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Proceedings of the 16th

Italian Association of Equine Veterinarians
Congress

Carrara, Italy
January 29-31, 2010

Next SIVE Meeting:

Feb. 4-6, 2011 – Montesilvano, Pescara, Italy

Reprinted in the IVIS website with the permission of the

Italian Association of Equine Veterinarians – SIVE

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Published in IVIS with the permission of SIVE
Antimicrobial therapy in neonates
Kevin Corley
BVM&S PhD DACVIM DECEIM DACVECC MRCVS
Anglesey Lodge Equine Hospital
Co. Kildare, Ireland
INTRODUCTION
Systemic and local bacterial infections are
common in neonatal foals, and cause signifi-
cant mortality and morbidity. Often signs of
infection can be quite subtle in neonatal foals,
and may be missed by inexperienced owners.
It has been shown in human critical care that
early administration of appropriate antimicro-
bials is critical to survival, and clinical experi-
ence suggests that this also holds for neonatal
foals. Therefore, both early recognition of in-
fection and choice of antimicrobial can make
a significant impact on outcome in foals.
SUCCESSFUL ANTIMICROBIAL
THERAPY
Successful antimicrobial therapy depends on a
number of different factors: Early institution
of therapy, appropriate dosage and selection
of appropriate antimicrobials. The require-
ment for early institution requires that good
“educated guesses” are made about possible
causative organisms and their likely antimi-
crobial sensitivities. Appropriate dosage re-
quires a good knowledge of the antimicrobial,
and particularly the differences in dose be-
tween neonates and adults. Selection of an-
timicrobial depends on its spectrum of activi-
ty, penetration into the tissue in question and
cost per dose.
Antimicrobial therapy is often not sufficient to
treat infection in neonatal foals, and support
of affected organs (from nutritional and fluid
therapy to full-out intensive care with me-
chanical ventilation) or surgical debridement
or lavage may also be necessary.
40
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BACTERIAL SPECIES COMMONLY
AFFECTING NEONATAL FOALS
Septicaemia
In studies, the most common bacteria isolated
in the blood of septicaemic foals were Es-
cherichia coli and Actinobacillus species.
Streptococcus and Enterococcus are also com-
mon. In contrast, the most common blood iso-
lates from foals with diarrhoea were Entero-
coccus species and Pantoea agglomerans,
with E. coli and Actinobacillus being isolated
much less frequently.
Some North American and Australian hospi-
tals and farms have recently experienced
high isolation rates of multi-drug resistant
bacteria, including Methicillin Resistant
Staphylococcus aureus (MRSA) and highly
resistant Enterobacter and Enterococcus
species 1,2. MRSA has also been isolated
from horses in Europe3, and 10.9% of hors-
es in one European study carried MRSA in
their nasal secretions4.
DIFFERENCES FROM ADULT HORSES
There are three reasons why the choice of an-
timicrobials is different in neonatal foals than
in mature horses. The first is that foals are not
(yet) hindgut fermenters, and antimicrobials
that can cause severe colitis in mature horses
do not carry the same risk in foals. Secondly,
given that a foal weighs approximately 1/10th
of a mature horse, antimicrobials that are cost-
prohibitive in mature horses can be used in
neonatal foals.
Lastly, toxicities may be different for foals
than for mature animals.
Published in IVIS with the permission of SIVE
One of the most important points to remember
about antimicrobial treatment in neonatal
foals is that, for many drugs, the dosage is
considerably higher than adult horses. A
much higher percentage of the body mass is
comprised of water in neonatal foals, as com-
pared to adults5.
In general the dosage of hydrophilic drugs
(such as the aminoglycosides) is higher in
foals, whereas the dosage is the same as adults
for lipophilic drugs.
