Antimicrobials

Bactericidal

drug that kills bacteria independent of host immune function

Bacteriostatic

drug that inhibits bacterial growth without killing them. immune system can then more rapidly eradicate the non-multiplying bacteria

Time dependent AMDs

antimicrobials whose effectiveness depends on the duration of exposure to the drug rather than the concentration.

• efficacy is associated with length of time drug conc remains above Minimum Inhibitory Concentration (MIC)

• levels should remain above MIC throughout course of therapy

Time dependent AMD groups

beta-lactams, tetracyclines,TMS, macrolides

Concentration dependent AMDs

are antimicrobials whose effectiveness is primarily related to the peak concentration achieved in the body. Higher concentrations lead to a more effective bacterial kill.

• efficacy depends on peak conc

• not necessary to maintain levels above MIC for the entire interval between doses

Conc dependent examples

Aminoglycosides, fluoroquinolones, metronidazole, azithromycin

Why do we not give antimicrobials to ruminants?

Antimicrobials can disrupt the normal gut flora of ruminants, leading to digestive issues and resistance development. Affect the fermentation process essential for ruminant digestion.

Why do we not give antimicrobials to hind-gut fermenters?

toxins are lethal to the beneficial gut microbiota, disrupting digestion and nutrient absorption

What bacteria are sensitive to Penicillin G?

Gram + aerobes, Anaerobes

MOA: Inhibit cell wall synthesis

Beta-lactams

MOA: Inhibition of protein synthesis

Aminoglycosides, tetracyclines, macrolides

MOA: Damage to DNA

Fluoroquinolones

MOA: Inhibition of folic acid synthesis

Sulfonamides

MOA: Damage to plasma membrane

Many antifungals

How do we perform a Kirby-Bauer test?

In the Kirby-Bauer test, inoculate a Mueller-Hinton agar plate with the bacterial isolate, place antibiotic disks on the surface, incubate at 35-37°C for 18-24 hours, and measure zones of inhibition.

Results of the Kirby-Bauer test

Results indicate bacterial sensitivity or resistance to antibiotics based on the size of the inhibition zones: larger zones suggest sensitivity, while smaller zones indicate resistance.

What to do if your antibiotic treatment is not working?

1. cytology & knowledge of the most common pathogens

2. Culture & Sensitivity testing

   1. Life threatening infections

   2. Non-critical resistant infections

When selecting a drug what should we consider?

• Bacterial sensitivity → want narrow spectrum and ones that avoid for commensal bacteria

• Bacteriostatic vs. bactericidal

• Adverse effects → outweigh likely adverse effects

• Distribution → make sure drug gets to site of infection

• Cost

When should we use antibiotic when there is no infection?

• Osteomyelitis → avascular bone fragments

• Foreign body

• Implants

If an abscess is localized with no pyrexia or neutrophilia, do we need to give systemic antibiotics?

May not be needed - give if suspicious that bacteria have traveled

What are some intracellular pathogens?

Mycobacterial, salmonella, legionella

• requires drug that enters the cells

When could we need drug dose higher than normal or for longer?

Dysfunction host defense

When do we use prophylactic antibacterials?

• high risk following trauma

• patients conditions

• surgery → opening GI, head & neck, joint, c-section, thoracic

Beta-Lactam class

Penicillin - related to Cephalosporins

• ring kills the bacteria

• -cillin

• effective growing bacteria

• warming or freezing can destroy BL ring

• very safe

• resistant bacteria have: penicillinase or beta-lactamases

What bacteria are killed by Penicillins?

• Gram + → due to unprotected peptidoglycan layer

Pharmacokinetics of Penicillins

• distribute well to extracellular fluids everywhere (not CNS & prostate)

• Acids stability varies

• Short half-life

• Elimination: no metabolism → excreted intact in urine → renal excretion of unaltered drug → good for bladder infections

What are the most common adverse effect of Penicillins

1. Hypersensitivity → mild to anaphylactic, if allergic to 1 then allergic to them all

2. Colitis in hindgut fermenters → do not give orally

3. Breakthrough seizures in epileptics → beta-lactams inhibit GABA in the brain → inc excitability

What bacteria are resistant to Penicillins?

Gram -

→ they have penicillinase, plasma encoded can be transferred to other bacteria

What bacteria are sensitive to Penicillin G?

• Gram + aerobes

• Anaerobes

• Sodium

  • 30 min half life

• Procaine

  • depot formulation → slower release, longer action

• Not acid stable

What bacteria are sensitive to Amoxicillin?

