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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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Antimicrobial therapy in neonates

Kevin Corley
BVM&S PhD DACVIM DECEIM DACVECC MRCVS
Anglesey Lodge Equine Hospital
Co. Kildare, Ireland

INTRODUCTION BACTERIAL SPECIES COMMONLY

AFFECTING NEONATAL FOALS
Systemic and local bacterial infections are
common in neonatal foals, and cause signifi- Septicaemia
cant mortality and morbidity. Often signs of In studies, the most common bacteria isolated
infection can be quite subtle in neonatal foals, in the blood of septicaemic foals were Es-
and may be missed by inexperienced owners. cherichia coli and Actinobacillus species.
It has been shown in human critical care that Streptococcus and Enterococcus are also com-
early administration of appropriate antimicro- mon. In contrast, the most common blood iso-
bials is critical to survival, and clinical experi- lates from foals with diarrhoea were Entero-
ence suggests that this also holds for neonatal coccus species and Pantoea agglomerans,
foals. Therefore, both early recognition of in- with E. coli and Actinobacillus being isolated
fection and choice of antimicrobial can make much less frequently.
a significant impact on outcome in foals. Some North American and Australian hospi-
tals and farms have recently experienced
high isolation rates of multi-drug resistant
SUCCESSFUL ANTIMICROBIAL bacteria, including Methicillin Resistant
THERAPY Staphylococcus aureus (MRSA) and highly
resistant Enterobacter and Enterococcus
Successful antimicrobial therapy depends on a species 1,2. MRSA has also been isolated
number of different factors: Early institution from horses in Europe3, and 10.9% of hors-
of therapy, appropriate dosage and selection es in one European study carried MRSA in
of appropriate antimicrobials. The require- their nasal secretions4.
ment for early institution requires that good
“educated guesses” are made about possible
causative organisms and their likely antimi- DIFFERENCES FROM ADULT HORSES
crobial sensitivities. Appropriate dosage re-
quires a good knowledge of the antimicrobial, There are three reasons why the choice of an-
and particularly the differences in dose be- timicrobials is different in neonatal foals than
tween neonates and adults. Selection of an- in mature horses. The first is that foals are not
timicrobial depends on its spectrum of activi- (yet) hindgut fermenters, and antimicrobials
ty, penetration into the tissue in question and that can cause severe colitis in mature horses
cost per dose. do not carry the same risk in foals. Secondly,
Antimicrobial therapy is often not sufficient to given that a foal weighs approximately 1/10th
treat infection in neonatal foals, and support of a mature horse, antimicrobials that are cost-
of affected organs (from nutritional and fluid prohibitive in mature horses can be used in
therapy to full-out intensive care with me- neonatal foals.
chanical ventilation) or surgical debridement Lastly, toxicities may be different for foals
or lavage may also be necessary. than for mature animals.
40
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One of the most important points to remember SELECTED ANTIMICROBIALS

about antimicrobial treatment in neonatal AS THEY RELATE TO THE FOAL
foals is that, for many drugs, the dosage is
considerably higher than adult horses. A Cephalosporins
much higher percentage of the body mass is Cephalosporins are very commonly used an-
comprised of water in neonatal foals, as com- timicrobials in neonatal foals. However,
pared to adults5. cephalosporins are a diverse group of drugs
In general the dosage of hydrophilic drugs both in their spectrum of activity and their
(such as the aminoglycosides) is higher in penetration into the tissues in the body. The
foals, whereas the dosage is the same as adults most commonly used cephalosporins in foals
for lipophilic drugs. are cefquinome and ceftiofur.
