Review of Antibacterial Drugs Used For Treatment of Ocular Infections

By Diane P. Yolton, PhD, OD, FAAO

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BACTERIA THAT CAUSE OCULAR INFECTIONS

Gram Stain Bacterial Classification

Figure. 1. Gram-stain of Staphylococcus epidermidis.

Figure 2. Gram stain of Staphylococcus aureus within a tissue sample.

Figure 3. Gram stain of Streptococcus pneumoniae seen as chains of two (diplococci)(arrow) within a tissue sample.

Figure 4. Gram stain of Neisseria gonorrhoeae seen as gram-negative diplococci (arrow) inside a polymorphonuclear neutrophil (two arrows).

Figure 5. Gram stain of Haemophilus influenzae. Arrows show very short, gram-negative rods and also long rods in the same specimen.

Figure 6. Gram stain of Pseudomonas aeruginosa.

Bacterial Classification Based on Structure

Figure 7. Chlamydia growing inside a conjunctival epithelial cell (intracellular inclusion body).

Figure 8. Treponema pallidum.

BACTERIAL RESISTANCE

Resistance/Susceptibility Testing

Minimal Inhibitory Concentration

Figure 9a. A minimal inhibitory concentration (MIC) test was run in the upper set of wells. The wells to the right are yellow indicating bacterial growth; the wells to the left are clear indicating no growth. The MIC is somewhere to the left where the bacterial growth halted.

Lab Report from Tuality Hospital Laboratory, Hillsboro, OR

Source: Tissue/Lt Bursa Elbow Wound Culture

Preliminary Report - 2+ Staphylococcus aureus

Antibiotic	MIC	Sensitive (S) or Resistant (R)
Amp/Sulbactam	< or = to 4	S
Cefazolin	< or = to 8	S
Ciprofloxacin	< or = to 0.5	S
Clindamycin	< or = to 0.5	S
Erythromycin	> or = to 8	R
Gentamicin	< or = to 2	S
Oxacillin	0.5	S
Penicillin	> or = to 16	R
Trimethoprim/Sulfa	< 0.5/9.5	S
Tetracycline	< or = to 1	S
Vancomycin	< or = to 0.5	S
Beta Lactamase	Positive

Figure 9b. An example of culture and susceptibility test results. This strain of Staphylococcus aureus isolated from an elbow infection is sensitive to ampicillin/sulbactam; that means it is also sensitive to amoxicillin/clavulanate. The strain is also sensitive to cefazolin; that means it is sensitive to all the cephalosporins. In addition it is sensitive to all the fluoroquinolones, the aminoglycosides, the tetracyclines, and vancomycin. It is not sensitive to erythromycin; that means it is also resistant to the other macrolides. The bacteria produces penicillinase (beta lactamase) so is resistant to penicillin but not to the penicillinase-resistant penicillins such as oxacillin.

High and Low Level Resistance

To evaluate the clinical significance of resistance to a topical antibiotic, it is helpful to quantify the level of resistance into low-level and high-level categories. Low-level in vitro resistance may not necessarily predict clinical treatment failure because the tissue levels that can be achieved with topical dosing may be much higher than levels achieved with systemic drug use. (Topically administered drug levels can be much higher in a localized area than levels produced by systemic administration because the risk of whole-body side-effects is less with topical administration.) By contrast, finding a high-level resistant bacteria is more likely to predict treatment failure because the MIC drug level may not be achievable, even with topical administration.

Development of Bacterial Mutants

Drug resistant bacterial mutants are more likely to arise after exposure to repeated courses of sub-lethal antibiotic levels. This means that antibiotics should not be used intermittently and at low dosage levels. Patients should be educated about using or taking antibiotics according to the dosage schedule and should use or take all of the antibiotics prescribed.

Sub-lethal bacterial exposure can also occur if antibiotic dosage levels are tapered. Thus, in most cases, antibiotics are not tapered but discontinued while at a high dose level.

RELATIONSHIP BETWEEN BACTERIAL STRUCTURE AND ANTIBACTERIAL DRUG ACTION

Several differences exist between bacterial and human cells, and these differences form the basis for selective toxicity of the antibacterial drugs (Figure 10). Knowledge about a drug's mode of action is clinically useful because if more than one antibiotic is required for treatment of an infection, the antibiotics chosen should have different modes of action.

Bacterial Structure

Bacteria have a unique outermost layer, a cell wall that is not found in any human cell. The bacterial cell wall is necessary for the bacterium's structural integrity; without it, the bacterium lyses and dies.

Obviously, this structural difference between bacterial and human cells provides a point of attack for antibiotic drugs.

Figure 10. The morphology of a bacterial cell.

A second structural difference between most bacteria and human cells is in the cell membrane. However, because membranes of both cell types are so similar, only a few drugs have been found that can selectively disrupt bacterial cell membranes while leaving those of the human cells intact.

A third difference between bacterial and human cells involves their ribosomes, which are involved for protein synthesis. Bacterial ribosomes are not the same size, nor do they have the same composition as human ribosomes. Thus, drugs that bind more to bacterial than to human ribosomes can inhibit bacterial protein synthesis and be selectively toxic for bacterial cells.

A fourth difference between bacterial and human cells involves biosynthetic pathways (intermediary metabolism). Bacterial cells usually synthesize their own folic acid, whereas humans receive folic acid in their food. Thus, drugs that can inhibit folic acid synthesis are selectively toxic for bacteria.

A fifth difference between bacterial and human cells involves the enzymes DNA gyrase and topoisomerase IV. These enzymes are involved in DNA synthesis; they are responsible for separating the stands of duplex bacterial DNA, inserting another stand of DNA through the break, and then resealing the originally separated strands. Human cells lack these enzymes so drugs that inhibit them are bactericidal.

DRUGS THAT AFFECT BACTERIAL CELL WALL SYNTHESIS

Penicillins

All penicillins contain a common nucleus composed of a thiazolidine ring and a beta-lactam ring connected to a side chain. An intact beta-lactam ring is necessary for bacterial cell wall disruption, but the side chain primarily determines which bacteria are most strongly affected, susceptibility to gastric acid and beta-lactamase enzymes, and other pharmacokinetic properties.

Penicillins act by inhibiting synthesis of the bacterial cell wall, ultimately resulting in death of the bacteria. Penicillins exert their bactericidal effect most strongly on actively dividing cells that are synthesizing new cell walls.

The basic penicillin nucleus has been chemically modified to produce penicillins with unique advantages. Based on their spectra of antibacterial activity and their clinical applications, the penicillins can be divided into four categories.

Penicillins Effective Against Gram-positive Bacteria

The two most important drugs in this category are penicillins G and V. Although the spectrum of activity of penicillin G and V includes most gram-positive cocci, the development of resistant bacteria has significantly reduced the useful spectrum of these antibiotics.

Because Treponema pallidum is sensitive to penicillin G, this antibiotic is the drug of choice for treatment of syphilis and syphilitic eye disease. Syphilitic eye disease can include interstitial keratitis (stromal inflammation and vascularization), episcleritis, scleritis, non-granulomatous or granulomatous iritis, iris papules (collections of dilated capillaries in iris), chorioretinitis, papillitis, retinal vasculitis, and exudative retinal detachment (Figures 11 and 12).

