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Original Article |

Auditory Function After a Prolonged Course of Ciprofloxacin-Dexamethasone Otic Suspension in a Murine Model FREE

Katherine R. Kavanagh, MD; Kourosh Parham, MD, PhD; Scott R. Schoem, MD
[+] Author Affiliations

Author Affiliations: Division of Otolaryngology–Head and Neck Surgery, Department of Surgery, University of Connecticut Health Center, Farmington (Drs Kavanagh and Parham); and Department of Otolaryngology, Connecticut Children's Medical Center, Hartford (Dr Schoem).


Arch Otolaryngol Head Neck Surg. 2009;135(3):238-241. doi:10.1001/archoto.2008.559.
Text Size: A A A
Published online

Objective  To test for ototoxicity after prolonged ototopical fluoroquinolone use in the middle ear space using a murine model.

Design  Nonrandomized controlled trial.

Subjects  Twelve CBA/J mice.

Interventions  The mice received daily intratympanic injections of ciprofloxacin-dexamethasone otic suspension for 21 days. The contralateral ear received daily intratympanic injections of sterile isotonic sodium chloride solution (saline) as a control.

Main Outcome Measures  Click-evoked auditory brainstem response (ABR) thresholds were obtained before injection and 10 days and 3 months after injection.

Results  Mean (SEM) preinjection ABR thresholds were 47.17 (2.74) dB peak equivalent sound pressure level (peSPL) in ciprofloxacin-dexamethasone–treated ears and 45.08 (1.56) dB peSPL in saline-treated ears (P = .38). Mean (SEM) postinjection ABR thresholds in ciprofloxacin-dexamethasone–treated ears were 44.25 (1.25) dB peSPL after 10 days and 43.00 (1.51) dB peSPL after 3 months. Mean (SEM) postinjection ABR thresholds in saline-treated ears were 48.00 (1.51) dB peSPL after 10 days and 45.92 (1.79) dB peSPL after 3 months. There were no significant differences in ABR thresholds for ciprofloxacin-dexamethasone–treated ears (P = .29, P = .10) or saline-treated ears (P = .07, P = .59).

Conclusion  Ciprofloxacin-dexamethasone suspension did not cause either immediate or delayed ototoxicity after 21 days of intratympanic administration in the CBA/J mouse model.

Figures in this Article

Topical antibiotic eardrops are indicated for the treatment of acute otitis externa, chronic suppurative otitis media, and acute otitis media through tympanostomy tubes or a tympanic membrane perforation in children and adults. Otic drops provide an advantage over systemic antibiotic drug therapy by providing a higher concentration of medication at the infection site and avoiding the adverse effects of systemic treatment.1 In addition, owing to the high concentration of medication with ototopical antibiotic agents, which can be 1000-fold higher than with systemic antibiotics, antibiotic resistance is unusual with this method of treatment.1

Typical pathogens involved in acute otitis media through tympanostomy tubes include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, and Moraxella catarrhalis.2,3 Topical antibiotic eardrops that provide adequate coverage against these pathogens include those that contain either aminoglycosides or fluoroquinolones.

Otic drops that contain aminoglycosides have been shown to be ototoxic in animal studies and case reports.47 This potential for ototoxicity is present when otic drops are applied to an open middle ear or mastoid space in contrast to an ear with an intact tympanic membrane.4 Owing to the potential for ototoxicity with aminoglycoside-containing otic preparations, studies have focused on fluoroquinolone-containing ototopical medications as alternatives when the tympanic membrane is not intact. Fluoroquinolone-containing otic preparations currently indicated for use in the middle ear space include ofloxacin, 0.3%, otic solution (Floxin; Daiichi Sankyo Inc, Parsippany, New Jersey) and ciprofloxacin, 0.3%, and dexamethasone, 0.1%, otic suspension (Ciprodex; Alcon Inc, Hünenberg, Switzerland).

