foundation volume 3, chapter 39, bacterial conjunctivitis

8/9/2019 Foundation Volume 3, Chapter 39, bacterial conjunctivitis

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Chapter 39

Topical Ophthalmic Antibiotics in the Management of

Bacterial Conjunctivitis and KeratitisRE NÉE SOLOMON and ERIC DONNENFELD

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BACTERIAL CONJUNCTIVITISBACTERIAL KERATITISPROPERTIES OF TOPICAL OPHTHALMIC ANTIBACTERIAL AGENTSREFERENCES

BACTERIAL CONJUNCTIVITIS

Bacterial conjunctivitis is common,1 generally mild to moderate in severity,

and usually self-limiting. Treatment with topical ophthalmic antibioticsspeeds resolution of the disease, decreases morbidity, prevents recurrenceand spread of the disease to social contacts, decreases the incidence of

permanent conjunctival changes, decreases the risk of corneal or intraocularinfection when surgery is anticipated, and prevents the development of chronic conjunctivitis with its greater treatment challenges and risk of progression to corneal damage or disease.2–4 The most frequently isolated

pathogens in acute bacterial conjunctivitis are Streptococcus pneumoniae andHaemophilus influenzae in pediatric patients and Staphylococcus epidermidisin adult patients.5,6

Chronic conjunctivitis is defined as any case of conjunctivitis that lasts longerthan 2 weeks. The most common pathogens associated with this conditionare Staphylococcus aureus and S. epid er midis, the most common organisms

found in normal lid and conjunctival flora. These pathogens produce toxinsthat can damage the conjunctiva and cornea producing the superficialpunctate keratopathy that is commonly seen. The punctate keratopathycharacteristically involves the inferior cornea and conjunctiva. Theseorganisms also commonly spread to other ocular structures, such as themeibomian orifices, lash follicles, and the lacrimal canaliculi, and may even

breach the corneal epithelium.2,3

Other, more serious types of infectious conjunctivitis include hyperacutebacterial conjunctivitis, usually caused by Neisseria gonorrhoeae andS.

pneumoniae. N. gonor rhoeae is often associated with oropharyngeal

infections and requires systemic and topical therapy.2,3

In the treatment of acute bacterial conjunctivitis, most physicians do notperform cultures and therefore prescribe broad-spectrum antibiotic agents.Because bacterial conjunctivitis is usually self-limiting, agents associatedwith a higher incidence of ocular toxicity or hypersensitivity reactions arebest avoided. Combination products with gram-positive and gram-negativecoverage are popular for their broad spectrum of activity, but some containagents that can be irritating or cause allergic reactions. Patient compliance isa common treatment challenge, particularly in pediatric patients becausethey are reluctant to let anyone instill anything into their eyes and aresensitive to irritating agents.

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BACTERIAL KERATITIS

Bacterial keratitis is an ophthalmic emergency that has the potential to causesignificant vision loss secondary to corneal scarring and perforation. Rapid

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diagnosis and immediate treatment with appropriate antimicrobial therapyare necessary to limit the extent of tissue damage and to improve the visualprognosis.3,7 Approximately 30,000 cases of microbial keratitis are

diagnosed each year in the United States.8 The most likely causative

organisms depend on geographic location, preexisting corneal disease, urbanor rural environment, history of contact lens wear, and climate.9–13

Approximately 87% of all cases of bacterial keratitis in the United States

result from infection by one of the following organisms: Gram-positiveinfections are most commonly secondary to streptococci or staphylococci,whereas the gram-negative organisms include Pseudomonas species orEnterobacteriaceae (especially Serratia marcescens but also Citrobacter,

Klebsiella, Enterobacter, and Proteus species).14–16 Currently, the mostcommon causes of microbial keratitis are S. aureus in the northern UnitedStates and Pseudomonas and Streptococcus species in the southern United

States.3,11,17 S. pneumoniae is the most common pathogen in manydeveloping countries. Staphylococcus species are the most commonorganism associated with photorefractive keratectomy or LASIK.18Pseudomonas species are frequently associated with overnight contact lens

wear but may also be seen with daily-wear contact lenses.19–27

In fact,Pseudomonas species have become a more common cause of bacte-rial

keratitis in the southern United States thanS. aureus.28,29 In childrenyounger than 3 years of age, Pseudomonas species have been identified as

the most common bacterial cause of keratitis.30,31

Many ophthalmologists diagnose and treat bacterial keratitis based on theirempirical observations and only perform a microbial analysis on particularlysevere ulcers (e.g., those encroaching on or involving the visual axis). Mostphysicians choose what they think to be a broad-spectrum antibiotic and

begin treatment immediately,3,32,33 but the choice of agent may also be

influenced by which pathogen is suggested by the disease presentation andthe physicians' knowledge of pathogen prevalence in the local environment

and patient population.28,34–36 Care must be taken in the choice of a broad-spectrum antibiotic because certain commercially available agents may havesignificant gaps in the spectra of their antimicrobial efficacy, may poorlypenetrate the cornea, or may be bacteriostatic rather than bactericidal. Anyof these characteristics would make them unsuitable for the treatment of bacterial keratitis.

For approximately 25 years, the mainstay for the treatment of theseinfections has been dual therapy using topically administered fortified

antibiotics.