PROPHYLACTIC USE
OF ANTIMICROBIALS IN FOALS
The high incidence of bacterial infections has
led to the practice of prophylactic administra-
tion of antimicrobials in the first days of life,
by some veterinarians. This practice is highly
controversial, because increased use of an-
timicrobials is thought to increase bacterial
resistance to those antimicrobials in the gen-
eral bacteria population, which may impact
on human as well as animal health. A recent
study found no difference in the incidence of
infectious disease between neonatal foals
treated with prophylactic antimicrobials and
those that were not treated6, however, the in-
cidence of infectious diseases in the study
population was very low, making it difficult
to draw definitive conclusions from this
study. In contrast, a study from the 1970s
demonstrated a reduction in the number of in-
fections in neonatal foals treated prophylacti-
cally with neomycin or framamycin during
the first 30 days of life7.
However, it is important to note that routine
foal management practices on stud farms
have significantly improved since this study
was carried out, which may make this finding
less directly relevant in the modern stud farm
situation.
There is some evidence that prophylactic an-
tibiotic treatment can be successful, at least
for a single problem disease. Prophylaxis with
azithromycin for the first two weeks of life re-
duced the incidence of Rhodococcus equi
from approximately 20% to 5% in one ran-
domised study8.
41
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SELECTED ANTIMICROBIALS
AS THEY RELATE TO THE FOAL
Cephalosporins
Cephalosporins are very commonly used an-
timicrobials in neonatal foals. However,
cephalosporins are a diverse group of drugs
both in their spectrum of activity and their
penetration into the tissues in the body. The
most commonly used cephalosporins in foals
are cefquinome and ceftiofur.
Cefquinome is a fourth-generation cephalo-
sporin, labelled in Europe for the treatment of
E. coli septicaemia in foals. The label dose is 1
mg/kg, IV or IM, q12h for foals. The author
uses a dose of 2.5 mg/kg IV q6-8h in foals
where there is confirmed or a very high suspi-
cion of infection. This is based on clinical ex-
perience both with this drug and with other
cephalosporins, and is not based on pharmaco-
kinetic studies. Cefquinome has good in vitro
activity against many of the important bacteria
found in foals, including E. coli, Actinobacillus
spp., streptococci, and other Enterobacteriacae
isolated from horses9. There is unpublished da-
ta showing that this drug reaches reasonable
concentrations in the CSF in pigs 12 hours af-
ter administration (1). Clinical experience sug-
gest that this drug can be effective in the treat-
ment of meningitis.
Some concern has been expressed by veterinar-
ians that the use of this cephalosporin in animals
may impact human health, by promoting resist-
ance to the fourth generation cephalosporin, ce-
fepime. The US Food and Drug Administration
studied this in relation to the treatment of respi-
ratory disease in cattle (2), and concluded that
the risk was medium and proposed no restric-
tions to extra-label use.
Ceftiofur is a third generation cephalosporin
that is widely used in foals, especially in the
USA. Very many dose regimes have been sug-
gested for ceftiofur. Published doses include
4.4 mg/kg IM q12h10, 4.4 to 6 mg/kg IV q6-12
(1) Pharmacokinetics of Cefquinome in Porcine Cere-
brospinal Fluid: E Thomas, M Allan, A Boettner, Intervet
International.
(2) http://www.fda.gov/cvm/Documents/VMAC0906Ce-
fqui-nome.pdf.
Published in IVIS with the permission of SIVE
hours11, 5 mg/kg IV q6h, decreasing to q24h
as the foal’s condition improved 12 and 10
mg/kg IV q6h13. In addition, as a time-de-
pendent antimicrobial, ceftiofur can be used
as a constant rate infusion, and has been used
at 1.5 mg/kg/h in the neonatal foal (J.E.
Palmer, personal communication). Limited
evidence in adult horses suggests that the in-
travenous dose is almost as effective as the in-
tramuscular dose, despite the manufacturer’s
recommendation to just use the intramuscular
dose14. Unlike other third and fourth genera-
tion cephalosporins, there is little penetration
of ceftiofur into the CSF in horses15.
Ceftiofur is rapidly metabolised in vivo to des-
furoylceftiofur16. Desfuroylceftiofur is less ac-
tive in vitro against Staphylococci and Strep-
tococci and therefore ceftiofur may be inef-
fective against these bacteria in vivo, despite
in vitro susceptibility16. Ceftiofur has good ac-
tivity (at least in vitro) against the anaerobes
Fusobacterium necrophorum and Peptostrep-
tococcus anaerobius, but not against Bac-
teroides fragilis17. In a study from the 1990s
from New Bolton Center, 65% of 84 Gram-
negative cultures and 29% of 28 Gram-posi-
tive isolates from the blood of neonatal foals
were susceptible in vitro to ceftiofur18.