For the treatment of acute otitis media through tympanostomy tubes, the standard course for Ciprodex otic drops is 7 days of twice-daily administration of 4 drops.8 Ciprodex otic suspension has been approved by the US Food and Drug Administration for this specific dosing regimen for acute otitis media through tympanostomy tubes.9 However, in practice, a patient may be prescribed multiple consecutive courses of ototopical antimicrobial agents. Such prescribing practices may be necessary in chronic causes of otorrhea, such as infected keratoma or tympanostomy tube–related otorrhea. Successive courses of these medications, which would include application of Ciprodex for longer than 7 days, are not Food and Drug Administration approved.

The safety of ototopical ciprofloxacin has been shown after standard treatment.7,1014 Despite the clinical use of ototopical medications in consecutive courses, no studies, to our knowledge, have assessed ototoxicity after a longer duration of administration of any ciprofloxacin-containing topical otic preparation. In vitro studies15,16 of ciprofloxacin have been performed on chinchilla outer hair cells. Chinchilla outer hair cells were isolated and exposed to various ototopical medications, including neomycin, 0.35%, 10 000 U of polymyxin B, and hydrocortisone, 1% (Cortisporin; Parkedale Pharmaceuticals Inc, Rochester, Michigan); ciprofloxacin, 0.2%, and hydrocortisone, 1% (Cipro HC; BayerHealthCare AG, Leverkusen, Germany); ciprofloxacin, 0.3%, ophthalmic solution (Ciloxan; Alcon Inc); and ofloxacin, 0.3%, otic solution (Floxin). All of the evaluated substances resulted in outer hair cell death, thereby demonstrating the potential for ototoxicity.15,16 In addition, moxifloxacin, a third-generation fluoroquinolone currently in use as an ophthalmic drop, has been shown to be ototoxic when applied to nonintact tympanic membranes for 7 days in a chinchilla model,17 further highlighting the importance of determining the safety of ciprofloxacin ototopical drops.

The goal of this study is to determine whether use of a fluoroquinolone topical otic suspension (ciprofloxacin, 0.3%, and dexamethasone, 0.1%) results in ototoxicity after an extended 21-day course using a murine model. Owing to the demonstrated potential for ototoxicity of fluoroquinolones as evidenced in the chinchilla model, we hypothesized that prolonged exposure of the middle ear to ciprofloxacin produces measurable ototoxicity as measured using the auditory brainstem response (ABR) threshold.

This study was approved by the University of Connecticut Health Center Animal Care Committee.

SUBJECTS

Twelve CBA/J mice were purchased from The Jackson Laboratory (Bar Harbor, Maine). The mice, 6 male and 6 female, were 8 weeks old at study onset. The male and female groups were each subdivided into groups of 3 animals who received intratympanic injections in the right or left ear. The contralateral ear received intratympanic injections of sterile isotonic sodium chloride solution (saline) as a control. In this way, each animal served as its own control to reduce animal numbers. The number of subjects (N = 12) was chosen based on the estimate by Berndtson18 of replicates needed to detect a 10% difference from control with a coefficient of variability of 6% for 95% power at P < .05.

SURGICAL PROCEDURE: INTRATYMPANIC INJECTIONS

The animals were anesthetized using an inhalation technique. Using a self-contained, closed-circuit setup, each mouse was placed into an induction chamber where isoflurane, 4%, with oxygen flow of 1 L/min, was administered. After adequate induction, the mouse was transferred to a snout mask for maintenance anesthesia. The isoflurane was delivered through the snout mask at 1.5% to 3%, with oxygen flow of 1 L/min.

The mouse was positioned under an otologic microscope. The external auditory canal and the tympanic membrane were examined using a speculum, were cleared of any debris, and were inspected to ensure that there was no acute otitis externa or media. After optimal visualization of the tympanic membrane under the otologic microscope, a sterile 28-gauge needle connected via a polyethylene tube to a Hamilton syringe was passed through the inferior portion of the tympanic membrane. Ciprofloxacin-dexamethasone otic suspension or sterile saline, 0.9%, was shaken and placed into the Hamilton syringe. Five microliters of ciprofloxacin-dexamethasone otic suspension (0.015 mg of ciprofloxacin and 0.005 mg of dexamethasone) or sterile saline, 0.9%, was injected into the middle ear space. This amount was sufficient to fill the middle ear space, consistent with the approximate volume of the mouse middle ear and bulla.19 Transtympanic injections were performed daily for 21 consecutive days.

