The evolution of ototopical therapy: from cumin to quinolones.The treatment of otorrhea has been described for more than 3,500 years, but a scientific basis for therapy was lacking until late in the 20th century. Among the remedies that were used over the centuries were mixtures of red lead, tree resin, and olive oil; frankincense frankincense: see incense-tree., goose grease, cream from cow's milk, and crushed soda; and vermilion, cumin, ass ear, hatet oil, and olive oil. (1) In the 1800s, purveyors pitched "rattlesnake oil," which was actually a mixture of turpentine, camphor, menthol menthol /men·thol/ (men´thol) an alcohol from various mint oils or produced synthetically; used topically to relieve itching and as an inhalation to treat upper respiratory tract disorders. men·thol (m, and sassafras. (1) During the first half of the 20th century, various non-specific methods--including the use of astringents and antiseptics--were the primary forms of treatment for otorrhea secondary to either acute otitis media, acute otitis externa, or chronic suppurative otitis media (CSOM CSOM - Carlson School of Management (University of Minnesota, Twin Cities) CSOM - Center for Sex Offender Management CSOM - Chronic Serous Otitis Media (middle ear infection) CSOM - Computer Security Operations Manager CSOM - Computer Software Operation Manual CSOM - Computer Software Operator's Manual CSOM - Computer System Operations Manager CSOM - Computer System Operator's Manual CSOM - Computer Systems: Operation and Management (University College of the Cariboo)). Although these treatments were potentially ototoxic, no other ototopical preparations were available, and physicians had no choice but to accept the risk. The development of antibiotics in the middle of the 20th century marked the beginning of a philosophical change in our approach to the treatment of otorrhea. Although practitioners continued to use a variety of preparations, the availability and effectiveness of antimicrobial therapy heralded a new age in the management of draining ears. (1) Choosing an antimicrobial When choosing a particular medication to treat any disease process, physicians today have the advantage of being able to base our choice on sound data regarding the particular characteristics of available drugs. When treating a patient with an infectious disease, rational decision making involves consideration of a drug's safety; efficacy, spectrum of coverage, and potential for bacterial resistance; cost; and ease of administration and patient compliance. In the management of otorrhea, antimicrobials can be administered either orally, parenterally, or topically. Depending on the particular disease process, one route might be favored over the others. In most patients with otorrhea, topical therapy is preferred because it is associated with all the advantages enumerated above. In refractory cases, however, systemic antimicrobial therapy is sometimes necessary and appropriate. In rare instances, tympanoplasty and mastoidectomy mastoidectomy /mas·toid·ec·to·my/ (mas?toi-dek´tah-me) excision of the mastoid cells or the mastoid process. mas·toid·ec·to·my (m  s are
required.Aminoglycosides aminoglycoside /ami·no·gly·co·side/ (-gli´ko-sid) any of a group of antibacterial antibiotics (e.g., streptomycin, gentamicin) derived from various species of Streptomyces or produced synthetically; they interfere with the function of bacterial ribosomes.. Until recently, the aminoglycoside class of antibiotics--which includes gentamicin, tobramycin, and neomycin--was the primary choice for treating otorrhea. The aminoglycosides are available as both ophthalmic and otic drops. Aminoglycosides are also combined with one of the peptide class of antibiotics (e.g., polymyxin B or polymyxin E) and/or with a steroid (e.g., hydrocortisonc or dexamethasone dexamethasone /dex·a·meth·a·sone/ (dek?sah-meth´ah-son) a synthetic glucocorticoid used primarily as an antiinflammatory in various conditions, including collagen diseases and allergic states; it is the basis of a screening test in the diagnosis of Cushing's syndrome; used also as the acetate or sodium phosphate salt.). Quinolones. In the 1990s, topical fluoroquinolones began to be used in the treatment of otorrhea. Since then, they have become the treatment of choice, for reasons specified later in this article. Steroids. Like aminoglycosides, quinolones are also combined with steroids. Before deciding to use any topical antibiotic/steroid preparation, we must consider the potential problems of steroid use and overuse, including immunologic suppression and hypersensitivity antibody-mediated hypersensitivity 1. type II h.; see Gell and Coombs classification, under classification. 2. occasionally, any form of hypersensitivity in which antibodies, rather than T lymphocytes, are the primary mediators, i.e., types I–III. cell-mediated hypersensitivity type IV h..
