), ciprofloxacin contains a piperazinyl group at position 7 of the quinolone nucleus. ^{3 5 8 32 33 37 38} The piperazinyl group in ciprofloxacin results in antipseudomonal activity.^{3 5 8 32 33 37 38} The drug also contains a cyclopropyl group at position 1, which enhances antimicrobial activity.^{3 5 8 37}

Ciprofloxacin is commercially available for topical (ophthalmic and otic) administration as ciprofloxacin hydrochloride, which is the monohydrochloride monohydrate of the drug.^{1 119 120 125} While USP states that potency of the bulk drug is expressed in terms of the monohydrochloride, calculated on the anhydrous basis, they also state that potency of commercial preparations of the monohydrochloride should be expressed in terms of the base.¹⁰⁸ Therefore, potency of ciprofloxacin hydrochloride ophthalmic solution, ophthalmic ointment, and otic suspension is expressed in terms of ciprofloxacin rather than in terms of the salt.^{1 119 120} Each 3.5 mg of ciprofloxacin hydrochloride monohydrate¹ or 3.33 mg of ciprofloxacin hydrochloride (calculated on the anhydrous basis)^{119 122} provides 3 mg of ciprofloxacin.¹

Ciprofloxacin hydrochloride occurs as a faintly yellowish to light yellow crystalline powder^{1 2 37} and has solubilities of approximately 36 mg/mL in water at 25°C^{2 30 37} and 0.16 mg/mL in alcohol.² The pK_as of the drug in water are 6 and 8.8.^{8 39}

Ciprofloxacin hydrochloride ophthalmic solution is a sterile, isotonic solution of the drug in purified water; hydrochloric acid and/or sodium hydroxide may be added to adjust pH to approximately 4.5 (range: 3.5–5.5).^{1 108} The commercially available ophthalmic solution also contains benzalkonium chloride as a preservative, acetic acid, sodium acetate, mannitol, and edetate disodium and has an osmolality of approximately 300 mOsm/kg.¹

Ciprofloxacin hydrochloride ophthalmic ointment is a sterile ointment containing ciprofloxacin hydrochloride in white petrolatum; the commercially available preparation also contains mineral oil.¹¹⁹

For otic use, ciprofloxacin hydrochloride in fixed combination with hydrocortisone is commercially available as a preserved nonsterile suspension.¹²⁰ Ciprofloxacin hydrochloride and hydrocortisone otic suspension contains benzyl alcohol as a preservative, polyvinyl alcohol, sodium chloride, sodium acetate, glacial acetic acid, phospholipon 90HB (modified lecithin), polysorbate, and purified water; sodium hydroxide or hydrochloric acid may be added to adjust pH.¹²⁰

For otic use, ciprofloxacin hydrochloride in fixed combination with dexamethasone is commercially available as a preserved sterile suspension.¹²⁵ Ciprofloxacin hydrochloride and dexamethasone otic suspension contains benzalkonium chloride as a preservative, boric acid, sodium chloride, hydroxyethyl cellulose, tyloxapol, acetic acid, sodium acetate, edetate disodium, and purified water; sodium hydroxide or hydrochloride acid may be added to adjust pH.¹²⁵

Stability

Ciprofloxacin hydrochloride ophthalmic solution should be stored in tight, light-resistant containers at 2–25°C.^{1 108} When stored as directed, the commercially available ophthalmic solution has an expiration date of 24 months following the date of manufacture.²

Ciprofloxacin hydrochloride ophthalmic ointment should be stored at 2–25°C.¹¹⁹

Ciprofloxacin hydrochloride and hydrocortisone otic suspension should be stored in light-resistant containers below 25°C; freezing should be avoided.¹²⁰

Ciprofloxacin hydrochloride and dexamethasone otic suspension should be stored at 15–30°C and protected from light; freezing should be avoided.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

* available by nonproprietary name

Ciprofloxacin Hydrochloride Combinations

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

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Selected Revisions January 2007, © Copyright, November 1993, 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.

55.

56.

57.

58.

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.