AUDITORY TESTING

All of the recordings were conducted with the anesthetized animal placed in a soundproof chamber. Before the recording sessions, the animals were examined for signs of middle ear infection, middle ear effusion, and accumulation of debris in the external auditory canal. The ABRs were measured using a real-time signal processing system (Tucker-Davis Technologies, Alachua, Florida). The ABRs were recorded by placing the active electrode, a sterile stainless steel needle, transcutaneously in the vertex. A second electrode was placed transcutaneously in the posterior neck to serve as the reference electrode. A third transcutaneous electrode was placed inferior to the animal's ear as a ground electrode. The ABR thresholds were determined using 100-microsecond alternating polarity clicks delivered at 21 per second. Stimuli were delivered through a Free Field Bose speaker (Bose Corporation, Framingham, Massachusetts) placed 5 cm above the animal's head in 5-dB steps between 23 and 83 dB peak equivalent sound pressure level (peSPL). The sound delivery system was calibrated by placing a-inch microphone (Brüel & Kjær, Nærun, Denmark) 5 cm from the Bose speaker. Signal averaging was performed after 500 presentations of the click stimulus. Monaural thresholds were obtained by occluding the contralateral ear using silicone ear molds. Auditory testing was performed before the initial intratympanic injections. Subsequent testing was performed 10 days after the treatment course to rule out possible middle ear damage from the injection protocol and again 3 months after completion of the injections to assess possible ototoxicity.

STATISTICAL ANALYSIS

The ABR thresholds were obtained at 3 points as described. Pairwise comparisons of the means were performed to assess statistical significance using 2-tailed t tests.

ABR THRESHOLDS

The ABR results are summarized in the Figure. The mean (SEM) baseline ABR thresholds were 47.17 (2.74) dB peSPL in ciprofloxacin-dexamethasone–treated ears and 45.08 (1.56) dB peSPL in saline-treated ears. There was no significant difference in the thresholds between the groups at baseline (P = .38). The auditory tests were repeated 10 days after completion of the intervention. Mean (SEM) thresholds were 44.25 (1.25) dB peSPL in ciprofloxacin-dexamethasone–treated ears and 48.00 (1.51) dB peSPL in saline-treated ears. Three months after the intervention, auditory tests revealed mean (SEM) thresholds of 43.00 (1.51) dB peSPL in ciprofloxacin-dexamethasone–treated ears and 45.92 (1.79) dB peSPL in saline-treated ears.

Place holder to copy figure label and caption
Figure.

Mean auditory brainstem response (ABR) thresholds before treatment. Error bars represent SEM. peSPL indicates peak equivalent sound pressure level.

Graphic Jump Location

The difference between the threshold of the ciprofloxacin-dexamethasone–treated ears at baseline and 10 days after the intervention was not significant (P = .29); in addition, there was no difference 3 months after the intervention (P = .10). There was no significant difference between the saline-treated ears at baseline and 10 days (P = .07) or 3 months (P = .59) after the injection protocol.

MIDDLE EAR EXAMINATION

Microscopic evaluation of the animal's ears was performed daily for 21 days of intratympanic injections and was repeated 10 days after treatment. On day 21 of intratympanic injections, 92% (11 of 12) of the mice had a tympanic membrane perforation in the ciprofloxacin-dexamethasone–treated ear, and 8% (1 of 12) had a tympanic membrane perforation in the saline-treated ear. Ten days after treatment, there was 1 perforation (8%) in the ciprofloxacin-dexamethasone–treated group and 1 (8%) in the saline-treated group.

