Download Infectious bovine keratoconjunctivitis antimicrobial therapy

PRODUCTION ANIMALS
Blackwell Publishing Asia
PRODUCTION ANIMALS
REVIEW ARTICLE
Infectious bovine keratoconjunctivitis
antimicrobial therapy
CS MCCONNEL, L SHUM and JK HOUSE
University of Sydney, Faculty of Veterinary Science, Camden NSW 2570 [email protected]
Infectious bovine keratoconjunctivitis (IBK) is one of the most
common diseases of cattle and is of major economic importance.
If the primary aetiological agent, Moraxella bovis, is successfully
eliminated from ocular tissues corneal ulcers heal at a constant
rate. If treatment is unsuccessful ulcer reoccurrence may follow
initial healing. Appropriate antimicrobial selection requires
knowledge of antimicrobial sensitivities and distribution in ocular
tissues and tears. Drugs may be delivered to the eye in several
ways: subconjunctival injection, topical application and systemic
administration. While therapeutic efficacy is affected by the frequency and mode of drug delivery, variations between intensive and
extensive enterprises dictate the practical method of antimicrobial
delivery. Specific recommendations for antimicrobial therapies
targeting Australian IBK outbreaks are dependent upon antimicrobial pharmacokinetics, drug regulations and associated costs.
Key words: Bovine, keratoconjunctivitis, Moraxella bovis,
antimicrobial, pinkeye
Aust Vet J 2007; 85:65–69
CCFA
IBK
IM
MIC
SC
doi: 10.1111/j.1751-0813.2006.00080.x
Ceftiofur crystalline-free acid
Infectious bovine keratoconjunctivitis
Intramuscular
Minimum inhibitory concentration
Subcutaneous
I
nfectious bovine keratoconjunctivitis (IBK) or ‘pinkeye’ is a
common and highly contagious ocular disease affecting cattle
worldwide that is caused by the Gram negative bacterium
Moraxella bovis.1 Although M bovis is the most commonly isolated
pathogen from IBK, the occurrence and clinical severity is mediated
by various factors such as the environment, season, M bovis strain
and host immune response.2 Concurrent pathogens such as
Moraxella ovis have also been implicated as contributors to IBK
pathogenesis.3 Tremendous economic losses stem from inappetance
and poor weight gain in affected animals suffering from ocular
pain and visual impairment. An Australian postal survey recorded
that 81.3% of participating cattle owners reported the occurrence
of IBK, and 75% observed a reduction in the weight gain of
affected cattle.4 Other major losses resulting from IBK include
the direct costs of repetitive drug treatments, loss of value of
show animals, and reduced milk production from infected dairy
© 2007 The Authors
Journal compilation © 2007 Australian Veterinary Association
animals.5 As early as 1979 in Australia, losses due to reduced
production were estimated to reach 22 million dollars, with
1.5 million dollars spent for treatment.6
Ideally, treatment of IBK will achieve elimination of M bovis
infection.7 If IBK is treated successfully corneal ulcers heal at a
constant rate; however, if M bovis is not eliminated from ocular
tissues ulcer reoccurrence may follow initial healing.8,9 Studies
conducted in the United States have demonstrated in vitro M bovis
antimicrobial susceptibility to ampicillin, cephalosporin, nitrofurans,
penicillin, sulfonamides, tilmicosin, and trimethoprim-sulfonamide,
and variable in vitro susceptibility to cloxacillin, erythromycin,
gentamicin, oxytetracycline and streptomycin.5,10–12 Resistance has
been demonstrated to tylosin and lincomycin. Appropriate antimicrobial selection for the treatment of cattle infected with M bovis
requires knowledge of the minimum inhibitory concentration (MIC)
for the bacterium, as well as an understanding of antibiotic distribution into ocular tissues and tears following administration.8
Drugs may be delivered to the eye in several ways: subconjunctival
injection, topical application and systemic administration.
