You are in: eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > PHARMACOLOGY Antibiotics, OtotopicalArticle Last Updated: Mar 21, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 8
  Author: Kathleen R Billings, MD, Division of Otolaryngology-Head and Neck Surgery, Clinical Instructor, Children's Memorial Hospital, Chicago, IL Kathleen R Billings is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, and Illinois State Medical Society Editors: Robert A Battista, MD, FACS, Assistant Professor of Otolaryngology, Northwestern University Medical School; Consulting Staff, Ear Institute of Chicago, LLC; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Peter S Roland, MD, Professor, Department of Neurological Surgery, Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, Director of Clinical Center for Auditory, Vestibular and Facial Nerve Disorders, Chief of Pediatric Otology, University of Texas Southwestern Medical Center; Adjunct Professor of Communicative Disorders, School of Human Development, Chief of Medical Services at Callier Center for Communicative Disorders, University of Texas at Dallas; Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders; Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine Author and Editor Disclosure Synonyms and related keywords: ototopical antibiotics, ear drops, otorrhea management, draining ear treatment, powders, creams, ointments, drops, ototopical drops, ototopicals OTOTOPICAL ADVANTAGESSection 2 of 8
  In treating ear infections with antibiotics, topical delivery has a number of advantages over systemic delivery. These advantages include the following:
A 0.3% antibiotic solution contains 3000 mcg/mL of antibiotic. For comparison, consider the following commonly accepted middle ear concentrations after oral administration of antibiotics.
Even parenteral ceftriaxone, which can deliver an exceptionally high middle ear fluid level (35 mcg/mL), cannot begin to compete with the concentration of antibiotic delivered into the middle ear by topical delivery. These high concentrations are pharmacodynamically important for antibiotics known to have a concentration-dependent mechanism of action. Aminoglycosides and quinolones are both concentration-dependent drugs. Consequently, bacteriocidal activity and lethality of bacteriocidal kill is progressively enhanced by the extent to which the delivered concentration exceeds the minimal inhibitory concentration (MIC). Although the MIC of ciprofloxacin for Pseudomonas is reported to be as high as 256 mcg/mL, this level is not the norm. End point MICs rarely exceed 64 mcg/mL, even for highly resistant Pseudomonas. Consequently, the concentration of delivered antibiotic, when topical administration is used, is always well above the MIC of the relevant organism. This makes the emergence of bacterial resistance extremely improbable. The possibility for the emergence of resistance seems to be vastly lower when topical routes of administration are used as compared to drugs that are administered systemically. An important consequence of the high concentration of antibiotics delivered when topical preparations are used is the recognition that MICs reported by clinical laboratories become irrelevant. The clinical laboratory determination of resistance is based entirely on the drug level that can be achieved by systemic administration. A Pseudomonas organism with an MIC of 8 mcg/mL for ciprofloxacin is considered resistant. Clearly, however, the same organisms are rapidly killed by 0.3% topical solution containing 3000 mcg/mL. Characteristic of topical delivery systems is the absence of systemic effects, which is an advantage if no systemic effect is required. Systemic toxicity requires systemic exposure. Consequently, systemic reaction to topical antibiotics is extremely uncommon. Because no appreciable systemic delivery of topically administered agents occurs, the normal flora in the respiratory and gastrointestinal tracts is not exposed to antibiotics. Topical administration, therefore, avoids selecting for resistant organisms in the upper aerodigestive tract, a common mechanism by which resistant organisms develop and propagate. The absence of systemic delivery is another reason that resistance to topical administration occurs with less frequency than resistance to systemically administered agents. The use of topical agents allows for the simultaneous modification of the local microenvironment. The pH of the external auditory canal, for example, is normally slightly acidic. The administration of an antibiotic in an acidic drop helps restore and fortify this normal host defense mechanism. Ototopical medications generally are less expensive than systemic medications. While the newer quinolone antibiotic drops are more expensive than some systemic antibiotics, such as amoxicillin, the quinolone drops are much less expensive than systemic quinolones. To compare the cost of amoxicillin, trimethoprim-sulfamethoxazole, or erythromycin to these ototopical preparations is not appropriate. These systemic antibiotics have a poor spectrum of activity against otic pathogens. OTOTOPICAL DISADVANTAGESSection 3 of 8
A number of disadvantages are associated with ototopical administration of antibiotics. These disadvantages include the following:
If the antibiotic cannot reach the infected area, the agent cannot be effective. Delivery can be impaired in a number of different ways, including the following:
Most failures of ototopical therapy are failures of delivery. Many of these problems are manageable. Swollen tissues in the external auditory canal are overcome by meticulous cleansing and placing of an otowick. The lumens of tympanostomy tubes can be cleared in the clinic using the microscope and microinstrumentation. Profuse otorrhea can be cleared from the external auditory canal long enough to apply drops using irrigation. An irrigation solution that is 50% sterile water and 50% hydrogen peroxide frequently eliminates enough material from the external auditory canal to allow passage of the medication if the agent is delivered within a few minutes after the irrigation is complete. When at home, the ear can be flushed with a half strength vinegar solution or acetic acid drops to facilitate placement of antibiotic drops. Managing granulation tissue is more difficult. Mechanical debridement, the use of silver nitrate, and steroid preparations often eliminate granulation tissue and permit effective entry of topical medications into the middle ear. Toxicity from topical preparations can involve both middle ear and inner ear structures. Middle ear toxicity takes the form of irritation of the middle ear mucosa accompanied by mucosal edema and metaplasia, if the inflammatory event is frequently repeated. Propylene glycol, a common vehicle in topical preparations, is fairly irritating to middle ear mucous membranes. Ototopical preparations vary in their ability to inflame middle ear mucosa. Hydrocortisone has a mildly irritating effect. Vasocidin, an ophthalmic drop used off-label as an otic preparation, has an intense inflammatory effect on middle ear mucous membranes. Inner ear toxicity can take 2 forms, cochlear and vestibular. Neomycin, polymyxin, and chloramphenicol are intensely ototoxic if these agents enter the inner ear. A single small dose of these preparations into the middle ear of chinchillas produces near total cochlear hair cell loss. The effect is clearly muted in humans, or anacusis would be widespread following the use of neomycin-containing otic preparations. A number of reasons may explain why cochlear ototoxicity is less likely in humans than in experimental animals. The round window membrane of experimental animals is considerably thinner than that of adult humans. The round window membrane of experimental animals is exposed, while this structure is relatively protected in humans. In humans the round window membrane is frequently covered with a mucous membrane that does not permit direct contact between medications placed into the ear and the round window membrane. Aminoglycoside antibiotic molecules have a negative charge, as does the round window membrane of humans; therefore, the charges discourage movement of the antibiotic across the round window membrane. Ototopical medications are generally administered when the mucous membrane is inflamed, edematous, thickened, and often hyperplastic. Many otolaryngologists are convinced that they have detected genuine cases of hearing loss due to aminoglycoside ototoxicity. The relative infrequency with which hearing loss occurs as a consequence of the installation of aminoglycoside drops is a tolerable risk when such preparations clearly are the most effective therapy for middle ear diseases. However, because quinoline drops lacking in ototoxic potential are currently available, the risk of aminoglycoside-induced ototoxicity is more difficult to justify. Most reports on ototoxicity focus principally on hearing loss. In a 1998 report, Marais and Rutka emphasize that for many aminoglycoside antibiotics, vestibular toxicity is much more likely than cochlear toxicity. Consequently, they have searched for vestibular manifestations of aminoglycoside ototoxicity and, unfortunately, have good evidence that clinical vestibular toxicity occurs with meaningful frequency. Rutka recently produced complete labyrinthine ablation using a commercially available ophthalmic gentamicin drop instilled twice a day through a patent tympanostomy tube. The first case of cutaneous sensitization to neomycin was reported to have occurred in the external auditory canal as a consequence of treatment for external otitis. Since that time, the incidence of topical sensitization to neomycin appears to have increased. In the 1970s, topical sensitization was detectable in about 8% of individuals with chronic external otitis. In the 1980s, this incidence doubled to 16%, and in the 1990s, the incidence doubled again to 30-35%. The incidence of cutaneous sensitization has apparently doubled each decade for the last 3 decades, presumably as a result of widespread exposure to neomycin-containing drops. The aminoglycosides are capable of cross-sensitization. Tobramycin sensitivity has been detected in the Netherlands, a country in which tobramycin-containing topical preparations are not approved for use. Florid sensitivity reactions are relatively easy to diagnose but are not terribly common. Low-grade sensitivity reactions, however, are much more difficult to diagnose. The approved labeling for polymyxin, neomycin, and hydrocortisone solutions warns that sensitivity reactions may be low grade and may simply manifest as drainage that does not cease. The practical consequence is that distinguishing between resistant infection and low-grade sensitivity reaction may be impossible. How many treatment failures of acute external otitis are the consequence of sensitivity reactions is unknown. Clearly, however, topical sensitization plays a significant role in chronic external otitis media. The absence of systemic effect transforms from an advantage to a disadvantage when a systemic effect is needed. If cellulitic changes occur outside the confines of the external auditory canal, including soft tissues of the cheek, auricle, or postauricular tissues, systemic antibiotics are required. Sometimes otorrhea in a child can be a manifestation of a diffuse upper respiratory infection with systemic manifestations. Children who have systemic signs and symptoms associated with otorrhea or who have an accompanying sinusitis or pharyngitis should not be treated with topical therapy alone. Withholding systemic antibiotics in such circumstances risks the development of either local complications from sinusitis or systemic complications, such as pneumonia, septicemia, or meningitis. The possibility of altering the microenvironment in a counterproductive way exists if the wrong solution or preparation is used as a vehicle for topical antibiotics. One might argue that the intense middle ear inflammation produced by Vasocidin is a good example of such inappropriate use. An alkaline antibiotic delivery system for external otitis creates a more hospitable environment for Pseudomonas and, thus, is counterproductive. TYPES OF DELIVERYSection 4 of 8