37

These antibiotics are not commercially available and arespecially formulated by hospital pharmacies or physicians when needed.Traditionally, one antibiotic provided coverage against gram-negativepathogens (an aminoglycoside such as tobramycin or gentamicin [13.6mg/ml]), and the second antibiotic covered the spectrum of gram-positivebacteria (vancomycin [25 mg/mL], cefazolin [50 mg/mL], or bacitracin[10,000 U/mL]). Together, they provided an initial empirical regimen for thetreatment of bacterial keratitis. During the past several years, thefluoroquinolone family of antibiotics has offered an alternative to fortifiedantibiotics as the mainstay of treatment for bacterial ulcerations. Twodouble-masked, controlled, clinical trials have supported the clinical efficacyof using the commercially available fluoroquinolones (ofloxacin 0.3% or

ciprofloxacin 0.3%) as compared with fortified tobramycin andcefazolin.38,39

There are various routes for administering antibiotics in the treatment of ocular infections and include topical, subconjunctival, oral, intravenous, and

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intramuscular. Topical application of antibiotics is the preferred route of

administration for bacterial conjunctivitis and keratitis because the dropsprovide therapeutically effective concentrations; the drops wash awaybacteria and bacterial antigens; adverse systemic effects of the drugs aredecreased or eliminated; and in reliable patients, they can be administered

on an outpatient basis.40–43 The factors that contribute to achieving effective

therapeutic concentrations of the drug in the cornea include the frequency of administration, the concentration of the drug, the lipophilic nature of thedrug where the epithelium is intact, the length of contact time of the drug

with the cornea, and the lack of an intact corneal epithelium.44,45 The next

section deals with the individual characteristics of the various topicalophthalmic antibiotics used to treat bacterial conjunctivitis and keratitis.

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PROPERTIES OF TOPICAL OPHTHALMIC ANTIBACTERIAL AGENTS

FLUOROQUINOLONES

Chemistry, Ophthalmic Preparation, and Pharmacologic Action

The fluoroquinolones, the newest class of agents to be developed, are basedon the prototype, nalidixic acid (1,8-naphthyridine), which was synthesized in

1962.46

In the 1980s, the fluoroquinolones were created from nalidixic acid by addinga fluorine atom to position 6 of the molecule (Fig. 1). This addition widenedthe antibacterial spectrum of activity and resulted in decreased developmentof resistant organisms. Three fluoroquinolones available for ophthalmic useare ofloxacin (Ocuflox, Allergan, Inc, Irvine, CA), ciprofloxacin (Ciloxan,Alcon Laboratories, Inc, Fort Worth, TX), and norfloxacin (Chibroxin, Merck & Co, Inc, West Point, PA). They are formulated as 0.3% solutions and their

structural formulas are shown in Figure 1.

Fig. 1. Chemical structure of the nalidixic acid(A) from which the fluoroquinolones, includingciprofloxacin (B) and ofloxacin (C), werederived.

The fluoroquinolones are bactericidal and work by inhibiting bacterial DNAgyrase (bacterial topoisomerase II), the enzyme responsible for maintaining

the superficial twists in bacterial DNA.47 They provide broad-spectrumactivity against gram-positive and gram-negative bacteria in vivo and invitro. They have less predictable activity against anaerobes and

streptococci.48

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The fluoroquinolones are also available for systemic use, but clinical profilesof the ophthalmic and systemic formulations are distinctly different. Forexample, topical ophthalmic ofloxacin and ciprofloxacin are indicated for usein children as young as 1 year of age, whereas systemic formulations areapproved only for use in older children and adults because of concerns aboutthe potential risk of drug deposition in cartilage and arthropathy. In addition,the prevalence of fluoroquinolone-resistant bacteria is much higher amongsystemic pathogens than among the ocular pathogens commonly associatedwith conjunctivitis and keratitis. Moreover, although the use of systemic

fluoroquinolones must be carefully considered to prevent further induction of resistant strains, this is of much less concern in ophthalmic use, because the

strains of bacteria affected are much lower.49 Although resistance has beenless of a concern in ophthalmic use, resistance to fluoroquinolone antibioticshas been increasing, and for this reason, their use is generally reserved forvision-threatening infections and infections not responding to conventional

therapy.50

Clinical Experience and Ophthalmic Uses for the IndividualOphthalmic Preparations of the Fluoroquinolones

OFLOXACIN 0.3% SOLUTION

Ofloxacin has been tested against many previously established antibiotics inthe treatment of external ocular infection and has been found to have a wide

spectrum of activity.51–53 The Ofloxacin Study Group compared theeffectiveness and safety of ofloxacin 0.3% with gentamicin 0.3% in thetreatment of bacterial external ocular disease. Clinical improvement rateswere 98% (51 of 52) in the ofloxacin group versus 92% (48 of 52) in thegentamicin group. Ofloxacin eradicated or controlled a similar proportion of cultured organisms as did gentamicin. There was no statistically significantdifference in activity between the two drugs. The incidence of adverseeffects attributable to ofloxacin treatment was 3.2% compared with 7.1% for

gentamicin.54

The Ofloxacin Study Group also compared the efficacy of a 10-day course of topical ofloxacin to topical tobramycin in the treatment of external ocularinfection. Initially, the clinical, microbiologic, and overall improvement rateswere not statistically significantly different between the two groups. Theofloxacin-treated patients' examination signs and symptoms on days 3 to 5were significantly more reduced than those of the tobramycin-treated

patients.55,56

Ofloxacin has also been proven to be comparable with chloramphenicol in the

treatment of external ocular infection57 while avoiding the risk of possiblyfatal systemic complications that have been associated with topicalchloramphenicol.

