Antimicrobials

What are the main endemic pathogens/disease that effect production animals?

• Respiratory disease

  • Mycoplasmas, Pasturellaceae and Escherichia (poultry)

• Gastrointestinal disease

  • Brachyspira and Lawsonia (pigs)

  • Clostridium perfingens (poultry)

  • Ruminal acidosis (feedlot, sheep and cattle)

• Mastitis

  • gram positive cocci

  • enterobacteriaceae

What are the main endemic pathogens/disease that effect companion animals?

• opportunistic pathogens

  • gram positive cocci

  • enterobacteriaceae

    • streptococcus equi (strangles)

    • rhodococcus equi

    • chlamydia felis

Purpose of antimicrobial therpay

Assist the body in eliminating infectious agents without toxicity to host

• enhance health, welfare and production

• treat diagnosed bacterial disease

• prevent predictable disease (seasonal bugs etc)

• attempt to treat undiagnosed disease

How:

• Natural defence - preventing + controlling

  • muscocillary escalator in the resp tract

  • flushing of urine

  • normal flora of GIT

• Host defence - combat invading

  • inflam response

  • cellular migration and phagocytosis

  • complement system

  • antibody production

Define Antibiotic vs Antimicrobial Agent

Antibiotic = chemical produced by microorganism that kills or inhibits the growth of another organism

Antimicrobial Agent = any agent capable of destroying or inhibiting the growth of microorganisms

• Eg: antibiotics, synthetic and semisynthetic agents

*Antibiotics are more properly referred to as antimicrobial agents or antimicrobials

Explain the 2 Classifications (4 branches) of Antimicrobials

Mode of Action = Bacteriostatic or Bactericidal

Bacteriostatic	Bactericidal
reversibly inhabits growth hot immune defences eliminate infection duration must be sufficient for host to defence to eradicate infec	irreversibly impair target structures cannot be controlled or eradicated by host mechanisms (either due to nature/site or reduced immunocompetence)

Spectrum of Action = Broad or Narrow

Broad Spectrum	Narrow Spectrum
wide range of microorganisms seriously ill or unidentified organism	small number of microorganisms / x1 taxonomic group identified organism (avoid disrupting microflora, and decreased resistance!)

How do you test antimicrobial agents?

• Disc diffusion susceptibility testing

  • Approximates whether the plasma conc attained by the antimicrobial is high enough to inhibit the growth of the bacteria

    • qualitative

  • Bacterial isolate classified as sensitive, intermediate or resistant (dependant on ring side)

• Minimum Inhibitory Concentration (MIC)

  • The lowest conc of drug at which inhibits bacterial growth occurs

    • quantitative (mg/L)

List the problems with antimicrobials

• Not selective in their elimination of microbiota → superinfections

  • Disrupt normal microflora

  • Hindgut fermenters (horses and g pigs) are most sensitive

    • Horses - antimicrobial associated colitis

    • G pigs - antibiotic toxicity

• Toxicity (or contraindications)

• Hypersensitivity / Allergy

  • more common w inj vs oral

  • once a hypersensitivity reaction occurs, increased likelihood repeat exposure = more intense reaction

  • manifest as acute anaphylaxis, cutaneous or haematological

• Antimicrobial resistance

  • microorganisms susceptible to the action of antimicrobial, not effected by it

    • enzymatic

    • decrease in intracellular accumulation

    • structural modification

What promotes antimicrobial resistance?