• Gram + aerobes

• Anaerobes

• Slight Gram - aerobes (enterobacteriaceae)

• oral bioavailability 90%

• Penicillinase inhibitor: clavulanic acid + amoxicillin

  • clavamox

Health Canada prudent use stance for Penicillins

First line: Penicillin G, Amoxicillin

Second line: Potentiated penicillins

How are Cephalosporins different from penicillins?

• Most are not acid stable → not effective if administered orally

• Gram - aerobes

• drugs enter CNS reasonably well

• drugs metabolized

• more resistant to beta-lactamases

• less likely to cause allergic reactions in patients with penicillin allergies

What bacteria will 1st generation Cephalosporin act against?

• Gram + aerobes

• Anaerobes

• Gram - aerobes

First line

What is a common oral cephalosporin?

Cephalexin

What are some common parenteral cephalosporins?

• Cefazolin → surgical prophylaxis

• Cephapirin → IM cattle

What bacteria will 3rd generation Cephalosporin act against?

• Gram - aerobes (enterobacterial)

• Gram + aerobes

• Anaerobes

Ceftiofur → resp infection, foot rot, metritis, UTI

Second line

Cefovecin (convenia)

SQ inj

• skin & resp infections in dogs and cats

• very long half-life → 2 weeks formulation

  • not good for infections that will be resolved in a few days

  • inappropriate use for short-term

• Cefpodoxime proxetil might be better second line drug use

Adverse effects with cephalosporin

• hypersensitivity

• oral may cause colitis in hindgut fermenters

• reduction of seizure threshold

PK features of cephalosporin

• few are acid stable

• not destroyed by penicillinases but may be beta-lactamases

• some 3rd gen drugs enter CNS readily

How can we use Aminoglycosides?

-micin, -mycin

• Topical → First line, Staph

• Systemic → Second line, for dangerous Gram - aerobic infections, life-threatening conditions

• atypical → mycoplasma

Highly ionized → limited ability to cross membranes, negligible oral or topical absorption

What is the most common Aminoglycoside?

Gentamicin → given parenterally

MOA of aminoglycosides

Inhibit bacterial protein synthesis → inhibition is incomplete → cause wrong AA to be place in growing protein → act as lethal porins → kills bacterial cell

What bacteria do Aminoglycosides affect the best?

• Gram - aerobe

• Gram + aerobes → Staph (MRSA/MRSP)

• Atypical bacteria → mycoplasma

Why are aminoglycosides ineffective against anaerobes?

entry of drug requires oxygen → absent in anaerobes → do not use for anaerobe bacteria

What are resistant to aminoglycosides?

• Anaerobes

• Plasmid ac

What are the main adverse effects of Aminoglycosides?

1. Nephrotoxicity → do not give to patients that are dehydrated or has renal disease

   1. Neomycin is the worst

   2. AGs accumulate in renal tubular cells → enhance free-radical formation → damage some renal tubular epithelial cells in every patient

2. Ototoxicity → damage to CNVIII & hair cell in cochlea & vestibular apparatus

   1. can cause hearing loss

   2. before putting it in the ear, ensure the tympanum is intact

Why should we not give aminoglycosides in two dose instead of one big dose?

Pump does not work very fast → the same amount of drug will be taken up regardless of initial dose → one big dose is safer, allows washout period

Can we give IM aminoglycosides to food animals?

NO → IM use of gentamicin in cattle may result in drug residues detectable for > 1yr

What are second line Aminoglycosides use for infections after gentamicin does not work?

• Tobramycin

• Amikacin → resistant to many aminoglycosides

What are Tetracyclines used to treat?

atypical bacteria(Rickettsia, Chlamydia, Mycoplasma) in all species → good for livestock

-cycline

MOA of tetracycline

Binds to bacterial ribosomes → inhibit to protein synthesis → bacteriostatic(does not kill, stops bacteria production)

What bacteria do Tetracyclines target?

Small → Atypical bacteria

Large → Atypical bacteria, Gram + & - aerobes, Anaerobes

Absorption of Tetracycline

• Divalent cations in food can inhibit oral absorption → cannot give this drug with food

• oral bioavailability is low → doxycyline has better bioavailability than most other tetracyclines

Distribution of Tetracycline

• Good for extracellular fluid compartment (not CNS) does not work for intracellular bacteria (except doxycycline)

• Lipid solubility → doxycycline is most lipid sol → enters host cells well including prostate & CNS

• They bind to multivalent cations like calcium, become incorporated into growing bone and teeth

• Food animal residue concern

Elimination of Tetracycline

• excreted primarily by glomerular filtration in Urine

• doxycycline metabolized in liver → not good for UTI → eliminated almost entirely through the intestinal tract into feces

What are the 2 common resistances bacteria have against Tetracycline?