Antibiotics can be characterized in a variety of ways. One method is to characterize antibiotics on the basis of delivery. Three types of delivery systems are available, ie, powders, creams or ointments, and drops. Powders have been used for many years, and a variety of different powders are compounded on a local or regional basis. The Food and Drug Administration (FDA) has not approved any powders, and the FDA is unlikely to ever approve powders. The potential market for such preparations is much too small to justify the expense associated with the FDA approval process. Powders have the advantage of adhering to moist surfaces and have long dwell times within the external auditory canal, middle ear, or mastoid cavities. In a healthy mastoid cavity, powders can persist for months. In a profusely draining ear, the dwell time is much shorter but is likely to exceed that of liquids. Powders appear to adhere tenaciously to granulation tissue, making them especially attractive for chronic suppurative otitis media. The powders are relatively easy to apply. A House-Sheehy powder insufflator is readily available and inexpensive ($10-15). A large variety of different components have been used in powders. Most preparations are a mixture of antibacterial antibiotics, antifungal agents, and steroids. Two preparations are used at the University of Texas (UT) Southwestern Medical Center. Gold dust is comprised of chloramphenicol, sulfanilamide, and hydrocortisone. Mastoid powder is comprised of ciprofloxacin powder, clotrimazole powder, dexamethasone powder, and boric acid. The mastoid powder appears more effective and is easier to apply than gold dust. Mastoid powder has a reduced tendency to clump, is much easier to disperse by blowing, and seems to distribute as a finer powder than gold dust. Creams are used only in the treatment of diseases of the external auditory canal. Aminoglycoside ointments, such as Neosporin and/or tobramycin, can be used as single-dose therapies for external otitis. Mycelex cream is frequently chosen to treat suspected candida infections of the external auditory canal and conchal bowl. A single application can be an effective treatment for candidiasis of the external auditory canal. At UT Southwestern, mupirocin ointment is used perioperatively and to fill the external auditory canal after surgical procedures. Preference is given to this ointment because no ototoxic potential exists. The most commonly used ototopical preparations are drops. Drops are available in 2 forms, as single agents or as combination products. Single agent antibiotic drops are usually available as solutions. They often have very low viscosities, approaching that of water. Combination products tend to be more viscous because they are dispensed as suspensions. The physicochemical properties of steroids are such that steroids do not go readily into solution and, consequently, must be emulsified. Microemulsions have fairly low viscosities and have the clarity of solutions (eg, TobraDex). A large variety of ototopical drops are available and can be separated according to 4 basic characteristics: presence/absence of antibiotic and type of antibiotic present, pH, viscosity, and single agents or combination products. ANTIBIOTIC COMPONENT DROPSSection 5 of 8
Some ototopical preparations do not contain antibiotics. These agents rely on pH or other physical chemical properties of the solution to kill bacteria or control bacterial growth. VoSol is an acidic solution that is quite viscous, with a pH of approximately 3. This solution can be obtained with or without hydrocortisone. Domeboro solution is a modified Burow solution acidified with 2% acetic acid. Although the pH is 5, this solution is more bacteriostatic than solutions of lower pH. Consequently, some of its bacteriocidal effect must rely on the aluminum acetate component of the mixture. Antiseptics are often used in ototopical preparations. The antiseptic can be dropped into the external auditory canal or painted on using small cotton swabs. Antiseptics are useful because of potential antibacterial and antifungal effects. Antiseptics are less likely to select for resistant organisms. Gentian violet (an aniline dye), mercurochrome (a mercury-containing compound), and cresylate (a substituted phenol) are used as topical otologic antiseptic agents. Of these agents, cresylate appears to have the most potent antibacterial and antimycotic effect. Chloramphenicol drops have been marketed in the past, and sulfanilamide-based drops are available for ophthalmic use. Ophthalmic preparations containing sulfanilamide are occasionally indicated for otic use. Ophthalmic drops have a neutral pH and, consequently, can generally be used in the ear if deemed appropriate. Polymyxin, a cationic detergent, is commonly used in combination preparations and remains an effective antibiotic against gram-negative organisms. However, similar to neomycin, polymyxin potentially is ototoxic. Aminoglycosides have been the mainstay of ototopical