71 Drug Therapy and

Prophylaxis
Robert M. Friendship and John F. Prescott

This chapter gives an overview of some of the major administration. Parenteral therapy of individual ani-
drugs and biological agents used in swine, with a partic- mals by IM injection is administered just behind the ear
ular focus on antimicrobial drugs and the basic princi- on the lateral side of the neck. This site is chosen in case
ples on which effective drug use are based. the drug preparation causes local tissue damage as well
as to prevent the possible additional effect of sciatic
nerve damage if the ham muscles were used.
USE OF DRUGS: MAJOR CONSIDERATIONS
Oral medication is easier to apply to groups of pigs
Managing the effective use of drugs or biological agents and reduces injection-related problems of broken nee-
for prevention and treatment of disease is an important dles, abscesses, and tissue damage. Water medication is
responsibility of swine veterinarians, which involves de- a more rapid method of treating a group of sick pigs
tailed knowledge of these agents, including the risks in- than feed medication, with the advantages of immedi-
volved in their use and the national and sometimes in- ate implementation and that sick pigs will drink when
ternational regulations governing their use. The major they will not eat. However, the disadvantages are that
regulatory and industry consideration is the production not all drugs are water soluble, that water may be spilled,
of safe, uncontaminated meat, followed by considera- and that some drug carriers may block nipple watering
tions of the welfare of the animals, cost, efficacy, and systems. Administration of drugs by water is through an
ease of application. However, many other factors need in-line proportioner containing a concentrated drug so-
to be considered (Table 71.1) before implementing drug lution or by a water tank containing the appropriately
treatment or prophylactic use, with the underlying dosed drug. Pigs drink about 8–10% of their body
recognition that all such use involves a calculation that weight daily (Table 71.2), depending on environmental
benefits of use exceed the risks involved in using most temperature and palatability of the drug. An approxi-
drugs or biological agents. The underlying goal is to mate rule is that pigs should be dosed through water at
make the minimum use of drugs in swine consistent 5–6 liters (1.32 U.S. gallons) per 60 kg weight (145 lbs).
with the production of healthy animals in a humane, In-feed medication is the most common route of ad-
cost-effective, and consumer and environmentally safe ministration of anthelmintic and antimicrobial drugs.
manner. Changes in swine production practices have re- The disadvantage for treatment of acute infections is not
duced reliance on antimicrobial drugs, but there is still only that sick pigs may not eat but also that existing
considerable room for further reduction in their untar- nonmedicated feed needs to be either removed or eaten.
geted use in many countries. For this reason, in-feed medication is often reserved for
long term use in the prevention or treatment of chronic
Routes of Drug Treatment infections.
In general, individual animal treatment through injec-
tion is reserved for serious, rapidly developing infec- Principles of Treatment
tions such as acute systemic infections (septicemia, The general principle of treatment is to maximize thera-
acute pneumonia, or streptococcal meningitis), but peutic efficacy while minimizing adverse effects such as
mass medication is preferred because of ease, efficacy, toxicity, antimicrobial resistance, harmful tissue resi-
and lack of necessity to handle and disturb animals. dues, or adverse environmental impact. This implies a
Intramuscular (IM) injection is preferred for serious in- confirmed or reasonable clinical diagnosis with the ac-
fections since it usually results in more complete absorp- tual drug chosen according to the required purpose and
tion of drug and higher tissue concentrations than oral administered to give optimal effect, consistent usually

1131
1132 SECTION V VETERINARY PRACTICE

Table 71.1. Considerations in drug use in swine

Major Consideration Further Considerations

Human safety Direct drug toxicity to user; toxicity to consumer through tissue residues.
Animal welfare Prevention or reduction of disease; ease of administration for animal.
Host damage and adverse effects Direct toxicity to pig; tissue damage; adverse drug interactions. Indirect adverse effects: resistance
in microorganisms; disruption of microflora.
Regulations Availability of products; national regulations on use; international regulations for export; extra-
label drug use (AMDUCA in U.S.); veterinary-client relationship; withdrawal period.
Efficacy and cost Assessment of efficacy; cost: benefit of treatment.
Drug dosage and application Route, ease of administration; physicochemical properties; pharmacokinetic properties; pharma-
codynamic properties.
Principles of treatment Dosage; dosage modification; duration; clinical evidence; drug trial data.
Principles of prophylaxis Dosage; duration; clinical evidence; drug trial data.
Record keeping Drug use records.
Stability of drug Storage conditions.

Table 71.2. Average daily water consumption secondary objectives the researchers may be interested
in improved growth rate and reduced weight variation.
Weight or Type of Pig Liters/Head/Day
The design of the trial would likely be different if the pri-
7–20 kg body weight 2–4 mary objective was reduced weight variation.
20–50 body weight 4–6 Other important elements of a clinical trial include a
50–100 body weight 6–8
defined study population, random allocation of sub-
Pregnant sow 8–12
Lactating sow 16–20 jects, masking or blinding of the observer, thorough
follow-up, and appropriate analysis (Dewey 1999). A
common error in the design of a trial is to base the sta-
tistical analysis on individual pigs but to assign treat-
with labeled dosage and always within regulations con- ments on the basis of pen or even barn. Statistical analy-
cerning the use of the drugs. For antimicrobial drugs, sis should be conducted at the smallest level at which
discussed below, many of the principles of optimal treat- the treatment can be applied. Therefore, in a feed trial
ment are well established. Duration of treatment de- where all the pigs in a pen are assigned one feed and all
pends on the drug and disease process but should be the pigs in the next pen are given a second feed, the pen
based on scientific data and/or on clinical experience. is the unit of concern. The number of animals or pens or
barns required to assess whether a drug is beneficial or
Evaluation of Clinical Trials not can be calculated using formulas that can be found
The best method for evaluating animal health interven- in standard statistics text books. The number of units
tions and to guide clinical decision-making is to con- will depend on the variation you expect and the magni-
duct on-farm clinical trials (Dohoo et al. 2003). In a clin- tude of the difference you consider important. For ex-
ical trial, exposure to disease occurs naturally and the ample, if one assumes a coefficient of variation (mean ÷
pigs are housed and managed under normal farm condi- standard deviation) of 7% for growth rate, one would
tions but the treatment is randomly assigned with a sec- need approximately 43 pens per treatment to detect a
ond group used as a control population. Clinical trials difference in average daily gain of 5%. Whereas it would
are difficult to conduct and there is considerable poten- require only 12 pens per treatment to detect an average
tial for errors in design and misinterpretation of find- daily gain of 10%.
ings. The consequences of these failings may be inap- Typically, the confidence interval is chosen to be
propriate therapeutic recommendations and overall 95%, implying that the probability that the results were
lack of success in treatment programs. Practitioners real and not due to chance alone is 95%. The P-value or
need to be aware of proper methodology as it relates to level of significance is the opposite (i.e., P = 0.05 means
design and interpretation in order to evaluate therapeu- there is a 5% chance that the results are due to chance
tics either by conducting a trial on a client’s farm, or in alone). Statistical power is typically set at 80%, implying
interpreting claims for a new drug as presented by a that there is an 80% probability that we will find a dif-
pharmaceutical company. ference when a difference truly exists. Therefore, 20% of
First, a study should have a limited number of objec- the time such a trial will not distinguish a difference be-
tives, generally one primary and possibly two or three tween treatment and control when there really is a dif-
secondary objectives, and these must be clearly stated ference. Statistical power can be increased by increasing
(Dewey 1999). For example, a trial examining the use of sample size.
a drug to control pneumonia in a finishing unit might It is important that bias is minimized wherever pos-
have decreased mortality as its primary objective, and as sible. Therefore, subjects need to be assigned to a treat-
 CHAPTER 71 DRUG THERAPY AND PROPHYLAXIS 1133