Ofloxacin has been compared with the traditional treatment regimen of afortified aminoglycoside combined with a fortified cephalosporin in thetreatment of bacterial keratitis. O'Brien and coworkers compared ofloxacin0.3% monotherapy with tobramycin 1.5% plus cefazolin 10% therapy. Theproportion of healed ulcers in both culture-positive treatment groups wassimilar (89% ofloxacin healed by 28 days and 86% of combination therapyhealed by 28 days). Adverse effects were higher in the fortified antibioticsgroup; five of the six culture-positive patients who discontinued study

medications were in the fortified antibiotics group.38 The Ofloxacin StudyGroup compared ofloxacin monotherapy to traditional dual therapy of fortified gentamicin 1.5% and cefuroxime 5%. This group found both

treatments to be equally effective in the 49 culture-positive cases studied.51

Ofloxacin is more efficacious against methicillin-resistant S. aureus than

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ciprofloxacin is.58

Of the currently available fluoroquinolones, ofloxacin has the highest intrinsic

solubility,59 is well tolerated because of its near-neutral pH (6.4), and has

the highest rate of penetration into ocular tissues.60,61 This high rate of tissue penetration may also be significant in those cases in which physicianswish to use a topical antibiotic for prophylaxis in intraocular surgery.

CIPROFLOXACIN 0.3% SOLUTION

In two randomized multicenter studies, ciprofloxacin 0.3% was comparedwith a placebo and with tobramycin 0.3% in the treatment of culture-positivebacterial conjunctivitis. Ciprofloxacin was statistically significantly moreeffective than placebo with reduction or eradication of pathogens in 93.6% of ciprofloxacin-treated patients versus 59.5% of the placebo group.Ciprofloxacin and tobramycin were equally effective, with improved cultures

in 94.5% and 91.9% of patients, respectively.62

Topical ciprofloxacin 0.3% has also been proven as safe and effective astobramycin 0.3% and fusidic acid gel 1% in the treatment of bacterial

conjunctivitis in a study of 257 pediatric patients. The investigatorsdetermined 87.0% of the ciprofloxacin-treated patients and 89.9% of thetobramycin-treated patients to be clinically cured after 7 days of treatment.

No adverse effects occurred in either of the treatment groups. 63–65

Monotherapy with ciprofloxacin 0.3% has been compared with combinationtherapy in the treatment of bacterial keratitis. Hyundik and coworkersstudied 176 culture-positive cases of bacterial keratitis randomized totreatment with ciprofloxacin 0.3% or with tobramycin 0.3% and cefazolin5%. There were no statistically significant differences between the treatmentregimens in terms of overall clinical efficacy (91.5% versus 86.2%), time tocure, or reduction in signs and symptoms. The incidence of treatmentfailures was less with ciprofloxacin than with combination fortified therapy.Several other studies have examined the effectiveness of ciprofloxacin in

treating ocular bacterial infections.66–73 There was a trend toward resistance

of S. pneumoniae to ciprofloxacin,39 but ciprofloxacin is more active againstStreptococcus viridans, Pseudomonas aeruginosa, H. influenzae, and S.

marcescens than ofloxacin is.58

Ciprofloxacin has shown potent in vitro activity against P. aeruginosa,

including the aminoglycoside-resistant strains.47,74 The overall in vivoeffectiveness of ciprofloxacin against pathogens, though high at

approximately 92 percent, has declined in the past few years,75

and there isconcern about the emergence of resistant strains of Staphylococcus andPneumococcus species. There also exists an ointment form of ciprofloxacin0.3% and one clinical trial has shown its effectiveness in treating bacterial

keratitis.76

NORFLOXACIN 0.3% SOLUTION

Norfloxacin is the least potent of the topical fluoroquinolones. 48,77,78 It has

been shown to be effective in the treatment of bacterial conjunctivitis79 but

not, with the exception of one small study, bacterial keratitis.80 In

conjunctivitis, it is comparable in efficacy to tobramycin 0.3%81 and

ciprofloxacin 0.3%.64 Norfloxacin has also been shown to be as effective as

gentamicin 0.3% in the treatment of blepharitis and conjunctivitis. 82 In thestudy by Miller and coworkers, norfloxacin suppressed or eliminated 89% of all organisms, based on pretreatment and posttreatment cultures.

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Norfloxacin has the highest rate of resistant bacteria among the

fluoroquinolones based on in vitro testing with ocular isolates.59,83,84

Generalizations on the Group of Ophthalmic Fluoroquinolones

Multiple articles have supported the effectiveness of the fluoroquinolones in

treating ocular bacterial infections.85–88

What are the advantages and disadvantages of the fluoroquinolones as

compared with other, so-called fortified antibiotics? The aforementionedclinical studies conclusively show that ciprofloxacin and ofloxacin arestatistically equal to fortified antibiotics in time to heal and cure rate of infectious corneal ulcers. However, other parameters should be analyzed.The acute management of bacterial corneal ulcers requires rapid access totherapy. In addition, the cost and toxicity of antibiotic therapy must beconsidered. Fortified antibiotics are not commercially available and must beprepared on request. The fluoroquinolones are superior with respect toaccessibility, cost, and low toxicity. The fluoroquinolones perform at least aswell as, and often better than, the aminoglycosides in the treatment of gram-negative corneal ulcers.

One of the main advantages of the fluoroquinolones is their high intrinsic

solubility.60,89,90 Although ofloxacin is more soluble than ciprofloxacin, both

achieve high intracorneal levels in patients with an intact epithelium. 71 In arabbit model with the epithelium intact, it was shown that ciprofloxacin

achieves 10.47 μg/mL in the deep cornea; ofloxacin achieved 21.50 μg/mL.60

Ofloxacin is more lipophilic than ciprofloxacin, which may make it more

effective in penetrating an intact epithelium.91 In most cases of bacterialkeratitis, the epithelium is partially denuded and lipid solubility is not asimportant an issue because of the loss of the barrier function of the

epithelium.92 However, when the more intact the overlying epithelium is,

such as in the cases of suture abscesses after penetrating keratoplasty, themore likely ciprofloxacin and ofloxacin are to offer an advantage. The highstromal levels of ciprofloxacin and ofloxacin may explain the excellentclinical response by patients with ulcers despite intermediate or resistantlaboratory susceptibility patterns in vitro.

