Safety and efficacy of topical quinolones.

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Introduction

Dr. Joseph E. Dohar: At the end of the day, infectious diseases are treated with antibiotics to eradicate the bacteria causing the infections. The only caveat we must consider when taking advantage of the fatal attraction between antibiotics and the bacteria that they kill is that the killing must be done safely! "Do no harm," cried Hippocrates. In this article, we examine the evidence on the safety as well as the efficacy of ototopical quinolone therapies.

Ototoxicity

Dr. John Rutka: We think of ototoxicity as primarily involving the inner ear, but middle ear toxicity occurs, as well. We have become aware that not only do systemic agents cause ototoxicity, but topical agents are also implicated (table 1).

If we were to stop using aminoglycosides and cytotoxic agents, we would probably eliminate much of the ototoxicity that occurs in the Western world. However, we have recently learned that many other compounds are ototoxic, as well, depending on the clinical situation (table 2).

For example, the macrolide antibiotic azithromycin can be quite toxic to the inner ear in patients who are undergoing treatment for human immunodeficiency virus (HIV) infection. Vancomycin is probably not toxic to the inner ear on its own, but when it is combined with an aminoglycoside, its effects are potentiated and it is quite possible that it will cause ototoxicity.

In 2004, a consensus panel of the American Academy of Otolaryngology-Head and Neck Surgery published its review of the efficacy and safety of topical antibiotics and made several recommendations (1):

* When possible, topical antibiotic preparations that are free of potential ototoxicity are preferable to those that do have the potential for otologic injury in patients with an open middle ear or mastoid.

* When a potentially ototoxic antibiotic is chosen, it should be used only in infected ears and it should be discontinued shortly after the infection has resolved.

* When a potentially ototoxic antibiotic drop is prescribed for a patient with an open middle ear or mastoid, the patient or parent should be warned of the risk of ototoxicity. The patient or parent should be specifically instructed to call the physician or return to the office if the patient develops: (1) dizziness or vertigo, (2) heating loss or a worsening of hearing if such an impairment was already present, or (3) tinnitus. The treating physician should consider the possibility of ototoxic injury when evaluating these new or exacerbated symptoms.

The panel added that if the tympanic membrane is known to be intact and the middle ear and mastoid are closed, the use of a potentially ototoxic preparation presents no risk of ototoxic injury.

Our role as physicians requires that we protect patients. If our treatment leads to ototoxicity, we have failed the patient, especially if it could have been prevented. Although many patients adapt well to a unilateral sensorineural hearing loss and compensate for a unilateral vestibular loss, such is not the case when bilateral ototoxicity occurs. When bilateral ototoxicity occurs as a result of ototopical therapy, the consequences can be devastating in terms of total deafness and a debilitating balance disorder.

No evidence of quinolone ototoxicity

Dr. Rutka: Systemic quinolones are associated with some significant adverse effects and drug interactions. Among the adverse effects are arthropathy and chondrotoxicity, Achilles tendon rupture in the elderly, photosensitivity, and QTc prolongation. Drug interactions include an increase in the risk of cardiac arrest when a quinolone is used with theophylline, an increase in the anticoagulation properties of warfarin, and an increase in phenytoin levels above their therapeutic range.

But are topical quinolones ototoxic? I performed an Ovid MEDLINE search using ciprofloxacin as the keyword search term, and I found almost 10,000 articles--9,916 to be precise--published from 1966 through the third week of February 2004 (table 3). I then searched for articles on diagnosis that contained deafness as a keyword, and I found 2,101 articles. But when I searched for peer-reviewed articles that contained both ciprofloxacin and deafness as keywords, I did not find a single article. In other words, there has not been a single report in the world literature in which ciprofloxacin has been implicated as a cause of deafness.

Not content with this result, I performed a more focused investigation. I searched for articles with the keywords hair cells, hearing disorders, cochlear, deafness, ototoxicity, or sensorineural hearing loss and found 43,794 articles. Only 25 of these articles included any mention of ciprofloxacin:

* 7 were reports of animal studies; only 1 included any mention of ototoxicity, and it concerned mild inner ear toxicity that had been caused by nalidixic acid, which is a ciprofloxacin precursor.

* 7 articles reported comparisons of the efficacy of systemic ciprofloxacin and aminoglycosides in humans; no case of ciprofloxacin ototoxicity was reported.

* 10 articles included the results of studies of topical ciprofloxacin, and none showed that it was ototoxic.

* 1 was a unique human study in which intratympanic ciprofloxacin drops were instilled into the middle ear space of 10 patients with an acoustic neuroma; the authors found no evidence of measurable absorption of the drug in the labyrinthine fluid, cerebrospinal fluid, or serum, which indicates that the chance of ciprofloxacin toxicity is low. (2)

Chronic suppurative otitis media (CSOM)

Dr. Rutka: In patients with CSOM, randomized controlled trials have shown that antibiotic and antiseptic treatment combined with aural toilet is better than no treatment, but aural toilet alone is not. (3) Also, topical antibiotics and antiseptics are better than systemic antibiotics. Finally, there is no significant difference in effectiveness between a topical antibiotic/antiseptic alone and a combination of a topical and systemic antibiotic.

These studies have also shown that quinolones, taken either topically or systemically, appear to be more effective than other types of antibiotics. A surprising finding is that antiseptics may be just as effective as antibiotics. Topical treatment is associated with negligible or no change in hearing.

Dr. Patrick J. Antonelli: I agree. The literature clearly shows that the ototopical quinolones are efficacious (table 4). (4-12)

References

(1.) Roland PS, Stewart MG, Hannley 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):S51-6.