Cefquinome is a fourth-generation cephalo-
sporin, labelled in Europe for the treatment of
PROPHYLACTIC USE E. coli septicaemia in foals. The label dose is 1
OF ANTIMICROBIALS IN FOALS mg/kg, IV or IM, q12h for foals. The author
uses a dose of 2.5 mg/kg IV q6-8h in foals
The high incidence of bacterial infections has where there is confirmed or a very high suspi-
led to the practice of prophylactic administra- cion of infection. This is based on clinical ex-
tion of antimicrobials in the first days of life, perience both with this drug and with other
by some veterinarians. This practice is highly cephalosporins, and is not based on pharmaco-
controversial, because increased use of an- kinetic studies. Cefquinome has good in vitro
timicrobials is thought to increase bacterial activity against many of the important bacteria
resistance to those antimicrobials in the gen- found in foals, including E. coli, Actinobacillus
eral bacteria population, which may impact spp., streptococci, and other Enterobacteriacae
on human as well as animal health. A recent isolated from horses9. There is unpublished da-
study found no difference in the incidence of ta showing that this drug reaches reasonable
infectious disease between neonatal foals concentrations in the CSF in pigs 12 hours af-
treated with prophylactic antimicrobials and ter administration (1). Clinical experience sug-
those that were not treated6, however, the in- gest that this drug can be effective in the treat-
cidence of infectious diseases in the study ment of meningitis.
population was very low, making it difficult Some concern has been expressed by veterinar-
to draw definitive conclusions from this ians that the use of this cephalosporin in animals
study. In contrast, a study from the 1970s may impact human health, by promoting resist-
demonstrated a reduction in the number of in- ance to the fourth generation cephalosporin, ce-
fections in neonatal foals treated prophylacti- fepime. The US Food and Drug Administration
cally with neomycin or framamycin during studied this in relation to the treatment of respi-
the first 30 days of life7. ratory disease in cattle (2), and concluded that
However, it is important to note that routine the risk was medium and proposed no restric-
foal management practices on stud farms tions to extra-label use.
have significantly improved since this study Ceftiofur is a third generation cephalosporin
was carried out, which may make this finding that is widely used in foals, especially in the
less directly relevant in the modern stud farm USA. Very many dose regimes have been sug-
situation. gested for ceftiofur. Published doses include
There is some evidence that prophylactic an- 4.4 mg/kg IM q12h10, 4.4 to 6 mg/kg IV q6-12
tibiotic treatment can be successful, at least
for a single problem disease. Prophylaxis with
azithromycin for the first two weeks of life re- (1) Pharmacokinetics of Cefquinome in Porcine Cere-
brospinal Fluid: E Thomas, M Allan, A Boettner, Intervet
duced the incidence of Rhodococcus equi International.
from approximately 20% to 5% in one ran- (2) http://www.fda.gov/cvm/Documents/VMAC0906Ce-
domised study8. fqui-nome.pdf.

41
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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hours11, 5 mg/kg IV q6h, decreasing to q24h The first is that it does not cross the blood-
as the foal’s condition improved 12 and 10 brain barrier21, unlike many of the injectable
mg/kg IV q6h13. In addition, as a time-de- third (and possibly fourth) generation
pendent antimicrobial, ceftiofur can be used cephalosporins. The second is that treatment
as a constant rate infusion, and has been used with this drug is comparatively very expensive
at 1.5 mg/kg/h in the neonatal foal (J.E. in many countries.
Palmer, personal communication). Limited
evidence in adult horses suggests that the in- Penicillin
travenous dose is almost as effective as the in- Penicillin is cheap, readily available, and an
tramuscular dose, despite the manufacturer’s effective first line antimicrobial for the treat-
recommendation to just use the intramuscular ment of Gram positive and anaerobic infec-
dose14. Unlike other third and fourth genera- tions in the neonatal foal. Procaine penicillin
tion cephalosporins, there is little penetration is available for twice daily intramuscular use,
of ceftiofur into the CSF in horses15. however the authors avoid its use where pos-
Ceftiofur is rapidly metabolised in vivo to des- sible due to the low muscle mass in the neona-
furoylceftiofur16. Desfuroylceftiofur is less ac- tal foal. In addition, repeated intramuscular
tive in vitro against Staphylococci and Strep- doses can increase the sensitivity to injection,
tococci and therefore ceftiofur may be inef- in part due to neuronal sensitisation to pro-
fective against these bacteria in vivo, despite caine22. Preparations of sodium penicillin and
in vitro susceptibility16. Ceftiofur has good ac- potassium penicillin are available and can be