Figure 11. Interstitial keratitis caused by syphilis.

Figure 12. Anterior uveitis.

The types of penicillin G and the dosages for treatment of syphilitic eye disease are outlined in Table 1 shown at the end of the course. As the table shows, probenecid can be added to procaine penicillin, which causes an increase in penicillin plasma levels.

Penicillins Resistant to Penicillinase

Modification of the penicillin structure has produced a group of drugs including methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin that staphylococcal penicillinase cannot break down. The appropriate use of these antibiotics is in the treatment of infections caused by strains of Staphylococcus aureus and S. epidermidis that produce penicillinase.

Because a meibomian gland infection (internal hordeolum, Figure 13) is typically caused by staphylococci, oral dicloxacillin can be used when the hordeolum is severe or not resolving with topical treatment such as hot compresses (Table 1).

Figure 13. An internal hordeolum.

Orbital Cellulitis

Orbital cellulitis is an infection of the orbital contents posterior to the orbital septum (Figure 14). Causes includes pre-existing paranasal sinusitis, dacryocystitis, dacryoadenitis, dental or intracranial infections, trauma, and postorbital surgery. Because this infection can have grave consequences, a gram-stained smear, culture, and sensitivity testing should be performed on any purulent material present to determine resistance patterns and MIC levels.

Figure 14. Orbital cellulitis.

Streptococci and staphylococci are common bacterial isolates from orbital cellulitis. Intravenous nafcillin can be used as initial therapy for this condition, especially when a staphylococcal infection is suspected or known. (Table 1)

The widespread prevalence of methicillin-resistant strains of S. aureus and S. epidermidis is a problem, especially in nosocomial (hospital-acquired) infections. As commonly used, the term “methicillin-resistant'' denotes bacteria that are resistant to all of the penicillinase-resistant penicillins. The resistance of these organisms is due to altered penicillin-binding proteins. Resistant strains are usually cross-resistant to the cephalosporins, aminoglycosides, and erythromycin. For this reason, vancomycin is the drug of choice for these organisms.

Penicillins with Extended Spectra of Activity

Further modification of the basic penicillin structure has produced drugs including ampicillin and amoxicillin with broader spectra of activity than the original penicillins, but both drugs are inactivated by bacteria that produce penicillinase.

The addition of a beta lactamase inhibitor to a penicillin preparation can protect the penicillin component from inactivation by penicillinase or beta lactamase. Beta lactamase inhibitors such as clavulanate (clavulanic acid) or sulbactam used alone have weak antimicrobial activity, but can inactivate bacterial beta lactamases and are therefore added to some penicillin preparations.

For example, amoxicillin/clavulanate (Augmentin®), which is taken orally and ampicillin/sulbactam, which is given intravenously are useful for treating ocular infections suspected or caused by penicillinase-producing strains of Staphylococcus aureus and Staphylococcus epidermidis, penicillin-susceptible stains of Streptococcus pneumoniae and beta-lactamase-producing strains of Haemophilus influenza.

These infections include orbital cellulitis, preseptal cellulitis, and dacryocystitis (Table 1). In a patient with orbital cellulitis, the antibiotic needs to be delivered IV so ampicillin/sulbactam is used.

Preseptal Cellulitis

In contrast to orbital cellulitis, which is an infection of the orbital contents, preseptal cellulitis is an infection in the connective tissue of the lid and anterior periorbital tissues anterior to the orbital septum. Preseptal cellulitis can follow a hordeolum, periorbital trauma, or skin infection. A gram-stained smear, culture, and sensitivity testing should be performed on any purulent material present.

Figure 15. Preseptal cellulitis. A hordeolum (one arrow) has extended into a preseptal cellulitis (two arrows).

Staphylococcus aureus and Streptococcus pyogenes are often isolated from patients with preseptal cellulitis. In children less than 5 years of age, Haemophilus influenzae is frequently found. In mild preseptal cellulitis, oral amoxicillin/clavulanate can be prescribed but in a more serious infections of the lids, ampicillin/sulbactam IV is used (Table 1).

Dacryocystitis

Dacryocystitis is an infection of the lacrimal sac, often with an overlying cellulitis. It occurs when the lacrimal drainage system is blocked and bacteria from the tears infect the lacrimal sac. Pressure over the sac can result in reflux of mucopurulent material from the punctum. Gram stain and culture and sensitivity testing should be performed on this material to direct the clinician in the choosing the most appropriate follow-up antibiotics if there is no response to the initial antibiotics used for treatment.

For most conditions, clinicians use a broad-spectrum antibiotic when the infection is initially diagnosed, and then change the drug later if no response to the initial treatment is found. In other than "garden-variety" infections, samples of infectious material should be obtained before an antibiotic is used because the antibiotic can reduce the number of culturable organisms, which will make drug susceptibility testing more difficult or impossible.

Acute Dacryocystitis

Bacterial causes of acute dacryocystitis include staphylococci, Streptococcus pneumoniae, Pseudomonas species and Haemophilus influenzae in children, all of which are susceptible to oral amoxicillin/clavulanate. More serious infections require IV administration of ampicillin/sulbactam. The bacterial infection needs to be treated before nasolacrimal duct irrigation, probing or surgery is done.

Figure 16. Acute dacryocystitis

In about 2 to 4% of full-term newborns, the membrane over the valve of Hasner at the nasal end of the duct has not perforated. This causes a recurrent conjunctivitis and sometimes a dacryocystitis. Because spontaneous opening frequently occurs 1 to 2 months after birth, management is not overly aggressive. Warm compresses, massage from the canaliculi down over the lacrimal sac, and a topical antibiotic if mucopurulent discharge is present are often all that are needed to resolve this condition (Table 1).

Side-Effects of Penicillins

The major adverse reactions to penicillins are hypersensitivity (allergic) responses. The overall chance of developing a reaction per course of oral therapy is approximately 2%. Manifestations of hypersensitivity include urticaria, angioedema and anaphylaxis (type I reaction), hemolytic anemia (type II reaction), interstitial nephritis, vasculitis and serum sickness (type III reaction), and contact dermatitis or Stevens-Johnson syndrome (type IV reaction).

Once a patient has had a hypersensitivity response to one form of penicillin, it is probable, but not certain, that a reaction will occur with repeat exposure to the same penicillin or to any other penicillin.

Penicillins alter the normal bacterial flora that live in areas of the body including the respiratory and intestinal tracts. If the normal flora are killed by oral penicillins, patients may experience nausea, vomiting, or diarrhea. This is usually of little clinical significance, because the normal flora reestablish themselves quickly after cessation of therapy. However, serious superinfection with resistant organisms such as Pseudomonas, Proteus, or Candida may follow long-term therapy with any penicillin. Superinfection with Clostridium difficile can lead to pseudomembranous colitis.

Very infrequently and unpredictably, the penicillins can cause oral contraceptives to fail. For maximal protection, a barrier contraceptive method should be used while taking a short course of penicillin therapy and for at least seven days afterward.

Cephalosporins

Like penicillins, cephalosporins contain a beta lactam ring that interferes with the final step in bacterial cell wall formation.