• sub-optimal levels of antimicrobial

• microbes with resistance genes

• inappropriate use

  • incorrect prescription

  • used for viral infections (only treat bacterial)

  • sold without medical supervision

  • spread resistance microbes (low hygiene)

  • low quality/outdated in manufacture

  • inadequate surveillance/defective susceptibility assays

  • poverty or war

  • antimicrobials in food

Explain antimicrobial residue vs resistances

• Residue = conc of drug remaining the animal product after treatment

  • Withholding periods (WHP)

  • Export slaughter intervals (ESI)

  • MRL = max residue limit

• Antimicrobial resistance = a property of bacteria that allows them to grow in the presence of antibiotic levels that would normally suppress growth/kill susceptible bacteria

Explain withholding periods vs export slaughter interval

Withholding Period (WHP)	Export Slaughter Interval (ESI)
Time set by statue Must elapse between last admin of med and slaughter/collection of product for human consumption	Time that should elapse between treatment and their slaughter
Residue in treated product will not exceed MRL (max residue limit) Vary w species and route of admin	Management differences between MRL allowed for chemicals and trading partners Voluntary meat industry standard = not legislated

How can you minimise risk of antimicrobial resistance?

• minimise exposure to animals = good biosecurity

• limit exposure to antibiotics

• handwashing + gloves for all husbandry procedures

• protect animals from human pathogens (and visa versa = zoonotic!)

Adverse reactions from antimicrobials

• tissue necrosis at the inj site

• impairment of host immunity

• hepatic microsomal enzyme induction or inhibition (interfere drug metabolism)

• adverse reactions with other drugs

Factors to consider when choosing antimicrobial

• Identification of microorganism

  • Diagnosis - smear, gram stain, culture, sensitivity

  • Symptoms and clinical data

• Pharmacokinetic properties

  • balance susceptibility vs safe concentration

  • Size, interval, duration, distribution

  • administration, absorption, distribution, metabolism, excretion

    • hepatic metabolism = active metabolite

    • excretion in bile

    • excreted renally

    • Therefore kidney or liver disease = increased toxic risk

• Classification

  • broad vs narrow spectrum

  • bactericidal vs bacteriostatic

• Life stage

• Cost

  • treatment vs value of animal vs loss of product

• Toxicity or concurrent disease

• Adjunctive treatment or concurrent drugs

• Client compliance

  • communication and instruction, med, frequency

• Guidelines/antimicrobial stewardship

What are the labelling requirements for antimicrobials?

• Antimicrobial = Schedule 4 - prescribed by vet

  • Off label use = approved drug, but not in accordance w approved label directions

  • Label = “do not…” or “not to be used…” = limitations

  • Restraints = “DO NOT…” “NOT TO BE USED…” = absolute prohibition

• must include

  • name, address, telephone number of prescriber

  • date

  • “For animal treatment only”

  • species of animal, name and name+address of owner

  • name of drug, strength and form

  • dosage instructions for safe use

  • quantity to be dispensed

  • prescriber signature

What is antimicrobial failure?

• physical barrier

  • blood brain barrier

  • blood aqueous barrier (eye)

• inactived by pus or necrotic tissue

• inadequate immune response

• antimicrobial resistance

Administer for at least 72 hrs before therapeutic failure can be presumed

Beta-Lactam

• Eg = penicillin’s, cephalosporins and clavulanate

  • Penicillin = low systemic toxicity, causes vomiting, diarrhoea, hypersensitivity reactions and super infections

    • Never use in: G pigs, ferrets, rabbits, hamsters

    • Not oral in: horses

  • Cephalosporins = short half life <1hr, may cause hypersensitivity reaction, GIT upset

  • Carbepanems = widest range, only for serious or multi-drug resistance infections

• Method = inhibit cell wall synthesis by blocking bacterial enzymes (essential for building the bacterial cell wall)

• Bactericidal

• Spectrum = narrow and broad

• Pharmacokinetics

  • orally and parentally

  • bioavailability decreases with the presence of food

  • do no pass cellular blood brain barrier or aqueous barrier

  • excreted unchanged via kidneys

Classes of Penicillin’s and Clinical indications

1. Narrow spectrum penicillin

   • effective against Gram Positive bacteria + obligate anaerobes

   • most Staphylococcus pseudintermedius resistant

   • Clinical indications: clostridial disease, anaerobic infection, listeriosis, actinomycosis, Beta haemolytic streptococci, erysipelas

2. Narrow spectrum beta-lactamase resistant penicillin

   • effective against Gram Positive bacteria + obligate anaerobes

   • staphylococcus Beta-lactamase resistant

   • Clinical indications: staphylococcal skin infect, surgical prophylaxes, bovine mastitis, osteomyelitis, disconspondylitis

