AHFS Class:

• Antibacterials 52:04.04

Generic Name(s):

• Gentamicin Sulfate

• Gentamicin Sulfate and Prednisolone Acetate

Gentamicin is an aminoglycoside antibiotic.101,102

Bacterial Ophthalmic Infections

Gentamicin sulfate ophthalmic ointment and ophthalmic solution are used for the topical treatment of superficial infections of the eye (e.g., conjunctivitis, keratitis, keratoconjunctivitis, corneal ulcers, blepharitis, blepharoconjunctivitis, acute meibomianitis, dacryocystitis) caused by susceptible Staphylococcus aureus , S. epidermidis , Streptococcus pyogenes , S. pneumoniae , Haemophilus influenzae , Enterobacter aerogenes , Escherichia coli , Klebsiella pneumoniae , Neisseria gonorrhoeae , Serratia marcescens , and Pseudomonas aeruginosa .101,102

Although mild, acute bacterial conjunctivitis often resolves spontaneously without anti-infective treatment,135,136,137,141 topical ophthalmic anti-infectives may shorten the time to resolution and reduce severity and risk of complications.135,136,137,141 Treatment of acute bacterial conjunctivitis generally is empiric and use of a broad-spectrum topical ophthalmic antibacterial usually is recommended;135,136,141 however, indiscriminate use of topical anti-infectives should be avoided.135,141 In vitro staining and/or cultures of conjunctival material may be indicated in the management of recurrent, severe, or chronic purulent conjunctivitis or when acute conjunctivitis does not respond to initial empiric topical treatment.135,136,141

Because many forms of bacterial keratitis are associated with subsequent loss of vision as the result of corneal scarring or topographic irregularities and because untreated or severe bacterial keratitis may result in perforation of the cornea with the potential for endophthalmitis and possible loss of the eye, optimal management involves rapid evaluation and diagnosis, timely initiation of treatment, and appropriate follow-up.138 Treatment of community-acquired bacterial keratitis generally is empiric and use of a broad-spectrum topical ophthalmic antibacterial usually is recommended.138 Subconjunctival therapy with an appropriate anti-infective may be necessary if scleral spread or perforation is imminent.138 In vitro staining and/or cultures are indicated in the management of keratitis involving corneal infiltrates that are central, large, and extending to the middle to deep stroma; when keratitis is chronic or unresponsive to treatment with a broad-spectrum topical anti-infective; or when atypical features are present suggesting fungal, amebic, or mycobacterial infection.138

Ocular Inflammation

Topical ophthalmic preparations containing gentamicin sulfate in fixed combination with a corticosteroid (i.e., prednisolone acetate) are used for the management of corticosteroid-responsive ocular conditions when a corticosteroid is indicated and superficial bacterial ocular infection or risk of such infection exists.107,108

Ophthalmic corticosteroids may be indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe where the inherent risk of corticosteroid use in certain infective conjunctivitides is accepted to obtain diminution in edema and inflammation.107,108 Ophthalmic corticosteroids also may be indicated in the treatment of chronic anterior uveitis and corneal injury from chemical, radiation, or thermal burns or penetration of foreign bodies.107,108

Although the manufacturers state that use of a fixed-combination ophthalmic preparation containing an anti-infective and a corticosteroid may be indicated in ocular inflammatory conditions when the risk of superficial ocular infection is high or when there is an expectation that potentially dangerous numbers of bacteria will be present in the eye,107,108 experts state that such preparations should be avoided in patients with bacterial conjunctivitis because of the risk of potentiating the infection.136

Clinicians should consider that use of fixed-combination ophthalmic preparations containing an anti-infective and a corticosteroid may mask the clinical signs of bacterial, fungal, or viral infections; prevent recognition of ineffectiveness of the anti-infective; and/or increase intraocular pressure.107,108 (See Precautions Related to Use of Fixed Combinations Containing Corticosteroids under Cautions: Precautions and Contraindications.)

For systemic uses of gentamicin, see the Aminoglycosides General Statement 8:12.02; for use in superficial infections of the skin, see 84:04.04.