The one species for which ciprofloxacin and ofloxacin are not of equalefficacy to fortified antibiotic solutions is streptococci. Neither in vitro norclinically do they provide as good gram-positive coverage as cefazolin,vancomycin, or bacitracin. In a multicenter prospective, but nonblindedevaluation of ciprofloxacin 0.3% versus fortified antibiotics performed by

Leibowitz,62 23.1% of S. pneumoniae corneal ulcers did not respond tociprofloxacin. Based on previous in vitro data, case reports, and the twoprospective evaluations, streptococci seem to be a weak point in thespectrum of activity of the fluoroquinolones. Therefore, any patient atincreased risk of developing a S. pneumoniae infection should be treatedwith an antibiotic, such as bacitracin, vancomycin, or cefazolin, in addition toa fluoroquinolone. There is a known increased incidence of streptococcalinfections in suture abscesses after penetrating keratoplasty andpseudophakic bullous keratopathy. S. pneumoniae is also commonly seen incorneal ulcers related to dacryocystitis and filtering bleb infections.Anaerobic streptococcal infections, such as those causing a crystallinekeratopathy, are unlikely to respond to fluoroquinolone monotherapy.

Finally, patients with hospital-acquired corneal ulcers, in which there is anincreased risk of methicillin-resistant S. aureus, should be treated at least inpart with fortified vancomycin drops.

Adverse Effects

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The fluoroquinolones have low rates of adverse effects.93 That of ofloxacin

(consisting primarily of transient local irritation) is less than 0.6%, 38,54–57,94

and there has never been any report of corneal epithelial toxicity with

ofloxacin.95 The Ofloxacin Study Group51 noted that fortified antibioticsshowed drug toxicity to the ocular surface (defined as punctate cornealstaining, papillary conjunctival reaction, or conjunctival fluoresecin staining)in 50.8% of patients receiving combination therapy versus only 10.2% of ofloxacin-treated patients.

As with ofloxacin, fewer patients treated with ciprofloxacin than treated with

fortified antibiotics, reported ocular discomfort.39 The most commonlyreported adverse effect from topical ciprofloxacin treatment is the formation

of a white crystalline precipitate in approximately 17% of treated eyes.39,63–

65 This results from precipitation of the drug (formulated at pH 4.5), which ispoorly soluble at the near-neutral pH of the tear film. The relationshipbetween this precipitate and antibacterial efficacy is unknown. Theprecipitate resolves spontaneously without sequelae after cessation of themedication. A few patients may also experience some local burning orirritation. There have been a few case reports of corneal precipitates with

norfloxacin use in bacterial keratitis,96 but the overall incidence of adverseeffects seems to be low.

Like the 0.3% solution, the ciprofloxacin ointment has also been shown tocause a white precipitate that resolves spontaneously without sequelae afterdiscontinuing it. Other adverse effects from the ointment include burning,

puntate epitheliopathy, blurred vision, and tearing.76

EXTEMPORANEOUSLY COMPOUNDED FORTIFIED ANTIBIOTICS

Extemporaneously compounded fortified antibiotic eyedrop preparationscontain high concentrations that are usually prepared from products

formulated for intravenous use. A typical treatment regimen might consist of a combination of a cephalosporin (e.g., 50 mg/mL cefazolin) for gram-positive bacteria coverage and an aminoglycoside (e.g., 13 mg/mLtobramycin or gentamicin) for gram-negative bacteria coverage. However,these agents are not compatible when combined in the same solution andmust be formulated separately and administered from different bottles.Another common extemporaneously fortified antibiotic is vancomycin 50

mg/mL.97 Most need to be refrigerated after dispensing to the patient,because, being derived from intravenous products, they do not contain apreservative. Instillation of the two agents must be separated by intervals of several minutes or more (e.g., 15 minutes might be ideal) to prevent

washout of the first agent by the second. The high concentrations used inthese preparations exacerbate their epithelial toxic potential. This is aspecial concern for the aminoglycosides.

In the treatment of bacterial keratitis, fortified cefazolin-aminoglycosidepreparations are as effective as the fluoroquinolones ofloxacin andciprofloxacin, but are more difficult to obtain and use. Not all pharmacies areequipped to formulate extemporaneously compounded agents and not allpharmacists are familiar with the procedures.

There has been some debate in the literature as to the efficacy of using acollagen shield as a vehicle to absorb and deliver drugs. Advocates argue

that collagen shields soak up antibiotics and continuously deliver them to thecornea for several hours, enabling higher concentrations to be delivered forlonger periods of time. However, some studies have found that collagen

shields are not more efficacious than using fortified antibiotics alone.98,99

According to several other studies, collagen shields are labor intensive yet as

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effective in treating bacterial keratitis, as frequent dosages of drops.100–104

AMINOGLYCOSIDES


The two most commonly used aminoglycosides are tobramycin sulfateavailable as a 0.3% solution or ointment (AKTOB [Acorn, Inc, Buffalo Grove,IL], Defy, Tobrex [Alcon Laboratories, Fort Worth, TX]) and gentamicin

sulfate (Fig. 2) available as a 0.3% solution (Garamycin, Genoptic [Allergan,Inc, Irvine, CA], Gentacidin, Gentak [Akorn, Inc, Buffalo Grove, IL], Ocu-mycin) and ointment (Garamycin, Genoptic). Neomycin [Bausch & LombPharmaceutical, Inc, Tampa, FL] is also used, but is only available as acomponent of combination products, not as a single agent. The basicstructure of aminoglycosides consists of two or more amino sugarsconnected by glycosidic bonds to a hexose nucleus. The individualcharacteristics of an aminoglycoside are determined by differences in theamino sugars attached to the nucleus.