3. Broad spectrum beta-lactamase sensitive penicillin

   • broad, but more effective against Gram Negative bacteria

   • destroyed by beta-lactamases

   • Clinical indications: soft tissue infec, UTI, cat bite abscess, enteric infec, leptospirosis

4. Broad spectrum beta-lactamase sensitive penicillin with extended spectra

   • broad, but more effective against Gram Negative + anaerobes

   • Clinical indications: otitis externa, pseudomonas infect

5. Augmented penicillin

   • effective against Gram Positive + Negative bacteria, +most anaerobes

   • Clinical indications: Staphylococcus/ Pseudomona infections, skin, soft tissue, UTI, surgical prophylaxis

Aminoglycosides and Aminocyclitols

• Eg = gentamicin, neomycin, streptomycin, kanamycin, apramycin, spectinomycin

• Method = inhibit protein synthesis of 30s ribosomal unit

• Bactericidal

• Effective against = Gram negative and aerobic bacteria

• Pharmacokinetics

  • parenterally (companion animals) or orally (food producing)

  • not pass cellular blood brain or aqueous barrier

  • excreted unchanged via kidneys

• Clinical indications = septicaemia, peritonitis, resp and uterine infect, osteomyelitis, cystitis and mastitis

• Toxicity

  • nephrotoxicity if used more than 7 days

  • can be reversed with a antagonist (chloramphenicol, tetracyclines or macrolides)

  • do not use if dehydrated or impaired renal function

  • will cross the placenta = toxic to foetus

  • cats have increased sensitivity

Tetracycline

• Eg = chlortetracycline, oxytetracycline, tetracycline or doxycycline

• Method = Inhibit protein synthesis of 30s ribosomal subuni

• Bacteriostatic

• Spectrum = broad, effective against Gram Positive + Negative

• Clinical indications = E col, salmonella, atypical bacterial disease, common production animal disease

• Pharmacokinetics

  • food reduces absorption

  • not used in young animals

  • broad distribution in body tissues, but concentrated in liver

  • excreted unchanged via urine, and saliva/tears

• Toxicity

  • GIT upset

  • immunosuppressive

  • do not give rapidly IV

  • do no give in young or pregnant animals

  • may cause superinfections in horses

Amphenicols

• Eg = chloramphinicol or florfenicol

• Method = inhibit protein synthesis of 50s ribosomal subunit

• Bacteriostatic

• Broad Spectrum

• Pharmacokinetics

  • well distributed

  • excreted unchanged via urine

Chloramphenicol	Florfenicol
Clinical indications = irreversible, not in production animals. For eye or CNS infections	Clinical indications = reversible, okay for cattle pink eye, resp disease, foot rot, fish disease
Toxicity = bone marrow depression, anaemia (zoonotic), may cause vomiting and diarrhoea	Toxicity = bone marrow suppression

Macrolides and lincosamides

• Eg = erythromycin, tylosin, clarithromycin, lincomycin or clindamycin

• Method = inhibit protein synthesis by reversibly binding to 50s ribosome

• Bactericidal or Bacteriostatic (high doses)

• Effective against Gram Positive, Mycosplasma, Anaerobes (not Gram negatives)

• Clinical indications = hypersensitivity reactions, bone, joints, soft tissue, osteomyelitis, foot rot, pneumonia, mastitis, oral infections, resp disease

Macrolids	Lincosamides
Pharmacokinetics oral tablet → absorbed in GIT distributed widely concentrates in spleen, liver, kidney, lungs, milk metabolised by liver excreted via urine or bile	Pharmacokinetics oral tablet → absorbed by intestines distributed to most tissues (skin, bone, prostate, milk) metabolised by liver excreted via urine and bile
Toxicity vomiting, diarrhoea + colits not in adult horses or small herbivores irritating inj cardiovascular toxicity in cattle and humans - cautious avoid in pigs and goats	Toxicity diarrhoea in horses, ruminants, rats and G pigs avoid if pre-existing liver or kidney disease

