Is there an ototoxicity risk from Cortisporin and comparable otic suspensions? Distortion-product otoacoustic emission findings

The purpose of this investigation was to use distortion-product otoacoustic emission (DPOAE) testing to address the issue of possible ototoxicity from the use of neomycin/ polymyxin B/hydrocortisone otic suspension following tympanostomy tube placement. We retrospectively reviewed our clinical records and identified 36 children (52 ears) who had met our three study criteria: (1) unilateral or bilateral placement of transtympanic ventilation tubes, (2) treatment for 3 to 5 days with neomycin/polymyxin B/ hydrocortisone drops, and (3)postoperative evaluation by DPOAE testing. We identified another set of 36 children (52 ears) who had not received these drops and who had not undergone tubeplacement but who had been evaluated by DPOAE testing to serve as a control group. We found no significant differences in DPOAE amplitudes between the treatment and control groups. Thesefindings are consistent with decades of clinical experience indicating that neomycin/polymyxin B/hydrocortisone otic suspension is safe when used responsibly.






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Publication: Ear, Nose & Throat Journal
Author: Berenholz, Leonard P
Date published: March 1, 2012

Introduction

For years, neomycin-based ear drops have been widely used for applications in which there is an open middle ear space. Two common examples are ( 1 ) the treatment of drainage in a patient with a ventilation tube or tympanic membrane perforation and (2) prophylaxis following tympanostomy tube placement. Although numerous studies have documented ototoxicity as a side effect of the use of neomycin-based drops in animals,1 only a few cases of ototoxicity in humans have been reported despite years of widespread use. These cases involved patients who had used the drops for prolonged periods of time-months or even more than a year.2 In 2004, Matz et al published a review covering nearly 40 years and reported only 11 possible cases of ototoxicity from neomycin drops.3

Our clinical impression that neomycin/polymyxin B/ hydrocortisone drops do not pose an ototoxicity risk in humans when used responsibly is clearly in conflict with findings from studies of animal models. Therefore, in 2006 we published a retrospective study of the incidence of ototoxicity associated with the routine use of neomycin/polymyxin B/hydrocortisone otic suspension.4 In conducting that study, we reviewed the charts of 500 children who had received neomycin/polymyxin B/hydrocortisone drops following ventilation tube placement.

In that study, we looked for ototoxic changes as evidenced by elevated hearing thresholds measured with conventional air-conduction audiometry at 0.5,1,2, and 4 kHz. We did not find any evidence of clinical cochlear ototoxicity. However, as Roland et al1 and Rutka5 have pointed out, some cases of ototoxicity may be missed because cochlear ototoxicity usually affects the higher frequencies before it affects the frequencies that are routinely tested. Also, it is possible that traditional audiometrie testing is not sensitive enough to detect early ototoxic effects.

Although an association between the prudent clinical use of neomycin/polymyxin B/hydrocortisone otic drops and ototoxicity in humans has not been proven, the perceived risk has led many physicians to switch from using these drops to using topical fluoroquinolone drops such as ciprofloxacin/dexamethasone and ofloxacin. While effective, these newer medications raise other concerns. For example, fluoroquinolone agents are much more costly than neomycin/polymyxin B/hydrocortisone.4 Another concern is that the widespread use of fluoroquinolones might result in drug resistance.

The purpose of this investigation was to use distortion-product otoacoustic emission (DPOAE) testing to address the issue of possible ototoxicity from the clinical use of neomycin/polymyxin B/hydrocortisone otic suspension following tympanostomy tube placement. Numerous studies indicate that DPOAE testing can reveal ototoxic changes before cochlear damage is detectable by conventional audiometry.6"9 Not only does DPOAE testing detect subclinical damage, but it also provides information from the high-frequency area of the cochlea where ototoxic injury is most likelyto occur. Although DPOAE testing is a powerful and proven tool for detecting ototoxicity, DPOAE results have not been applied to the debate about neomycin/polymyxin B/hydrocortisone.

Patients and methods

We retrospectively reviewed our clinical records in reverse chronological order from December 2007 back to January 2005 to find children who had ( 1 ) undergone unilateral or bilateral placement of transtympanic ventilation tubes, (2) who had been treated with neomycin/ polymyxin B/hydrocortisone eardrops, and (3) who had been evaluated postoperatively with DPOAE testing. In our clinic, we perform DPOAE testing on patients who are difficult to test by other means, such as some small children who cannot or will not respond to conventional audiometry. The DPOAE data that were available for the purposes of this study were obtained from these types of children.