tivity (at least in vitro) against the anaerobes administered intravenously at 22,000-44,000
Fusobacterium necrophorum and Peptostrep- IU/kg q6-8h. Both preparations should be ad-
tococcus anaerobius, but not against Bac- ministered slowly, as potassium penicillin can
teroides fragilis17. In a study from the 1990s lead to abdominal discomfort and transient
from New Bolton Center, 65% of 84 Gram- loose faeces, probably due to increased myo-
negative cultures and 29% of 28 Gram-posi- electrical activity of the caecum and pelvic
tive isolates from the blood of neonatal foals flexure23, and there is anecdotal evidence
were susceptible in vitro to ceftiofur18. suggesting that sodium penicillin can cause
Ceftriaxone is an injectable third generation transient hypotension and tachycardia. As a
cephalosporin, which has been shown to reach time-dependent antimicrobial agent, potassi-
therapeutic concentrations in the cere- um (or sodium) penicillin is also particularly
brospinal fluid (CSF) of adult horses19. Phar- suitable for use as a constant rate infusion. Af-
macokinetic studies have suggested a dose ter a loading dose of 22,000-44,000 IU/kg, the
rate of 25 mg/kg intravenously every 12 hours authors use the same total dose per 24 hours as
in foals20. This antimicrobial may be particu- is used for intermittent dosing, giving a rate of
larly useful for cases of suspected bacterial 2,750-7,333 U/kg/h. The use of a constant rate
meningitis. infusion is probably more efficacious than in-
Cefpodoxime protexil is an oral third gener- termittent dosing, as the concentration of
ation cephalosporin. Pharmacokinetics in penicillin will constantly remain above the
foals demonstrated a dose of 10 mg/kg q6-12h MIC of the targeted bacteria, and is particu-
per os to be predicted to be effective against larly useful in animals that demonstrate the
90% of equine isolates of Salmonella enteri- aforementioned transient problems. Theoret-
ca, Escherichia coli, Klebsiella spp, Pas- ically, constant rate infusions can be used at
teurella spp, Enterobacter spp, and β- lower total doses than intermittent dosing, but
haemolytic streptococci21. Oral drugs are con- using them as such requires calculations based
venient and practical for owners to administer, on the volume of distribution and knowledge
and an oral cephalosporin could be an exciting of the MIC of the specifically targeted organ-
addition to our treatment options. However, ism. For ease of use, the authors tend to use
two factors limit the utility of cefpodoxime in the aforementioned doses rather than calcu-
the author’s clinical practice. late exact pharmacokinetically accurate doses.
42
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When considering penicillin as a treatment quency of resistance of organisms commonly

for a known enterococcal infection, it is also isolated from neonatal foals18,27. Ideally, ther-
important to note a unique property of Ente- apeutic drug monitoring (TDM) would al-
rococcus spp against the actions of penicillin. ways be undertaken to ensure adequate peak
Despite the in vitro sensitivity of Enterococ- and low trough concentrations in neonatal
cus spp to penicillin, the same may not be foals, maximising the efficacy and minimis-
true in vivo. They have unique enterococcal ing nephrotoxicity in these animals, especial-
penicillin binding proteins that allow synthe- ly as the pharmacokinetics change with age
sis of the cell wall in the presence of peni- in the neonatal foal28.
cillin (and other ß lactams such as the The recommended doses of amikacin are 20-
cephalosporins), which may lead to in vitro 25 mg/kg q24h28,29. These dose rates are used
stasis but not in vivo killing, and a subsequent as the starting point for TDM. Since TDM is
loss of correlation between the susceptibility often unavailable or impractical outside of
test results and actual clinical efficacy24. In university practice, these doses are often used
addition, there is an “inoculum effect”, where for the duration of treatment.
a small in vitro Enterococcus inoculum ap- The relatively broad spectrum activity and
pears to be susceptible to penicillin because concentration-dependent activity of amikacin
of a relatively small amount of penicillinase makes it particularly useful for local therapy.
being produced, whereas a larger in vivo in- In foals, it has a particular role in local thera-
oculum of Enterococcus may produce enough py of septic joints or osteomyelitis via region-
penicillinase to be clinically important25. al limb perfusions or direct inoculation into
These factors combine to make Enterococcus the joint in question. Typically, one third of
spp “tolerant” to penicillin and other ß lactam the systemic dose is administered via the re-
antimicrobial agents, with their MIC being gional limb perfusion, and the remaining two
much higher than is apparent from in vitro thirds of the systemic dose is administered at
susceptibility results26. the time of tourniquet removal.