An important mechanism of acquired resistance to cephalosporins is drug inactivation by beta-lactamases produced by bacteria. However, the beta-lactamases produced by S. aureus are only penicillinases and do not affect the cephalosporins. Thus, cephalosporins are usually active against penicillinase-producing S. aureus. In contrast, gram-negative bacteria produce beta lactamases that inactivate many of the cephalosporins.

Adding different side-chains to cephalosporins has extensively modified the parent drug and created a whole family of cephalosporin antibiotics. For the sake of convenience, cephalosporins are considered as first-, second-, or third-generation drugs based on their spectra of bacterial activity and their clinical uses.

Progression from first to third generation cephalosporins generally produces a broadening gram-negative spectrum, loss of efficacy against gram-positive organisms, greater efficacy against resistant organisms, and increased cost. However, the first- through third-generation classification scheme is becoming less clear as newer cephalosporins become available.

First-Generation Cephalosporins

First-generation cephalosporins include cefazolin (e.g., Ancef®), cephalexin (e.g., Keflex®), and cefadroxil (e.g., Duricef®). All are effective against gram-positive bacteria but have relatively modest activity against gram-negative bacteria.

Oral cephalexin can be used to treat non-resolving internal hordeola (Table 1).

Corneal Ulcers

Corneal ulcers involve destruction of the corneal epithelium and stroma due to inflammation from a bacterial infection. Risk factors are those conditions or diseases that compromise the corneal epithelium such as contact lens wear, trauma, dry eyes, exposure keratopathy, neurotrophic cornea, and lid abnormalities.

Bacteria that cause corneal ulcers include staphylococci (half of the infections are caused by these organisms), streptococci, Haemophilus, and other gram-negative rods, especially Pseudomonas and Serratia in contact lens wearers.

Figure 17. A bacterial corneal ulcer with hypopyon.

Because of the risk of blindness and the variety of bacteria that can cause corneal ulcers, the initial antibiotic treatment must be aggressive and broad spectrum. Before applying any antibiotic, the infected cornea should be scraped so that gram-stained smears and cultures can be made. Sensitivity studies should be performed on any bacterial pathogen cultured.

Initial treatment can include cefazolin because its spectrum of activity encompasses the gram-positive cocci including penicillin-resistant staphylococci. (The penicillinase produced by staphylococci does not inactivate the cephalosporins.) Cefazolin is administered topically as specially prepared (fortified) eye drops, which are made from a concentrated intravenous preparation. Cefazolin is used every hour alternating with fortified gentamicin or tobramycin for gram-negative coverage. (Table 1)

Second-Generation Cephalosporins

The second-generation cephalosporins include cefamandole, cefaclor (e.g., Ceclor®), cefprozil (e.g., Cefzil®), cefoxitin (e.g., Mefoxitin®), and cefuroxime (e.g., Ceftin®). These drugs are generally more active against gram-negative enteric bacteria than are first-generation drugs, but they are much less active against these organisms than are third-generation cephalosporins.

Compared to first generation cephalosporins, second-generation drugs have improved activity against beta-lactamase producing H. influenzae. Oral cefaclor, a commonly prescribed second-generation cephalosporin, can be used to treat dacryocystitis and mild preseptal cellulitis (Table 1).

Intravenous administration of cefuroxime along with ampicillin/sulbactam is a recommended treatment for moderate to severe preseptal cellulitis. (Table 1)

Third-Generation Cephalosporins

Third-generation cephalosporins include ceftriaxone (e.g., Rocephin®), cefixime (e.g., Suprax®), and ceftazidime (e.g., Fortaz®). These drugs are much more active against gram-negative organisms than are first- or second-generation drugs, but they are less active against gram-positive bacteria.

Most of the third-generation drugs are considerably more resistant to bacterial beta lactamase activity than are the first-generation cephalosporins. Thus, third-generation cephalosporins are especially useful for treating infections caused by gram-negative bacteria that produce beta lactamase or that have become resistant to the aminoglycosides. These infections include orbital cellulitis for which ceftriaxone is combined with nafcillin, and endophthalmitis for which ceftazidine is combined with vacomycin (Table 1).

Endophthalmitis

Endophthalmitis is an infection of the inside of the eyeball. It may be localized or can involve both the anterior and posterior segments. Most cases of endophthalmitis occur after intraocular surgery such as for cataract removal. Staphylococcus epidermidis is the leading cause of this infection.

Endophthalmitis can also occur after trauma or can spread from another place in the body. In this case, a wide variety of bacteria might be causing the infection.

Figure 18. Endophthalmitis.

Because of the severity and potentially eye-threatening outcome of endophthalmitis, antibiotics are administered intravitreally (especially if a vitrectomy was performed), topically, and subconjunctivally. A wide variety of organisms can cause this condition so a broad-spectrum approach must be used. Ceftazidime is used to cover the gram-negative organisms and vancomycin is used to cover the gram-positive organisms. (Table 1)

Gonococcal Infections

Because of the ubiquitous distribution of penicillinase-producing Neisseria gonorrhoeae, a recommended regimen for treating infections, including gonococcal conjunctivitis, involves use of intramuscular ceftriaxone, a third-generation cephalosporin (Table 1).

Cefixime, another third-generation cephalosporin, can be also used for the treatment of gonorrhea and is advantageous because it can be administered orally.

Figure 19. Gonococcal conjunctivitis.

Gonococcal conjunctivitis most often occurs when an individual with gonorrhea self-contaminates his/her own eye. Because N. gonorrhoeae can invade the cornea, this infection needs to be treated aggressively and systemically. Presumably the patient also has gonorrhea and should be tested and treated for this infection. (If gonorrhea is diagnosed, the state health department must be notified because gonorrhea is a reportable disease.) Systemic treatment of the eye disease is the same as that used for gonorrhea, i.e., injected ceftriaxone.

Figure 20. Gonococcal conjunctivitis of the newborn (ophthalmia neonatorum).

If a woman with gonorrhea gives birth, there is a risk that the eyes of the newborn will be infected. Intramuscular or intravenous ceftriaxone is the recommended treatment for gonococcal conjunctivitis of the newborn.

Side-Effects of Cephalosporins

As with the penicillins, hypersensitivity reactions are the most common adverse systemic effects caused by cephalosporins. Maculopapular rash, urticaria, fever, bronchospasm, anaphylaxis, and eosinophilia have been associated with the use of these drugs. Because the molecular structures of the penicillins and cephalosporins are similar, patients who are allergic to penicillins may manifest a cross-sensitivity to a cephalosporin. Immunologic studies have found cross-reactivity in as many as 20% of penicillin-allergic patients, but clinical reports suggest a lower range (5% to 10%) of cephalosporin reactions in penicillin-allergic patients. This risk is greatly influenced by the severity of the prior reaction to penicillin. Therefore, a cephalosporin may be an effective substitute for penicillin in patients with an equivocal history of penicillin allergy or a history of mild reactions, but a cephalosporin should be avoided for patients who have experienced a severe, immediate hypersensitivity reaction.