ment group in a truly random manner, and if this is not To some extent, drug dosage can be tailored to the
possible, an alternatively systematic assignment may be susceptibility of the organism, the site of infection, and
used. The intervention given to the control group needs the pharmacokinetic and pharmacodynamic properties
to be similar to the treatment group. For example, if the of the selected antimicrobial agent. However, in vitro
treatment group needs to be restrained and injected susceptibility data are laboratory-derived and the stan-
with a product, the controls need to be handled in a dardized conditions under which the susceptibility data
similar manner and given a placebo. Ideally, the animal are generated do not exist at the site of infection. Factors
care givers and whoever records the clinical observa- involved in tailoring a dosing regimen include, among
tions should be kept blind to which animals are in the other things, the susceptibility of the pathogen in terms
treatment group and which are in the control group. of minimum inhibitory concentration (MIC), the con-
Even when animals are assigned in a random man- centration of the antimicrobial agent at the site of infec-
ner and trials are carefully designed, confounding fac- tion in active form (pharmacokinetic properties of the
tors and other sources of error can be introduced so that drug), and the pharmacodynamic properties of the an-
a great deal of care is needed in assessing the informa- timicrobial agent. Some antimicrobials (aminoglyco-
tion gained from a clinical trial, but this is still the best sides, fluoroquinolones) are concentration-dependent
basis to judge efficacy of therapeutic measures, and no (optimum action of the drug depends on concen-
amount of in vitro studies can match the value of this tration of the drug above MIC), whereas others (beta-
type of on-farm assessment. lactams, lincosamides, macrolides, trimethoprim-
sulfamethazine) are time-dependent (optimum activity
depends on time above MIC). The complex issues in-
ANTIMICROBIAL DRUGS
volved in optimal antimicrobial therapy are beyond the
Major Classes of Antimicrobial Drugs scope of this chapter although it can be concluded that
A brief overview of some key aspects of the major classes some dosage recommendations for drugs licensed in the
of antimicrobial drugs, their antimicrobial activities, past have not taken modern understanding into ac-
pharmacokinetic properties, toxic or other adverse ef- count and are suboptimal or inappropriate. Labeled rec-
fects, and major clinical applications is given in Table ommendations can therefore be expected to change in
71.3. Further details are available through manufac- the future. In the United States, the Food and Drug
turer’s package inserts or through pharmacology and re- Administration’s professional flexible labeling approach
lated textbooks (Prescott et al. 2000). allows veterinarians to adjust the dose based on the MIC
of the pathogen. Although a number of factors deter-
Antimicrobial Therapy mine optimal dosage, the factor that most frequently
Rational use of antimicrobial therapy first requires a di- limits dosage is toxicity. The upper level of the recom-
agnosis. This may be made clinically and preferably con- mended dosage should not be exceeded, because this is
firmed by laboratory diagnosis, which would include often determined by toxicity. Sometimes, however, a
antimicrobial susceptibility testing. Antimicrobial treat- drug’s antibacterial effects may be limiting and may de-
ment will, however, usually start before laboratory re- termine the upper level of dosage. For example, the
sults are available. The selection of a particular drug de- killing rate of beta-lactam drugs has an optimal concen-
pends on knowledge of the likely or actual susceptibility tration, whereas that of the aminoglycosides or fluoro-
of the microorganism, knowledge of factors affecting quinolones is proportional to drug concentration.
drug concentration (dosage, pharmacokinetic proper- Penicillin G is virtually nontoxic in nonallergenic pa-
ties) and activity (pharmacodynamic properties) at the tients, but its dosage is limited by its antibacterial ac-
site of infection, knowledge of drug toxicity and factors tion. By contrast the dosage of aminoglycoside is lim-
that enhance it, cost of treatment, and consideration of ited not by antibacterial effects but by its toxicity.
regulations about drug use, including withdrawal times. In terms of duration of treatment, the variables af-
The ideal drug is one to which the organism is most sus- fecting length of treatment have not been defined.
ceptible and that achieves effective concentration at the Responses of different types of infections to antimicro-
site of infection without damaging the host. Bacterici- bial drugs vary, and clinical experience with many in-
dal drugs are required in serious life-threatening infec- fections is important in assessing response to treatment.
tions, when host defenses are impaired, and in infec- For acute infections, it will usually be clear within 2 days
tions of vital tissues such as meninges, endocardium, whether or not therapy is clinically effective. If no re-
and bones where host defenses are also not fully func- sponse is seen by that time, both the diagnosis and
tional. In other cases bacteriostatic agents may be treatment should be reconsidered. Treatment of acute
equally useful. Where feasible, a narrow spectrum drug infections should be continued for at least 2 days after
may be more appropriate than a broad spectrum anti- clinical and microbiologic resolution of infection. For
bacterial because the narrow spectrum drug interferes serious acute infections, treatment should probably last
less with the normal microbial flora and is less likely to 7–10 days. For chronic infections, treatment will be con-
select for widespread resistance. siderably longer.
Table 71.3. Overview of major classes and identities of antimicrobial drugs used in swine, their antimicrobial activities, pharmacoki-
netic properties, toxic or other adverse effects, and major clinical applications