Fig. 2. The aminoglycosides, with some of themore commonly used ophthalmic formulationspictured, tobramycin (A), and gentamicin (B),which contain the characteristic two or moreamino sugars connected by glycosidic bonds toa hexose nucleus.

The aminoglycosides cause bacterial cell death by irreversibly binding to 30Sribosomes and causing misreading of the genetic code and decreased or

abnormal protein synthesis.

105

Aminoglycosides are valued in the treatmentof external ocular infections because they are active against aerobic gram-negative organisms, including Pseudomonas species, Proteus species,Klebsiella species, Escherichia coli, Salmonella species, Shigella species, S.

marcescens, Haemophilus species and many gram-positive staphylococci.106

In vitro, tobramycin is three times as effective as gentamicin against

Pseudomonas.107 The aminoglycosides have limited use as broad-spectrumagents because of resistance caused by aminoglycoside-modifying enzymes.

This occurs at an unacceptably high frequency (29%–41%).108 Of particularconcern is their lack of relative efficacy against S. epidermidis and S.

pneumoniae.

Clinical Experience and Ophthalmic Uses

Gentamicin and tobramycin have been shown to be effective in the treatment

of conjunctivitis, blepharoconjunctivitis, and bacterial keratitis.105,109–111

The commercially available concentrations are acceptable for the treatmentof bacterial conjunctivitis, but the highly concentrated, fortified preparationsare preferred for bacterial keratitis and are best used in conjunction with anantibiotic more active against gram-positive bacteria.

Adverse Effects

Gentamicin and tobramycin have been shown to be safe, but tobramycin mayhave fewer adverse effects.112 The most significant safety concern with

aminoglycosides is corneal epithelial toxicity.108,113,114 This is especially so

for neomycin and gentamicin.113 Lass et al. evaluated the concentration-dependent toxicities of neomycin, amikacin, gentamicin, and tobramycin

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using a rabbit epithelial cell culture model.113 Subfortified concentrations of neomycin and gentamicin significantly inhibited epithelial cell metabolismafter 5 minutes of exposure; all the aminoglycosides significantly inhibitedcell metabolism at all tested concentrations after 30 and 60 minutes of exposure. Fortified doses may cause a reversible punctate epithelial keratitis

or pseudomembranous conjunctivitis.115,116 Several cases of conjunctival

defects or necrosis have been reported with the use of fortified

gentamicin,114,117 and at least one case of conjunctival necrosis has been

attributed to fortified tobramycin use.114 Two cases of pseudomembranousconjunctivitis secondary to topical gentamicin have been reported: one caseafter use of commercial-strength gentamicin and one in response to fortified

1.36% gentamicin.118 Neomycin has a high rate of associated allergicreactions; in one study, 18.5% of 27 patients with chronic conjunctivitis had

patch test sensitivity to neomycin.119 Other neomycin toxic manifestations

are conjunctivitis, eyelid edema, punctate corneal erosions, and in high

concentrations, reduced corneal sensation.120

BACITRACIN


Bacitracin is a polypeptide antibiotic that contains a thiazolidine ring

structure (Fig. 3). Bacitracin is bactericidal by binding to cell membranes121

and is commercially produced as a topical ophthalmic ointment (AK-Tracin,Akorn, Inc, Buffalo Grove, IL) or in combination with polymyxin B (AK-poly-bac [Akorn, Inc, Buffalo Grove, IL], Polysporin, Polytracin [MedicalOphthalmics, Tarpon Springs, FL]) or with polymyxin B and neomycin (AK-Spore [Akorn, Inc, Buffalo Grove, IL], Neosporin [Monarch Pharmaceuticals,Bristol, TN], Ocu-spor B). All these preparations contain bacitracin in aconcentration of 500 U per gram of ointment. Unlike most of the otherantibacterial agents discussed in this chapter, bacitracin is only available fortopical use because of its systemic toxicity and poor solubility.

Fig. 3. Structural formula of bacitracin, thepolypeptide antibiotic that contains athiazolidine ring.


Bacitracin is efficacious against most gram-positive organisms and selectgram-negative organisms, including penicillinase-producing staphylococci,Neisseria species, Haemophilus species, and Actinomyces species. Bacitracinpenetrates an intact cornea poorly, but its penetration may be increased by a

corneal epithelial defect.122

Adverse Effects

Commercially available preparations and fortified dosages of bacitracingenerally do not irritate the ocular surfaces. Hypersensitivity reactions,namely skin eruptions, have been reported. There is one report of an acute

anaphylactic reaction associated with topical application of bacitracin.123

BETA-LACTAM ANTIBIOTICS


This class of antibiotics includes the penicillins and cephalosporins. Penicillins

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(Fig. 4) are composed of a thiazolidine ring connected to a beta-lactam ringto which a side chain is connected. The side chain is responsible for theindividual characteristics of the penicillins. Like the penicillins, thecephalosporins (Fig. 5) contain a beta-lactam ring, are bactericidal, andinhibit cell wall synthesis. By preventing the synthesis of polysaccharidesneeded for bacterial cell wall structure, they cause bacterial death. Theytend to be more active against gram-positive organisms, with increasedgram-negative activity in the extended-spectrum penicillins and the second-and third-generation cephalosporins. Bacteria become resistant to penicillins

by producing beta-lactamase; cephalosporins tend to be resistant todegradation by beta-lactamase. All methicillin-resistant S. aureus andenterococci are also resistant to cephalosporins. Approximately 10% of patients allergic to penicillin will also be allergic to cephalosporins.