Inclusion of a steroid with a topical medication is appropriate when the
clinician believes that the benefits outweigh the potential risks, which
they do in most cases. In fact, in a phase III study, Roland et al compared a topical quinolone/steroid combination (ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt. cip·ro·flox·a·cin (s/ dexamethasone) with a quinolone alone (ofloxacin) in 599 patients with acute otitis media with otorrhea through tympanostomy tubes (AOMT). (2) Patients in the ciprofloxacin/dexamethasone group received 4 drops twice a day for 7 days, and those in the ofloxacin group received 5 drops twice a day for 10 days (both regimens represent the respective approved dosages for the AOMT indication). The median time to cessation of otorrhea was 4 days in the ciprofloxacin/dexamethasone group and 6 days in the ofloxacin group (table). Clinical cure rates on day 18 (test-of-cure visit) were 90 and 79%, respectively, and the corresponding microbiologic cure rates were 91 and 82%. Failure rates were 5 and 15%, respectively. All of these differences were clinically and statistically significant. Safety No commercially available oral agents have an acceptable safety profile for the treatment of Pseudomonas aeruginosa in children. Topical agents are an effective empiric treatment that obviates the need for baseline cultures. In general, the use of a single antimicrobial agent is preferable to the use of multiple antibiotics, because the latter increases the potential for adverse effects. Ototoxicity. Although it is uncommon, ototoxicity is a known risk of using aminoglycosides. During the time when no other choices were available, this risk was considered acceptable, and it generally did not merit discussion with a patient prior to the initiation of therapy. However, since the introduction of the topical quinolones, we now have an alternative that minimizes the risk of hearing loss and vestibulotoxicity. As a result, one must question the wisdom of using any topical antimicrobial agent other than a quinolone. Although some of the ototoxic risk of the amino-glycosides cardiac glycoside any of a group of glycosides occurring in certain plants (e.g., Digitalis, Strophanthus, Urginea ), acting on the contractile force of cardiac muscle; some are used as cardiotonics and antiarrhythmics. digitalis glycoside any of a number of cardiotonic and antiarrhythmic glycosides derived from Digitalis purpurea and D. is
obviated in an intact tympanic membrane, clinicians must still remain
aware of the possibility that a patient with significant edema of the
ear canal might have an unsuspected membrane perforation. Therefore,
even in a patient with known acute otitis externa, complications
associated with the use of topical antimicrobials other than quinolones
are potentially severe.Hypersensitivity, Another drawback to the use of aminoglycoside-containing drops is their potential for hypersensitivity. Unfortunately, the clinician might not diagnose hypersensitivity because the patient's major signs and symptoms can include redness, pain, itching, and other signs of inflammation. The clinician might misinterpret these findings as a failure to heal rather than a hypersensitivity reaction. Similarly, inflammation can be caused by agents such as propylene glycol, a solvent that is often used in topical neomycin/polymyxin B/hydrocortisone formulations. Propylene glycol has been shown to cause inflammation in the middle ear, probably secondary to local mucosal irritation. Efficacy, coverage, and resistance The quinolones' broad spectrum of coverage is in contrast to the limited spectrum that characterizes oral preparations that are frequently used in the pediatric population. Likewise, the antibacterial spectrum of ototopical aminoglycosides is also limited. The quinolones represent an improvement over other topical antimicrobials because they cover all of the organisms that are commonly encountered in acute otitis media, acute otitis externa, and CSOM. Because the topical quinolones kill bacteria in a concentration-dependent manner, local administration of high concentrations is effective in causing a rapid decrease in the density of bacteria. For this reason, bacterial resistance is quite rare. (3-5) Although a recent article (6) described the emergence of ciprofloxacin-resistant P aeruginosa in pediatric otitis media, one must interpret this information with caution, because the minimum inhibitory concentration for pathogen eradication with quinolones is reported by the laboratory for systemic drug administration, not topical. Cost Although the initial cost of treatment with an amino-glycoside or a sulfonamide might be lower, the clinician must keep in mind that their limited antimicrobial spectrum might require the subsequent use of additional parenteral antibiotics or the prolonged use of topical therapy, which then increases the overall cost of treatment. Moreover, the higher incidence of complications and side effects associated with topical antibiotics other than quinolones might also result in higher costs. Finally, we physicians tend not to think in global terms, but the rapid resolution of otorrhea will result in less antibiotic resistance and, ultimately, less cost to the healthcare system. Administration and compliance Depending on the individual patient, compliance issues are sometimes an important factor in the choice of an antimicrobial agent. If one accepts that topical therapy is preferred to parenteral therapy for otorrhea, quinolone drops are preferred to other topical antibiotics because their dosing schedule calls for less frequent administration. In addition, patient acceptance of topical quinolones is good because these drugs are generally less acidic than the older agents. (3-5) Summary A radical change has occurred in the management of otorrhea over the past decade. Multiple studies have supported the efficacy of topical quinolones in the management of acute otitis media, acute otitis externa, and CSOM. For the first time, otolaryngologists have a scientific foundation on which to base our treatment protocols for these conditions. We no longer must rely solely on out clinical experience and prejudices. The quinolone drops have a superior safety profile and a broad antimicrobial spectrum, their overall cost is lower than the alternatives, and their convenient dosing schedule is tolerated well by most patients. When one takes all these factors into consideration, it becomes clear that topical quinolone therapy, with or without a steroid additive, is the treatment of choice for otorrhea in patients with a tympanic membrane perforation or ventilating tube. The development of ototopical medications has followed along the lines of Darwinian evolution, and the quinolone drops have clearly demonstrated the concept of "survival of the fittest."
Table. Phase III study results for the AOMT *
indication (N = 599)
Ciprofloxacin/
Clinical variable dexamethasone Ofloxacin
Median time (days) to 4 ([dagger]) 6
cessation of otorrhea
Clinical cure rate at 90% ([dagger]) 79%
the test-of-cure visit
Microbiologic success rate 91% ([dagger]) 82%
at the test-of-cure visit
Treatment failure rate 5% ([dagger]) 15%
* AOMT = acute otitis media with otorrhea through tympanostomy tubes.
([dagger]) Statistically significant difference (p<0.05).
References (1.) Myer CM III. Historical perspective on the use of otic antimicrobial agents. Pediatr Infect Dis J 2001;20:98-101. (2.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/ dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2004; 113:40-6. (3.) Ramsey AM. Diagnosis and treatment of the child with a draining ear. J Pediatr Health Care 2002; 16:161-9. (4.) Myer CM III. Post-tympanostomy tube otorrhea. Ear Nose Throat J 2001;80(Suppl):4-7. (5.) Dohar JE. Evolution of management approaches for otitis externa. Pediatr Infect Dis J 2003;22:299-305. (6.) Jang CH, Park SY. Emergence of ciprofloxacin-resistant pseudomonas in pediatric otitis media. Int J Pediatr Otorhinolaryngol 2003;67:313-16. |
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