Antimicrobial susceptibility testing of Australian M bovis isolates
suggests that antimicrobial resistance is uncommon in Australian
field isolates.13 Despite this, the variable antimicrobial susceptibility observed in the United States indicates that antimicrobial
resistance could develop and antimicrobial susceptibility testing
should be conducted in the event of treatment failure.8 Therapeutic decisions are influenced by numerous factors such as efficacy,
cost, animal husbandry implications, labour requirements and
availability, withholding times, availability and quality of facilities,
and availability of veterinary support. Therefore the best therapeutic
strategy for a particular herd is dependent on the final analysis of
the current situation. This review discusses comparative efficacy data
for a number of antimicrobials available world-wide for IBK treatment. Our recommendations of several treatment options pertain
only to those drugs with labelling for treatment in Australia.
Subconjunctival treatment
Subconjunctival administration of antimicrobials aims to reduce
treatment costs and total dosages of drug while achieving higher
ocular drug concentrations.5 Subconjunctival injections probably
Australian Veterinary Journal Volume 85, Nos 1 & 2, January, February 2007
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lead to some direct diffusion across the sclera and choroid;
alternatively, the drug may gradually leak from the injection site,
entering the tear film and eventually the eye via the cornea as
if it were applied topically.14 Although subconjunctival drug
dosages are variable, they are generally given in volumes up to
1 ml and typically maintain therapeutically effective tear concentrations for 24 hours or longer. Nonetheless, the elimination of
an ocular M bovis infection may be more dependent on achieving
therapeutic drug concentrations in infected ocular tissues rather
than tears.14–16
In calves given a bulbar subconjunctival injection of a conventional (100 mg/ml) oxytetracycline formulation, the antibiotic
concentration in tears was above MIC for 24 hours.8,17 Although
a single subconjunctival dose of a long-acting oxytetracycline
formulation achieved tear concentrations above MIC for longer
than 72 hours, severe tissue necrosis at the injection site precludes such therapy.8 The reported efficacy of sub-conjunctival
penicillin administration is variable, with notable differences in
efficacy reported between superior palpebral subconjunctival
and bulbar conjunctival routes of administration. Following
a single administration of procaine penicillin (3 × 105 IU)
into the superior palpebral subconjunctival tissues, therapeutic
drug levels within the conjunctival sac fluid were maintained
for 35 hours. However, injecting a larger volume of penicillin
(6.25 × 105 IU) resulted in therapeutically effective tear concentrations for 40 hours, increasing to 67.6 hours if injected into
the skin of the eyelid.16 Nevertheless, the efficacy of penicillin
may not be as good as pharmacokinetic data suggest. Three daily
injections of beef calves with procaine penicillin G (3 × 105 IU)
or a combination of procaine penicillin G and dexamethasone (4 mg)
into the superior palpebral subconjunctiva did not affect the outcome
of naturally developing IBK when compared to no treatment.15
In contrast, comparisons between calves naturally infected with
IBK and treated with bulbar subconjunctival penicillin versus
parenteral long-acting oxytetracycline have shown similar reductions in corneal ulcer healing times, but increased corneal ulcer
recurrence and a greater post-treatment shed of M bovis in ocular
secretions from the bulbar subconjunctival penicillin treated
calves.5 Similarly, administration of two bulbar subconjunctival
treatments of procaine penicillin G (300,000 IU, 48 to 72 hours
apart) has comparable therapeutic efficacy to parenteral treatment
with a long-acting oxytetracycline formulation (20 mg/kg IM,
repeated at 72 hours if corneal ulcers were present on days 1 or
2) when administered in tandem with feeding lucerne pellets
containing oxytetracycline (1 g/0.45 kg of pellets) at a dosage of
2 g per 250 kg calf daily. Although corneal ulcer healing time
was equally reduced, calves treated with oxytetracycline had a
lower prevalence of IBK and fewer recurrences of corneal ulcers
together with a lower frequency of M bovis isolation.18
Subconjunctival treatment options
Procaine penicillin G
Procaine penicillin G is at present not labelled within Australia
for the treatment of IBK. Any use of such would be considered
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Australian Veterinary Journal Volume 85, Nos 1 & 2, January, February 2007
an off-label application. Bulbar subconjunctival dosages of 1 to
2 ml should be administered at 36 hour intervals for 2 to 3
treatments. Both eyes should be treated even if only a single
eye is clinically affected. Unaffected eyes should be treated prior
to affected eyes and procedures should be in place to limit
transmission between animals, such as changing gloves between
treatments. Blanket administration of the drug to all animals
simultaneously may not prove a practical or economic means
for reducing IBK incidence. The cost of the drug is low, but the
labour involved with moving, restraining and treating animals
may prove expensive. Although this treatment reduces healing time
and ocular scarring, the incidence of IBK is not reduced due to
relapses and the failure to eliminate the carrier state. There are
anecdotal recommendations for subconjunctival administration
of corticosteroids in tandem with penicillin. However, the single
study reported above15 suggests that such a combination has no
significant effect on the outcome of naturally developing IBK.