Fig. 4. Chemical formulas of the penicillinagents, which contain beta-lactam ringsattached to thiazolidine rings (e.g., penicillin[A] and methicillin [B]).

Fig. 5. Illustrations of the cephalosporins,which contain modifications to positions of thebeta-lactam ring of cephalosporin (A), tocreate cefazolin (B), and ceftazidime (C).


The beta-lactam antibiotics are not available in pharmaceuticallymanufactured topical ophthalmic preparations because of their poor stability.The most commonly used topical agent in this class is a first-generationcephalosporin, cefazolin 50 mg/mL, and is made from a parenteralpreparation. As mentioned, cefazolin is used with a topical aminoglycoside inthe treatment of bacterial keratitis. However, ceftazidime alone or incombination with an aminoglycoside or vancomycin has also been explored

as an initial agent for topical therapy of bacterial keratitis.124 A third-generation cephalosporin, ceftazidime, was found to be as effective ascefazolin in treating rabbit corneal ulcers caused by S. aureus and S.

pneumoniae and as effective as tobramycin against P. aeruginosa.125,126

The cefazolin-aminoglycoside combination has been proven to be equivalentto monotherapy with ofloxacin and ciprofloxacin in bacterial keratitis. Topicalcefazolin may also have an important role in combination with

fluoroquinolones. Bower and coworkers127 have predicted that 98.7% of their laboratory's ocular bacterial isolates would be susceptible to afluoroquinolone-cefazolin combination versus 88.2%, 82.3%, and 80.4%,respectively, with ofloxacin, ciprofloxacin, and norfloxacin. Thus, in severecases of bacterial keratitis, cefazolin may be a desirable addition tofluoroquinolone therapy while culture results are pending and may supplant

the need for fortified aminoglycosides.128

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Adverse Effects

The most common adverse effects are allergic reactions to the penicillinswith some cross-allergenicity with the cephalosporins. Topical penicillin canresult in anaphylaxis, and less significantly, there is a high incidence of

contact allergic blepharitis.129 The cephalosporins have relatively few side

effects,129 and approximately only 5% of patients manifest allergicreactions.

CHLORAMPHENICOL


Chloramphenicol, a nitrobenzene derivative (Fig. 6), available as a 1%ointment or a 0.5% solution (AK-Chlor, Chlormycetin [MonarchPharmaceuticals, Bristol, TN], Chloroptic [Allergan, Inc, Irvine, CA], Ocu-Chlor), was the first broad-spectrum antibiotic with gram-positive and gram-negative coverage. It has been widely used in ointment form for the

treatment of external ocular infection.130

Fig. 6. Structure of chloramphenicol, aderivative of nitrobenzene.

Chloramphenicol inhibits bacterial protein synthesis by binding to the 50Sribosomal subunit. It is primarily bacteriostatic but may be bactericidal tosome organisms (e.g., H. influenzae).


Chloramphenicol has good antimicrobial activity against most gram-positiveocular isolates and limited gram-negative coverage. Chloramphenicol shouldnot be used to treat infections in which gram-negative bacteria, especially

Pseudomonas or Serratia species131 are suspected. Because it is usuallybacteriostatic, not bacteriocidal, and because of its limited spectrum,chloramphenicol should not be used in vision-threatening circumstances.

In some studies, chloramphenicol has been shown to be as effective asciprofloxacin, norfloxacin, and trimethoprim-polymyxin B in the treatment of

bacterial conjunctivitis.79,132,133

Adverse Effects

Much has been written about a possible link between topical ophthalmic use

of chloramphenicol and aplastic anemia. Oral chloramphenicol can affect thebone marrow in two ways; one is a dose-related, reversible bone marrowsuppression and the other is an idiopathic, usually lethal effect. Topicalchloramphenicol has been associated with dose-related and idiopathic bone

marrow suppressions.134–140 Chloramphenicol should best not be used inpatients who have a family history of drug-related bone-marrow

failure.141,142 Concern about the risk of aplastic anemia and thedevelopment of more effective antibiotics have been sufficient to drasticallyreduce the use of chloramphenicol in the United States, although it is stillwidely used in other countries.

Burning may occur with topical instillation of chloramphenicol, but it isrelatively nonirritating to ocular structures and allergic reactions areuncommon.

ERYTHROMYCIN

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Erythromycin 0.5% is a macrolide antibiotic (Fig. 7) that inhibits bacterial

protein synthesis by irreversibly binding to the 50S ribosomal subunit.143 Itis bacteriostatic in low concentrations but can be bactericidal in highconcentrations. Other determinants of its bactericidal activity include

organism susceptibility, growth rate of the bacteria, and pH. 144 Erythromycinis available in ointment form (0.5%) for topical ophthalmic use (Ak-mycin,Ilotycin).

Fig. 7. Chemical structure of the macrolideantibiotic, erythromycin.


Erythromycin is used as prophylaxis against neo-natal conjunctivitis causedby C. trachomatis andN. gonorrhoeae. It is also used to treat mild bacterial

conjunctivitis. It has a broad spectrum of antibacterial activity145 and is welltolerated by the ocular surface, but many resistant strains have developed.For example, several strains of H. influenzae, one of the most commonpathogens in pediatric conjunctivitis, are resistant to erythromycin.Therefore, its usefulness in the treatment of external ocular infections islimited.