bacterial antibiotics. The oldest of these agents is neomycin, which has been available for over 40 years. Neomycin remains reasonably effective against gram-positive organisms, but its effectiveness against gram-negative organisms has declined in recent years. Pseudomonas, the most common bacterial pathogen in chronic otorrhea, has developed substantial resistance to neomycin. In Dohar's 1996 publication, fewer than 20% of the Pseudomonas organisms recovered from infected ears retained sensitivity to neomycin. Neomycin is a potent cochleotoxic agent and is highly sensitizing. Gentamicin and tobramycin are used as ototopical preparations, despite never receiving FDA approval for otic use. Tobramycin is used more widely in the United States, while gentamicin is used more commonly in Canada and Europe. Both aminoglycosides are highly effective against relevant bacteria, with tobramycin being slightly more effective against Pseudomonas in the United States. Both drugs have ototoxic potential. In their 1998 report, Marais and Rutka showed compelling evidence for vestibulotoxic effects from gentamicin otic drops. The most recently introduced topical antibacterial agents are the quinolones. These agents have an excellent spectrum of activity against relevant pathogens and lack any capacity for ototoxicity. From a strictly theoretical point of view, the quinolones are the antimicrobial agents of choice for antibacterial otic drops. Because they lack the potential for ototoxicity, quinolones are preferred to aminoglycosides for any application within the middle ear space. The American Academy of Otolaryngology - Head and Neck Surgery endorses this recommendation. No FDA-approved ototopical agents are specifically designed to treat otomycosis. Many agents with antifungal properties are suggested in the treatment of otomycosis, but consensus is lacking regarding the best agent for this condition. Nystatin, a polyene macrolide antibiotic, is available as a cream, ointment, or powder and has a wide spectrum of activity against mycotic organisms. Miconazole cream can be applied to the ear, although clotrimazole is the most widely used topical azole. Its antibacterial effect is advantageous in treating mixed bacterial-fungal infections, but the carrier vehicle for this agent in liquid form can irritate the surrounding skin and mucosa, affecting compliance. Tolnaftate, a popular antifungal agent, can be instilled into the ear, inhibiting growth of susceptible fungi. In studies using guinea pigs, this agent did not exhibit ototoxic effects, although nystatin left a persistent residue in the round window niche. OTHER COMPONENTSSection 6 of 8
The pH is an important element of antibiotic drops. As mentioned above, some preparations rely on low pH for their antibacterial and antimycotic activity. While this works well within the external auditory canal, a low pH can be extremely painful when applied to the middle ear space. Drops of low pH can produce severe discomfort when they pass through a perforation or tympanostomy tube. Drops with a pH varying between 5 and 6 are generally tolerated well, even if they reach the middle ear space. The drops at least have a theoretical advantage of restoring the external auditory canal to normal and have some advantage in the treatment of external otitis. No evidence is available to support the fact that low pH enhances the activity of an appropriate antibiotic. Antibiotic drops of neutral pH are unlikely to sting or cause significant discomfort and, therefore, are preferred in children with an open middle ear. Viscosity is an important attribute of ototopical medications. Drops of high viscosity tend to have long dwell times but may not pass readily through small-diameter lumens such as tympanostomy tubes or small perforations. Combination products, usually suspensions, almost always have high viscosities. These products usually combine an antibiotic with a steroid. When hydrocortisone is used, the emulsion generally is fairly viscous. For example, Cortisporin otic and Cipro HC have a viscosity of 4-8 centipoises. TobraDex, a microemulsion, has a lower viscosity of 2-4 centipoises. Solutions such as Ciloxan or Floxin have a viscosity of approximately 1 centipoise, roughly that of water. Combination products, as mentioned previously, tend to be more viscous because the steroid component does not go readily into solution. The steroid component has a potential advantage in treating the inflammation in external otitis or in reducing granulation tissue. CONCLUSIONSSection 7 of 8
Ototopical preparations are both more effective and safer than systemic preparations when used appropriately. Not all ototopical preparations are the same. Two ototopical formulations containing the same antibiotic may differ in pH, viscosity, and the presence of steroids. Thus, 2 preparations containing the same antimicrobial agent can be different in every other respect. Consequently, substitution of one preparation for the other is unreasonable. Substituting a solution of ciprofloxacin for a solution of ofloxacin rather than choosing a suspension of ciprofloxacin with a low pH and high viscosity as a substitute is more reasonable. Substituting a combination of tobramycin and dexamethasone for a drop containing ciprofloxacin and hydrocortisone may be more appropriate, even though the active agents are different. At least these drops share the features of low pH, high viscosity, and are combination products. Characteristics of Available Ototopical Agents
For excellent patient education resources, visit eMedicine's Public Health Center. Also, see eMedicine's patient education article Antibiotics. REFERENCESSection 8 of 8
Antibiotics, Ototopical excerpt Article Last Updated: Mar 21, 2006 |
