Dechra Pharmaceuticals

New Concepts In Ear Cleaning TrizEDTA (EDTA tris)

Sue Paterson MA VetMB DVD DipECVD MRCVS


Introduction

Ethylene diamine tetra acetic acid tris (EDTA tris) is unique amongst the ear cleaning products currently available to veterinary surgeons. Although not a licensed veterinary drug this compound has been found to possess a whole range of novel properties that can be harnessed in the topical management of bacterial otitis. Much of the work on the action of EDTA-tris was undertaken 20 – 30 years ago but it’s true potential in Veterinary medicine has only recently been established. Recent work particularly by Gotthelf in America has reinforced the action of this compound.

The potentiating effects of EDTA-tris in otitis have been described in a whole range of veterinary articles dating back as far as 1974 when Blue, Wooley and Eagon described the treatment of an experimentally induced Pseudomonas aeruginosa otitis externa by lavage with EDTA tromethamine lysozyme. Since this earliest article many other workers have looked at EDTA-tris in a whole range of clinical applications. Its use as an adjunct lavage for multiple fistulas in a dog was described by Bjorling and colleagues (1982), as well as its use in combination with antibiotics to treat cystitis (Wooley, 1974,1975, Farca, 1997) and rhinitis (Wooley, 1979). More recently its use in otitis externa has been described by several authors (Sparks, 1994, Farca, 1997, Foster, 1998).

EDTA- tris has three principal functions in ear management

  • As an antibacterial flush
  • As an alkalinising solution
  • As an antibiotic potentiating agent


Action of EDTA tris as an antibacterial flush

The cell surface of Gram-negative bacteria are damaged by exposure of cells to EDTA. Tris buffer enhances the effect of the EDTA (Goldschmidt and Wyers, 1967). Amongst many other damaging changes that are invoked periplasmic enzymes and cell membrane associated proteins are released (Heppel, 1972) and lipopolysaccharides, proteins and phospholipids and divalent cations are released from the cell wall. (Leive et al. 1968). (see figure 1). Soaking of the ear canal in a solution of EDTA-tris can thus damage bacterial cell walls.

This action can cause lysis of the bacteria and has been shown to be particularly active against Pseudomonas aeroginosa. (Gray and Wilkinson, 1965). The fact that EDTA-tris is water based means that it is well tolerated even in ulcerated ears. Although Gram positive bacteria are also susceptible to the action of EDTA the structure of their cell walls makes them more robust to it’s direct action. No product can ever be used with complete safety in the ear canal of a dog or cat with a ruptured tympanic membrane.

However EDTA-tris is advocated by many authors as being safe as a pre-treatment flush in otitis media suggesting it has little direct ototoxic effects. EDTA-tris can also be used for long term maintenance in animals that have recovered from severe bacterial otitis especially those where Pseudomonas has been identified and successfully treated. However due to the aqueous nature of the solution EDTA-tris has no benefit in the therapy of yeast infections in the dog and cat. Infact prolonged use of EDTA-tris like many water-based cleaners can predispose to Malassezia infection. The flush creates almost a “swimmers ear syndrome” due to the constant wetting of the inside of the ear canal. This can be counteracted by the occasional use of a boric acid containing cleaner either before or after EDTA-tris application.

Action of EDTA tris as a neutralising solution

There are many different acidic ear cleaners available for veterinary use. These are generally products that contain weak acids such as acetic acid, lactic acid and salicylic acid. Although the creation of an acid pH within the ear canal produces good antibacterial protection, the low pH will inactivate many of the useful antibiotics employed in licensed veterinary eardrops.

This is particularly applicable to the aminoglycosides and fluorinated quinolones. If an acid ear cleaner is thus to be used in isolation before the institution of antibiotics a suitable time, of up to several hours, should be allowed to elapse so that the pH in the ear can rise and not inactivate the antibiotic. Alternatively if the ear is flushed with EDTA tris between acidic flush and ear drop then it can act to neutralise the canal and allow the antibiotic in the ear drops to work at their full potential when applied. Interestingly the antibacterial action of acetic acid is not thought to be pH dependent meaning that this “acid” will probably continue to provide antibacterial activity even after it has been neutralised by the EDTA tris.


Action of EDTA tris to potentiate antibiotic activity

It appears that the EDTA binds to metal ions, which compete with aminoglycosides for cell wall receptors that allow them into bacteria. EDTA-tris has been shown to have good synergistic effects when used in combination with amikacin (Sparks, 1994) and neomycin (Sparks, 1994). The latter is of course a common component of many licensed Veterinary eardrops making the EDTA a useful pre-flush solution. However by extrapolation EDTA probably has the ability to enhance the activity of all aminoglycosides.