Ceftriaxone is an injectable third generation
cephalosporin, which has been shown to reach
therapeutic concentrations in the cere-
brospinal fluid (CSF) of adult horses19. Phar-
macokinetic studies have suggested a dose
rate of 25 mg/kg intravenously every 12 hours
in foals20. This antimicrobial may be particu-
larly useful for cases of suspected bacterial
meningitis.
Cefpodoxime protexil is an oral third gener-
ation cephalosporin. Pharmacokinetics in
foals demonstrated a dose of 10 mg/kg q6-12h
per os to be predicted to be effective against
90% of equine isolates of Salmonella enteri-
ca, Escherichia coli, Klebsiella spp, Pas-
teurella spp, Enterobacter spp, and β-
haemolytic streptococci21. Oral drugs are con-
venient and practical for owners to administer,
and an oral cephalosporin could be an exciting
addition to our treatment options. However,
two factors limit the utility of cefpodoxime in
the author’s clinical practice.
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Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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The first is that it does not cross the blood-
brain barrier21, unlike many of the injectable
third (and possibly fourth) generation
cephalosporins. The second is that treatment
with this drug is comparatively very expensive
in many countries.
Penicillin
Penicillin is cheap, readily available, and an
effective first line antimicrobial for the treat-
ment of Gram positive and anaerobic infec-
tions in the neonatal foal. Procaine penicillin
is available for twice daily intramuscular use,
however the authors avoid its use where pos-
sible due to the low muscle mass in the neona-
tal foal. In addition, repeated intramuscular
doses can increase the sensitivity to injection,
in part due to neuronal sensitisation to pro-
caine22. Preparations of sodium penicillin and
potassium penicillin are available and can be
administered intravenously at 22,000-44,000
IU/kg q6-8h. Both preparations should be ad-
ministered slowly, as potassium penicillin can
lead to abdominal discomfort and transient
loose faeces, probably due to increased myo-
electrical activity of the caecum and pelvic
flexure23, and there is anecdotal evidence
suggesting that sodium penicillin can cause
transient hypotension and tachycardia. As a
time-dependent antimicrobial agent, potassi-
um (or sodium) penicillin is also particularly
suitable for use as a constant rate infusion. Af-
ter a loading dose of 22,000-44,000 IU/kg, the
authors use the same total dose per 24 hours as
is used for intermittent dosing, giving a rate of
2,750-7,333 U/kg/h. The use of a constant rate
infusion is probably more efficacious than in-
termittent dosing, as the concentration of
penicillin will constantly remain above the
MIC of the targeted bacteria, and is particu-
larly useful in animals that demonstrate the
aforementioned transient problems. Theoret-
ically, constant rate infusions can be used at
lower total doses than intermittent dosing, but
using them as such requires calculations based
on the volume of distribution and knowledge
of the MIC of the specifically targeted organ-
ism. For ease of use, the authors tend to use
the aforementioned doses rather than calcu-
late exact pharmacokinetically accurate doses.
Published in IVIS with the permission of SIVE
When considering penicillin as a treatment
for a known enterococcal infection, it is also
important to note a unique property of Ente-
rococcus spp against the actions of penicillin.
Despite the in vitro sensitivity of Enterococ-
cus spp to penicillin, the same may not be
true in vivo. They have unique enterococcal
penicillin binding proteins that allow synthe-
sis of the cell wall in the presence of peni-
cillin (and other ß lactams such as the
cephalosporins), which may lead to in vitro
stasis but not in vivo killing, and a subsequent
loss of correlation between the susceptibility
test results and actual clinical efficacy24. In
addition, there is an “inoculum effect”, where
a small in vitro Enterococcus inoculum ap-
pears to be susceptible to penicillin because
of a relatively small amount of penicillinase
being produced, whereas a larger in vivo in-
oculum of Enterococcus may produce enough
penicillinase to be clinically important25.
