Absorption of intratympanic topical antibiotics

Ear, Nose & Throat Journal, Sept, 2004 by Zoran Becvarovski

For decades, otologists, physiologists, and anatomists have studied the mechanism of systemic and ototopical drug uptake by the inner ear. During that time, otologists have searched for a safe and effective topical medication to treat otitis externa, otitis media, and other otomastoid infections in patients with and without tympanic membrane perforations.

Topical ciprofloxacin has become a widely used medication for treating otitis media in patients with a perforated tympanic membrane. Its popularity can be attributed to its potency, broad spectrum of coverage, and safety. To the best of our knowledge, intratympanic ciprofloxacin has never been implicated as a cause of ototoxicity.

Still, some questions remain about its absorption. Specifically:

* Do intratympanic ciprofloxacin drops enter the human inner ear?

* Are they absorbed by the systemic circulation?

* Are they absorbed by the cerebrospinal fluid (CSF)?

A number of animal studies have been performed with various topical antibiotics and other agents in an attempt to answer questions about absorption of topical agents. (1-6) The results of some of these studies have been extrapolated to humans, and in many cases they have dictated our choice of drug dosages, patient management and treatment protocols, informed consent, and laboratory guidelines. In one of these studies, Bagger-Sjoback et al applied 5 [micro]l of Gelfoam powder mixed with 0.1 mg/ml of ciprofloxacin to the round window membrane (RWM) of 16 chinchilla ears for a mean of 75 minutes. (6) After the Gelfoam was removed, they irrigated the middle ear with saline and aspirated the labyrinthine fluid by puncturing the RWM with a glass capillary pipette. The mean level of ciprofloxacin in the inner ear remained constant at only 0.165 [micro]g/ml.

Factors that affect RWM permeability

Both substance and anatomic factors affect RWM permeability.

Substance factors. Substance factors include molecular size and configuration, concentration, electrical charge, and lipid solubility. Animal studies have also shown that substances with a molecular weight of less than 1,000 (e.g., gentamicin, streptomycin, neomycin, and tetracycline) are transported actively through the RWM over a short period of time. (7,8) Substances with a molecular weight of more than 1,000 (e.g., human serum albumin, ferritin, and endotoxins) can be transported via pinocytosis. Steroids have been shown to diffuse through the RWM.

Anatomic factors. Among the anatomic factors are the thickness of the RWM and the presence of false membranes, tissue plugs, and bony obliteration. In humans, the round window niche has a triangular shape and forms a well, with the true RWM at the bottom. The RWM separates the niche from the scala tympani. The RWM is thickest at its edges and thinnest in the center. Its outer layer is made of epithelium and a continuous basement membrane. The middle layer contains fibroblasts, collagen, elastic fibers, blood vessels, and nerves. The inner layer is made up of mesothelium with micropinocytotic vesicles.

In a study of 202 temporal bones in 117 patients, Alzamil and Linthicum found that the incidence of false RWMs was 21% and the incidence of fat or fibrous plugs was 11%. (7) Of 85 patients who underwent examination of both ears, 22% had some form of obstruction in both ears; 56% had no obstruction.

Interspecies differences. There are two primary differences in the RWMs of humans and animals:

* The RWM in animals does not contain the three layers seen in humans. (9)

* The RWM in animals is thinner. For example, its thickness is 10 to 14 [micro]m in chinchillas, 20 to 40 [micro]m in cats, and 40 to 60 [micro]m in rhesus monkeys. (10) The thickness of the human RWM ranges from 63 to 67.7 [micro]m.

Human labyrinth study

During my time at the Michigan Ear Institute in Farmington Hills, my senior colleagues and I developed the Human Labyrinthine Sampling Model (HLSM). This model allows investigators to accurately determine the intralabyrinthine concentration of systemic and topical drugs at different times following administration. Using the HLSM, we were able to determine that the human RWM is freely permeable by gentamicin (inner ear levels of gentamicin were 16 [micro]g/ml within 30 min) and that intratympanic gentamicin may even be absorbed into the systemic circulation. (11) We also found that intravenous gentamicin was present in the inner ear in significant levels within only a few minutes.

With these findings in mind, we then conducted a prospective study to investigate whether intratympanic ciprofloxacin is absorbed through the human RWM. (12) We believe this is the first such investigation in living humans. Our study population was made up of 10 patients--6 men and 4 women, aged 55 to 73 years (mean: 66)--who were undergoing translabyrinthine acoustic tumor removal.

During surgery, we instilled 0.5 ml of 0.3% ciprofloxacin ophthalmic solution into each ear; 0.1 ml was applied directly to the RWM using a small piece of Gelfoam, and 0.4 ml was injected into the middle ear. Between 9 and 120 minutes later, we opened the lateral semicircular canal and vestibule and aspirated the labyrinthine fluid with a microsyringe. We also drew serum and CSF samples.