Administration

Ophthalmic Administration

Gentamicin sulfate is applied topically to the eye as an ophthalmic ointment102 or ophthalmic solution101 containing 0.3% gentamicin.101,102

Gentamicin sulfate also is commercially available in fixed combination with a corticosteroid (i.e., prednisolone acetate) for topical application to the eye as an ophthalmic ointment or suspension.107,108

Gentamicin ophthalmic preparations and fixed-combination ophthalmic preparations containing gentamicin and a corticosteroid are for topical ophthalmic use only ;101,102,107,108 these preparations should not be injected subconjunctivally or directly into the anterior chamber of the eye.101,102,108

Care should be taken to avoid contaminating the container tip with material from the eye, eyelid, or any other source.101,102,107,108

The fixed-combination ophthalmic suspension containing gentamicin and prednisolone acetate should be shaken well prior to use.108

Dosage

Dosage of gentamicin sulfate is expressed in terms of the base.101,102

Dosage of fixed-combination preparations containing gentamicin sulfate and prednisolone acetate is expressed in terms of gentamicin base and the prednisolone salt.107,108

Bacterial Ophthalmic Infections

For the topical treatment of superficial bacterial infections of the eye in adults and pediatric patients 1 month of age or older, a ribbon of gentamicin 0.3% ophthalmic ointment approximately 1.25 cm (½ inch) in length should be placed in the affected eye(s) 2 or 3 times daily.102

If gentamicin 0.3% ophthalmic solution is used for the topical treatment of superficial bacterial infections of the eye in adults and pediatric patients 1 month of age or older, 1 or 2 drops of the ophthalmic solution should be instilled into the affected eye(s) every 4 hours.101 For severe eye infections, up to 2 drops may be instilled into the affected eye(s) every hour.101

The usual duration of topical anti-infective treatment for bacterial conjunctivitis is 5-10 days;135,136,141 some experts state that 5-7 days of such treatment usually is adequate for mild bacterial conjunctivitis.135

Ocular Inflammation

When the fixed-combination ophthalmic ointment containing gentamicin and prednisolone acetate (gentamicin 0.3% and prednisolone acetate 0.6%) is used in adults, a ribbon of the ointment approximately 1.25 cm (½ inch) in length should be placed into the conjunctival sac of the affected eye(s) 1-3 times daily.107

When the fixed-combination ophthalmic suspension containing gentamicin and prednisolone (gentamicin 0.3% and prednisolone acetate 1%) is used in adults, 1 drop of the suspension should be instilled into the conjunctival sac of the affected eye(s) 2-4 times daily.108 During the initial 24-48 hours, 1 drop of the suspension may be instilled into the conjunctival sac of the affected eye(s) every hour if necessary.108

If there is no improvement after 2 days of treatment with a fixed-combination preparation, the patient should be reevaluated.107,108 Care should be taken not to discontinue therapy prematurely.107,108

Adverse Effects

The most frequent adverse effects reported following topical application of gentamicin ophthalmic preparations are ocular burning and irritation, nonspecific conjunctivitis, conjunctival epithelial defects, and conjunctival hyperemia.101,102

Bacterial and fungal corneal ulcers have developed during treatment with gentamicin ophthalmic preparations.101,102

Allergic reactions, thrombocytopenic purpura, and hallucinations have been reported rarely.101,102

Precautions and Contraindications

Gentamicin ophthalmic ointment and solution are contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.101,102

Fixed-combination ophthalmic preparations containing gentamicin and a corticosteroid (i.e., prednisolone acetate) are contraindicated in patients with known or suspected hypersensitivity to gentamicin, prednisolone or other corticosteroids, or any ingredient in the formulation.107,108 In addition, these fixed-combination preparations are contraindicated in patients with viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and in patients with mycobacterial infections of the eye or fungal diseases of ocular structures.107,108

Patients should be advised to immediately discontinue gentamicin ophthalmic preparations if irritation or hypersensitivity occurs.101,102 Appropriate therapy should be initiated.101,102 Patients also should be advised to discontinue the ophthalmic preparation and contact a clinician if there is an increase in purulent discharge or aggravation of inflammation or pain.101,102

Prolonged use of topical gentamicin may result in overgrowth of nonsusceptible organisms, including fungi.101,102 Bacterial resistance to gentamicin may occur.101,102

The manufacturer cautions that ophthalmic ointments may delay corneal healing.102

Precautions Related to Use of Fixed Combinations Containing Corticosteroids

When ophthalmic preparations containing gentamicin in fixed combination with a corticosteroid (i.e., prednisolone acetate) are used, the usual cautions, precautions, and contraindications associated with the corticosteroid also must be considered.107,108

Initial prescriptions for fixed-combination ophthalmic preparations containing a corticosteroid or renewal prescriptions (beyond 8 g of ophthalmic ointment or beyond 20 mL of ophthalmic solution) should be made only after measuring intraocular pressure and examining the patient with slit lamp microscopy and, when appropriate, fluorescein staining.107,108