Trimethoprim and Sulphonamides

• Method

  • Individually = inhibit synthesis of essential metabolites

  • Together = blocks enzyme in folic acid synthesis

• Sulphonamides = Bacteriostatic

• Trimethoprim = Bactericidal

• Broad Spectrum against Gram Positive + Negative, and anaerobes

• Clinical indications = coccidia, toxoplasma, chlamydia, prostate infections, kennel cough

• Pharmacokinetics

  • oral

  • widely distributed to all body tissues

  • will cross blood brain barrier and aqueous barrier

  • minimal effects to gut flora

  • antagonised by pus or necrotic tissue

  • metabolised by liver and renal excreted

• Toxicity

  • chronic use (2+ weeks) = urinary, blood and derm issues

  • cause hypothyroidism and lower T4

  • will pass placenta = toxic to foetus

  • avoid in dobermans, samoyeds and mini schnauzer

Fluorquinolones

• Eg = enrofloxacin, ciprofloxacin, marbofloaxacin, pradofloxacin

• Method = inhibits nucleic acid synthesis

• Bactericidal

• Broad spectrum = Gram Positive and Negative

• Clinical indications = not for food producing animals, good in exotics for urinary, skin and resp infections

• Pharmacokinetics

  • oral

  • lipophilic so penetrates kidney, liver, lungs, bones, joints, eye

  • excreted unchanged via urine

• Toxicity

  • cartilage damage in young animals

  • acute retinal degeneration in cats

Pradofloxacin

• Eg = Veraflox (Bayer)

• Bacteriostatic or bactericidal??

• Broad Spectrum = gram positive and negative bacteria, anaerobic

• Pharmacokinetics

  • absorbed via digestive tract

  • penetrates skin, soft tissue, urinary tract, gingiva, periodontal tissue

• Toxicity

  • only use for dogs/cats if poor response to other antimicrobials

  • not used if less than 1 yr

  • not used in breeding animals, pregnant or lactating

  • causes retinal degeneration in cats

Metronidazole or Imidazoles

• Method = damages DNA

• Bactericidal

• Narrow Spectrum = anaerobic bacteria and protozoa (Giardia)

• Clinical indications = anaerobic infections like acute gingivitis, periodontal disease, enteric/systemic anaerobic infections, Giardia, undiagnosed diarrhoea

• Pharmacokinetics

  • oral

  • absorption increased with food

  • highly lipophilic so penetrates tissues, bones, CNS, abscesses

• Toxicity

  • dose related neurotoxicity (ataxia, nystagmus, head tilt)

  • carcinogenetic = not in food producing animals

  • tetragenic (negative impact to embryo/foetus)

Griseofulvin

• Method = disrupts mitosis, nucleic acid synthesis and cell wall synthesis in susceptible fungi

• Anti-fungal

• Clinical indications = dermatophytes, microsporum, trichophyton

• Toxicity

  • cats increased risk of anorexia, vomiting, bone marrow suppression

  • tetragenic (negative impact to embryo/foetus)

Amphotericin B

• Method = alter cell membrane permeability

• Anti-fungal

• Clinical indications = most fungi will die

• Pharmacokinetics

  • must be IV

  • distribution is limited

  • excreted slowly unchanged via urine

• Toxicity

  • nephrotoxic

  • fever

  • vomiting

  • myalgia

  • anaphylaxis

Azole Antifungals

• Eg = ketoconazole, itraconazole, fluconazole, miconzaole

• Method = damage fungal cell membrane function

• Anti-fungal

• Clinical indications = dermatophytes and deep mycoses

• Pharmacokinetics

  • oral or topical

  • poor penetration to CNS

  • takes 14-21 days to reach stead state

  • metabolised by liver

  • excreted via urine

• Toxicity

  • vomiting and anorexia

  • hepatotoxicity (liver damage)

  • tetragenic (negative impact to embryo/foetus)