Specific Agent or Antibacterial Pharmacokinetic Toxic or

Drug Class Example of Agents Activity, Resistance Properties Adverse Effects Major Applications
Sulfonamides Sulfamethazine Bacteriostatic; broad- Rapidly absorbed from Violative kidney Minor value; largely
intermediate spectrum, gram+, intestine, well dis- residues from feed growth promo-
acting; others gram— aerobes; tributed in tissues use through recy- tional, possible dis-
also used anaerobes; acquired cling, feed contami- ease prevention
resistance very wide- nation if feed not
spread. Active intra- withdrawn 15 days
cellular bacteria, pro- before slaughter
tozoa
Sulfonamide- Sulfamethazine- Bactericidal; gram+, Rapidly absorbed from Wide safety margin Largely IM use for
diaminopy- trimethoprim gram— aerobes; intestine, well dis- acute infections
rimidine anaerobes. Myco- tributed in tissues; (pneumonia, strep-
combinations plasma, Leptospira crosses uninflamed tococcal meningi-
resistant blood-brain barrier tis). In feed for at-
rophic rhinitis
Beta-lactam Penam penicillins, Bactericidal; highly ac- Poorly absorbed from Safe drug; possible Excellent for IM use in
Group 1: tive many gram+, intestine, relatively anaphylaxis or pro- erysipelas, strepto-
Penicillin G some fastidious poorly distributed caine-induced ex- coccal infections in-
gram— aerobe, e.g., H. in tissues; crosses citement cluding meningitis,
parasuis, P. multocida; only inflamed clostridial infec-
anaerobes; Leptospira. blood-brain barrier. tions. Some bacter-
Enteric bacteria and Procaine penicillin ial pneumonias
Mycoplasma resistant is long-acting form
for IM use since un-
conjugated drug
rapidly excreted
Beta-lactam Penam penicillins, As penicillin G, broader As penicillin G, but Safe drug Similar to penicillin G.
Group 4: ampi- activity against better absorbed Addition of beta-
cillin, amoxy- gram— aerobes, but orally and distrib- lactamase inhibitors
cillin resistance widespread uted through tissues (e.g., clavulanic
acid) has resurrected
penam penicillins
use in other species
Beta-lactam Group 4, “third Bactericidal; gram— Poorly absorbed from May predispose to Excellent for IM use in
generation” aerobes especially, intestine, relatively Clostridium difficile gram— aerobic in-
cephalosporins; including E. coli, poorly distributed colitis if used in fections, including
ceftiofur Salmonella, gram+ in tissues; crosses neonatal pigs. colibacillosis, sal-
aerobes, anaerobes. only inflamed Resistance emerging monellosis, gram—
Mycoplasma resistant blood-brain barrier in Salmonella may bacterial pneumo-
represent human nias
health hazard
Aminoglycoside Gentamicin, Bactericidal; gram— Poorly absorbed from Nephrotoxic with pro- Gentamicin IM for
neomycin aerobes, including intestine, relatively longed parenteral neonatal E. coli in-
enterics poorly distributed use; persistent kid- fections; neomycin
in tissues ney residues orally for E. coli
infection
Aminocyclitol Apramycin, Bactericidal; gram— Poorly absorbed from Nephrotoxic with pro- Orally for E. coli infec-
spectinomycin aerobes, including intestine, relatively longed parenteral tion
enterics poorly distributed use; persistent kid-
in tissues ney residues
Lincosamide Lincomycin Bacteriostatic; gram+ Well absorbed from Safe drug in swine Oral use for control of
aerobes, anaerobes in- intestine and well Brachyspira; oral or
cluding B. hyodysente- distributed in tis- IM use for control of
riae; Mycoplasma sues Mycoplasma
Macrolide Tylosin Bacteriostatic; gram+ Well absorbed from Safe drug in swine; IM Oral use for control of
aerobes, anaerobes, intestine and well irritant, may cause proliferative en-
some gram— aerobes; distributed in edema, pruritis, teropathy, atrophic
Mycoplasma tissues anal protrusion rhinitis, possibly
leptospirosis

1134
 CHAPTER 71 DRUG THERAPY AND PROPHYLAXIS 1135

Table 71.3. (continued)

Specific Agent or Antibacterial Pharmacokinetic Toxic or

Drug Class Example of Agents Activity, Resistance Properties Adverse Effects Major Applications
Pleuromutilin Tiamulin Bacteriostatic; gram+ Well absorbed from Safe drug in swine Oral use for control of
aerobes, anaerobes, intestine and well Brachyspira, Myco-
some gram— aerobes; distributed in tis- plasma, chronic
Mycoplasma. More sues pneumonias, prolif-
active than tylosin erative enteropathy,
leptospirosis
Tetracyclines Oxy-, Chlor-, Bacteriostatic; classi- Well absorbed from Safe drugs in swine Oral use as “feed”
tetracycline cally broad-spectrum, intestine and well drugs for growth
gram+, gram— but ac- distributed in tis- promotion and
quired resistance ex- sues nonspecific disease
tremely widespread. prophylaxis in
Erysipelothrix, Haemo- countries where al-
philus, Leptospira, lowed. Used in feed,
Pasteurella are excep- occasionally IM, for
tions treatment of infec-
tions caused by bac-
teria listed as being
susceptible

