Absorption of intratympanic topical antibiotics.

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.

The specimens were express-shipped in dry ice to the Mayo Clinic in Rochester, Minn., for chemical analysis. All samples were then diluted according to standard laboratory practices and analyzed by high-performance liquid chromatography with fluorescence, which can detect ciprofloxacin levels as low as 0.5 [micro]g/ml. Analysis found no measurable amount of ciprofloxacin absorption in either the labyrinthine fluid or the CSF in any patient. The absence of measurable ciprofloxacin absorption into the human inner ear, serum, or CSF reinforces its margin of safety.

It should be noted that during middle ear infections, there is often an abundance of mucosal edema, microorganisms, and fluid that might occlude the round window niche and further inhibit the absorption of ciprofloxacin and other topical medications. Although we made an effort to inspect the RWM in all 10 of our patients, this was possible only in 5. Therefore, a theoretical possibility exists that the lack of ciprofloxacin absorption was the result of a blockage of the RWM, but we find this highly unlikely. In our earlier investigation of topical gentamicin, we noted absorption in nearly all 13 patients.

The absence of measurable ciprofloxacin absorption into the human inner ear, serum, or CSF in our study illustrates the degree of safety of this drug. It appears to be an appropriate antibiotic for the treatment of otologic disease, even in patients without an intact tympanic membrane.

As for the HLSM, it is a safe, reliable, easy-to-perform, repeatable, and inexpensive model that provides valuable information. It can thus be used to better understand the uptake of medications by the inner ear and to assess the RWM permeability of clinically relevant medications, such as steroids and ototopical antibiotics. This model will help us develop safer and more effective ways of delivering medications to inner ears.

References

(1.) Morizono T, Johnstone BM. Ototoxicity of chloramphenicol ear drops with propylene glycol as solvent. Med J Aust 1975;2: 634-8.

(2.) Morizono T, Johnstone BM. Ototoxicity of topically applied gentamicin using a statistical analysis of electrophysiological measurement. Acta Otolaryngol 1975;80:389-93.

(3.) Smith BM, Myers MG. The penetration of gentamicin and neomycin into perilymph across the round window membrane. Otolaryngol Head Neck Surg 1979;87:888-91.

(4.) Juhn SK, Hamaguchi Y. Biochemical study of protease inhibitors in experimental otitis media with effusion. Ann Otol Rhinol Laryngol Suppl 1988;132:10-13.

(5.) Jung TT, Park YM, Miller SK, et al. Effect of exogenous arachidonic acid metabolites applied on round window membrane on hearing and their levels in the perilymph. Acta Otolaryngol Suppl 1992 ;493: 171-6.

(6.) Bagger-Sjoback D, Lundman L, Nilsson-Ehle I. Ciprofloxacin and the inner ear--a morphological and round window membrane permeability study. ORL J Otorhinolaryngol Relat Spec 1992;54: 5-9.

(7.) Alzamil KS, Linthicum FH, Jr. Extraneous round window membranes and plugs: Possible effect on intratympanic therapy. Ann Otol Rhinol Laryngol 2000;109:30-2.

(8.) Wersall J, Lundquist PG, Bjorkroth DB. Ototoxicity of gentamicin. J Infect Dis 1969;119:410-16.

(9.) Spandow O, Anniko M, Moller AR. The round window as access route for agents injurious to the inner ear. Am J Otolaryngol 1988;9: 327-35.

(10.) Goycoolea MV, Muchow D, Schachern P. Experimental studies on round window structure: Function and permeability. Laryngoscope 1988;98(suppl 44): 1-20.

(11.) Becvarovski Z, Bojrab DI, Michaelides EM, et al. Round window gentamicin absorption: An in vivo human model. Laryngoscope 2002;112:1610-13.

(12.) Becvarovski Z, Kartush JM, Bojrab DI. Intratympanic ciprofloxacin and the human labyrinthine sampling model Laryngoscope 2002;112:686-8.