Like penicillins, cephalosporins alter the normal microflora of the intestinal tract and can cause anorexia, nausea, vomiting, and diarrhea. In some cases the diarrhea can become severe enough to warrant discontinuing the drug. Antibiotic-associated pseudomembranous colitis due to Clostridium difficile can also occur with the cephalosporins; this condition should be considered in the differential diagnosis of diarrhea associated with cephalosporin use.

Bacitracin

Bacitracin inhibits bacterial cell wall synthesis but it acts at a different step in the process than the beta lactam antibiotics such as the penicillins and cephalosporins. Bacitracin prevents the formation of polysaccharide chains that would normally be cross-linked to form the rigid peptidoglycan of the cell wall.

Most gram-positive bacteria such as staphylococci, streptococci, and Clostridium difficile are susceptible to bacitracin. Although this drug is active against Neisseria, most gram-negative bacteria are resistant.

Clinical Uses

Bacitracin is seldom used systemically because renal necrosis has occurred after such use. In addition, safer and more effective drugs with similar antibacterial spectra, such as the penicillins, are available.

Bacitracin is primarily used topically to treat skin and mucous membrane infections caused by gram-positive organisms because only a few of these bacteria have become resistant to it.

Bacitracin is available in topical preparations either as a single-drug product or as a component of fixed-combination products. Because bacitracin is unstable in solution, it is available only in ointment form in either formulation.

Topical ophthalmic bacitracin is effective for staphylococcal blepharitis, because most staphylococci have not become resistant to it (Table 1).

Figure 21. Staphylococcal blepharitis with crusts clinging to the lashes and lid margin.

Figure 22. Staphylococcal blepharitis. Arrow points to an infected lash follicle.

Staphylcoccal Blepharitis

Staphylcoccal blepharitis is an infection of the lid margin and lash follicles. The bacteria involved can either be S. aureus, an overgrowth of a normal lid flora member, S. epidermidis, or both. Typical clinical signs are crusts on the lashes and lid margins, and/or infected lash follicles with trichiasis or madarosis.

Staphylococcal blepharitis is rarely cured but with treatment, can be controlled. Topical bacitracin ointment is applied to the lid margins after warm compresses and lid scrubs. After the infection is under control, the bacitracin is discontinued, and warm compresses and lid scrubs can usually control the disease. (Table 1)

The rationale for making drugs containing bacitracin combined with other antibacterial agents such as polymyxin B is that drugs with complementary antibacterial spectra covering most of the common pathogens can be produced.

The combination of bacitracin and polymyxin B (Polysporin®) is an ointment useful for infection prophylaxis (e.g., under a pressure patch) because bacitracin covers the gram-positive bacteria and polymyxin B covers the gram-negative bugs.

Side-Effects of Bacitracin

Hypersensitivity reactions, usually presenting as contact dermatitis, are rare but can occur with topically applied bacitracin.

Vancomycin

Like the other drugs discussed in this section, vancomycin acts by inhibiting biosynthesis of peptidoglycan during bacterial cell wall formation. It is highly active against gram-positive cocci including staphylococci and streptococci, as well as Clostridium difficele, Corynebacterium diphtheriae, and Neisseria gonorrhoeae.

Clinical Uses

Because of its toxicity, vancomycin is reserved for serious infections when less toxic antibiotics are ineffective or not tolerated. Vancomycin is an acceptable alternative to penicillins or cephalosporins for the treatment of serious infections caused by staphylococci and streptococci. It is the drug of choice for treating infections caused by methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae.

Because of its excellent activity against gram-positive bacteria including methicillin- and cephalosporin-resistant staphylococci, vancomycin (along with ceftazidime) is recommended for intravitreal, topical, and sometimes subconjunctival therapy in bacterial endophthalmitis. (Table 1)

Side-Effects of Vancomycin

The use of vancomycin in large oral doses, with prolonged therapy, in concomitant or sequential use with other ototoxic or nephrotoxic drugs, or in patients with impaired renal function has caused permanent deafness and fatal uremia. Hearing and renal functions should be checked frequently when administering systemic vancomycin.

DRUGS AFFECTING THE BACTERIAL CELL MEMBRANE

Polymyxin B

Of the large number of compounds that affect the bacterial cell membrane, only a few have sufficient selective toxicity to be therapeutically useful. Polymyxin B is a cationic detergent or surfactant that interacts with the phospholipids of the cell's membranes, disrupting the membranes and killing the bacteria.

Clinical Uses

Polymyxin B is effective against gram-negative bacteria including Pseudomonas. In combination with bacitracin (Polysporin® ointment), it is an excellent broad-spectrum antibiotic combination used to treat common bacterial infections of the conjunctiva and lids.

Because polymyxin B is available only as an ointment, it is not very patient-friendly for daytime use in adults. However, if antibiotic coverage is needed at nighttime, Polysporin® is an excellent choice. Polysporin® ointment is also used in young children who “cry out” antibiotic drops. Another use for Polysporin® is for prophylaxis after a corneal abrasion, either alone or under a pressure patch.

Side-Effects of Polymyxin B

Adverse reactions to topical application of polymyxin B including irritation and allergic reactions of the eyelids and conjunctiva are infrequent and typically mild.

DRUGS AFFECTING BACTERIAL PROTEIN SYNTHESIS

Aminoglycosides

The aminoglycosides include gentamicin, tobramycin, neomycin, and amikacin. These drugs inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. The consequences of this interaction include inhibition of bacterial protein synthesis and an infidelity in correctly reading the genetic code during bacterial replication.

Aminoglycosides are used to treat infections caused by gram-negative bacilli such as P. aeruginosa, Proteus, Klebsiella, E. coli, Enterobacter, and Serratia. Aminoglycosides are also effective against many strains of staphylococci; however, they are not often used for systemic staphylococcal infections because numerous alternative antibiotics are effective and less toxic.

Gram-negative bacilli show widespread resistance to the aminoglycosides. Cross-resistance among aminoglycosides is often complete. For example, bacteria resistant to gentamicin are usually also resistant to tobramycin.

Aminoglycosides are poorly absorbed from the gastrointestinal tract and must be given parenterally when systemic administration is required. Note that penicillins may inactivate aminoglycosides if mixed together in the same solution for injection or for topical application; each must be administered separately.

Gentamicin

Topical ophthalmic gentamicin is available in solution and ointment forms and is used to treat a variety of bacterial infections such as conjunctivitis (Table 1).

Bacterial Conjunctivitis

Bacterial conjunctivitis is a surface infection of the epithelium. Because the bacteria do not usually invade the tissue and the body's immune system kills them, the disease is self-limiting. Treatment is used to shorten the infection time and prevent spread of the infection to other parts of the body (and to others).

The bacteria that cause conjunctivitis include S. epidermidis and S. aureus (about 50% of the time), Streptococcus pneumoniae, Haemophilus influenzae, and other gram-negative rods. Because both gram-positive and gram-negative bacteria cause conjunctivitis, antibiotics used to treat this infection must be broad spectrum. Most causative bacteria are still sensitive to gentamicin so this antibiotic is efficacious for the treatment.

Figure 23. Bacterial conjunctivitis.