These factors combine to make Enterococcus
spp “tolerant” to penicillin and other ß lactam
antimicrobial agents, with their MIC being
much higher than is apparent from in vitro
susceptibility results26.
However, high doses of penicillin combined
with an aminoglycoside have a synergistic ef-
fect against these pathogens, and are the treat-
ment of choice for confirmed enterococcal in-
fections26.
Aminoglycosides
Aminoglycosides have excellent activity
against Gram negative and some Gram posi-
tive bacteria, and have synergistic action with
penicillins against certain organisms, particu-
larly streptococci and enterococci. They are
ineffective against anaerobic bacteria or in
anaerobic environments. The penetration of
aminoglycosides is relatively poor, with poor
penetration across the blood-brain barrier and
into bone and abscesses. As previously dis-
cussed, the therapeutic dose of the aminogly-
cosides is considerably higher in neonatal
foals than that used in mature horses due to
their higher volume of distribution.
Amikacin is often considered the aminogly-
coside of choice in the neonatal foal due to
its reduced nephrotoxicity and the low fre-
43
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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quency of resistance of organisms commonly
isolated from neonatal foals18,27. Ideally, ther-
apeutic drug monitoring (TDM) would al-
ways be undertaken to ensure adequate peak
and low trough concentrations in neonatal
foals, maximising the efficacy and minimis-
ing nephrotoxicity in these animals, especial-
ly as the pharmacokinetics change with age
in the neonatal foal28.
The recommended doses of amikacin are 20-
25 mg/kg q24h28,29. These dose rates are used
as the starting point for TDM. Since TDM is
often unavailable or impractical outside of
university practice, these doses are often used
for the duration of treatment.
The relatively broad spectrum activity and
concentration-dependent activity of amikacin
makes it particularly useful for local therapy.
In foals, it has a particular role in local thera-
py of septic joints or osteomyelitis via region-
al limb perfusions or direct inoculation into
the joint in question. Typically, one third of
the systemic dose is administered via the re-
gional limb perfusion, and the remaining two
thirds of the systemic dose is administered at
the time of tourniquet removal.
Gentamicin is also used in the neonatal foal,
at doses of 11-15 mg/kg q24h. It is important
to note that doses of 6-10 mg/kg are inade-
quate in the foal29. Whilst gentamicin is asso-
ciated with an increased risk of cumulative
nephrotoxicity, it is much cheaper than
amikacin in most countries. therefore gentam-
icin may be a more practical drug to use ini-
tially or for empirical treatment. Ideally, TDM
should also be used for gentamicin to min-
imise the risk of nephrotoxicity whilst opti-
mising its action.
Neomycin is often administered as part of a
commercial penicillin/neomycin preparation.
However, the dose of neomycin that is given
when this combination is used as recommend-
ed is very low and is probably inadequate in
the foal. The reported dose in the mature horse
is 10-20 mg/kg once daily IM30. However, bio-
chemical evidence of nephrotoxicity has been
seen after 4 days of treatment at 10 mg/kg
twice daily IM in the normal mature horse31,
although this dose did not result in histopatho-
logical changes in the kidney or liver32. As
Published in IVIS with the permission of SIVE
with other aminoglycosides, it is likely that
the dose of neomycin needs to be higher in the
neonatal foal. However in the absence of phar-
macokinetic evidence, the authors reserve
neomycin use for organisms where the sensi-
tivity profile dictates its use, administer a dose
of 10 mg/kg IM once a day, and carefully
monitor urinalyses and renal function when
prolonged therapy is required.
Amoxycillin / Clavulanic acid
Amoxycillin/clavulanic acid has been suc-
cessfully used at 30 mg/kg, q6-8h PO, based
on published pharmacokinetics in foals33.
This broad-spectrum oral antimicrobial agent
has considerable utility in the neonatal foal
for the treatment of selected infections such
as pneumonia. The authors have had a good
clinical impression of amoxycillin/clavulanic
acid in foals up to 4 months old, although the
oral absorption in mature horses is very
poor34,35 so there are concerns with its useful-
ness in older foals.