Adverse Effects

Topical application of erythromycin is not usually irritating to ocular tissues.

POLYMYXIN AND COMBINATION PRODUCTS


Many of the combination products currently available in the United Statescontain polymyxin B sulfate (Fig. 8). It provides efficacy against commonlyencountered gram-negative pathogens such asH. influenzae. Polymyxin is abactericidal polypeptide antibiotic that interferes with cell wall synthesis andforms false pores in bacterial cell membranes. It is less effective againstProteus, Providencia, Serratia, and Brucella species. It came into use inophthalmology in the 1950s, when it was shown that polymyxin was effective

in treating Pseudomonas corneal ulcers in rabbits.146 The effectiveness of this agent was then shown in treating human corneal ulcers infected with

Pseudomonas species.147,148

Fig. 8. Polymyxin B sulfate, a polypeptideantibiotic, which is the most commonpolymyxin in clinical use.

Combinations of polymyxin B with neomycin and gramicidin or trimethoprim

are available as solutions, and combinations with bacitracin, neomycin, andbacitracin, or oxytetracycline are available as ointments only. The ointmentscontain 10,000 U per gram of polymyxin B.

Two antibiotics commonly combined with poly-myxin are gramicidin andtrimethoprim. Gramicidin alters bacterial cell wall permeability. Like

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bacitracin, it is only used topically because of systemic toxicity.Trimethoprim is a competitive inhibitor of bacterial dihydrofolate reductase,

an enzyme that is necessary for purine synthesis.149 The other compoundsthat polymyxin B are combined with are addressed elsewhere in this chapter.


All polymyxin combination products have shown efficacy against bacterial

conjunctivitis,150,151 but no clinical studies of their use in the treatment of bacterial keratitis have been conducted. Clinical studies have shown thatpolymyxin B-trimethoprim andpolymyxin B-neomycin-gramicidin are as

effectiveas each other152–153 and gentamicin sulfate,154 sodium

sulfacetamide,154 and chloramphenicol138,150 in the treatment of bacterialconjunctivitis.

Adverse Effects

Those combination antibiotic products that do not contain the highlyallergenic agent neomycin are commonly recommended in the

literature.4,149,150 Polymyxin B rarely causes a hypersensitivity reaction.

Chronic use of polymyxin B may result in toxic conjunctivitis.

SULFACETAMIDE


Sulfacetamide (Fig. 9) 10% ointment (AK-Sulf, Cetamide, Sulamyd Sodium)and sulfacetamide 10% to 30% solutions (10% AK Sulf [Akorn, Inc, BuffaloGrove, IL], Bleph-10 [Allergan, Inc, Irvine, CA], Ophthacet, Ocusulf, Sulf-10[CIBA Vision, Duluth, GA], Sulamyd Sodium, and Isopto Cetamide) act bypreventing the incorporation of para-aminobenzoic acid into folic acid, thusinhibiting bacterial purine biosynthesis. Sulphonamides are bacteriostatic.

Fig. 9. Chemical structure of sulfacetamide oneof the more commonly used sulfonamides inophthalmic preparations.


Sulphonamides were used in the treatment of external ocular infectionsbefore the need to perform efficacy studies. It is difficult to finddocumentation of their value in the medical literature. In a study of 158cases of culture-positive pediatric conjunctivitis, topical sulfacetamide wasfound to be equivalent in efficacy to trimethoprim-polymyxin B and

gentamicin sulfate solutions.154 Like erythromycin, sulfacetamides have abroad spectrum of antibacterial activity, but many strains of resistantbacteria have developed. Sulfacetamide is still effective against H.influenzae but is ineffective against many staphylococcal isolates, S.marcescens, and P. aeruginosa, which makes it a poor choice as a first-line

treatment for bacterial keratitis.155 It remains a drug of choice for the

treatment of Nocardia species.156

Adverse Effects

Topical sulfacetamide is generally well tolerated. However, there is a small

but significant risk of Stevens-Johnson syndrome associated with the use of

topical sulfacetamide.157–159

TETRACYCLINES

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Tetracycline (Fig. 10) inhibits bacterial protein synthesis by binding to the30S ribosome, and it is among the broadest spectrum agents available. Formost organisms, tetracycline is bacteriostatic.

Fig. 10. The basis of the tetracyclines, shownabove, is a four-ringnaphthacencecarboxamide.


Systemic and topical (ointment) tetracycline are used concurrently to treatC. trachomatis conjunctivitis. Tetracycline can also be used for prophylaxisagainst ophthalmia neonatorum from N. gonorrhoeae or chlamydial

infections.160,161 In newborns developing ophthalmia neonatorum, coexistingoropharyngeal involvement usually requires more than topical drug use.

Adverse Effects

Adverse reactions from tetracyclines, including deposition in the teeth andbones, may be seen with both systemic use and topical application.

VANCOMYCIN


Vancomycin is a complex bactericidal tricyclic glycopeptide (Fig. 11) that

inhibits bacterial cell wall synthesis.162,163 It is active primarily againstgram-positive bacteria, including methicillin-resistant S. aureus, S.

epidermidis, and Enterococcus species.

Fig. 11. Vancomycin is a complex bactericidaltricyclic glycopeptide.