Bacterial Corneal Ulcers

Gentamicin is also used as an antibiotic for treatment of bacterial corneal ulcers, but the commercially available strength of ophthalmic gentamicin solution is considered inadequate for this condition. Consequently, solutions containing fortified concentrations are prepared from sterile products intended for parenteral use. Therapy with fortified gentamicin drops along with a penicillinase-resistant cephalosporin (e.g., cefazolin) is used until the causative organism and susceptibility are known from culture testing. An initial loading dose (1 drop every minute for 5 minutes) increases the antibiotic concentration in the cornea rapidly. Drops then can be applied every hour, with the fortified gentamicin applied on the hour and the cephalosporin on the half hour.

Tobramycin

The antibacterial activity and pharmacokinetic properties of tobramycin resemble those of gentamicin, and tobramycin's therapeutic uses are essentially identical to those for gentamicin. One difference between gentamicin and tobramycin is that, in vitro, tobramycin is more potent against Pseudomonas aeruginosa.

When used in the commercial concentration for treatment of surface infections, there is no conclusive proof that tobramycin is clinically superior to gentamicin. However, fortified tobramycin is often substituted for gentamicin in treatment of bacterial keratitis (Table 1).

Neomycin

Neomycin is found only in combination with other antibiotics and/ or steroids. One combination is Neosporin® solution that contains neomycin, gramicidin and polymyxin B. In Neosporin® ointment, bacitracin replaces gramicidin because bacitracin is unstable in water.

These antibiotic combinations are effective against most gram-positive and gram-negative bacteria and in the past have been used extensively for prophylactic and active treatment of ocular surface infections. However, they are now rarely used because of frequent contact allergic reactions to neomycin.

A classic neomycin allergic reaction consists of erythema and mild edema of the lids, conjunctival injection, and punctate epithelial erosions of the cornea. Even though only about 5% of patients experience a reaction, other antibiotics are equally effective without the unnecessary risk of neomycin side-effects.

Figure 24. Contact allergic reaction

Amikacin

Amikacin was the first semi-synthetic aminoglycoside marketed. Because a chemical modification present in amikacin protects the molecule from aminoglycoside-inactivating bacterial enzymes, it has become the preferred drug for treatment of gram-negative bacillary infections in which resistance to both gentamicin and tobramycin is encountered.

At the clinical level, however, evidence is lacking that amikacin is more efficacious than gentamicin or tobramycin for infections caused by susceptible organisms.

Because amikacin is active in vitro against many gram-negative bacilli that are resistant to other aminoglycosides, and because amikacin is less toxic when injected intravitreally, it has become an alternative antibiotic (along with vancomycin) for treatment of bacterial endophthalmitis. (Table 1)

Side-Effects of Aminoglycosides

Both topical gentamicin and tobramycin can cause corneal toxicity seen as punctate epithelial erosions, delayed re-epithelialization, along with corneal ulceration and conjunctival toxicity seen as chemosis, hyperemia, and necrosis. These responses are usually not serious and occur after the drug has been used more than a week or two. Allergic reactions to topical gentamicin occur infrequently, but approximately 50% of patients who are allergic to neomycin are also allergic to gentamicin.

Tetracyclines

Tetracyclines are broad-spectrum antibacterial drugs active against gram-positive and gram-negative bacteria as well as Chlamydia. Based on differences in pharmacokinetics, tetracyclines are usually divided into 3 groups: short-acting including tetracycline, intermediate-acting, and long-acting including doxycycline. All the tetracyclines are closely related chemically and in general have similar patterns of bacterial susceptibility and resistance.

Tetracyclines bind to the 30S subunit of the bacterial ribosome, blocking protein synthesis.

Clinical Uses

Although tetracyclines are broad spectrum, their clinical usefulness is limited for most of the common microbial pathogens such as S. aureus due to bacterial resistance. However, the tetracyclines still remain drugs of choice (or very effective alternative drugs) for a wide variety of infections caused by less common pathogens such as Chlamydia.

Chlamydial Infections

Chlamydia need to grow inside epithelial cells because they lack the ability to produce sufficient energy to grow independently. To eradicate these bacteria, oral antibiotic treatment must be used.

In the US, the typical infection with Chlamydia is genital and the eye becomes infected through self-inoculation. Chlamydial infection of the eye (inclusion conjunctivitis) is characterized by a chronic, follicular conjunctivitis and corneal subepithelial infiltrates.

Trachoma

Trachoma, the leading cause of blindness in the world, is rarely seen in the US. It is caused by different strains of Chlamydia than those that cause genital infection and is typically transmitted by fingers, towels, etc. from eye to eye.

Trachoma is clinically characterized by a follicular conjunctivitis with upper tarsal scarring that causes damage to the cornea. Bacterial corneal infection, scarring and blindness can follow.

Figure 25. Chlamydial conjunctivitis showing the upper palpebral conjunctiva (top) and lower palpebral conjunctiva with follicles (bottom).

Doxycycline is a recommended treatment for chlamydial genital infection. Similarly, oral doxycycline or tetracycline can be used to treat ocular chlamydial infections in adults, inclusion conjunctivitis or trachoma (Table 1). Compared with tetracycline, doxycycline can be taken without regard to meals, and the twice-daily regimen enhances patient compliance.

Oral tetracycline or doxycycline can be an effective therapy for non-infectious conditions involving the eye such as acne rosacea and meibomianitis, as well as for recalcitrant or chronic staphylococcal blepharitis.

Acne Rosacea

Rosacea (acne rosacea) is an idiopathic, chronic disorder with frequent ocular manifestations.

Figure 26. Acne rosacea. Note the crusts on the lashes of the right eye indicating a blepharitis associated with the rosacea.

Rosacea patients are often of Northern European decent and have erythema, pustules, papules, and telangiectasis of the nose, chin, forehead and cheeks; rhinophyma occurs late in the disease course. Common ocular findings are blepharitis, chalazia, meibomianitis, conjunctival infection, and dry eye.

Meibomianitis

Meibomianitis is a partial or complete blockage of the meibomian glands. Clinically, patients can have the “toothpaste sign.” Gentle pressure on the lids produces thick, white sebaceous material from the glands.

Figure 27. Meibomianitis. Note the thickened secretions being expressed from the meibomian glands.

When patients with rosacea or meibomianitis receive an oral tetracycline, two changes occur: amelioration of the symptoms and reduction of free fatty acids in the surface sebum. These free fatty acids released from sebum by bacterial lipases are irritating and inflammatory. A tetracycline causes a significant decrease in lipase production in sensitive or resistant S. epidermidis without affecting bacterial growth.

Thus, tetracycline exerts its therapeutic effect by causing substantial decreases in the lipolytic activity of the normal bacteria without necessarily eliminating them. The treatment for rosacea, meibomianitis, and chronic or severe staphylococcal blepharitis is 100 mg of doxycycline twice a day for a month and then a very long taper (Table 1). Although some patients can discontinue their medication without recurrence of symptoms, others must continue on low dose maintenance for extended periods.

Side-Effects of Tetracyclines

Hypersensitivity reactions to tetracyclines can occur but are uncommon. Photosensitivity reactions, manifested as exaggerated sunburn, can occur with all tetracycline analogs and patients should avoid the sun (or use sunscreen) when using these medications.

