Wednesday, August 20, 2014

Suspension Or Solution In The Setting Of Ruptured TMs

Topical antibiotic therapy for ear infections isn’t something you’re going to see as an earth shaking presentation at a good conference, or in a heated debate between the Swami and anyone who dare challenge him. It’s not even something that you would think is driven by dogma and anecdote rather than evidence.  Rarely is it even a thought that is questioned upon reviewing an order or writing a prescription. Generally, the whole subject is held in a state of apathy.  But you, my friends, (cue the pyrotechnics) would be foolish to think anything in emergency medicine is anything but filled with dissent, dogma and more questions than answers.

Acute otitis externa, we’re talking about AOE, an infection and inflammation of the external auditory canal. For which, topical antibiotic therapy is generally recommended.[1] It’s recommended that initial therapy include topical antibiotics that cover Pseudomonas aeruginosa, Staphylococcal spp., S. pneumonia, H. Influenzae, and M. catarrhalis. Luckily, most available ototopical antibiotics cover these pathogens.   But determining which agent is best; we must turn to the evidence.  The Cochrane folks conducted a systematic review of 18 trials (approx. 3300 pts) on this very subject.[2] While the data was tremendously heterogeneous, the authors concluded that there is no difference in the clinical outcome with an antiseptic (such as acetic acid) versus an antibacterial (such as an aminoglycoside) or with a steroid plus an antimicrobial versus an antimicrobial alone. However, there was suggested to be a benefit with an antimicrobial plus a steroid over a steroid alone. Steroids on their own do seem to reduce the duration of pain and itching (small rct of 51 patients using betamethasone).  But again, no benefit of any one antibiotic over another.

See enough earaches and eventually someone will say they can’t view the tympanic membrane so they want a suspension not a solution.  In an attempt to qualifying that request, they voice their concern that a solution will lead to higher risk of inner ear penetration and thus, ototoxicity.  This, of course, is base upon years and years of data.

According to Rosen’s – there is no mention that in the setting of presumed or confirmed TM rupture a solution is superior to a suspension (or vice versa).[3]  Tintinalli’s, however, does: “Acetic acid suspension should be used and not a solution; theoretically, this has less chance of middle ear penetration.”[4] While acetic acid was once used as an ototopical antiseptic, it is better used now for jellyfish stings or French fries. 

The guidelines for AOE recommend that in the setting of known or suspected TM perforation, including tympanostomy tube, the clinician should prescribe a non-ototoxic topical preparation.1  Solution or suspension? Does it even matter?

Let’s back up. To understand what formulation is best, we have to understand the mechanism of ototoxicity in this setting. The concern with ototoxic topical drugs I that if there is a ruptured TM, they may penetrate the inner ear structures and exert their damaging effects.  The ototoxic drugs that we’re concerned of are the aminoglycosides that are thought to be vestibulotoxic (gentamicin) or cochelotoxic (amikacin, neomycin and tobramycin), or both, acetic acid altering PH and affecting cochlear function and ploymixin B with an unknown mechanism.[5,6]

But to penetrate the inner ear and exert their toxicities, these drugs must pass through the round window membrane. RWM allows molecules < 1000 KDA to pass through. Lo, behold all aminoglycosides are below this size. Furthermore, all aminoglycoside otic products are solutions; they are only suspensions if the are co-formulated with a steroid. But, reviewing the basic chemistry concepts of a solution vs suspension: it’s the steroid that is in suspension – the AG is still in solution, is still the same size and theoretically still carries the same risk of ototoxicity.  Fortunately however, the incidence of ototoxicity from topical AG is relatively rare – 1994 study in Canada 1 in 10,000 have hearing loss after being exposed to topical AGs.[5,6]

So if neomycin/polymixin b/hydrocortisone is a suspension but contains two ototoxic drugs, is it still ototoxic? Probably.

Via process of elimination, and some knowledge of medication ADRs, fluoroquinolones (FQ) are the only remaining ototopical antibiotics that cover the spectrum of AOE but are not ototoxic.  They are unfortunately expensive… Unless you use ophthalmic FQs in the ear. Yup, you can do that. And they’re cheaper. On average, an otic Rx for ofloxacin 0.3% / 10mL is going to run about $119.00 USD, cash. Compared to ofloxacin 0.3% / 10mL ophthalmic is about $65.00 USD, cash. 



There is some limited data to support this change of routes. Further, all data uses AG products (which we’re avoiding here). But we may be able to make some assumptions to FQs. A RCT out of UC Davis in the late 1980’s randomized patients undergoing tympanostomy tube placement (majority of whom had persistent AOM with effusion) to topical OPHTHALMIC gentamicin to be used optically or no treatment.[7] Fourteen days post-op there were 9 (19.6%) patients with purulent otorrhea from one or both ears vs zero (0%) in the gentamicin ophthalmic group.  Then in 1991, a case series of 3 patients who received tobramycin ophthalmic drops for otic use all had clinical cure within 2 weeks with no evidence of ototoxicity.[8]

Pharmaceutically, the difference between ophthalmic products and otic products is that ophthalmic products are 1) sterile, and 2) buffered to a neutral pH. Otherwise, they are identical to their otic cousins.  

Ultimately, it depends on cost to the patient and presence of ruptured TM. If they may have trouble affording a $150 script for something that is likely self-limiting or a Rx that is about half the cost – but may mystify the pharmacist in the community. 

Reference:
  1. Rosenfeld RM, Schwartz SR, Cannon CR, et al. Clinical Practice Guideline: Acute Otitis Externa. Otolaryngology – Head and Neck Surgery 2014; 150(2): 161-168
  2. Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004740
  3. Pfaff JA, Moore GP. Chapter 72 – Otolaryngology. In: Marx: Rosen's Emergency Medicine - Concepts and Clinical Practice, 8th ed. Philadelphia, PA. Saunders, An Imprint of Elsevier; 2010
  4. Silverberg M, Lucchesi M. Chapter 237. Common Disorders of the External, Middle, and Inner Ear. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. http://accessmedicine.mhmedical.com.proxy.libraries.rutgers.edu/content.aspx?bookid=348&Sectionid=40381723. Accessed August 20, 2014.
  5. Roland PS, Stewart MG, Hannley M, et al. Consensus panel on the role of potentially ototoxic antibiotics for topical middle ear use: introduction, methodology and recommendations. Otolaryngol Head Neck Surg 2004;130(Suppl 3):S51–6.
  6. Haynes DS, et al. Ototoxicity of ototopical drops: An update. Otolaryngol Clin N Am, 2007; 40: 669-683
  7. Baker S, Chole RA. A randomized clinical trial of topical gentamicin after typmanostomy tube placement. Arch Otolaryngol Head Neck Surg, 1988; 114:755-757
  8. Hoffman RA, Goldofsky E. Topical ophthalmologics in otology. Ear, nose & throat journal, 1991; 70(4):201-205