Intravitreal antibiotic selection may be daunting

Fort Lauderdale, FL-Intravitreal injection of antibiotics is the primary treatment of endophthalmitis. But not just any antibiotic will do the job-a number of considerations go into choosing an appropriate drug. Travis Meredith, MD, described those clinically relevant factors at the annual meeting of the Association for Research in Vision and Ophthalmology.

"Soon after antibiotics were introduced, ophthalmic researchers realized that these drugs might be injected directly into the vitreous cavity, and penicillin and sulfathiazole were injected into the vitreous as early as the mid-1940s," said Dr. Meredith, professor and chairman, department of ophthalmology, University of North Carolina, Chapel Hill.

"However, intravitreal antimicrobial injections were not accepted in clinical ophthalmology until they were routinely administered in the late 1970s," he continued. "There was considerable controversy surrounding this practice."

Because of the importance of antimicrobial therapy for addressing endophthalmitis, selecting the ideal antimicrobial has received considerable attention, but a single antimicrobial to cover all forms of the disease has not been developed.

Clinical considerations

"To choose the ideal antimicrobial to treat intraocular infection, we must consider the therapeutic window of the antimicrobial, pharmacokinetic considerations, particularly the half-life, microbial killing characteristics, and the spectrum of coverage," Dr. Meredith explained.

The first factor, the therapeutic window, is defined as the concentration range over which the drug is effective without undue toxicity, he explained.

"Toxicity considerations determine the maximum dosage of drug that may be injected intravitreally, but there is difficulty in defining toxicity," Dr. Meredith said. "Once injected, the drug concentration must remain at a certain level over time to be effective. Therefore, if a one-time injection is chosen, the duration of action is extremely important."

Determining retinal toxicity is difficult because most studies are typically done in rabbits due to familiarity, convenience, cost, and an existing literature of comparative data. Because the rabbit retina is not identical to that of humans, some forms of toxicity may be missed; a classic example was aminoglycoside toxicity that occludes the small retinal vessels. Because of the differences in the vascular structure between human and rabbit retinas, this catastrophic complication was not discovered until aminoglycoside injections were used in patients, Dr. Meredith stated.

Pharmacokinetics

In addition to toxicity, pharmacokinetics and pharmacotherapeutics should play a role in selecting intraocular antimicrobials.

"We know more about the pharmacokinetics of intraocular antimicrobial injections than about the pharmacotherapeutics; the pharmacokinetics is the study of the kinetics of a drug in the body, including absorption, distribution, metabolism, and elimination," Dr. Meredith said. "Multiple factors, including the route of elimination, the vitreous cavity volume, ocular blood barriers, inflammation, lens status, and drug diffusability in the vitreous, determine the half-life of an antimicrobial injected into the vitreous."

Hydrophilic drugs, such as vancomycin and the aminoglucosides, tend to be cleared from the eye by the anterior route, traversing around the lens and exiting through aqueous routes. These drugs have a relatively long half-life, i.e., about 24 hours in normal eyes. Other medications including the beta-lactams and clindamycin are eliminated posteriorly through the retina, retinal pigment epithelium, and possibly the retinal vessels. Active pumping mechanisms are sometimes involved as demonstrated by the prolonged half-life of these drugs when probenecid is administered. These half-lives are short, typically about 7 to 10 hours.

Disease states and ocular surgeries affect the half-life. Inflammation increases the half-life of some posteriorly eliminated drugs, presumably by altering the active pump. However, vitrectomy and lens removal tend to shorten the half-life of most antimicrobials.