It’s activity appears to be more effective when used in combination with antibiotics with activity against Gram negative than Gram positive bacteria. This is due to the difference in the cell wall structure of the two groups. Gram negative bacteria contain more phospholipid and peptidoglycans in their cell walls than Gram positive bacteria. A clinical study undertaken looking at the use of EDTA-tris with antimicrobial agents in chronic otitis due to resistant bacteria suggested possible synergistic effects when EDTA was used with antimicrobial agents compared to the antimicrobial agent alone. EDTA has also been shown to have synergistic effects with fluorinated quinolones.

Recent work undertaken by Gotthelf (2003) has shown that EDTA-tris is capable of reducing the minimum inhibitory concentration of enrofloxacin against ciprofloxacin resistant Pseudomonas aeruginosa. His findings suggested that EDTA-tris exhibits a sparing in vitro effect on the MIC of enrofloxacin against ciprofloxacin resistant Pseudomonas aeroginosa and may benefit treatment of otitis externa infections with both susceptible and resistant Pseudomonas bacteria.


Using EDTA tris (TrizEDTA) for Yeast otitis

EDTA tris is not indicated for this type of infection

 
Gram positive otitis

EDTA tris can be used as a pre treatment flush prior to the instillation of antibiotic therapy. The ear should be flooded with the EDTA tris and then left to soak where possible for 10 – 15 minutes. The residual solution can then be gently sucked out or absorbed onto swabs or cotton wool. After this topical antibiotics may be used either on an empirical basis where cytology has been performed or based on culture and sensitivity.

In most cases Gram positive infection tends to found in the earliest stages of the otitis and the ear drum is less likely to be damaged giving the clinician a much wider choice of drugs than that in Gram negative otitis. Antibiotics with good activity against both staphylococcus and streptococcus such as aminoglycosides and fusidic acid can be used after flushing. In the authors opinion it is inappropriate to use topical fluorinated quinolones for Gram positive infections unless dictated by appropriate culture and sensitivity. These drugs are best reserved for Gram negative infections.


Gram negative otitis

The protocol may be followed in the same way as that for Gram positive infections. However whereas antibiotic selection can usually be made on an empirical basis in Gram positive infections and resistance is rare the reverse is true in Gram negative problems. In the earliest stages of otitis the predominant infectious flora is Gram positive as the disease progresses there is a switch to Gram negative organisms. These pathogens tend to lead to the production of more aggressive clinical signs and an extension of the infection into the middle ear via a ruptured tympanum. In the author’s opinion when Gram negative rods are identified on cytology from these cases, culture and sensitivity is essential.

Often the clinician is faced with a multiply resistant population of bacteria without a licensed product to use or with an appropriate sensitivity but without a licensed product that can safely be used in an ear with a ruptured ear drum. In these case antibiotics are used in a non-licensed fashion at the discretion of the clinician following the cascade to treat the infection. Three antibiotics that have been described as being useful in such cases of Pseudomonas otitis externa/media are the fluorinated quinolones enrofloxacin and marbofloxacin and ticarcillin. The injectable forms of these drugs can be used topically in the ears with minimal risk of ototoxicity. As EDTA tris has been shown to be synergistic with fluorinated quinolones it can provide a safe non acid vehicle for topical application of these drugs.

Many different non-licensed recipes have been designed a few of the more common are annotated in the table (table 1) below. In addition to the application of antibiotics into the ear of dogs with Gram negative infection most authors would agree that topical steroids are indicated in the acute stages of the disease. These act to decrease the intense inflammation, open up the ear canal to allow passage of topical medication and reduce the exudation in the middle ear. Again where licensed products are available and safe to use then they should be used before the extra-label use of medication. However rarely can licensed drugs be used when the eardrum is ruptured so that injectable dexamethasone can be instilled into the ear. This can be used after an EDTA tris flush or can be combined with the flush to provide more long-term anti-inflammatory benefits.


Table 1

 

Enrofloxacin Use a dilution of 1 part enrofloxacin (2.5% injectable solution) to 6 parts EDTA-tris solution. Use a good squeeze of the solution into each ear twice daily. Alternatively the ear can be flushed with EDTA tris and the enrofloxacin can be mixed in sterile water/saline and added after the flush. 0.5ml of diluted antibiotic solution can be instilled into each ear twice daily.
Marbofloxacin Use 1% solution and dilute 1 part of marbofloxacin to 4 parts of EDTA tris. Use a good squeeze into each ear once daily. Alternative the 1% solution can be mixed with sterile water/saline and 1-2 ml instilled into each ear once daily after flushing. Solution is light sensitive and must be kept in dark container.
 