Patients should be advised to discontinue the fixed-combination ophthalmic preparation and contact a clinician if inflammation or pain persists for more than 48 hours or becomes aggravated.107,108

Prolonged use of fixed-combination ophthalmic preparations containing a corticosteroid may result in glaucoma, with damage to the optic nerve, defects in visual acuity and fields of vision, and posterior subcapsular cataract formation.107,108 If an ophthalmic preparation containing a corticosteroid is used for 10 days or longer, intraocular pressure should be routinely monitored, even though this may be difficult in children and uncooperative patients.107,108 Such preparations should be used with caution in patients with glaucoma and intraocular pressure should be checked frequently in such patients.107,108

Use of fixed-combination ophthalmic preparations containing a corticosteroid after cataract surgery may delay healing and increase the incidence of bleb formation.107,108

Various ocular diseases and long-term use of topical corticosteroids have caused corneal and scleral thinning.107,108 Use of topical ophthalmic corticosteroids in patients with thin corneal and scleral tissue may result in perforation.107,108

Prolonged use of fixed-combination ophthalmic preparations containing a corticosteroid may suppress host responses and increase the risk of secondary ocular infections.107,108 Use of such preparations in patients with acute purulent conditions of the eye may mask infection or enhance existing infection.107,108

Use of ophthalmic preparations containing a corticosteroid may prolong the course and exacerbate severity of many viral infections of the eye (including herpes simplex).107,108 Such preparations should be used with great caution in patients with herpes simplex and frequent slit lamp microscopy is recommended.107,108

The possibility of fungal infections of the cornea should be considered after prolonged use of ophthalmic preparations containing a corticosteroid.107,108 Fungal cultures should be taken when appropriate.107,108

Pediatric Precautions

Safety and efficacy of gentamicin ophthalmic ointment and ophthalmic solution have not been established in neonates.101,102

Safety and efficacy of fixed-combination ophthalmic preparations containing gentamicin and prednisolone acetate have not been established in pediatric patients.107,108

Geriatric Precautions

No overall differences in safety or efficacy of fixed-combination ophthalmic preparations containing gentamicin and prednisolone acetate have been observed between geriatric and younger adults.107,108

Mutagenicity and Carcinogenicity

Data are not available regarding the mutagenic and carcinogenic potential of gentamicin.101,102,107,108 Aminoglycosides have not been found to be mutagenic.101,102,107,108

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies indicate that gentamicin can depress body weights, kidney weights, and median glomerular counts in newborn rats when given systemically to pregnant rats in daily doses approximately 500 times the maximum recommended ophthalmic human dose.102

There are no adequate and well-controlled studies using gentamicin ophthalmic preparations in pregnant women.102 Gentamicin ophthalmic preparations, including fixed-combination preparations containing gentamicin and prednisolone acetate, should be during pregnancy only if potential benefits justify potential risks to the fetus.101,102,107,108

Lactation

Systemic gentamicin is distributed into milk.140

A decision should be made whether to discontinue nursing or discontinue gentamicin ophthalmic preparations, taking into account the importance of the drug to the woman.107,108

Mechanism of Action

Gentamicin is usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drug appears to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits.

Spectrum

In general, gentamicin is active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria. Gentamicin is inactive against fungi, viruses, and most anaerobic bacteria.

Gentamicin is active in vitro against some gram-positive bacteria, including Staphylococcus aureus , S. epidermidis , Streptococcus pneumoniae , and S. pyogenes (group A β-hemolytic streptococci).101,102

Gentamicin also is active in vitro against some gram-negative bacteria, including Haemophilus influenzae , Enterobacter aerogenes , Escherichia coli , Klebsiella pneumoniae , Neisseria gonorrhoeae , Serratia marcescens , and Pseudomonas aeruginosa .101,102

Resistance

Natural and acquired resistance to gentamicin has been demonstrated in both gram-negative and gram-positive bacteria. Gentamicin resistance may be due to decreased permeability of the bacterial cell wall, alterations in the ribosomal binding site, or the presence of a plasmid-mediated resistance factor which is acquired by conjugation. Plasmid-mediated resistance enables the resistant bacteria to enzymatically modify the drug by acetylation, phosphorylation, or adenylylation and can be transferred between organisms of the same or different species. Resistance to other aminoglycosides and several other anti-infectives (e.g., chloramphenicol, sulfonamides, tetracycline) may be transferred on the same plasmid.