Multiple studies have examined the ototoxicity of ciprofloxacin-containing otic preparations. An early investigation10 examined the effects of a single dose of 0.31 mg/0.2 mL of ciprofloxacin directly applied to the round window membrane of a guinea pig. This revealed no decrease in the ABR threshold 14 days after single-dose administration.10 Several later studies1113 used an otic preparation containing ciprofloxacin, 0.2%, in rodent models. Immediately after daily administration for 5 to 7 days, no functional ototoxic effect was noted. The researchers found no morphologic changes in the outer hair cells of these animals. To test higher concentrations of ototopical fluoroquinolones, Brownlee et al14 investigated a solution containing ciprofloxacin, 0.75%, with twice-daily dosing for 7 days. They found no evidence of functional or morphologic ototoxicity.14 Similarly, ciprofloxacin-dexamethasone solution applied for 7 days in the chinchilla model did not produce any functional deficits.20

In the present study, the specific aim was to determine whether continued, repetitive application of a ciprofloxacin, 0.3%, and dexamethasone, 0.1%, suspension would result in ototoxicity in a murine model. This otic preparation has been approved by the Food and Drug Administration for a 7-day course of administration; however, long-term application had not been previously studied. Many patients with nonintact tympanic membranes have been prescribed successive courses of this medication to treat infections and prevent complications that may arise should their conditions go untreated. As a result, the tympanic cavity and round window membrane of these patients have been exposed to the medication for an extended length of time previously untested even in an animal model.

The present results show no ototoxicity from prolonged application of ciprofloxacin-dexamethasone suspension based on comparison of pretest and posttest click-evoked ABR thresholds. These results corroborate and expand on the findings of previous researchers1014,20 who tested varying concentrations of ciprofloxacin-containing ototopical medications for a shorter duration. Future research regarding ciprofloxacin-dexamethasone otic suspension could examine tone-specific ABRs after long-term administration.

We observed a delay in healing of tympanic membrane perforations in the ciprofloxacin-dexamethasone group compared with the saline-treated group. At the completion of the intratympanic injections, there were more perforations in the ciprofloxacin-dexamethasone–treated ears than in the saline-treated ears (92% vs 8%). However, 10 days after treatment, there was no difference in the number of tympanic membrane perforations (8% in both groups). This observation, which may be related to the presence of corticosteroids, is consistent with data reported by Hebda et al21 regarding rats treated for 13 days with ciprofloxacin-dexamethasone after myringotomy. The present results support the conclusion by Hebda et al that ciprofloxacin-dexamethasone may temporarily alter tympanic membrane healing but is not likely to adversely affect normal healing of tympanic membranes after pressure equalization tube extrusion.

We conclude that prolonged administration of ciprofloxacin-dexamethasone otic suspension at concentrations commonly used clinically does not seem to cause either immediate or delayed ototoxicity in a murine model.

Correspondence: Kourosh Parham, MD, PhD, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030 (parham@neuron.uchc.edu).

Submitted for Publication: January 2, 2008; final revision received June 26, 2008; accepted July 6, 2008.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kavanagh, Parham, and Schoem. Acquisition of data: Kavanagh and Parham. Analysis and interpretation of data: Kavanagh, Parham, and Schoem. Drafting of the manuscript: Kavanagh, Parham, and Schoem. Critical revision of the manuscript for important intellectual content: Parham and Schoem. Statistical analysis: Parham. Obtained funding: Parham and Schoem. Administrative, technical, and material support: Kavanagh and Parham. Study supervision: Parham and Schoem.

Financial Disclosure: Dr Schoem serves on the speakers’ bureau of Alcon Inc.