However, high doses of penicillin combined Gentamicin is also used in the neonatal foal,
with an aminoglycoside have a synergistic ef- at doses of 11-15 mg/kg q24h. It is important
fect against these pathogens, and are the treat- to note that doses of 6-10 mg/kg are inade-
ment of choice for confirmed enterococcal in- quate in the foal29. Whilst gentamicin is asso-
fections26. ciated with an increased risk of cumulative
nephrotoxicity, it is much cheaper than
Aminoglycosides amikacin in most countries. therefore gentam-
Aminoglycosides have excellent activity icin may be a more practical drug to use ini-
against Gram negative and some Gram posi- tially or for empirical treatment. Ideally, TDM
tive bacteria, and have synergistic action with should also be used for gentamicin to min-
penicillins against certain organisms, particu- imise the risk of nephrotoxicity whilst opti-
larly streptococci and enterococci. They are mising its action.
ineffective against anaerobic bacteria or in Neomycin is often administered as part of a
anaerobic environments. The penetration of commercial penicillin/neomycin preparation.
aminoglycosides is relatively poor, with poor However, the dose of neomycin that is given
penetration across the blood-brain barrier and when this combination is used as recommend-
into bone and abscesses. As previously dis- ed is very low and is probably inadequate in
cussed, the therapeutic dose of the aminogly- the foal. The reported dose in the mature horse
cosides is considerably higher in neonatal is 10-20 mg/kg once daily IM30. However, bio-
foals than that used in mature horses due to chemical evidence of nephrotoxicity has been
their higher volume of distribution. seen after 4 days of treatment at 10 mg/kg
Amikacin is often considered the aminogly- twice daily IM in the normal mature horse31,
coside of choice in the neonatal foal due to although this dose did not result in histopatho-
its reduced nephrotoxicity and the low fre- logical changes in the kidney or liver32. As
43
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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with other aminoglycosides, it is likely that bination is therefore extremely useful for
the dose of neomycin needs to be higher in the Gram negative septicaemia in foals where the
neonatal foal. However in the absence of phar- bacteria are resistant to aminoglycosides, or
macokinetic evidence, the authors reserve where these are contraindicated by compro-
neomycin use for organisms where the sensi- mised renal function. The pharmacokinetics
tivity profile dictates its use, administer a dose have been described in adult horses and in
of 10 mg/kg IM once a day, and carefully foals38,39, with the recommended dose being
monitor urinalyses and renal function when 50 mg/kg IV every 6 hours. Doses of up to
prolonged therapy is required. 100 mg/kg q6h have been used, and ticar-
cillin-clavulanic acid also lends itself to a
Amoxycillin / Clavulanic acid constant rate infusion, at 8-16 mg/kg/h (J.E.
Amoxycillin/clavulanic acid has been suc- Palmer, personal communication).
cessfully used at 30 mg/kg, q6-8h PO, based
on published pharmacokinetics in foals33. Marbofloxacin
This broad-spectrum oral antimicrobial agent The routine use of enrofloxacin in neonatal
has considerable utility in the neonatal foal foals is not recommended due to concerns with
for the treatment of selected infections such cartilage damage in young animals. As broad-
as pneumonia. The authors have had a good spectrum antimicrobials with good penetration
clinical impression of amoxycillin/clavulanic and high efficacy against Gram negative in-
acid in foals up to 4 months old, although the fections, fluoroquinolones have a lot of desir-
oral absorption in mature horses is very able properties for use in the neonatal foal.
poor34,35 so there are concerns with its useful- The pharmacokinetics of marbofloxacin has
ness in older foals. been studied in adult horses, with a dose of 2
mg/kg IV q24hours being recommended for
Doxycycline the treatment of Gram negative infections40,41.