Treatment group. A total of 36 children (52 ears-33 in boys and 19 in girls), aged 7 months to 9.75 years (mean: 2.75 yr) at the time of surgery, met our three inclusion criteria. These children had undergone tube placement only once prior to DPOAE data collection.

The surgical procedures had been performed in essentially the same manner for all patients. Under microscopic guidance, an anterior or anteroinferior myringotomy incision was made. Any middle ear fluid was aspirated, and a Donaldson tube was placed.

Postoperatively, 3 drops of neomycin/polymyxin B/ hydrocortisone drops were placed 3 times daily for 3 to 5 days. To help ensure drop infiltration into the middle ear, caregivers were taught to have the children tilt their heads to the side while the drops were being administered and to massage the tragus.

The indication for myringotomy and tube placement in these patients was persistent serous otitis or recurrent serous otitis of at least 3 months' duration. These patients had previously received multiple antibiotic treatments for suspected purulent otitis media.

Control group. Baseline DPOAE testing in the treatment group was not practical prior to treatment because of the children's otitis media, so our best option was a comparison group. We identified 36 children (52 ears) whose demographic characteristics were similar to those of the treatment group to serve as the control group (table 1). These children had no history of ear surgery, including tympanostomy tube placement, and they had not used ear drops. Their tympanometric and otoscopie examinations revealed normal ears.

DPOAE testing. Because DPOAE amplitudes are often depressed by the presence of ventilation tubes or middle ear dysfunction, including abnormal middle ear pressure and abnormal middle ear compliance,10" we needed to control for or eliminate these factors. We eliminated the presence of ventilation tubes as a confounding variable in the treatment group by including only those DPOAE test results that had been obtained after the tubes had extruded. Furthermore, in both groups, only those children whose tympanograms were normal were included in this study.

The length of time from tympanostomy tube placement to DPOAE testing ranged from 5 months to 6.3 years (mean: 16 mo). This delay was necessary in order to obtain accurate DPOAE results. However, during the delay, we could not monitor patients for any possible temporary effects immediately following neomycin/ polymyxin B/hydrocortisone use. We were able to monitor for possible permanent damage.

DPOAE testing was performed with the AuDX measurement system (Bio-logic Systems Corp.; Mundelein, 111.) in a double-walled soundproof room. "Distortionproduct-grams" (DP-grams) were generated by simultaneously presenting two pure tones to the ear (fl and f2, with > fl and 2/fl ratio = 1.22; Ll = 65 dB sound-pressure level [SPL] and L2 = 55 dB SPL), acoustically mixing them to elicit two fl -2 emissions recorded from the 2,3,4,5,6,7,8,9, and 10 kHz areas.

DPOAE testing was not extended below 2 kHz because of difficulty with noise interference during lower-frequency testing, especially during testing of children. The DPOAE amplitudes were determined by comparing the emission level to the level of the noise floor.

The study protocol was approved by the Forum Health/Western Reserve Care System Institutional Review Board.

Results

At the initial postoperative appointment 1 to 2 weeks following ventilation tube placement, none of the children who had been treated with neomycin/polymyxin B/hydrocortisone drops were found to have any infection or drainage, and all tubes were found to be in place and patent. All but 1 of the children returned for this first postoperative appointment; thefamilyofthechildwhodidnot return for her first postoperative appointment did not report any postoperative problems.

Statistical analyses to compare DPOAE data between the two groups were performed with the independent-samples f test for equality of means, including the Levene test for equality of variances. We found no statistically significant differences in DPOAE amplitudes between the two groups (table 2).

Discussion

To the best of our knowledge, this investigation is the first study that employed DPOAE testing to look for signs of ototoxicity in humans secondary to the use of neomycin-based drops. Because evaluation of high-frequency DPOAE responses is more sensitive to cochlear dysfunction from ototoxicity than is pure-tone audiometry in the conventional frequency range,6'9 and because there were no significant differences in DPOAE amplitudes between the treatment and control groups in our study, we can be more certain of the safety of neomycin/polymyxin B/hydrocortisone drops when used for a brief period following tympanostomy tube placement.

While the result of this one small study cannot by itself be considered definitive, it was consistent with the result of our 2006 study,4 with results of other studies,12,13 and with our clinical observations over the years.