Topical vancomycin has been used successfully to treat chronic methicillin-

resistant S. aureus in institutionalized patients.164 Vancomycin has not beentested against other antibiotics in the treatment of bacterial keratitis, butthere are numerous reported cases of keratitis caused by resistant

organisms that resolved with topical vancomycin therapy.165,166 Vancomycin50 mg/mL has been tested against ciprofloxacin 0.3% in a rabbit model of methicillin-resistant S. aureus keratitis; ciprofloxacin was found to be more

effective in that study.167 These results have not been verified in clinicalstudies. Vancomycin should be considered as a first-line therapy in severecases of keratitis in patients at high risk for infection by methicillin-resistantorganisms, such as healthcare workers or institutionalized patients.

Adverse Effects

Vancomycin is rarely used in routine ocular infections because it is notcommercially available in a topical ophthalmic form. Its use should belimited because of the risk of the development of bacterial resistance.Topical application of vancomycin produces discomfort because of its low pH

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in solution. Adverse effects include conjunctival injection, chemosis, papillaryconjunctivitis, and superficial punctate keratopathy. In rabbits, topical

application was noted to retard corneal epithelial wound healing.168

SELECTING THE OPTIMAL OPHTHALMIC ANTIBIOTIC

The Goals of Treatment

In all bacterial infections, the goal of treatment is to rapidly eradicate the

specific pathogen while minimizing adverse side effects and treatment costs.An ideal agent does not exist and the choice of the most appropriate agentmust be based on a rational compromise. The nature of this compromisemust be patient- and disease-specific.

CLINICAL JUDGMENT IN CHOOSING AN OPHTHALMIC ANTIBIOTIC

In uncomplicated acute bacterial conjunctivitis, the need for treatmentefficacy, though still important to limit the rate of recurrence and spread topersonal contacts, must be balanced by a strong assurance of treatmentsafety and comfort, particularly in children, and a reasonable concern fortreatment cost. A further consideration is to limit the use of antibiotics

needed for systemic infections so that widespread resistance does not occur.The preparation chosen is usually commercially available in a topicalophthalmic form and has a broad spectrum of efficacy against the mostcommonly implicated pathogens. The ophthalmologist and the patient canusually rest assured that they are dealing with a self-limited and usuallybenign process. In the treatment of acute bacterial conjunctivitis, no safetyrisks can be justified, and agents with known toxicity or a high incidence of hypersensitivity reactions should not be considered. However, in chronic orrecurrent bacterial conjunctivitis, the ideal agent is the most effective broad-spectrum antibiotic available that the patient will tolerate, unless antibioticsusceptibility testing suggests that a specific narrow-spectrum agent may bemore effective.

The sight-threatening nature of bacterial keratitis means that treatmentspeed and efficacy must take on more importance. Guidance in the choice of an antibiotic by knowing the specific organism and its sensitivity can becrucial to the outcome. The cost of treatment should only be taken into

account if two or more treatment options are equal in efficacy and safety.153

BACTERIAL CONJUNCTIVITIS

Common Prescribing Practices

Physicians vary widely in their prescribing practices. Most cases of acutebacterial conjunctivitis are treated by nonophthalmologist physicians.Identification of the causative organism (e.g., by gram stain or culture) israre. The use of a mild, broad-spectrum antibiotic preparation, such as oneof the polymyxin B combination products (e.g., polymixin B-trimethoprim orpolymixin B-zinc bacitracin) can be recommended. Sodium sulfacetamide isalso commonly used, despite its bacteriostatic nature and limited spectrumbecause of its low cost and long clinical history. The use of chloramphenicol,because of the fear of aplastic anemia, and the use of neomycin, because of its relatively high rate of allergic reactions, are on the decline. Erythromycincannot be recommended because of its lack of broad spectrum and theemergence of resistant H. influenzae. In more serious cases, a

fluoroquinolone may be indicated because of its broad spectrum and efficacyagainst H. influenzae, as mentioned earlier, a common pathogen in pediatricconjunctivitis.

When bacterial conjunctivitis becomes chronic or recurrent culturing andsensitivity of the causative agent is recommended. In such cases, more

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aggressive treatment with a topical fluoroquinolone is recommended. Of the

fluoroquinolones, ofloxacin followed by ciprofloxacin has the best coverage,and the lowest incidence of resistance. Their excellent tissue penetrationcapabilities will allow them to eradicate any bacteria that have breached thecorneal epithelium and may also help reduce self-reinfection from pathogenssequestered in the meibomian orifices or lacrimal canaliculi.

BACTERIAL KERATITIS

Common Prescribing Practices

The medical literature documents the value of fortified antibiotics and thecommercially available topical fluoroquinolone preparations in the treatmentof bacterial keratitis. In a 1996 survey of 124 ophthalmologists from Florida,

New York, and Illinois,169 82% reported that they would use afluoroquinolone for initial treatment of less severe corneal ulcers, and 6%said that they would use fortified antibiotics. For more severe ulcers,prescribing practices shifted slightly toward fortified antibiotics, with 62%reporting that they would use fluoroquinolones for these cases and 23%stating that they would use fortified antibiotics. One common combination of extemporaneously compounded fortified antibiotics is cefazolin 10% and

tobramycin 1.5% administered as separate solutions. Vancomycin 50 mg/mLshould be substituted for cefazolin for those cases in which antibioticsusceptibility testing suggests that it will be the most effective agent or thereis a significant risk of methicillin-resistant S. aureus. In vitro susceptibilitytesting has shown that the use of a fluoroquinolone in combination withfortified cefazolin is effective against more ocular isolates than ofloxacin,ciprofloxacin, or norfloxacin used alone. Therefore, fortified tobramycin may

be replaced with commercially available ofloxacin or ciprofloxacin.127 It isnot known whether the precipitation of ciprofloxacin has any detrimentaleffect on efficacy. Norfloxacin is the least effective of the availablefluoroquinolones and has not been shown effective in the treatment of

bacterial keratitis.

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