Hannley  MTDenneny  JC  IIIHolzer  SS Use of ototopical antibiotics in treating 3 common ear diseases. Otolaryngol Head Neck Surg 2000;122 (6) 934- 940
PubMed Link to Article
Roland  PSParry  DAStroman  DW Microbiology of acute otitis media with tympanostomy tubes. Otolaryngol Head Neck Surg 2005;133 (4) 585- 595
PubMed Link to Article
Ruohola  AMeurman  ONikkari  S  et al.  Microbiology of acute otitis media in children with tympanostomy tubes: prevalences of bacteria and viruses. Clin Infect Dis 2006;43 (11) 1417- 1422
PubMed Link to Article
Roland  PSStewart  MGHannley  M  et al.  Consensus panel on role of potentially ototoxic antibiotics for topical middle ear use: introduction, methodology, and recommendations. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S51- S56
PubMed Link to Article
Roland  PSRybak  LHannley  M  et al.  Animal ototoxicity of topical antibiotics and the relevance to clinical treatment of human subjects. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S57- S78
PubMed Link to Article
Matz  GRybak  LRoland  PS  et al.  Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S79- S82
PubMed Link to Article
Wright  CGMeyerhoff  WL Ototoxicity of otic drops applied to the middle ear in the chinchilla. Am J Otolaryngol 1984;5 (3) 166- 176
PubMed Link to Article
 Ciprodex otic suspension product information. Alcon Inc Web site. http://www.ciprodex.com. Accessed December 17, 2008
 Drugs@FDA. Center for Drug Evaluation and Research Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed December 17, 2008
Lutz  HLenarz  TGotz  R Ototoxicity of gyrase antagonist ciprofloxacin? Adv Otorhinolaryngol 1990;45175- 180
PubMed
Kaplan  DMJames  ALThorp  MAMount  RJHarrison  RV Effects of middle ear application of Cipro HC otic suspension in an animal model. J Otolaryngol 2004;33 (3) 160- 164
PubMed Link to Article
Claes  JGovaerts  PJVan de Heyning  PHPeeters  S Lack of ciprofloxacin ototoxicity after repeated ototopical application. Antimicrob Agents Chemother 1991;35 (5) 1014- 1016
PubMed Link to Article
Ikiz  AOSerbetcioglu  BGeneri  EASutay  SCeryan  K Investigation of topical ciprofloxacin ototoxicity in guinea pigs. Acta Otolaryngol 1998;118 (6) 808- 812
PubMed Link to Article
Brownlee  REHulka  GFPrazma  JPillsbury  HC  III Ciprofloxacin: use as a topical otic preparation. Arch Otolaryngol Head Neck Surg 1992;118 (4) 392- 396
PubMed Link to Article
Russell  PTChurch  CAJinn  THKim  DJJohn  EOJung  TTK Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells. Acta Otolaryngol 2001;121 (2) 135- 139
PubMed Link to Article
Jinn  THKim  PDRussell  PTChurch  CAJohn  EOJung  TTK Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells. Laryngoscope 2001;111 (12) 2105- 2108
PubMed Link to Article
Daniel  SJDuval  MSahmkow  SAkache  F Ototoxicity of topical moxifloxacin in a chinchilla animal model. Laryngoscope 2007;117 (12) 2201- 2205
PubMed Link to Article
Berndtson  WE A simple, rapid and reliable method for selecting or assessing the number of replicates for animal experiments. J Anim Sci 1991;69 (1) 67- 76
PubMed
Huangfu  MSaunders  JC Auditory development in the mouse: structural maturation of the middle ear. J Morphol 1983;176 (3) 249- 259
PubMed Link to Article
Daniel  SJ Safety of ciprofloxacin/dexamethasone eardrops in a chinchilla animal model.  Paper presented at: American Society of Pediatric Otolaryngology May 20, 2006 Chicago, IL
Hebda  PAYuksel  SDohar  JE Effects of ciprofloxacin-dexamethasone on myringotomy wound healing. Laryngoscope 2007;117 (3) 522- 528
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Mean auditory brainstem response (ABR) thresholds before treatment. Error bars represent SEM. peSPL indicates peak equivalent sound pressure level.