Doxycycline
Doxycycline has broad-spectrum activity
against Gram positive, Gram negative and
some anaerobic bacteria. Its activity against
intracellular bacteria means it has been advo-
cated for treatment of Lawsonia intracellu-
laris infections36. Additionally, doxycycline is
highly active in acidic environments, making
it especially useful for the treatment of ab-
scesses and infected umbilici. The authors
have used doxycyline as a second choice an-
timicrobial to treat Rhodococcus equi infec-
tions, where the foal has been unable to toler-
ate macrolide therapy. Whilst doxycycline is
poorly absorbed orally in the mature horse, in
foals the oral bioavailability is excellent. The
recommended oral dose in the foal is 10 mg/kg
twice daily37.
Ticarcillin
Ticarcillin is an antipseudomonal penicillin
whose spectrum is extended by the addition of
clavulanic acid to include activity against
many enterobacteriaceae. Aminoglycoside-re-
sistant Gram negative bacteria are often sus-
ceptible to ticarcillin-clavulate, and this com-
44
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bination is therefore extremely useful for
Gram negative septicaemia in foals where the
bacteria are resistant to aminoglycosides, or
where these are contraindicated by compro-
mised renal function. The pharmacokinetics
have been described in adult horses and in
foals38,39, with the recommended dose being
50 mg/kg IV every 6 hours. Doses of up to
100 mg/kg q6h have been used, and ticar-
cillin-clavulanic acid also lends itself to a
constant rate infusion, at 8-16 mg/kg/h (J.E.
Palmer, personal communication).
Marbofloxacin
The routine use of enrofloxacin in neonatal
foals is not recommended due to concerns with
cartilage damage in young animals. As broad-
spectrum antimicrobials with good penetration
and high efficacy against Gram negative in-
fections, fluoroquinolones have a lot of desir-
able properties for use in the neonatal foal.
The pharmacokinetics of marbofloxacin has
been studied in adult horses, with a dose of 2
mg/kg IV q24hours being recommended for
the treatment of Gram negative infections40,41.
The authors have used marbofloxacin in over
fifty neonatal and young foals and have not
observed any joint swellings or other adverse
effects, although there is the theoretical risk of
arthropathy in these animals.
Chloramphenicol / Florfenicol
Chloramphenicol is a broad-spectrum, oral an-
timicrobial whose availability is limited in
many countries due to substantial public health
concerns regarding its potential to cause aplas-
tic anaemia. It has activity against most Gram
positive, Gram negative, and anaerobic bacte-
ria, including B. fragilis. It has excellent pene-
tration, including into bone and the cere-
brospinal fluid, and is therefore particularly
useful for osteomyelitis, meningitis, and in the
treatment of abscesses. Florfenicol has a simi-
lar spectrum of activity, does not have the as-
sociated public health concerns, and is avail-
able for use in Europe as an intramuscular
preparation licensed for use in food animals.
Florfenicol has been associated with the devel-
opment of loose faeces and altered gastroin-
testinal flora in adult horses42,43, but the authors
Published in IVIS with the permission of SIVE
have used it successfully in several foals aged
less than 4 months, without any apparent ad-
verse effects, at 20 mg/kg q24-48h IM.
Metronidazole
Metronidazole is used to treat anaerobic in-
fections in the foal, and is especially useful
for the treatment of clostridial diarrhoea. It is
one of the treatments of choice for infections
caused by Clostridium difficile44. In one
study, 34.6% of neonatal foals hospitalised
with diarrhoea tested ELISA positive for
Clostridial toxins45. Oral metronidazole thera-
py should therefore be strongly considered for
all foals with severe diarrhoea. Oral metron-
idazole is typically administered at 15-25
mg/kg q8h46, but doses of 25 mg/kg q12h
have recently also been recommended47.
Metronidazole is also available for intra-
venous use. The authors use a loading dose
of 15 mg/kg, and then administer 7.5 mg/kg
q6h, based on the dose recommendation for
humans48.