Treatment failure has many causes. The antimicro- One reasonable prophylactic practice is that of
bial selected may be inappropriate because of misdiag- “pulse medication,” whereby a therapeutic level of a
nosis, inactivity at the site of infection, failure to culture specific drug is included in the feed at therapeutic con-
infections, inaccurate or inapplicable laboratory results, centrations for a short period for the prevention of en-
resistance of pathogens, chronic nature of the infection demic diseases, such as proliferative enteropathy or en-
(which may affect metabolic state of the pathogen), or zootic pneumonia before the predictable onset of these
errors in sampling. These factors are more likely to cause diseases in a particular setting.
failure than inadequate dosage although this may also
be important. It is important that producers comply Regulations
with dosing instructions. When failure occurs, diagno- The use of antimicrobial drugs in animals is regulated by
sis must be reassessed and samples collected for labora- law in many countries, so that veterinarians need to
tory analysis. know and abide by the regulations. The regulations in-
volve an approval process of drugs produced by a partic-
Principles of Prophylaxis ular manufacturer only if they meet human and animal
Antimicrobial drugs are administered to swine for the safety standards as well as being shown to be efficacious
prevention of particular diseases. The generally ac- at specified dosages for particular purposes (the labeled
cepted principles of antimicrobial prophylaxis are: dose/purpose). An example of regulated use of antimi-
crobial drugs, that of the United States, is outlined in
• Medication should be directed against specific patho- Table 71.4. In the United States, failure to comply with
gens or diseases. the regulations may result in fines or imprisonment.
• Prophylaxis should be used only where efficacy is es-
tablished. Prophylaxis should be of a duration that is Antimicrobial Drug Withdrawal
as short as possible consistent with efficacy. Most antimicrobial drugs must not be used near slaugh-
• Dosage should be the same as that used therapeu- ter, to avoid any significant residues in meat products.
tically. The precise period varies with the drug and the dosage.
• Adverse effects itemized earlier should be minimized. For drugs used at the labeled dosage, this will be speci-
fied on the package insert. For extra-label drug use,
In general, as discussed below, antimicrobial drugs of withdrawal information may be obtained from the
therapeutic importance in both humans and animals manufacturer or in some cases from national or interna-
have been markedly overused for both growth promo- tional databases such as, in the United States, the Food
tional and disease prophylactic purposes in swine, in a Animal Residue Avoidance Databank (toll-free number
manner inconsistent with generally accepted principles in the United States, 1-800-USFARAD). Examples of
of prophylaxis. Alternatives to these antimicrobial use preslaughter medication withdrawal time in the United
practices need to be found, as discussed below. States are shown in Table 71.5.
1136 SECTION V VETERINARY PRACTICE

Table 71.4. Regulation of antimicrobial drug use for food animals in the United States.

Drug Category or Regulation Description

Production feed drugs Growth promotion and feed efficiency including subtherapeutic or therapeutic use for specified
purposes in feed. Strict dose, duration, withdrawal period specified. Nonprescription.
Over-the-counter drugs Drugs for oral or parenteral use available without prescription. Strict dose, duration, withdrawal
period specified.
Prescription drugs Veterinary prescription parenteral use only. Strict dose, duration, withdrawal period specified.
Professional flexible labeling Approved products have expanded dosage ranges for veterinarian use.
Veterinary Feed Directive Used in feed only under direction of a veterinarian. Strict recording requirements.
Extra-label use Regulation under Animal Medicinal Drug Clarification Act (AMDUCA) when actual or intended
use of a drug is not in accordance with approved labeling. Only when available labeled products
ineffective. Strict recording and other requirements, including prohibited uses.

Table 71.5. Examples of preslaughter withdrawal times from last medication for swine in the United States

Dosage Form Drug for Labeled Use Days

Parenteral drug Ceftiofur 0
Gentamicin (neonatal pigs only) 40
Procaine penicillin 7
Oral, water-soluble drugs Bacitracin 1
Chlortetracycline 5
Neomycin 20
Tylosin 2
Oral, feed forms (maximum time Apramycin 28
may vary with dose) Chlortetracycline, procaine penicillin, sulfamethazole 15
Tiamulin 0–2

The Antimicrobial Resistance Crisis and Its tional to the extent and type of antimicrobial use in pigs
Impact on Antimicrobial Drug Use in Swine (Dunlop et al. 1998). On a broader scale, the use of
There is both need and considerable scope to reduce the antimicrobial drugs over many years may not only have
use of antimicrobial drugs in swine. Human medicine is selected for resistant bacterial pathogens and an enor-
experiencing an antimicrobial resistance crisis because mous reservoir of resistance genes in commensal bac-
of the surge of resistance in important human patho- teria, but it may also have promoted or enhanced the
gens in the last decade. The emergence of this crisis has ability of bacteria to move resistance and other genes
resulted from many causes, including widespread use through enhancement of mobile genetic elements such
and overuse of some drugs for many years, changing so- as transposons, plasmids, and integrons, and thus per-
cial practices including daycare centers and group haps to change more rapidly. There is a high frequency
homes for the elderly, the increasing number of im- of resistance to multiple antimicrobial drugs in porcine
munosuppressed people, and possibly changes in the enterotoxigenic E. coli, with some evidence that the
drugs being used. As medical science tries to reduce re- emergence of resistant new serotypes with apparently
sistance, it again focuses on the widespread use of an- enhanced virulence may have virulence genes linked to
timicrobial drugs in farm animals. Agriculture uses those of resistance (Noamani et al. 2003), so that use of
about half of all antimicrobials produced, with use in antimicrobial drugs may not only maintain resistant
swine being a major component. Why antimicrobials but also virulent bacteria.
can be administered to animals on a wide scale over long In 1999, the European Union banned the use of
periods to promote growth and prevent endemic disease growth-promoting antimicrobial drugs in food animals.
cannot be understood by physicians desperate to pre- The impetus for the ban on avoparcin, bacitracin, spi-
serve effective antimicrobials. The extent of the contri- ramycin, tylosin, and virginiamycin was because of the
bution of farm animal use to resistance in human entry of Sweden into the Union. Sweden had banned
pathogens has been the subject of vigorous debate for these growth promoters in 1986 but, because it needed to
many years. Although it is easy to document that bacte- harmonize its regulations with those of the EU, it per-
ria, including resistant bacteria, move from farm ani- suaded the EU to change the Union’s regulations. This
mals including swine to people, the scale and to some ban was supported by Denmark and Danish pork produc-
extent the importance of the movement is unclear. The ers, who had agreed on a voluntary ban shortly before
extent and type of resistance in commensal E. coli iso- 1999. The impetus for the Danish ban was the convincing
lated from swine has been shown to be directly propor- evidence that avoparcin use in poultry, swine, and calves
 CHAPTER 71 DRUG THERAPY AND PROPHYLAXIS 1137