Graphic Jump Location

Tables

References

Hannley  MTDenneny  JC  IIIHolzer  SS Use of ototopical antibiotics in treating 3 common ear diseases. Otolaryngol Head Neck Surg 2000;122 (6) 934- 940
PubMed Link to Article
Roland  PSParry  DAStroman  DW Microbiology of acute otitis media with tympanostomy tubes. Otolaryngol Head Neck Surg 2005;133 (4) 585- 595
PubMed Link to Article
Ruohola  AMeurman  ONikkari  S  et al.  Microbiology of acute otitis media in children with tympanostomy tubes: prevalences of bacteria and viruses. Clin Infect Dis 2006;43 (11) 1417- 1422
PubMed Link to Article
Roland  PSStewart  MGHannley  M  et al.  Consensus panel on role of potentially ototoxic antibiotics for topical middle ear use: introduction, methodology, and recommendations. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S51- S56
PubMed Link to Article
Roland  PSRybak  LHannley  M  et al.  Animal ototoxicity of topical antibiotics and the relevance to clinical treatment of human subjects. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S57- S78
PubMed Link to Article
Matz  GRybak  LRoland  PS  et al.  Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2004;130 (3) ((suppl)) S79- S82
PubMed Link to Article
Wright  CGMeyerhoff  WL Ototoxicity of otic drops applied to the middle ear in the chinchilla. Am J Otolaryngol 1984;5 (3) 166- 176
PubMed Link to Article
 Ciprodex otic suspension product information. Alcon Inc Web site. http://www.ciprodex.com. Accessed December 17, 2008
 Drugs@FDA. Center for Drug Evaluation and Research Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed December 17, 2008
Lutz  HLenarz  TGotz  R Ototoxicity of gyrase antagonist ciprofloxacin? Adv Otorhinolaryngol 1990;45175- 180
PubMed
Kaplan  DMJames  ALThorp  MAMount  RJHarrison  RV Effects of middle ear application of Cipro HC otic suspension in an animal model. J Otolaryngol 2004;33 (3) 160- 164
PubMed Link to Article
Claes  JGovaerts  PJVan de Heyning  PHPeeters  S Lack of ciprofloxacin ototoxicity after repeated ototopical application. Antimicrob Agents Chemother 1991;35 (5) 1014- 1016
PubMed Link to Article
Ikiz  AOSerbetcioglu  BGeneri  EASutay  SCeryan  K Investigation of topical ciprofloxacin ototoxicity in guinea pigs. Acta Otolaryngol 1998;118 (6) 808- 812
PubMed Link to Article
Brownlee  REHulka  GFPrazma  JPillsbury  HC  III Ciprofloxacin: use as a topical otic preparation. Arch Otolaryngol Head Neck Surg 1992;118 (4) 392- 396
PubMed Link to Article
Russell  PTChurch  CAJinn  THKim  DJJohn  EOJung  TTK Effects of common topical otic preparations on the morphology of isolated cochlear outer hair cells. Acta Otolaryngol 2001;121 (2) 135- 139
PubMed Link to Article
Jinn  THKim  PDRussell  PTChurch  CAJohn  EOJung  TTK Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells. Laryngoscope 2001;111 (12) 2105- 2108
PubMed Link to Article
Daniel  SJDuval  MSahmkow  SAkache  F Ototoxicity of topical moxifloxacin in a chinchilla animal model. Laryngoscope 2007;117 (12) 2201- 2205
PubMed Link to Article
Berndtson  WE A simple, rapid and reliable method for selecting or assessing the number of replicates for animal experiments. J Anim Sci 1991;69 (1) 67- 76
PubMed
Huangfu  MSaunders  JC Auditory development in the mouse: structural maturation of the middle ear. J Morphol 1983;176 (3) 249- 259
PubMed Link to Article
Daniel  SJ Safety of ciprofloxacin/dexamethasone eardrops in a chinchilla animal model.  Paper presented at: American Society of Pediatric Otolaryngology May 20, 2006 Chicago, IL
Hebda  PAYuksel  SDohar  JE Effects of ciprofloxacin-dexamethasone on myringotomy wound healing. Laryngoscope 2007;117 (3) 522- 528
PubMed Link to Article

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