anti-infective therapy
Anti-Infective Update
This article will walk you through the basics of treating ocular infections with anti-infectives, particularly fluoroquinolones.
BY DEEPAK GUPTA, O.D., F.A.A.O., Stamford, Conn.

As primary eyecare providers, we're all licensed and capable of managing ocular infections. However, with all of the options available, we have to keep up to date on the latest in anti-infective therapy. And that's just what this article will do -- update you on current thoughts behind anti-infective therapy.

ILLUSTRATION BY JEAN CALDER

Making a diagnosis

The hallmark symptom of a bacterial infection is a purulent, sticky discharge that often has the patient waking up in the morning with their lids stuck together. In fact, this single symptom is pathognomic for this disease. On slit lamp exam, both eyes are usually involved, and there's usually mild conjunctival vasodilation. Before diagnosing bacterial conjunctivitis, you need to rule out the two other common forms of conjunctivitis: viral and allergic.

Viral conjunctivitis follows a similar clinical pattern as bacterial conjunctivitis, but patients who have this condition are more likely to demonstrate tearing, follicular conjunctival reaction, preauricular lymphadenopathy and corneal infiltrates.

Allergic conjunctivitis. Patients who have this kind of infection often demonstrate severe hyperemia, which can mimic the redness of bacterial conjunctivitis, but the differentiating signs include a significant history of itching and a waxing and waning of symptoms instead of a gradual and progressive worsening.

With the vast majority of typical bacterial conjunctivitis cases, most practitioners opt not to culture. However, it is indicated if there's an associated iritis or corneal involvement, or if there's a pattern of repeated or nonclearing infection. Culture easily with one of the popular culture kits now available. Just position a sterile, wet swab in the lower fornice, inoculate the transport media with the culture sample, and forward the kit to the microbiology laboratory for analysis. If you've already started a patient on antibiotic therapy and he isn't responding, you may want to discontinue therapy for 24 to 48 hours before culturing for more accurate results.

Managing infections

The most common organism involved in bacterial conjunctivitis is Staphylococcus aureus, but researchers have also implicated Staphylococcus pneumoniae, Haemophilus influenzae and Haemophilus aegyptius.

In general, a bacterial infection is self-limited; the signs and symptoms will gradually resolve over the course of one or two weeks regardless of whether the patient uses an antibiotic. However, medical treatment hastens recovery, decreases the incidence of complications and rapidly restores patient comfort. Although serious sequellae are rare, bacterial conjunctivitis can lead to corneal ulcers, resulting in scarring and vision loss. In pseudophakic patients or post-trabulectomy patients, endophthalmitis may result.

Bring in the drugs

Anti-infective agents work by either killing the target organism (bactericidal) or by preventing growth while the host's own normal defenses kill the organisms (bacteriostatic).

Bactericidal. Examples of anti-infectives that kill the target organism include:

• Polymyxin B sulfate, gramicidin and the imidazoles (e.g., ketoconazole) each disrupt the cytoplasmic membrane.
• Sulfonamides and trimethoprim also disrupt the cytoplasmic membrane.

Bacteriostatic. Examples of anti-infectives that prevent growth while the host's defenses kill the organisms include:

• Bacitracin, b-lactamases (penicillin and cephalosporin) and vancomycin all inhibit cell wall synthesis
• The fluoroquinolones (ciprofloxacin, norfloxacin and ofloxacin) and the systemic rifampin inhibit nucleic acid synthesis
• Aminoglycosides (streptomycin, gentamycin and tobramycin), tetracyclines, chloramphenicol and the macrolides (erythromycin and clindamycin) all inhibit ribosome function.

Telling them apart

We can divide antibiotics into five basic groups according to their mechanisms of action.

1. Drugs that inhibit bacterial cell wall synthesis. (E.g., bacitracin and cephalosporins.)

2. Drugs that disrupt the bacterial cell membrane. (E.g., Polymixin B.)

3. Drugs that inhibit bacterial protein synthesis. (E.g., aminoglycosides [neomycin, gentamicin, tobramycin], tetracyclines, erythromycin and chloramphenicol.)

4. Drugs that inhibit folic acid synthesis. This includes sulfonamides and trimethoprim.

5. Drugs that disrupt bacterial DNA synthesis. This class consists of the newest group of drugs, fluoroquinolones, which I'll go into more detail below.

Infection meets its match

The fourth-generation fluoroquinolones, which include gatifloxaxin (Zymar) and moxifloxacin (Vigamox), are our newest allies in the fight against ocular infection. These agents offer the following advantages over previous anti-infective agents.

► Broader-spectrum bactericidal activity -- including effective coverage against Gram-positive, anaerobic and atypical pathogens

► Better permeability

► Better solubility. Numerous studies show that both drugs have greater solubility than older-generation fluoroquinolones partly because of their more neutral pH levels

► Greater concentrations

► Greater bacterial susceptibility, which is a huge advantage of the fourth-generation fluoroquinolones

► Less resistance, which is also a critical feature of the new fluoroquinolones over past generations of fluoroquinolones.

Understanding resistance. Bacteria develop resistance mainly through genetic mutation. The bacteria also feature decreased cell wall permeability, altered enzymes that block antibiotic complexing and efflux pumps that remove antibiotic molecules from the cell. Bacteria can acquire resistance to older antibiotic regimens through a single mutation in the gyrA gene that codes for the DNA gyrase enzyme. Because fourth-generation fluoroquinolones attack two different toposomerases, simultaneous independent mutations in two bacterial genes would have to occur to enable resistance. This dual mutation is far less likely than the single mutation necessary for a mutation to overcome previous generation fluoroquinolones.

Using fourth-generation fluoroquinolones off label. Although both moxifloxacin and gatifloxacin are approved only for treatment of conjunctivitis, off-label use for other ocular infections such as microbial keratitis and surgical prophylaxis has already begun.

• Because bacterial keratitis is potentially devastating, the fourth-generation fluoroquino-lones are already the drugs of choice for infectious keratitis because of their excellent penetration, rapid kill rate and broad spectrum of activity. When used in this manner, the dosing is typically q.1.h. during the day following a recommended loading dose of one to two drops every 15 minutes for two hours.

Many practitioners (including me) also prescribe an antibiotic ointment overnight so the patient can rest. The alternative is to have the patient wake up every hour or two during the night to instill drops. I usually reserve this ordeal for severe cases or for cases in which the infection is close to the visual axis.

You should also administer cycloplegic agents such as homatropine 5% or cyclopentolate HCl 1% b.i.d. and prescribe pain medications depending on the patient's level of discomfort. Also, monitor these patients daily until their infection resolves.

• The superior solubility, excellent penetration and pharmacokinetics/pharmacodynamics profile has made the fourth-generation drugs a popular choice for surgical prophylaxis.

Armed and ready to fight

Today's primary care O.D. has a large arsenal of antibiotics to choose from when confronted with bacterial infections. Making the correct therapeutic choice involves keeping up with the latest additions to that arsenal and paying careful attention to patient signs and symptoms. The new fluoroquinolones are a welcome addition to our toolbox, and others will surely follow.