Topical treatment
Topical administration of antimicrobial formulations has been
recommended as a potentially cost-effective and less labour intensive
method for treatment of IBK.5 However, topically applied
aqueous antimicrobial suspensions have a short tear half-life.
Antimicrobials sprayed into the eye may prove irritating and
remain only a few minutes before tears wash them away. Although
topical application of oxytetracycline aerosol or powder is potentially
effective based on MIC data,11 application is required three to four
times daily for 4 to 7 days.14
Topical ointments can achieve an increased ‘contact’ time due to
increased viscosity and sustained release of drug from small
droplets that settle into the inferior cul-de-sac after application.
Oil-based benzathine cloxacillin applied topically either once17
or twice10 (72 hour interval) has proven efficacy against M bovis
infections. Calves affected with naturally occurring IBK treated
with two topical applications of benzathine cloxacillin (250 mg,
72 hours apart) had a similar reduction in corneal lesion healing
times and M bovis isolations to those treated with a single dosage
of cloxacillin. However, the early treatment of corneal ulcers was
a prerequisite for therapeutic efficacy in that initiating treatment
on corneal ulcers ≤0.5 cm as opposed to >0.5 cm led to significantly shorter healing times.19 Although one US study demonstrated an MIC for cloxacillin (≥2 μg/ml) suggesting the uniform
resistance of all M bovis isolates,11 others have shown lacrimal
fluid cloxacillin concentrations exceeding this MIC for 31
hours.20 Another study determined lower MIC levels (0.6 –1.25
μg/ml) that were surpassed by lacrimal fluid cloxacillin concentrations up to 86 hours after a single topical administration of
125 mg of oil-based benzathine cloxacillin.17 In a separate study,
topical application of a single 250 or 375 mg dose of oil-based
benzathine cloxacillin maintained tear cloxacillin concentration
above the established MIC (3.13 μg/ml) for M bovis isolate
Tifton 1, for 8 and 10 hours respectively. No cloxacillin activity
was detectable in the lacrimal fluid by 36 hours after topical
administration and no cloxacillin was detected in serum at any
time after drug administration.21 Following the treatment of
© 2007 The Authors
Journal compilation © 2007 Australian Veterinary Association
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There is limited information comparing the efficacy of topical
formulations to subconjunctival or parenteral treatments.5 Two
topical administrations of oil-based formulations of benzathine
cloxacillin (250 or 375 mg, 72 hours apart) reduced the shedding of M bovis in ocular secretions and hastened the healing of
corneal ulcers in experimentally induced IBK. This treatment was
as effective as two intramuscular (IM) dosages of the long-acting
oxytetracycline formulation (20 mg/kg, 72 hours apart) and
there was no significant difference between treatments in the
number of M bovis isolations at any sample collection interval.10
This study indicated that elimination of M bovis from ocular
tissues may require the maintenance of a lacrimal fluid cloxacillin
concentration above the MIC for M bovis rather than a high
peak concentration of short duration.21
Topical treatment options
Oxytetracycline hydrochloride aerosol and powder
Oxytetracycline hydrochloride ophthalmic aerosol or powder
in a puffer pack are registered in Australia for treatment of IBK.
No efficacy trials have been published relating to this mode of
drug delivery. Material sprayed into the eye remains for only a
few minutes before tears wash it away. Directions for use mandate
three daily applications of the aerosol or two to three daily applications
of the powder to affected eyes. These products provide an alternative
choice of treatment on properties lacking the necessary facilities
to restrain animals for the application of topical ointment or
injection of parenteral drugs. However, they require significant
labour for an as yet uncertain outcome. An advantage is that
there are nil withdrawal periods for both these products.