At usual dosage levels, all tetracyclines have relatively low toxicity, but oral administration can produce varying degrees of gastrointestinal irritation. Anorexia, heartburn, nausea, vomiting, flatulence, and diarrhea may occur. Although not usually disabling, these reactions can become severe enough to require discontinuation or interruption of therapy. When diarrhea persists or becomes severe, pseudomembranous colitis caused by Clostridium difficile must be considered.

The administration of tetracycline with food may reduce its irritative effects, but food can adversely affect the drug's absorption. In contrast, the absorption of doxycycline is only slightly affected by the presence of food, including dairy products.

Because all tetracyclines can form complexes with divalent cations, the absorption of tetracyclines is markedly decreased when they are administered with iron-containing tonics or antacids containing calcium, magnesium, or aluminum. Sodium bicarbonate also adversely affects tetracycline absorption.

Tetracyclines are attracted to embryonic and growing bone tissue and form a tetracycline-calcium orthophosphate complex, temporarily depressing bone growth. They can also cause changes in both deciduous and permanent teeth during the time of tooth development; these changes include dysgenesis, staining, and an increased tendency to caries. Tooth discoloration may be progressive and can vary from yellowish brown to dark gray. Because of bone growth depression and tooth discoloration, women in the last half of pregnancy, lactating women, and children under 8 years of age should avoid tetracyclines.

Intracranial hypertension (pseudotumor cerebri) secondary to the use of many tetracycline analogs can occur in infants and adults. When the antibiotic is discontinued, cerebral fluid pressure and any accompanying visual and ophthalmoscopic changes usually return to normal over a period of days or weeks.

Tetracyclines can interact significantly with other drugs, and these interactions should be considered when the patient is taking multiple medications. Tetracyclines can increase the effects of coumadin-type anticoagulants and seriously interfere with blood clotting.

Macrolides

The macrolide antibiotics include erythromycin, clarithromycin, and azithromycin. These drugs inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing elongation of the peptide chain. They have low toxicity because they do not bind to mammalian ribosomes.

The spectrum of activity for the macrolides includes gram-positive cocci (streptococci and staphylococci) and gram-positive bacilli, Neisseria, and Chlamydia. The macrolides have variable activity against Haemophilus influenzae.

Resistance is developing to erythromycin and probably also to clarithromycin and azithromycin among the gram-positive cocci including Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes and Streptococcus pneumoniae. This resistance might limit the future clinical usefulness of these antibiotics.

Erythromycin

Erythromycin is a widely used macrolide antibiotic because of its relative lack of toxicity and good activity against susceptible organisms. (It has poor activity against H. influenzae.)

Erythromycin is available in topical, oral, and intravenous preparations. When given orally, however, gastric acid inactivates the erythromycin base, resulting in decreased absorption. Because of this, a large number of formulations and derivatives have been developed to optimize stability and absorption.

One approach involves adding a protective coating to shield the erythromycin base from acid degradation in the stomach. Another chemically modifies the erythromycin molecule to decrease acid inactivation.

When oral erythromycin is administered in the correct dose and with proper timing in relation to food intake, no single preparation appears to offer a significant therapeutic advantage in treating mild to moderate infections. However, erythromycin estolate usually is not recommended for adults because of an increased risk of cholestatic hepatitis. In children this form of erythromycin rarely causes hepatitis, and some pediatric specialists prefer this formulation because of better bioavailability.

Staphylococcal Infections of the Eyelid

For topical application, erythromycin is only available as an ointment. A common application of this ointment is treatment of staphylococcal eyelid infections. Warm, moist compresses should be applied to the lid and the lid margins should be gently cleaned with dilute baby shampoo or a commercial lid cleanser before applying the drug to the eyelid margins. Erythromycin ointment can be applied at bedtime or more often if required by infection severity.

Prophylaxis of Neonatal Conjunctivitis

The Centers for Disease Control (CDC) recommends erythromycin ointment as an alternative to silver nitrate for the prophylaxis of neonatal conjunctivitis. Approximately a 0.5 to 1 cm ribbon of ointment is instilled into each conjunctival sac of the newborn and is not flushed from the eyes following application.

Chlamydia

Chlamydia trachomatis infections in infants and children are primary indications for the use of oral erythromycin. This antibiotic is equally as effective as the tetracyclines for chlamydial infections and is safer for pregnant women, nursing mothers, and children under 8 years of age.

Erythromycin can be used for the treatment of adult chlamydial genital disease. Adults should receive 2 g of erythromycin daily in 4 divided doses for at least 7 days.

Trachoma and inclusion conjunctivitis in older children or adults can also be effectively treated with oral erythromycin with a 3-week course of 2 g daily in 4 divided doses. Patients receiving full oral therapeutic doses of antibiotic do not need topical treatment with ophthalmic erythromycin ointment.

Clarithromycin

Clarithromycin is a more recently developed macrolide antibiotic. It is stable in gastric acid and is well absorbed. Because the half-life of clarithromycin is approximately twice that of erythromycin, patients take clarithromycin only twice daily compared to 4 times a day for erythromycin. Clarithromycin is active against H. influenzae and is considerably more active than erythromycin against Chlamydia.

Azithromycin

Azithromycin is another recently developed macrolide antibiotic. Following oral administration on an empty stomach, azithromycin is rapidly absorbed and widely distributed throughout the body. Because azithromycin has an extended half-life, once-daily dosing is effective, which encourages patient compliance. Compared with erythromycin, azithromycin is more active against gram-negative bacteria such as H. influenzae.

Skin Infections

Azithromycin is indicated for mild infections of the skin caused by susceptible strains of S. pneumoniae, H. influenzae, Staphylococcus aureus, and S. pyogenes. Treatment is 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 through 5 (Zithromax Z-Pak).

Chlamydia

A single 1-gram dose of azithromycin is recommended treatment for chlamydial urethritis and cervicitis. Azithromycin as a single 1 gram dose is also effective for the treatment of gonorrhea, which makes treatment for both gonococcal and chlamydial diseases cost effective. A single 1gram dose is effective for the treatment of trachoma in adolescents and adults, and a single oral dose of 20 mg/kg can be used for treatment in children. A single 1gram dose of azithromycin can also be used to treat inclusion conjunctivitis.

Side-Effects of Macrolides

Erythromycin is one of the safest antibiotics in current clinical use. Gastrointestinal irritation (abdominal cramps, nausea, vomiting, and diarrhea) is the most common adverse reaction produced by erythromycin and is usually associated with oral administration of 2 g or more daily. Some brands of enteric-coated tablets and the ester derivatives (e.g., ethylsuccinate) can be taken with food to minimize adverse effects.

Like erythromycin, the most common side-effects of azithromycin and clarithromycin are gastrointestinal, with diarrhea, nausea, and abdominal pain being the most frequently reported. Other side-effects of azithromycin include palpitations, vaginitis, headache, dizziness, fatigue, and hypersensitivity reactions. Clarithromycin can also cause headache and dyspepsia.