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

(3.) Acuin J, SmithA, Mackenzie I. Interventions for chronic suppurative otitis media. Cochrane Database Syst Rev 2000;(2):CD000473, updated Nov. 15, 2004.

(4.) Yuen PW, Lau SK, Chau PY, et al. Ofloxacin eardrop treatment for active chronic suppurative otitis media: Prospective randomized study. Am J Otol 1994;15:670-3.

(5.) Tutkun A, Ozagar A, Koc A, et al. Treatment of chronic ear disease. Topical ciprofloxacin vs topical gentamicin. Arch Otolaryngol Head Neck Surg 1995;121:1414-16.

(6.) Tong MC, Woo JK, van Hasselt CA. A double-blind comparative study of ofioxacin otic drops versus neomycin-polymyxin B-hydrocortisone otic drops in the medical treatment of chronic suppurative otitis media. J Laryngol Otol 1996; 110:309-14.

(7.) Fradis M, BrodskyA, Ben-David J, et al. Chronic otitis media treated topically with ciprofloxacin or tobramycin. Arch Otolaryngol Head Neck Surg 1997;123:1057-60.

(8.) Miro N. Controlled multicenter study on chronic suppurative otitis media treated with topical applications of ciprofloxacin 0.2% solution in single-dose containers or combination of polymyxin B, neomycin, and hydrocortisone suspension. Otolaryngol Head Neck Surg 2000;123:617-23.

(9.) Nawasreh O, Fralhat A. Topical ciprofloxacin versus topical gentamicin for chronic otitis media. East Mediterr Health J 2001;7:2630.

(10.) Couzos S, Lea T, Mueller R, et al. Effectiveness of ototopical antibiotics for chronic suppurative otitis media in Aboriginal children: A community-based, multicentre, double-blind randomised controlled trial. Med J Aust 2003;179:185-90.

(11.) Jaya C, Job A, Mathai E, Antonisamy B. Evaluation of topical povidone-iodine in chronic suppurative otitis media. Arch Otolaryngol Head Neck Surg 2003;129:1098-1100.

(12.) Macfadyen C, Gamble C, Garner P, et al. Topical quinolone vs. antiseptic for treating chronic suppurative otitis media: A randomized controlled trial. Trop Med Int Health 2005;10:190-7.

Table 1. Major groups of traditional ototoxic agents
in humans

Aminoglycosides                Cytotoxic agents
Amikacin                       Bleomycin
Dihydrostreptomycin            Carboplatinum
Gentamicin                     Cisplatinum
Kanamycin                      Nitrogen mustard
Neomycin                       Vincristine
Netilmicin
Streptomycin                   Others
Tobramycin                     Acetylsalicylic acid
                               Arsenicals
                               Loop diuretics
                               Quinine

Table 2. More recently identified ototoxic agents

Antiseptics/disinfectants      Topical antibiotics
Alcohol                        All aminoglycosides
Chlorhexidine                  Chloramphenicol
                               Polymyxin
Macrolide antibiotics
Azithromycin                   Others
Clarithromycin                 Iron chelating agents
Erythromycin                   Nonsteroidal
                                 anti inflammatory drugs

Table 3. Results of the MEDLINE search

Search   Search                                                No.
no.      target                                                articles

#1       All articles with keyword "ciprofloxacin"                9,916

#2       #1, human studies, English language only                 6,341

#3       All articles on diagnosis with keyword "deafness"        2,101

#4       #1 and #3                                                    0

#5       #2 and #3                                                    0

#6       All articles with keywords "hair cells," "hearing       43,794
         disorders," "cochlear," "deafness," "ototoxicity,"
         or "sensorineural hearing loss"

#7       #1 and #6                                                   25

Table 4. Selected studies of the efficacy of topical quinolones in CSOM

Author                        Comparator agent                No. pts.

Yuen et al, (4) 1994          Oral amoxicillin/clavulanate       56

Tutkun et al, (5) 1995        Gentamicin                         44

Tong et al, (6) 1996          Neomycin/polymyxin B/              52
                                hydrocortisone

Fradis et al, (7) 1997        Tobramycin                         60

Miro, (8) 2000                Neomycin/polymyxin B/             232
                                hydrocortisone

Nawasreh and                  Gentamicin                         88
  Fraihat, (9) 2001

Couzos et al, (10) 2003       Framycetin (neomycin)/            147
                                gramicidin/dexamethasone

Jaya et al, (11) 2003         Povidone-iodine                    40

Macfadyen et al, (12) 2005    Boric acid in alcohol             427

Author                        Findings/comment

Yuen et al, (4) 1994          Ofloxacin superior (cure rates: 76
                                vs. 26%)

Tutkun et al, (5) 1995        Ciprofloxacin superior (cure rates:
                                88 vs. 30%)

Tong et al, (6) 1996          Ofloxacin marginally superior (cure
                                rates: 89 vs. 79%)

Fradis et al, (7) 1997        Ciprofloxacin equivalent (cure rates: 79
                                vs. 72%)

Miro, (8) 2000                Ciprofloxacin equivalent, but combination
                                was associated with hearing loss

Nawasreh and                  Ciprofloxacin superior (cure rates:
  Fraihat, (9) 2001             88 vs. 30%)

Couzos et al, (10) 2003       Ciprofloxacin superior (cure rates:
                                76 vs. 52%)

Jaya et al, (11) 2003         No difference

Macfadyen et al, (12) 2005    Ciprofloxacin superior (cure rates:
                                59 vs. 32%)