Benzathine cloxacillin ointment
Benzathine cloxacillin ointment is registered for topical treatment
of IBK in Australia using a pre-packed plastic application
syringe. Two doses of topical benzathine cloxacillin (minimum
of 250 mg up to 375 mg, 72 hours apart) should be administered
to affected cattle early in the disease process.10 Both eyes should
be treated even if only a single eye is clinically affected and,
preferably, unaffected eyes should be treated prior to affected
eyes. Procedures should be in place to limit transmission between
animals.5 Again, blanket administration of the drug to all animals
simultaneously may not prove a practical or economic means for
reducing IBK incidence. Advantages of this therapeutic regime
include nil meat and milk withdrawal times.
© 2007 The Authors
Journal compilation © 2007 Australian Veterinary Association
Systemic treatment
Systemic antimicrobial therapy has been recommended as a
means of targeting M bovis located within lacrimal glands and
nasal passages. Drugs administered systemically may enter the eye
via the tear film or through the perilimbal or intraocular circulation.
Generally, lipophilic drugs achieve higher intracorneal and intraocular
concentrations and are more effective at penetrating the blood:tear
barrier than hydrophilic drugs.5,14,23 Nonetheless, the attainment
of bacteriostatic tear concentrations is not necessarily predictive
of efficacy. Trimethoprim and erythromycin are non-polar, basic,
lipophilic drugs that concentrate within tears following parenteral
injection yet are not used commercially due to either poor activity
against M bovis, the production of excessive tissue inflammation,
or cost.5
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cattle with a single topical dose of benzyl penicillin in a paraffin
ointment (5000 IU). Concentration profiles for formulations of
procaine penicillin and benzathine penicillin in an ointment
base equated to durations of therapeutic concentration (5 X
MIC) in conjunctival sac fluid of 37 and 56 hours respectively.22
As the antimicrobial action of cloxacillin and penicillin are time
dependent it is evident that the duration of therapeutic efficacy
achieved with ophthalmic ointments containing these drugs is
dependent on the MIC of the infecting strain and the drug concentration of the formulation. In the experimental studies cited
therapeutic drug concentrations were maintained for 8 to 86 hours.
Elimination of M bovis in calves with IBK has been demonstrated
following parenteral treatment with oxytetracycline24 or florfenicol.25
Oxytetracycline is an amphoteric molecule that should theoretically diffuse into tears; however, parenteral administration of
long-acting oxytetracycline leads to a tear concentration less than
1 μg/ml although conjunctival levels are >2 μg/ml for 72 hours.26,27
The efficacy of parenterally administered oxytetracycline in the
treatment of IBK8,24,26 is likely linked to these higher tissue levels.5
Substantial conjunctival concentrations of oxytetracycline are
present for as long as 20 hours after a single 20 mg/kg IM injection.
The drug is shown to localize within the lacrimal gland, conjunctiva,
and cornea but not within tear film or aqueous humor.27,28
Treatment with two doses of long-acting oxytetracycline
(20 mg/kg, 72 hours apart) has been shown to ameliorate
clinical signs of naturally occurring IBK through a reduction in
M bovis ocular infection and consequent decrease in corneal ulcer
healing time and recurrence.9,27,29 Similarly, treatment of all herdmates with IM long-acting oxytetracycline followed by daily
feeding of oral oxytetracycline (2 g per 250 kg calf ) daily for 10
days has been shown to reduce IBK incidence to 3% within
a season.18
Florfenicol provides a treatment option in Anaplasma endemic
regions where oxytetracycline use is restricted. Florfenicol has
high lipid solubility and low ionic partitioning suggesting that it
may distribute well to ocular tissues. Recent work has demonstrated that florfenicol administered subcutaneously (SC) (one
dose; 40 mg/kg) or IM (two doses 48 hours apart; 20 mg/kg) is
effective for treatment of calves with naturally occurring IBK.
Relative to controls, treated calves had smaller corneal ulcers 1
and 2 weeks after treatment and shorter ulcer healing times.7,30
Administering the drug to all animals simultaneously would be
expected to reduce IBK incidence. Further, another study has
demonstrated shorter healing times for eye lesions when calves
naturally infected with M bovis were treated twice IM 48 hours
apart with florfenicol (20 mg/kg) as opposed to long-acting
oxytetracycline (20 mg/kg). Relapses were observed in calves
treated with oxytetracycline but not in those calves treated with
florfenicol. Antimicrobial examination of M bovis strains isolated from affected calves indicated that 16.67% of the isolates
were resistant to oxytetracycline whereas all isolates were sensitive
Australian Veterinary Journal Volume 85, Nos 1 & 2, January, February 2007
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to florfenicol.30 Florfenicol is not registered for use in lactating
dairy cattle and heifer calves destined to produce milk for human
consumption.