The most serious toxicity of erythromycin involves cholestatic hepatitis that occurs mainly in adults and only when the estolate preparation of erythromycin is used. This syndrome appears to be a hypersensitivity reaction to the specific structure of the estolate compound. Thus, despite the rarity of this reaction, erythromycin estolate should be used with caution in adults.

Because clarithromycin can have adverse effects on embryo-fetal development in animals, this drug should be avoided in pregnant women unless no other therapy is appropriate.

Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Concurrent administration of the macrolides and astemizole or terfenadine can cause elevated antihistamine levels resulting in life-threatening cardiac arrhythmias including torsades de pointes.

DRUGS AFFECTING INTERMEDIARY BACTERIAL METABOLISM

Sulfonamides

The sulfonamides are rarely used in contemporary eye care because of widespread resistance and poor effectiveness.

Trimethoprim

Because bacterial cells are impermeable to folic acid, they need to synthesize it. Trimethoprim blocks this synthesis by binding to and reversibly inhibiting certain enzymes. (Specifically it reversibly inhibits dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, the metabolically usable form of folic acid.) Trimethoprim-binding affinity is much stronger for the bacterial form of the enzyme than for the corresponding mammalian enzyme so the drug produces true selective toxicity.

Clinical Uses

A combination of trimethoprim and polymyxin B (Polytrim®) is available as a topical ophthalmic solution and an ointment with a broad spectrum of activity for treatment of surface ocular infections.

Trimethoprim has significant in vitro activity against gram-positive and gram-negative organisms including staphylococci, streptococci, Haemophilus, and gram-negative enterics. However, because it is not active against Pseudomonas, polymyxin B is included in the combination to cover gram-negative bacteria, including Pseudomonas aeruginosa.

Bacterial Eye Infections in Children

Trimethoprim-polymyxin B is effective for the treatment of blepharitis, conjunctivitis, and blepharoconjunctivitis. Side-effects are very rare. Because it is clinically effective against Haemophilus influenzae and Streptococcus pneumoniae, the most common causes of bacterial eye infections in children, it is a drug of choice for treating bacterial eye infections in children.

Figure 28. Bacterial conjunctivitis.

Side-Effects of Sulfonamides

Trimethoprim-polymyxin B is well tolerated with few reported serious adverse reactions following topical ophthalmic use. The most frequent adverse reaction reported (about 4%) is local irritation including transient burning or stinging, itching, or redness following instillation.

Less than 2% of patients experience a hypersensitivity reaction consisting of lid edema, itching, increased redness, tearing, or periocular rash. Trimethoprim does not cross react with sulfonamides.

Although the presence of thymine and thymidine in pus could allow some bacteria to escape the blockage of dihydrofolate reductase produced by trimethoprim, clinical studies suggest that a purulent discharge is not a contraindication to the use of trimethoprim-polymyxin B.

DRUGS AFFECTING BACTERIAL DNA SYNTHESIS

Drugs that inhibit bacterial DNA synthesis include the fluorinated quinolones (fluoroquinolones) that are structurally related to nalidixic acid: ciprofloxacin, ofloxacin, levofloxacin, norfloxacin, lomefloxacin, enoxacin, sparfloxacin, grepafloxacin, and trovafloxacin/alatrofloxacin.

Pharmacology

Fluoroquinolones interfere with DNA synthesis during bacterial replication by inhibiting DNA gyrase and/or topoisomerase activity. Human cells lack these enzymes so they are ideal targets for antibiotic activity.

In older fluoroquinolones including ciprofloxacin and ofloxacin, DNA gyrase tends to be the primary fluoroquinolone target for gram-negative bacteria whereas topoisomerase is typically the primary target for gram-positive bacteria.

With years of fluoroquinolone use, resistance has developed. Staphylococcal strains including strains of methicillin-resistant staphylococci have become resistant to ciprofloxacin despite initial in vitro indications of susceptibility. Strains of Staphylococcus epidermidis resistant to ciprofloxacin have been isolated from corneal ulcers. Other organisms developing resistance include the gram-negative rods Pseudomonas aeruginosa, Klebsiella pneumoniae, Citrobacter species, and Enterobacter species.

The newer fluoroquinolones (gatifloxacin and moxifloxacin) likely have a dual-binding mechanism of action, inhibiting both DNA gyrase and topoisomerase in gram-positive species. Owing to the rarity of double mutations, the preferential use of the newer fluoroquinolones could potentially limit the emergence of resistance to them and their use could be preferential to use of an older fluoroquinolone.

Clinical Uses

Oral fluoroquinolones are indicated for the treatment of infections of the skin.

Ciprofloxacin (e.g., Ciloxan®), ofloxacin (e.g., Ofloxacin®), norfloxacin, levofloxacin (Iquix® and Quixin®), gatifloxacin (Zymar®), and moxifloxacin (Vigamox®) are available as topical ophthalmic solutions and ciprofloxacin is also available as an ophthalmic ointment.

These drugs are broad spectrum, effective against both gram-positive and gram-negative bacteria. However, resistance by staphylococci and other organisms is appearing.

Although the clinical benefits of two of the most recently introduced ophthalmic fluoroquinolones, gatifloxacin, and moxifloxacin, have yet to be fully established, they may address the rising incidence of fluoroquinolone resistance. These two fluoroquinolones also offer another advantage over the older fluoroquinolones (e.g., ciprofloxacin and ofloxacin) by having lower MICs for gram-positive cocci.

All of the available fluoroquinolones are effective for bacterial conjunctivitis. Again, it may be advantageous to use one of the newer fluoroquinolones for treatment of this condition.

Bacterial Ulcers

Ciprofloxacin and ofloxacin are indicated for the treatment of bacterial ulcers caused by a variety of pathogens. These two antibiotics offer the convenience of “off-the-shelf” treatment of bacterial keratitis (specially compounded fortified eye drops are not required).

Application of these antibiotics is intensive. The suggested initial regimen for ciprofloxacin therapy is one to two drops in the affected eye every 15 minutes for the first six hours and then every 30 minutes for the rest of the day (Table 1). The dosage on day two is one to two drops every hour.

Figure 29. Bacterial corneal ulcer.

Monotherapy with ciprofloxacin or ofloxacin, although usually successful, is becoming more controversial as resistance develops to these antibiotics. Some suggest that fluoroquinolone monotherapy be used only for small, off-visual axis corneal ulcers and that larger, more visual-threatening ulcers still be treated with specially compounded fortified antibiotics.

Side-Effects of Fluoroquinolones

As a group, the fluoroquinolones are generally well tolerated with a low incidence of adverse reactions. Following systemic administration, the most common side-effects include nausea, headache, dizziness, rash, bitter taste, elevation of liver enzymes, and eosinophilia.

The frequency of adverse reactions to topical ophthalmic fluoroquinolones is low. The most frequently reported adverse reactions are local burning or discomfort following instillation; bitter taste following instillation; foreign body sensation; itching; and conjunctival hyperemia, chemosis and photophobia.

Frequent instillation of ciprofloxacin for treatment of corneal ulceration resulted in white precipitates occurring in 17% of the patients, but the precipitates did not require discontinuation of therapy. One report, however, suggested that the precipitates can form an adherent plaque on the cornea that interferes with healing.