When one considers the numerous animal experiments114,15 that have demonstrated ototoxicity from the use of topical neomycin/polymyxin B/hydrocortisone, one must ask, What could explain the differences in the way these drops affect experimental animals and humans? As pointed out by Roland and colleagues, there are several anatomic and nonanatomic differences between humans and the animals used in the experiments, and these differences likely make humans less vulnerable than animals to ototoxicity.1,2 For example, in humans, the round window membrane is recessed within a deep bony niche, which protects it from contact with ear drops that may be in the middle ear space. In animals, the round window membrane is much more exposed, and therefore drops in the middle ear space are likely in prolonged contact with the round window membrane.

Moreover, the human round window membrane is significantly thicker and has a more densely packed cell structure than that of rats, chinchillas, and guinea pigs. Baboons have thicker round window membranes than rodents, and experiments have shown that they experience less ototoxicity than do rodents.' This suggests that the human round window membrane, which is typically even thicker than that of baboons, may provide even more protection from ototoxicity.

Another advantage of the human anatomy is that false membranes and fibrous or fatty plugs are common in the round window niche, and these membranes and plugs can help protect the round window membrane from contact with fluids in the middle ear space. Finally, the presence of mucosal edema and exudates in the middle ear space may protect the round window membrane from contact with potentially ototoxic substances that are placed in the middle ear.

In our study, drops were placed in essentially dry ears because any fluid or mucus that was present was aspirated in surgery just prior to administration of the drops. This is noteworthy in that there was no sign of ototoxicity even when drops were placed in ears that did not have the added protective effect of pus or middle ear fluid. While it is possible that mucosal inflammation might have offered some protective function, this would likely also be the case for other patients for which drops would be prescribed.

Various authors have raised concerns regarding the possibility of vestibulotoxicity from topical aminoglycosides.3,16,17 In our study, vestibular testing was not performed; doing so would have been an extremely difficult undertaking given the young age of many of our patients. It is encouraging, though, that none of the caregivers of the children in our study reported any signs of dizziness, vertigo, or symptoms ofbilateral peripheral vestibular loss, including imbalance, ataxia, andoscillopsia immediately following or in the several months after their use of the neomycin/polymyxin B/hydrocortisone drops. This was also true in our 2006 study.4

Another area of concern is whether neomycin/polymyxin B/hydrocortisone drops are as effective as fluoroquinolone drops in preventing drainage, infection, and tube obstruction. In a 2001 study, Morpeth et al found no statistically significant difference in postoperative rates of otorrhea between patients who used neomycin/ polymyxin B/hydrocortisone drops and those who used ciprofloxacin/dexamethasone drops.18

Similarly, Poetker et al found that neomycin/polymyxin B/hydrocortisone drops and ofloxacin drops were equally effective in preventing postoperative otorrhea and tube nonpatency.19 They also found that patients who used either agent had significantly lower rates of postoperative otorrhea and tube occlusion than did a control group made up of patients who did not receive any otic drops postoperatively. Consistent with the results of these studies, the treatment group in our study did not experience any otorrhea or tube obstruction.

In addition to safety and effectiveness, cost must be considered in treatment decision making. In our 2006 study, we detailed a 3-to-l cost differential between ciprofloxacin/dexamethasone and neomycin/polymyxin B/hydrocortisone.4 Also, even though there is now a generic form of ofloxacin, there remains a cost differential of greater than 2-to-l.

Although concerns about the development of antibiotic resistance are perhaps speculative, they must nevertheless be considered. If resistance to topical fluoroquinolones becomes a problem, we will have lost a valuable means of treating difficult chronic ear infections. The use of neomycin-based antibiotics for the treatment of basic infections and as prophylaxis after ventilation tube placement might help decrease the risk of development of resistance to fluoroquinolones.

In conclusion, our study provides additional evidence that short-term treatment with neomycin/polymyxin B/ hydrocortisone otic drops is safe in humans. However, the underlying question remains: Is it reasonable to rule out neomycin/polymyxin B/hydrocortisone ear drop use based on ototoxic effects in animal models when there is no evidence that short-term application is harmful in humans?