was selecting for vancomycin-resistant enterococci Prudent Use Guidelines

(VREs), which were reaching the European population The widespread concern about antimicrobial resist-
through the food chain (Bager et al. 1997). Vancomycin- ance and the animal-human resistance link has led
resistant enterococci have become major nosocomial most major national veterinary organizations to im-
pathogens in human hospitals, particularly in the United prove antimicrobial drug use by development of pru-
States. Enterococcus faecium are innately highly resistant dent use guidelines. Such guidelines represent first
bacteria for which vancomycin is often the only drug to steps in the more judicious use of antimicrobial drugs
which they are susceptible; VREs are essentially untreat- that may become considerably more complex over
able infections. The ban on these growth promoters in time if they address antimicrobial drug choice for par-
Denmark led to an over 50% reduction in antimicrobial ticular diseases. An example of such guidelines, that of
drug use, a dramatic reduction in enterococci resistant to the American Association of Swine Veterinarians, is
the growth promoters and a minor increase in the cost of shown in Table 71.6.
production of swine estimated at about one Euro (World
Health Organization 2002). Drug Selection for Specific Diseases
Numerous reports have recommended that all stake- Table 71.7 contains recommendations for treatment of
holders concerned with the use of antimicrobials in specific bacterial disease conditions commonly encoun-
both food animals and humans must be involved in an tered in North America. It is beyond the scope of this
overarching global strategy to contain resistance (e.g.,
World Health Organization 2000a) and have recom-
mended steps to enhance the prudent use of antimicro- Table 71.6. American Association of Swine Veterinarians Basic
bials in animals, including the removal of growth pro- Guidelines of Judicious Therapeutic Use of Antimicrobials in Pork
Production
moters if these drugs are important in human medicine
(e.g., World Health Organization 2000b). At the interna- (1) Preventive strategies, such as appropriate husbandry and
tional level, the World Organization for Animal Health hygiene, routine health monitoring, and immunization,
(Office International des Epizooties) (2003, 2004) con- should be emphasized.
tinues to formulate recommendations and options for (2) Other therapeutic options should be considered prior to or
in conjunction with antimicrobial therapy.
risk management relating to antimicrobial use in ani-
(3) Judicious use of antimicrobials, when under the direction of
mals. Outside the EU, other countries are in the process a veterinarian, should meet all requirements of a veterinarian-
of assessing or starting to reassess the use of antimicro- client-patient relationship.
bial drugs in food animals based on the importance of (4) Prescription, Veterinary Feed Directive, and extra-label use
the drug in human medicine and the likelihood of ex- of antimicrobials must meet all the requirements of a valid
veterinarian-client-patient relationship.
posure of humans to resistant bacteria or resistance
(5) Extra-label antimicrobial therapy must be prescribed only in
genes arising from animals (e.g., Health Canada 2002; accordance with the Animal Medicinal Drug Use
Center for Veterinary Medicine, U.S. Food and Drug Clarification Act amendments to the Food, Drug, and
Administration 2004). Cosmetic Act and its regulations.
In recent years many countries have started to moni- (6) Veterinarians should work with those responsible for the
care of animals to use antimicrobials judiciously regardless
tor resistance in both important pathogens (e.g., Cam-
of the distribution system through which the antimicrobial
pylobacter jejuni, Salmonella) as well as “indicator” com- was obtained.
mensal bacteria (e.g., Enterococcus species) isolated from (7) Regimens for therapeutic antimicrobial use should be opti-
animals, foodstuffs, and humans. For example, in the mized using current pharmacological information and prin-
United States the National Antimicrobial Resistance ciples.
(8) Antimicrobials considered important in treating refractory
Monitoring System (NARMS) established in 1996 is de-
infections in human or veterinary medicine should be used
signed to document emerging resistance problems, as in animals only after careful review and reasonable justifica-
well as to provide data on which public health policy de- tion. Consider using other antimicrobials for initial therapy.
cisions can be made for the use of antimicrobial drugs in (9) Utilize culture and susceptibility results to aid in the selec-
food-producing animals. In Canada, the Canadian Inte- tion of antimicrobials when clinically relevant.
(10) Therapeutic antimicrobial use should be confined to appro-
grated Program for Antimicrobial Resistance Surveil-
priate clinical indications.
lance has taken a similar approach to NARMS. (11) Therapeutic exposure to antimicrobials should be mini-
One emerging resistance problem that will likely be- mized by treating only for as long as needed for the desired
come of even greater concern in the future is expanded- clinical response.
spectrum cephalosporin resistance in multidrug- (12) Limit therapeutic antimicrobial treatment to ill or at risk
animals, treating the fewest animals indicated.
resistant E. coli and Salmonella serovars (Winokur et al.
(13) Minimize environmental contamination with antimicro-
2001; Zhao et al. 2003), in which the cmy-2 gene encod- bials whenever possible.
ing expanded-spectrum cephalosporin resistance may (14) Accurate records of treatment and outcome should be used
be found on several different plasmids that can readily to evaluate therapeutic regimens.
be transferred through bacterial conjugation (Caratolli Note: The AASV website elaborates on these basic guidelines
et al. 2002). listed above (http://www.aasp.org/aasv/jug.html).
Table 71.7. Antimicrobial drug selection for specific bacterial diseases (Warning—These dosages may not conform to government
regulations or label instructions.)