Doxycycline has broad-spectrum activity The authors have used marbofloxacin in over
against Gram positive, Gram negative and fifty neonatal and young foals and have not
some anaerobic bacteria. Its activity against observed any joint swellings or other adverse
intracellular bacteria means it has been advo- effects, although there is the theoretical risk of
cated for treatment of Lawsonia intracellu- arthropathy in these animals.
laris infections36. Additionally, doxycycline is
highly active in acidic environments, making Chloramphenicol / Florfenicol
it especially useful for the treatment of ab- Chloramphenicol is a broad-spectrum, oral an-
scesses and infected umbilici. The authors timicrobial whose availability is limited in
have used doxycyline as a second choice an- many countries due to substantial public health
timicrobial to treat Rhodococcus equi infec- concerns regarding its potential to cause aplas-
tions, where the foal has been unable to toler- tic anaemia. It has activity against most Gram
ate macrolide therapy. Whilst doxycycline is positive, Gram negative, and anaerobic bacte-
poorly absorbed orally in the mature horse, in ria, including B. fragilis. It has excellent pene-
foals the oral bioavailability is excellent. The tration, including into bone and the cere-
recommended oral dose in the foal is 10 mg/kg brospinal fluid, and is therefore particularly
twice daily37. useful for osteomyelitis, meningitis, and in the
treatment of abscesses. Florfenicol has a simi-
Ticarcillin lar spectrum of activity, does not have the as-
Ticarcillin is an antipseudomonal penicillin sociated public health concerns, and is avail-
whose spectrum is extended by the addition of able for use in Europe as an intramuscular
clavulanic acid to include activity against preparation licensed for use in food animals.
many enterobacteriaceae. Aminoglycoside-re- Florfenicol has been associated with the devel-
sistant Gram negative bacteria are often sus- opment of loose faeces and altered gastroin-
ceptible to ticarcillin-clavulate, and this com- testinal flora in adult horses42,43, but the authors
44
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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have used it successfully in several foals aged longest half-life. Clarithromycin has been shown
less than 4 months, without any apparent ad- to be the most effective against R equi50,51, al-
verse effects, at 20 mg/kg q24-48h IM. though the activity of azithromycin against
Pasteurella and Salmonella is superior in vit-
Metronidazole ro. Both azithromycin and clarithromycin
Metronidazole is used to treat anaerobic in- have better oral bioavailability than erythro-
fections in the foal, and is especially useful mycin, and are equally effective against beta-
for the treatment of clostridial diarrhoea. It is haemolytic streptococci and staphylococci.
one of the treatments of choice for infections These properties, along with their excellent
caused by Clostridium difficile44. In one penetration into the lung, make them particu-
study, 34.6% of neonatal foals hospitalised larly suitable for the treatment of pneumonia
with diarrhoea tested ELISA positive for in neonatal foals.
Clostridial toxins45. Oral metronidazole thera-
py should therefore be strongly considered for Imipenem
all foals with severe diarrhoea. Oral metron- Imipenem is a carbapenem antimicrobial
idazole is typically administered at 15-25 agent that has been used to treat highly resist-
mg/kg q8h46, but doses of 25 mg/kg q12h ant infections in horses and should be reserved
have recently also been recommended47. for these, rather than used as a first line an-
Metronidazole is also available for intra- timicrobial agent. The pharmacokinetics in
venous use. The authors use a loading dose adult horses have been described, with doses
of 15 mg/kg, and then administer 7.5 mg/kg of 10-20 mg/kg by slow intravenous infusion
q6h, based on the dose recommendation for every 6 hours being advocated as the dosing
humans48. regime of choice52. The pharmacokinetics
have not been described in the foal, however,
Clindamycin and doses of 10-15 mg/kg q6-12 hours intra-
Clindamycin is a broad-spectrum antimicro- venously (or intramuscularly when diluted in
bial agent with excellent Gram positive and 1% lignocaine), have been used by the authors
anaerobic cover, but with a relatively limited for the treatment of severe infections. Addi-
Gram negative spectrum. Clindamycin is an tionally, imipenem has been used as a constant
orally administered agent that has excellent rate infusion at 0.4-0.8 mg/kg/h in the neona-
penetration into bone, making it a potentially tal foal (J.E. Palmer, personal communica-
useful therapy for osteomyelitis caused by tion 2008).