There is partial cross-resistance between gentamicin and other aminoglycosides.

Pharmacokinetics

Studies in rabbits suggest that gentamicin is absorbed into the aqueous humor following topical application of the ophthalmic ointment or solution to the eye; the drug was detected in the vitreous humor. Absorption of the drug is greatest when the cornea is abraded.

Chemistry and Stability

Chemistry

Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora purpurea .101,102 The commercially available drug is a mixture of the sulfate salts of gentamicin C₁, C₂, and C_1A; all 3 components appear to have similar antimicrobial activity.101,102 Gentamicin sulfate occurs as a white powder and is soluble in water and insoluble in alcohol.101

Gentamicin sulfate is commercially available for topical ophthalmic use as an ophthalmic ointment or ophthalmic solution containing 0.3% gentamicin.101,102 Gentamicin sulfate also is commercially available for topical ophthalmic use in fixed combination with a corticosteroid (i.e., prednisolone acetate).107,108

Gentamicin 0.3% ophthalmic ointment is a sterile ointment containing the drug in a white petrolatum and mineral oil ointment base.102 The ophthalmic ointment contains methylparaben and propylparaben as preservatives.102

Gentamicin 0.3% ophthalmic solution is a sterile aqueous solution of the drug and has a pH of 6.8-7.3.101 The ophthalmic solution contains benzalkonium chloride as a preservative.101

The fixed combination of gentamicin sulfate and prednisolone acetate is commercially available as a sterile ophthalmic ointment (gentamicin 0.3% and prednisolone acetate 0.6%)107 and a sterile ophthalmic suspension (gentamicin 0.3% and prednisolone acetate 1%).108 The fixed-combination ophthalmic ointment contains gentamicin and prednisolone acetate in a petrolatum and lanolin alcohol and white petrolatum and mineral oil ointment base and contains chlorobutanol (chloral derivative) as a preservative.107 The fixed-combination ophthalmic suspension has a pH of 5.4-6.6 and contains benzalkonium chloride as a preservative.108

Stability

Gentamicin 0.3% ophthalmic ointment should be stored at 2-30°C.102

Gentamicin 0.3% ophthalmic solution should be stored at 20-25°C and protected from excessive heat.101

The fixed-combination ophthalmic ointment containing gentamicin and prednisolone acetate (gentamicin 0.3% and prednisolone acetate 0.6%) should be stored at 15-25°C.107

The fixed-combination ophthalmic suspension containing gentamicin and prednisolone acetate (gentamicin 0.3% and prednisolone acetate 1%) should be stored at 15-25°C.108 The suspension should be protected from excessive heat (40°C or greater) and should not be frozen.108

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

101. Akorn, Inc. Gentamicin sulfate ophthalmic solution USP 0.3% prescribing information. Lake Forest, IL; 2016 Jun.

102. Akorn. Gentak^® (gentamicin sulfate) ophthalmic ointment USP, 0.3% prescribing information. Lake Forest, IL; 2015 Oct.

107. Allergan, Inc. Pred-G^® (gentamicin and prednisolone acetate) ophthalmic ointment, USP 0.3%/0.6% prescribing information. Irvine, CA; 2017 Mar.

108. Allergan, Inc. Pred-G^® (gentamicin and prednisolone acetate) ophthalmic suspension, USP 0.3%/1.0% prescribing information. Irvine, CA; 2017 Mar.

135. American Academy of Ophthalmology. Preferred practice pattern (PPP) guidelines: conjunctivitis PPP - 2013. From American Academy of Ophthalmology website. Accessed 20 Dec 2017. [Web]

136. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA . 2013; 310:1721-9. [PubMed 24150468]

137. Sheikh A, Hurwitz B, van Schayck CP et al. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev . 2012; :CD001211. [PubMed 22972049]

138. American Academy of Ophthalmology. Preferred Practice Pattern (PPP) guidelines: bacterial keratitis - 2013. From the American Academy of Ophthalmology website. Accessed 5 Dec 2016. [Web]

140. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation, 7th ed. Lippincott Williams & Wilkins: Philadelphia, PA; 2005:720-22.

141. Barnes SD, Kumar NM, Pavin-Langston D et al. Microbial Conjunctivitis. In: Bennett JE, Dolin R, and Blaser MJ, eds. Mandell, Douglas, and Bennett's principles and practices of infectious diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:1392-1401.