Diagnosis Causative Agent Comments Suggested Drug(s)

ENTERIC DISEASES
Clostridial enteritis Clostridium perfringens Treatment of sick piglets affected Bacitracin in sow diet (100 gm per
type A and C with type C is not effective. ton of feed)
Medicate sows to reduce shedding. Ampicillin (6 mg/kg, oral)
Coccidiosis Isospora suis Treatment must begin before diarrhea Toltrazuril (20–30 mg/kg, oral)
occurs (3- to 6-day-old piglets). Amprolium 9.6%, (2 ml per
piglet/day for days 3–5)
Colibacillosis Escherichia coli Neonatal piglets must be treated promptly Neonates:
and provision of electrolytes helps Gentamicin (5 mg per kg, oral)
minimize effects of dehydration. Post- Neomycin (7 mg per kg, oral)
weaned pigs best treated with antibiotics Spectinomycin (50 mg twice a day)
in water. Weanlings:
Apramycin (12.5 mg/kg per day, in water)
Colitis Brachyspira pilosicoli Disease is often mild and responds to
change in feed, but if more severe, treat
in similar fashion to swine dysentery
Proliferative Lawsonia intracellularis All-in/all-out management and good hy- Tylosin (100 g per ton of feed)
enteropathy giene may minimize the need for anti- Lincomycin (100 g per ton of feed)
biotics. Feed medication can prevent Tiamulin (35 g per ton of feed)
clinical signs.
Salmonellosis Salmonella typhimurium Antimicrobials may be contraindicated in
and other serovars that they prolong shedding and promote
resistance.
Swine dysentery Brachyspira hyodysen- Resistance against older drugs is common. Tiamulin (200 g/ton of feed to treat)
teriae Treatment for extended period after (35 g/ton to prevent)
clinical signs disappear is necessary. Carbadox (50 g/ton of feed)
Water medicate in acute outbreak.
MULTISYSTEMIC DISEASES
Actinobacillus Actinobacillus suis A. suis is sensitive to most antibiotics but Procaine penicillin G 20,000 IU/kg IM
Septicemia disease occurs acutely so treatment may
not be in time.
Erysipelas Erysipelothrix rhusio- Resistance to penicillin does not appear to Procaine penicillin G 20,000 IU/kg IM
pathiae be a problem. but also tylosin, tetracyclines, or
lincomycin
Glasser’s disease Haemophilus parasuis High dosages, administered parenterally to Procaine penicillin G 20,000 IU/kg IM or
all members of the affected group. Some higher
resistance to penicillin. Ceftiofur, 3 mg/kg IM
Trimethoprim-sulfadoxine 16 mg/kg IM
Mycoplasma poly- Mycoplasma hyorhinis High dosages, administered parenterally, Lincomycin 10 mg/kg IM
serositis but results tend to be poor. Tylosin 9 mg/kg IM
Tiamulin 11 mg/kg IM
Salmonellosis Salmonella choleraesuis Vigorous treatment early can reduce dura- Ceftiofur 3 mg/kg IM
tion and severity. Trimethoprim-sulfadoxine 16 mg/kg IM
MUSCULOSKELETAL DISEASES
Foot rot Arcanobacterium pyogenes Improved flooring and sanitation. Topical Procaine penicillin G 20,000 IU/kg IM
Fusobacterium necro- disinfectants may help. Generally poor Oxytetracycline 6.6 mg/kg IM
phorum response to treatment.
Mycoplasma arthritis Mycoplasma hyosynoviae Injectable antibiotics and possibly corti- Lincomycin 10 mg/kg IM
costeroids. Tiamulin 11 mg/kg IM
Tylosin 9 mg/kg IM
Neonatal polyarthritis Staphylococcus spp. Treatment is ineffective unless started early. Procaine pencillin G 20,000 IU/kg IM
Streptococcus spp.
and others
Suppurative arthritis Arcanobacterium pyogenes Treatment is generally ineffective. Procaine penicillin G 20,000 IU/kg IM
Oxytetracycline 6.6 mg/kg IM
NEUROLOGICAL DISEASES
Edema disease Escherichia coli Sick pigs eat and drink very little and must Trimethoprim-sulfadoxine 16 mg/kg IM
be treated parenterally. Ceftiofur 3mg/kg IM
Otitis media (Middle Staphylococci spp. Abscesses can occur and relapses are Trimethoprim-sulfadoxine 16 mg/kg IM
ear infection) Streptococci spp. common. Ceftiofur 3 mg/kg
Arcanobacterium pyogenes
Tetanus Clostridium tetani Poor prognosis.

1138
 CHAPTER 71 DRUG THERAPY AND PROPHYLAXIS 1139

Table 71.7. (continued)

Diagnosis Causative Agent Comments Suggested Drug(s)

REPRODUCTIVE DISEASES
Leptospirosis Leptospira spp. Antibiotics may not eliminate carrier state. Streptomycin 25 mg/kg IM
Chlor or oxytetracycline at 600–800
g/ton of feed
Mastitis and/ Generally gram- Attention needs to be paid to cross-fostering Ampicillin 6 mg/kg IM
or metritis negative bacteria piglets. Treatment varies depending on
microorganism and sensitivity.
RESPIRATORY DISEASES
Enzootic pneumonia Mycoplasma hyopneu- Preferably sick animals are treated parenter- Oxytetracycline 6.6 mg/kg
moniae and secon- ally to achieve high tissue levels. Trimethoprimsulfadoxine 3 mg/kg IM
daries Ceftiofur 3 mg/kg IM
Tulathromycin 2.5 mg/kg IM
Pleuropneumonia Actinobacillus pleuro- Parenteral treatment because acutely sick Same as above
pneumoniae pigs eat and drink very little. Tilmicocin (181–363 g/ton of feed)
Progressive Atrophic Bordetella bronchiseptica Responsive to housing/management and Oxytetracycline 20 mg/kg IM
Rhinitis and toxigenic strains vaccination programs. Sulfamethazine 400–2000 g/ton of feed
of Pasteurella multocida in nursery ration
SKIN DISEASE
Exudative epidermitis Staphylococcus hyicus May see resistance to penicillin, need to Procaine penicillin G 20,000 IU/kg IM
(Greasy pig disease) treat fresh wounds topically.
URINARY TRACT DISEASE
Cystitis Actinobaculum suis and Relapses are common. Procaine penicillin G 20,000 IU/kg IM
possibly others Ampicillin 6 mg/kg IM
Chlor or oxytetracycline 600–800
gm/ton of feed