Recent studies have evaluated the parenteral treatment of
naturally occurring IBK utilizing additional antimicrobials. The
lipophilic nature of macrolides allows for concentration at sites
of infection. Antimicrobial susceptibility testing has predicted
that tilmicosin will favourably control M bovis infections.12 In
fact, tilmicosin administered SC (5 or 10 mg/kg) was effective
in resolving corneal lesions associated with an Argentinean outbreak of IBK in Hereford cattle.31 Ceftiofur crystalline-free acid
(CCFA) has also been assessed for efficacy against IBK, administration being in the posterior aspect of the ear. The pinna site was
chosen due to the reduced risk for tissue residue and the lower
potential for injection-site trimming at slaughter. Concentrations
of ceftiofur metabolites in plasma have been shown to remain
well above published M bovis modal MIC values for more than 7
days when administered via this particular route.12,32,33 A single
dose of CCFA (6.6 mg of ceftiofur equivalents/kg, SC) proved
effective in the treatment of IBK in beef calves, resulting in
shorter mean healing times, smaller corneal ulcer surface areas,
amelioration of ocular discharge and photophobia, and a 50%
increase in the percentage of calves healed by day 14.32 Neither
tilmicosin nor ceftiofur are registered for treatment of IBK in
Australia. Comparative efficacies of tilmicosin and CCFA relative
to oxytetracycline or florfenicol have not been established.
Systemic treatment options
Long-acting oxytetracycline
Long-acting oxytetracycline is registered within Australia for
treatment of IBK. Two IM or SC dosages of 20 mg/kg should
be administered 72 hours apart. Simultaneous administration
of the drug to all animals reduces the incidence of IBK.5 The longacting oxytetracycline formulation’s extensive milk withdrawal period
makes this mode of treatment less desirable for lactating dairy
cattle.5 Antimicrobial resistance to tetracycline has been reported
in M bovis isolates in the United States.12,34,35 Blanket systemic
treatment with oxytetracycline is not recommended in the
Anaplasma endemic regions of northern and north-eastern Australia.
Florfenicol
Florfenicol is registered within Australia for treatment of IBK.
Two IM dosages of 20 mg/kg 48 hours apart or a single 40 mg/
kg SC dosage should be administered to affected cattle.7,30 Again,
administering the drug to all animals simultaneously would
be expected to reduce IBK incidence. This drug is not labelled
for dairy cattle, cattle intended for breeding or calves to be
processed for veal. Florfenicol provides a treatment option in
areas with potential oxytetracycline microbial resistance and/or
anaplasmosis.
Ceftiofur and Tilmicosin
Ceftiofur and Tilmicosin are not labelled for the treatment of
IBK in Australia.
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Conclusions
Despite the efficacy of antimicrobial therapy, treatment of affected
cattle has many disadvantages and the prevention of IBK is therefore
preferable.12,36 Affected animals should be segregated from normal
cattle and face flies should be controlled using insecticides.5 If
possible, exposure to environmental irritants such as grass awns
and dust should be limited. Preventative vaccination may be
warranted if an Australian IBK vaccine becomes available. When
preventative measures fail, IBK lesions should be treated early in
the disease process. Vigilant observation for clinical signs such as
increased lacrimation and blepharospasm allows for immediate
therapeutic intervention. Treatment failure may reflect delayed
therapeutic intervention or inappropriate route or frequency
of antimicrobial therapy. Given that variable antimicrobial
sensitivity patterns have been reported in other countries, the
emergence of antimicrobial resistance should be considered in
the future if treatment failures occur in the face of appropriate
application of labelled therapeutic drugs.
References
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© 2007 The Authors
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29. Edmondson AJ, George LW, Farver TB. Survival analysis for evaluation of
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22. Abeynayake P, Cooper BS. The concentration of penicillin in bovine conjunctival sac fluid as it pertains to the treatment of Moraxella bovis infection. (II) Topical
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(Accepted for publication 1st November 2006)
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