Clindamycin
Clindamycin is a broad-spectrum antimicro-
bial agent with excellent Gram positive and
anaerobic cover, but with a relatively limited
Gram negative spectrum. Clindamycin is an
orally administered agent that has excellent
penetration into bone, making it a potentially
useful therapy for osteomyelitis caused by
Gram positive bacteria and other sensitive or-
ganisms. There is a risk of causing diarrhoea,
and clindamycin has been used, prior to in-
fection with vegetative spores, to induce
Clostridium difficile diarrhoea in foals.49 In
the neonatal foal, where hind-gut fermentation
does not take place, clindamycin appears to be
safe and the authors have used it with no ap-
parent ill effects in a limited number of foals.
Macrolides
Erythromycin, clarithromycin, and azithromycin
are frequently used for the treatment of
Rhodococcus equi in older foals, however
they are broad-spectrum, oral antimicrobial
agents with excellent penetration. The phar-
macokinetics of all three have been studied in
the foal, and of these, azithromycin has the
45
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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longest half-life. Clarithromycin has been shown
to be the most effective against R equi50,51, al-
though the activity of azithromycin against
Pasteurella and Salmonella is superior in vit-
ro. Both azithromycin and clarithromycin
have better oral bioavailability than erythro-
mycin, and are equally effective against beta-
haemolytic streptococci and staphylococci.
These properties, along with their excellent
penetration into the lung, make them particu-
larly suitable for the treatment of pneumonia
in neonatal foals.
Imipenem
Imipenem is a carbapenem antimicrobial
agent that has been used to treat highly resist-
ant infections in horses and should be reserved
for these, rather than used as a first line an-
timicrobial agent. The pharmacokinetics in
adult horses have been described, with doses
of 10-20 mg/kg by slow intravenous infusion
every 6 hours being advocated as the dosing
regime of choice52. The pharmacokinetics
have not been described in the foal, however,
and doses of 10-15 mg/kg q6-12 hours intra-
venously (or intramuscularly when diluted in
1% lignocaine), have been used by the authors
for the treatment of severe infections. Addi-
tionally, imipenem has been used as a constant
rate infusion at 0.4-0.8 mg/kg/h in the neona-
tal foal (J.E. Palmer, personal communica-
tion 2008).
Vancomycin
Vancomycin (7.5 mg/kg IV q12h) has been
used to treat methicillin resistant staphylococ-
ci and enterococci in horses2. In this report,
the youngest foal administered vancomycin
was approximately 5 weeks old. Neither of the
two foals less than 2 months age treated with
vancomycin survived, but this was not attrib-
uted to a direct effect of the drug2. The infec-
tions treated were in soft tissue and bone, and
vancomycin appeared to be an effective treat-
ment for infections in these areas. Methicillin
resistant Staphylococcus aureus (MRSA) has
been reported in neonatal foals53, and in the
authors’ experience, the majority of infections
cause morbidity (such as catheter site infec-
tions and subsequent jugular vein thrombosis)
Published in IVIS with the permission of SIVE
rather than mortality in neonatal foals. These
infections have not required specific, targeted
therapy, and resolved with minimal conse-
quences. However, the authors have isolated
MRSA from joint fluid in neonatal foals with
septic synovitis. Furthermore, the most com-
monly reported manifestations of MRSA in
horses appear to be wound or post-operative
infections54. Joint and wound infections may
have more serious consequences and require
specific treatment. In addition to the treatment
of MRSA, vancomycin or metronidazole are
the drugs of choice for treatment for Clostrid-
ium difficile44,55,56. The authors always use
metronidazole as a first line treatment for this
condition. In addition, vancomycin has also
been used for the treatment of macrolide-re-
sistant Rhodococcus equi in foals57. Some vet-
erinarians believe that it is wrong to use this
drug in animals, because of its current impor-
tance in treating multi-resistant bacteria in hu-
man medicine.
CONCLUSIONS
Early antimicrobial therapy is essential for the
successful treatment of infections in neonatal
foals. The selection of suitable drugs is limit-
ed by availability and financial concerns, and
there are many specific considerations when
administering antimicrobial agents to this age
group. However, the lack of hindgut fermenta-
tion allows safe use of some antimicrobial
agents that are unsuitable for administration to
the mature animal.
Anna Hollis co-authored the original review
(published in Equine Veterinary Education),
on which these notes were based.
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Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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