text to discuss all product indications and cautions, but Vaccines

the user should always review the information provided Vaccines are extensively used in swine production, and
by the package insert and the product label. Nor is it in fact there are few diseases for which a vaccine is not
within the scope of this text to include all possible treat- available. Unfortunately, the fact that a vaccine is li-
ment options; instead, this table should be considered a censed and available does not mean it works (Ribble
general guideline. 1990). The usefulness of vaccination varies from disease
to disease and even from herd to herd. Despite rapid ad-
vances in the fields of immunology and molecular biol-
ALTERNATIVES TO ANTIMICROBIAL DRUGS
ogy there are still diseases for which vaccines have only
Management and Biosecurity moderate to poor efficacy (Haesebrouck et al. 2004).
Modern housing and husbandry methods that tend to Details of the mechanisms of pathogenesis and immune
segregate age groups, allow for cleaning of the environ- response are covered elsewhere in this text.
ment between production groups, and minimize the There are a number of important considerations that
risk of disease introduction through strict biosecurity a veterinarian needs to evaluate in order to decide upon
measures, are the most important methods of reducing a vaccination program for a particular herd. The cost-
the use of antimicrobials and other therapeutic prod- benefit of vaccination needs to be considered, and this
ucts. Immune system stimulation results in decreased includes estimating the cost of the program, including
feed efficiency and growth rate whether or not clinical labor to administer the vaccine; estimating the improve-
disease occurs. The value of in-feed antibiotics is ques- ment one would expect from the vaccination program,
tionable when high-health status grower-finisher pigs which requires a knowledge of the vaccines efficacy and
are raised in a clean, biosecure environment (Van Lunen an understanding of the disease costs present in the
2003). However, even under ideal management there herd; and evaluating the value of alternative control
are circumstances when treatment is required and suc- measures. In addition, the veterinarian needs to be
cess of therapy very much depends on the diligence of aware of possible negative side effects, such as a poten-
stockpeople to identify clinical signs of illness early, to tial tissue reaction that might lead to trimming losses or
treat appropriately, and to provide an environment for a transient loss of appetite that could cause a reduction
the sick pig that promotes healing. in growth.
1140 SECTION V VETERINARY PRACTICE

The decision to institute a vaccination program is specific egg-yolk products to prevent postweaning E. coli
complex, and unfortunately there is a scarcity of unbi- diarrhea have produced inconsistent results (Cherny-
ased data regarding the efficacy of vaccines used under sheva et al. 2004). Stability of the product during feed
practical farm conditions (Moon and Bunn 1993). There processing and passage through the pig’s gastrointesti-
are good examples of vaccines that have worked well in nal system are major concerns.
controlled experimental infection models but are of no
value in the field. Many of the important diseases of Other Biological Products
swine are a complex of one or more infectious agents Direct-Fed Microbials (Probiotic). Probiotics are de-
and of host, environmental, and management factors. fined as live microbials provided in the feed in an at-
Swine practitioners are sometimes faced with an un- tempt to encourage proliferation in the intestine of the
expected vaccination failure in a situation when using a specific microorganism fed with the objective of provid-
product that has worked well under similar circum- ing health benefits to the host animals (Fuller 1989).
stances in the past. Possible causes of a failure include The most commonly used probiotics include species of
improper storage and handling of the vaccine, such as Lactobacillus, Enterococcus, Bifidobacterium, and Saccha-
failure to refrigerate or protect from light; incorrect ad- romyces (Alverez-Olmos and Oberhelman 2001; Holzap-
ministration, such as subcutaneous injection when an fel et al. 2001; Rolfe 2000). Most studies involving probi-
intramuscular injection is required; or possibly omitting otics have concentrated on improving intestinal health,
to vaccinate whole groups of animals. In the case of vac- particularly during the weaning period when the pig gut
cines administered via the drinking water, there are a microflora undergoes dramatic change.
number of concerns but possibly the most important is It is generally accepted that with careful attention to
chlorine present in the water, which may kill live atten- the criteria used to select the particular probiotic strain,
uated bacteria in vaccines (Kolb 1996). there may be a place for probiotics in prevention of en-
Timing of a vaccination program is often a problem. teric disease, but results to date are inconsistent. There
In order to maximize compliance and minimize labor, are a number of criteria that potential probiotic strains
the swine industry prefers to use combination vaccines must meet in order to be considered for use as a probi-
that require a single injection to be given at a time otic, including the ability to demonstrate predictable
when animals are ordinarily handled (such as at wean- and measurable health benefits. The screening and se-
ing). Among the problems associated with this ap- lection of a probiotic includes testing in vitro or in vivo
proach is the concern that for newly weaned pigs there of the following criteria:
may still be high levels of passive immunity present to
interfere with the stimulation of immunity from vacci- • It must be nonpathogenic and proven safe.
nation. Therefore, one has to weigh the consequences • It must have stability in an acid environment, in the
of vaccinating at a time of greatest convenience versus presence of bile, and resistant to degradation by diges-
the extra labor costs and stress to the animals of vacci- tive enzymes.
nating at the most appropriate time to ensure vaccine • It must adhere to gut epithelial tissue and be able to
efficacy. persist in the gastrointestinal tract of the host.