References
 

New combination for the therapy of canine otitis externa. I. Microbiology of otitis externa.
Kiss G, Radvanyi S, Szigeti G. J Small Animal Pract. 1997 Feb 38(2) 51-6


Potentiating effect if EDTA-Tris on the activity of antibiotics against resistant bacteria associated with otitis, dermatitis and cystitis.
Farca AM, Piromalli G. Maffei F, Re G. J Small Animal Pract. 1997 Jun 38(6): 243-5

Antimicrobial effect of combinations of EDTA-Tris and amikacin or neomycin on the microorganisms associated with otitis externa in dogs.

Sparks TA, Kemp DT, Wooley RE, Gibbs PS. Vet Res Commum. 1994 18(4): 241-9

In vitro action of combinations of antimicrobial agents and EDTA-tromethamine on Pseudomonas aeruginosa.
Wooley RE, Jones MS, Gilbert JP, Shotts EB Jr. Am J Vet Res. 1983 Aug 44(8): 1521-4.

Action of EDTA-Tris and antimicrobial agent combinations on selected pathogenic bacteria.
Wooley RE, Jones MS. Vet Microbiol. 1983 Jun 8(3): 271-80.

Treatment of experimentally induced Pseudomonas aeruginosa otitis externa in the dog by lavage with EDTA-tromethamine-lysozyme.
Blue JL, Wooley RE, Eagon RG Am J Vet Res. 1974 Sep 35(9): 1221-3.

The role of Pseudomonas in Canine Ear Disease
Foster AP, DeBoer DJ Compendium on Continuing Education. Volume 20 (8) August 1998. 909-918.

Effect of EDTA-tris on an Escherichia coli isolate containing R plasmids.
Wooley RE, Dickerson HW, Simmons KW, Shotts EB jr, Brown J. Vet Microbiol. 1986 Jun 12

In vitro action of combinations of antimicrobial agents and EDTA-tromethamine on Eschenchia coli.Wooley RE, Jones Ms, Gilbert JP, Shotts EB Jr. Am J Vet Res. 1983 Jun 44(6) 1154-8

Antibacterial action of combinations of oxytetracycline, dimethyl sulfoxide, and EDTA-tromethamine on Proteus, Salmonella, and Aeromonas.
Wooley RE, Gilbert JP, Shotts EB Jr. Am J Vet Res. 1982 Jan 43(1) 130-3

Antibiotic-tromethamine-EDTA lavage for the treatment of bacterial rhinitis in a dog.
Wooley RE, Berman AP, Shotts EB Jr. J Am Vet Med Assoc. 1979 Oct 15 175(8) 817-8.

Attempted reversal of oxytetracycline resistance of Proteus mirabilis by EDTA-tromethamine Lavage in experimentally induced canine and feline cystitis.
Wooley RE, Blue JL, Campbell LM. Am J Vet Res. 1975 Oct 36(10) 1533-5.

Efficacy of EDTA-tris-lysozyme lavage in the treatment of experimentally induced Pseudomonas aeruginosa cystitis in the dog.
Wooley RE, Schall WD, Eagon RG, Scott TA. Am J Vet Res. 1974 Jan 35(1) 27-9.

EDTA-tromethamine lavage as an adjunct treatment for multiple fistulas in a dog.
Bjorling DE, Woolwy RE. J Am Vet Med Assoc. 1982 Sep 15 181(6) 596-7.

In vitro effect of combinatins of antimicrobial agents and EDTA-tromethamine on certain gram-positive bacteria.
Wooley RE, Jones Ms, Gilbert JP, Shotts EB Jr. Am J Vet Res. 193 Nov 44(11) 2167-2169.

Inhibitory effects of combinations of oxytetracycline dimethyl sulfoxide and EDTA-tromethamine on Escherichia coli.
Wooley RE, Gilbert JP, Shotts EB Jr. Am J Vet Res. 1981 Nov 42(11) 2010-3.

Evaluation of the in vitro effect of Tris-EDTA on the minimum inhibitory concentration of enrofloxacin against ciprofloxacin resistant Pseudomonas Aeruginosa
Gotthelf L.N. Proceedings 19th Annual Congress of ESVD-ECVD, Tenerife 2003 145.

 

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21 March 2011

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