Gram positive bacteria and other sensitive or-
ganisms. There is a risk of causing diarrhoea, Vancomycin
and clindamycin has been used, prior to in- Vancomycin (7.5 mg/kg IV q12h) has been
fection with vegetative spores, to induce used to treat methicillin resistant staphylococ-
Clostridium difficile diarrhoea in foals.49 In ci and enterococci in horses2. In this report,
the neonatal foal, where hind-gut fermentation the youngest foal administered vancomycin
does not take place, clindamycin appears to be was approximately 5 weeks old. Neither of the
safe and the authors have used it with no ap- two foals less than 2 months age treated with
parent ill effects in a limited number of foals. vancomycin survived, but this was not attrib-
uted to a direct effect of the drug2. The infec-
Macrolides tions treated were in soft tissue and bone, and
Erythromycin, clarithromycin, and azithromycin vancomycin appeared to be an effective treat-
are frequently used for the treatment of ment for infections in these areas. Methicillin
Rhodococcus equi in older foals, however resistant Staphylococcus aureus (MRSA) has
they are broad-spectrum, oral antimicrobial been reported in neonatal foals53, and in the
agents with excellent penetration. The phar- authors’ experience, the majority of infections
macokinetics of all three have been studied in cause morbidity (such as catheter site infec-
the foal, and of these, azithromycin has the tions and subsequent jugular vein thrombosis)
45
Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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rather than mortality in neonatal foals. These staphylococcal and enterococcal infections in 15
infections have not required specific, targeted horses. Can J Vet Res 69:278-286, 2005.
3. O’Mahony R, Abbott Y, Leonard FC, et al: Methi-
therapy, and resolved with minimal conse- cillin-resistant Staphylococcus aureus (MRSA) iso-
quences. However, the authors have isolated lated from animals and veterinary personnel in Ire-
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septic synovitis. Furthermore, the most com- 4. Van den Eede A, Martens A, Lipinska U, et al:
monly reported manifestations of MRSA in High occurrence of methicillin-resistant Staphy-
lococcus aureus ST398 in equine nasal samples.
horses appear to be wound or post-operative Vet Microbiol, 2008.
infections54. Joint and wound infections may 5. Spensley MS, Carlson GP, Harrold D: Plasma, red
have more serious consequences and require blood cell, total blood, and extracellular fluid vol-
specific treatment. In addition to the treatment umes in healthy horse foals during growth. Am J
of MRSA, vancomycin or metronidazole are Vet Res 48:1703-1707, 1987.
6. Wohlfender FD, Barrelet FE, Doherr MG, et al:
the drugs of choice for treatment for Clostrid- Diseases in neonatal foals. Part I: The 30 day inci-
ium difficile44,55,56. The authors always use dence of disease and the effect of prophylactic an-
metronidazole as a first line treatment for this timicrobial drug treatment during the first three
condition. In addition, vancomycin has also days post partum. Equine Vet J In press, 2008.
been used for the treatment of macrolide-re- 7. Platt H: Joint-ill and other bacterial infections on
thoroughbred studs. Equine Vet J 9:141-145, 1977.
sistant Rhodococcus equi in foals57. Some vet- 8. Chaffin MK, Cohen ND, Martens RJ: Chemopro-
erinarians believe that it is wrong to use this phylactic effects of azithromycin against Rhodococ-
drug in animals, because of its current impor- cus equi-induced pneumonia among foals at equine
tance in treating multi-resistant bacteria in hu- breeding farms with endemic infections. J Am Vet
man medicine. Med Assoc 232:1035-1047, 2008.
9. Thomas E, Thomas V, Wilhelm C: Antibacterial ac-
tivity of cefquinome against equine bacterial
pathogens. Vet Microbiol 115:140-147, 2006.
CONCLUSIONS 10. Kol A, Steinman A, Levi O, et al: Congenital py-
loric stenosis in a foal. Isr J Vet Med 60:59-62,
Early antimicrobial therapy is essential for the 2005.
11. Benedice D: Septicemia in foals, in Merck Veteri-
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there are many specific considerations when 2008.
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Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010
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Proceedings of the Annual Meeting of the Italian Association of Equine Veterinarians, Carrara, Italy 2010