Passive Immunity In addition, the microbials used as probiotics must re-

Spray-dried animal plasma has been widely used in diets tain viability and stability during commercial produc-
for newly weaned pigs and is associated with increased tion, feed processing, storage, and delivery, and must be
growth rates in the order of 27% (van Dijk et al. 2001). cost-effective.
The mode of action of spray-dried animal plasma is not The main mechanisms whereby probiotics exert pro-
fully understood but is assumed to be at least partly due tective or therapeutic effects are not fully understood,
to the presence of immunoglobulins, which may pro- but several ways have been postulated. Probiotics pro-
vide a certain level of protection to the newly weaned duce antimicrobial substances such as organic acids,
piglet at a time when the supply of immunoglobulins fatty free acids, ammonia, hydrogen peroxide, and bac-
from sow’s milk has ceased. The ability of plasma pro- teriocins (Alverez-Olmos and Oberhelman 2001). In ad-
teins to neutralize the effect of specific organisms is de- dition, probiotics may enhance specific and nonspecific
pendent on the immunizations and disease history of host immunity (Kailasapathy and Chin 2000), and pro-
the pigs from which the blood is collected. biotics may prevent colonization of pathogenic mi-
Specific antibodies from chicken egg-yolk have been croorganisms by competitive inhibition for microbial
examined as a source of passive immunity for newly adhesion sites.
weaned pigs as well. Laying hens are vaccinated against Inconsistent findings have been observed when pro-
specific pig pathogens such as E. coli. Antibodies are se- biotics have been used in trials to control pig disease or
creted into the yolk of the egg (IgY) in large quantities improve growth performance (Conway 1999). It is un-
(up to 200 mg/egg) (Marquardt and Li 2001), and dried likely they will be capable of replacing antibiotics in the
yolk is incorporated in nursery pig rations. Trials using control of disease but they may have a place alongside
 CHAPTER 71 DRUG THERAPY AND PROPHYLAXIS 1141

other techniques for improving the health of the gut for the growth-promoting effect of organic acids include
microflora and reducing the shedding of pathogens decreased gastric pH, reduced coliform population,
such as Salmonella. stimulated pancreatic exocrine secretion, increased
There is considerable interest in the use of fermented pepsin activation, altered gut morphology, and im-
liquid feed and there appears to be an association be- proved intake and digestibility (Partanen 2001).
tween its use and a reduction in Salmonella prevalence Response to acidification has been variable and may
(van der Wolf et al. 2001). A possible explanation for the be attributed to feed and animal factors as well as differ-
beneficial effect of fermented liquid feed is that the re- ences in the properties of the various organic acids. Two
duced pH of the diet and the presence of large numbers problems that are associated with the use of high levels
of organic acid producing bacteria in the feed have a of organic acids are the acids may have a negative effect
positive effect on the gut microflora and create an envi- on palatability and the feed is corrosive to cement and
ronment unsuitable for Salmonella and other coliform steel in swine housing (Canibe et al. 2001).
bacteria. An alternative approach to altering the gut mi-
croflora is to feed nondigestible material that provide a
Bacteriophages. Bacteriophages or phages are bacter- substrate for beneficial bacteria such as lactic acid-
ial viruses that invade bacterial cells and in the case of producing bacteria. These products are often referred to
lytic phages, disrupt bacterial metabolism and cause the as prebiotics. In order for a feed to be classified as a pre-
bacterium to lyse (Sulakvelideze et al. 2001). From a clin- biotic it must be neither hydrolyzed nor absorbed in the
ical standpoint, phages appear to be innocuous, do not upper part of the gastrointestinal tract, be a selective
attack normal gut flora, and are extremely common in substrate for one or a limited number of potentially ben-
the environment. In spite of all the positive properties eficial commensal bacteria, and induce luminal or sys-
of lytic phages, they are not commonly used prophylac- temic effects that are beneficial to the host’s health
tically or therapeutically and their efficacy is still a mat- (Roberfroid 2001). Nondigestible oligosaccharides are
ter of controversy almost 100 years after their initial the most common type of prebiotics, including fructo-
discovery. oligosaccharides and mannan-oligosaccharides. In gen-
eral, prebiotics are considered to provide small but posi-
Nutrients tive improvements in growth rate, and are widely used
There are a plentiful supply of physiologically active in the swine industry. However, their role in providing
feed ingredients that can improve pig performance and health benefits, such as reducing Salmonella shedding,
health by modifying the environment of the digestive needs to be clarified.
tract (Pettigrew 2003). Zinc oxide added to nursery ra- Enzymes added to feed to encourage improved feed
tions at a level of 2500 ppm for 2 weeks will result in in- efficiency and in some cases potential health benefits
creased growth rate and reduced prevalence of diarrhea are used widely. For example, feed can be supplemented
(Jensen-Waern et al. 1998). In vitro studies have shown with phytase to allow swine to digest plant phosphorus
that zinc has antimicrobial effects, but in vivo studies that is in the form of phytate. It has been hypothesized
show no reduction in E. coli numbers and no change in that the use of enzymes may allow the industry to uti-
function of circulating neutrophils. There are concerns lize coarse feed particle size as a means of reducing gas-
that high levels of zinc oxide will cause liver toxicity if tric ulcers and the prevalence of Salmonella but still
fed longer than 3–4 weeks. maintaining acceptable feed conversion.
Likewise, copper sulfate at levels of up to 250 ppm There is a possibility that in-feed antimcriobials for
has been added to pig feed to promote growth. However, growth promotion could be reduced through a combi-
the combination of zinc and copper does not result in nation of feeding manipulations, such as the use of var-
an additive growth response (Hill et al. 2000). In the ious combinations of liquid feeds or coarse particle size,
case of both copper and zinc, there are environmental enzymes, probiotics, prebiotics, and acidifiers.
concerns regarding their use because of the build up of
these minerals in manure.
OTHER THERAPEUTICS
The quest for alternatives to antibiotics in pig feed
has caused interest in natural remedies, including herbs, Anesthetics, Tranquilizers
spices, botanicals, and essential oils. These products There are few products licensed for use in swine. Most
may improve performance by improving feed palatabil- commonly a combination of drugs used in an off-label
ity and by exerting antibacterial effects, but there needs manner are employed in order to provide satisfactory
to be further evidence of their effectiveness (Pettigrew anesthesia in the field. This has become a controversial
2003). area because the swine industry has come under pres-
Organic acids (fumaric, formic, and lactic) are com- sure to reduce the potential suffering of pigs during and
monly added to feed or water in order to improve following routine surgical procedures, such as castration
growth and reduce diarrhea during the postweaning pe- or after a traumatic injury, and yet minimize the use of
riod (Tsiloyiannis et al. 2001). Modes of action claimed drugs without proper licensing approval.
1142 SECTION V VETERINARY PRACTICE

Table 71.8. Common swine anthelminitics and dosages REFERENCES

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Piperazine 275–440 mg/kg body weight in feed or water vancomycin-resistant Enterococcus faecium in Danish poultry
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