Erosion of cartilage in the weight-bearing joints and other signs of arthropathy have been reported in several species of immature animals. Although such lesions have not been described in humans, these drugs are not recommended for systemic administration in children, adolescents below the age of 18 years, or pregnant women. Topical administration to immature animals does not cause arthropathy, and the ophthalmic dosage form does not appear to affect the weight-bearing joints in humans. All of the topical ophthalmic fluoroquinolones are approved for use in patients one year of age and older.

SUMMARY

Summary Table 1. Antibacterial Drugs of Choice and Dosages for Initial Treatment of Ocular Infections

Ocular Infection	Drug Choices and Initial Dosages
Blepharitis
Staphylococcal (1)	Bacitracin or Erythromycin; Apply 1/4 inch of ointment to each lid margin qhs
Meibomianitis (2)	Tetracycline; 250 to 500 mg qid or Doxycycline; 100 mg bid
Acne rosacea (3)	Tetracycline; 250 to 500 mg qid or Doxycycline; 100 mg bid
Hordeolum
External	Bacitracin or Erythromycin; Apply 1/4 inch of ointment to inferior fornix (prophylactic) bid to tid
Internal (nonresolving)	Dicloxacillin; 250 mg po q6h or Cephalexin (4); 250 to 500 mg po q6h
Conjunctivitis
Acute Mucopurulent	One of the following 1 to 2 drops q2h to qid: Gentamicin, Tobramycin, Trimethoprim/Polymyxin (5), Ciprofloxacin (6), Ofloxacin (7), Norfloxacin, Levofloxacin (8), Gatifloxacin (9), Moxifloxacin (9);
Adult Gonococcal (10)	Ceftriaxone; 1 gm im in single dose
Neonate Gonococcal (10)	Ceftriaxone; 25 to 50 mg/kg iv or im in single dose not to exceed 125 mg
Adult Chlamydial (11)	Doxycycline; 100 mg po bid or Azithromycin; 1 gm po in a single dose
Neonate Chlamydial (11)	Erythromycin (Base or Ethylsuccinate); 50 mg/kg/day po divided into four doses
Dacryocystitis
Acute Mild (12)	Amoxicillin/clavulanate; 250 to 500 mg po tid or Cefaclor; 250 to 500 mg po tid
Acute Moderate/Severe (12)	Ampicillin/sulbactam; 15 to 30 mg IV q6h
Neonate (13)	Erythromycin; 1/4 inch ointment into inferior fornix bid (prophylactic)
Preseptal Cellulitis (14)
Mild	Amoxicillin/clavulanate; 250 to 500 mg po tid or Cefaclor; 250 to 500 mg po tid
Moderate to Severe	Cefuroxime; 1 g iv q8h and Ampicillin/sulbactam; 15 to 30 mg iv q6h
Orbital Cellulitis (15)
All Types	Nafcillin; 1 to 2 g iv q4h and Ceftriaxone; 1 to 2 g iv q12-24 hr or Ampicillin/sulbactam; 1.5 to 3 g iv q6h
Keratitis
Small	Ciprofloxacin (16); 2 drops q15m for the first 6 hrs, then q30m or Ofloxacin (17); 1 to 2 drops q30m while awake
Large	Fortified cefazolin (50mg/ml) and fortified tobramycin (13.6 mg/ml); 1 or 2 drops q30m alternating drops on a q1h cycle (use a drop every 30 min)
Endophthalmitis (18)
Intravitreal	Vancomycin; 1mg/0.1ml injected and amikacin; 0.4mg/0.1ml injected or Vancomycin; 1mg/0.1ml injected and ceftazidime; 2.25mg/0.1ml injected
Topical	Vancomycin; 50mg/ml q1h and ceftazidime; 50mg/ml q1h; alternate q30min
Subconjunctival	Vancomycin; 125mg and ceftazidime; 100 mg
Syphilitic Eye Disease (Neurosyphilis)
Adult (19)	Aqueous Crystalline Penicillin G; 18-24 million U/d administered as 3 to 4 million U iv q4h or continuous infusion for 10-14 days or Procaine Penicillin; 2.4 million U im qd and Probenecid; 500 mg po qid both for 10-14 days
Neonatal (20)	Penicillin G; Type and dosage depend on probability of infection

References

1. Everett SL, Kowalski RP, Karenchak LM, et al. An in vitro comparison of the susceptibilities of bacterial isolates from patients with conjunctivitis and blepharitis to newer and established topical antibiotics. Cornea1995;14:382-387.

2. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis Sci 1991;32:2970-2975.

3. Auarterman MJ, Johnson DW, Abele DC, et al. Ocular rosacea. Signs, symptoms, and tear studies before and after treatment with doxycycline. Arch Dermatol 1997;133:49-54.

4. Bartlett JD, Fiscella RG, Bennett E, et al. Ophthalmic Drug Facts 2002. Facts and Comparisons. Wolters Kluwer 2002, pg 340.

5. Lohr JA, Austin RD, Grossman M, et al. Comparison of three topical antimicrobials for acute bacterial conjunctivitis. Pediatr Infect Dis J 1988;7:626-629.

6. Leibowitz HM. Antibacterial effectives of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis. Am J Ophthalmol 1991;112(suppl):29S-33S.

7. Gwon A. Topical ofloxacin compared with gentamicin in the treatment of external ocular infection. Ofloxacin study group. Br J Ophthalmol 1992;76:714-718.

8. Hwang DG, Schanzlin DJ, Rotberg MH, et al. A phase III, placebo controlled clinical trial of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. Br J Ophthalmol 2003;87:1004-1009.
9. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol 2004;49(suppl 2):S79-S83.

10. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;6-51(No.RR-6):38-40.

11. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;6-51(No.RR-6):32-35.

12. Friedman NJ, Pineda R, Kaiser PK. The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Saunders 1998; pgs 81-83.

13. MacEwen CJ, Phillips MG, Yound JD. Value of bacterial culturing in the course of congenital nasolacrimal duct (NLD) obstruction. J Pediatr Ophthalmol Strabismus 1994;31:246-250.

14. Friedman NJ, Pineda R, Kaiser PK. The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Saunders 1998; pgs 11-12.

15. Friedman NJ, Pineda R, Kaiser PK. The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Saunders 1998; pgs12-14.

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

17. The Ofloxacin Study Group. Ofloxacin monotherapy for the primary treatment of microbial keratitis. A double-masked, randomized, controlled trial with conventional dual therapy. Ophthalmology 1997;104:1902-1909.

18. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol 1995;113:1479-1496.

19. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;6-51(No.RR-6):23.

20. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;6-51(No.RR-6):26-28.

Images used in this course have been derived from a number of sources including: Spalton, Hitchings, Hunter: Slide Atlas of Clinical Ophthalmology, 1994, Mosby Year Book Europe Limited; Kanski: Clinical Ophthalmology Slide Sets,1992, Butterworth-Heinemann; Catania: Primary Eyecare, 1986, Educational Services; various Web sites.

Contact the author:

Diane P. Yolton, PhD, OD

Pacific University College of Optometr

2043 College Wa

Forest Grove OR 97116 US

yoltond@Pacificu.edu

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