New Concepts In Ear Cleaning TrizEDTA (EDTA tris)
by
Sue Paterson MA VetMB DVD DipECVD MRCVS
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
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.
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.
| 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 |
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