Finally, we caution that our study addressed only short-term use; use of this agent over a longer period of time in an open ear remains a matter of concern. We also acknowledge two weaknesses of this study: the relatively small size of our patient population and the fact that the only hearing evaluation performed was DPOAE testing. We encourage a follow-up study of patients who can undergo valid, reliable audiometry before and after treatment. It is likely that definitive data regarding these issues already exist in patient records at numerous medical centers.

References

1. Roland PS, Rybak L, Hannley M, et al. Animal ototoxicity of topical antibiotics and the relevance to clinical treatment ofhuman subjects. Otolaryngol Head Neck Surg 2004;130(3 Suppl):S57-78.

2. Roland PS. Clinical ototoxicity of topical antibiotic drops. Otolaryngol Head Neck Surg 1994;110(6):598-602.

3. Matz G, Rybak L, Roland PS, et al. Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2004; 130(3 Suppl):S79-82.

4. Berenholz LP, Burkey JM, Farmer TL, Lippy WH. Topical otic antibiotics: Clinical cochlear ototoxicity and cost consideration. Otolaryngol Head Neck Surg 2006;135(2):29I-4.

5. Rutka J. How serious a problem is topical aminoglycoside ototoxicity? Ear Nose Throat J 2006;85(10 Suppl 1): 19-21.

6. Ress BD, Sridhar KS, Balkany TJ, et al. Effects of cis-platinum chemotherapy on otoacoustic emissions: The development of an objective screening protocol. Otolaryngol Head Neck Surg 1999;121(6): 693-701.

7. Stavroulaki P, Vossinakis IC, Dinopoulou D, et al. Otoacoustic emissions for monitoring aminoglycoside-induced ototoxicity in children with cystic fibrosis. Arch Otolaryngol Head Neck Surg 2002; 128(2): 150-5.

8. Stavroulaki P, Apostolopoulos N, Segas J, et al. Evoked otoacoustic emissions-an approach for monitoring cisplatin induced ototoxicity in children. Int J Pediatr Otorhinolaryngol 2001;59(l):47-57.

9. Knight KR, Kraemer DF1 Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: Use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol 2007;25(10):1190-5.

10. Topolska MM, Hassman E, Baczek M. The effects of chronic otitis media with effusion on the measurement of distortion products of otoacoustic emissions: Presurgical and postsurgical examination. Clin Otolaryngol Allied Sci 2000;25(4):315-20.

11. Owens JJ, McCoyMJ, Lonsbury-Martin BL, Martin GK. Otoacoustic emissions in children with normal ears, middle ear dysfunction, and ventilating tubes. Am J Otol 1993;14(l):34-40.

12. Welling DB, Forrest LA, Goll F III. Safety of ototopical antibiotics. Laryngoscope 1995;105(5 Pt l):472-4.

13. Rakover Y, Keywan K, Rosen G. Safetyof topical ear drops containing ototoxic antibiotics. J Otolaryngol 1997;26(3):194-6.

14. MeyerhoffWL, Morizono T, Wright CG, et al. Tympanostomy tubes and otic drops. Laryngoscope 1983;93(8): 1022-7.

15. Morizono T. Toxicity of ototopical drugs: Animal modeling. Ann Otol Rhinol Laryngol Suppl 1990;148:42-5.

16. Haynes DS, Rutka J, Hawke M, Rolad PS. Ototoxicity of ototopical drops-an update. Otolaryngol Clin North Am 2007;40(3):669-83, xi.

17. Rutka J. Other topical agents are safer and just as effective. Ear Nose Throat J 2003;82(Suppl 1):15.

18. Morpeth JF, Bent JP, Watson T. A comparison of cortisporin and ciprofloxacin otic drops as prophylaxis against post-tympanostomy otorrhea. Int J Pediatr Otorhinolaryngol 2001;61(2):99-104.

19. Poetker DM, Lindstrom DR, Patel NJ, et al. Ofloxacin otic drops vs neomycin-polymyxin B otic drops as prophylaxis against early postoperative tympanostomy tube otorrhea. Arch Otolaryngol Head Neck Surg 2006;132(12):1294-8.

Author affiliation:

Leonard P. Berenholz, MD; Dyana L. Rossi, MA; William H. Lippy, MD;

John M. Burkey, MA

Author affiliation:

From the Lippy Group for ENT, Warren, Ohio.

Corresponding author: Leonard Berenholz, Lippy Group for ENT, 3893 E. Market SL, Warren, OH 44484. Email: info@lippygroup.com

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