1. Efflux pump → removes drug from bacterial cell, can get overwhelmed with high drug concentration

2. Ribosomal protection protein

What are adverse effects of Tetracycline

• Incorporation into growing bone & teeth → food animal residue

• Nephrotoxicity → do not give to dehydrated animals

• Tissue irritation → very painful to administer and may vomit with oral administration

• Esophageal lesions from doxycycline in cats → pill is too big → esophageal lesion & strictures in cats

Why do we combine other drugs with Sulfonamides?

Creates a formula that is a bactericide, sulfonamide alone does not kill the bacteria → TMS (trimethoprim sulfonamide)

MOA of Sulfonamides

Inhibit the synthesis of folic acid in the bacteria by binding to dihydropteroate synthetase → do not use these drugs for pus

What bacteria do Sulfonamides target?

Small → Atypical bacteria

Large → Atypical bacteria, Gram + & - aerobes, Anaerobes

Used in humans and small animals for sporadic bacterial cystitis where high concentration of drug in urine overwhelms resistance mechanisms → used for bladder infections

Absorption & distribution for Sulfonamides

• good oral absorption

• distributes well to all tissues

• pus reduces efficacy → don’t use

Elimination of Sulfonamides

• renal excretion and hepatic metabolism

• renal damage severe in dehydrated patient

Resistance to Sulfonamides

Bacteria can encode plasmid encoded proteins to block drug site

Adverse effects of Sulfonamides

• Allergenic than most drugs

• Cause dry eye in dogs → They destroy lacrimal tissue in dogs → KCS(keratoconjunctivitis)

• Nephrotoxicity in dehydrated patients

What drug classes cause Nephrotoxicity?

DO NOT give to dehydrated animals!!

Sulfonamides, Tetracycline, Aminoglycocides(will always cause renal toxicity, only give to animals that will die without it)

What are the safest class of antibacterials to use?

Macrolides → they sting very badly though

Pharmacokinetics of Macrolides

• penetrate cells very well

• concentrate in lung & lung macrophages

• have long half-lives (erythromycin have short half life)

• weak bases

-osin or -mycin

MOA of Macrolides

Inhibit protein synthesis → bacteriostatic effect → bactericidal if conc high enough

What bacteria do Erythromycin target?

Broad spectrum → First line

• Gram + aerobes

• Anaerobes

• Gram - aerobes

• Atypical

If you have an animal that has a lung infection and is known to be intracellular, what drug class do we use?

Erythromycin → Macrolides

What enzymes does Erythromycin inhibit?

P450 → other drugs administered might accumulate and cause problems

Stimulate motilin receptors

What bacteria do Macrolides target?

Second line

• Gram - aerobes → most effective

• Gram + aerobes

• Anaerobes

• Atypical

Longer half life → bacterial pneumonia

What is Tilmicosin used for?

Macrolides

• beef, lambs, rabbits

• bacterial pneumonia

• Gram - aerobic lung pathogens

• DO NOT GIVE IV

• do not give sc to swine

What is Tulathromycin/Gamithromycin used for?

Macrolides

• bacterial pneumonia

• Gram - aerobic

What do bacteria have that cause resistance to Macrolides?

Plasmid encoded efflux pump

Adverse effects of Macrolides

• Tissue irritation → IM pain, vomiting w/ erythromycin

• Oral toxicity in herbivores → fatal rumen stasis, colitis in hindgut fermenters

• Tilmicosin can cause rapid cardiac fatalities when given parenterally

Where do we use Fluoroquinolones?

Second-line use → use when other drugs have failed

• Small animals & exotics (some in horses and food animals)

• High oral bioavailability, long half life, good tissue penetration

What are some Fluoroquinolones?

-floxacin

• Enrofloxacin

• Orbifloxacin

• Marbofloxacin

• Difloxacin

• Danofloxacin

MOA for Fluoroquinolones

Damage DNA → inhibit DNA gyrase & topoisomerases → bactericidal effect

What bacterial do Fluoroquinolones target?

• Gram - aerobes

• Atypical bacteria

• Gram + aerobes → staph

Absorption of Fluoroquinolones

well absorbed orally by monogastrics → close to 100% bioavailability

Distribution of Fluoroquinolones

Goes well to the lungs, and most other tissues including the prostate

Poor CNS, skin distribution

Elimination of Fluoroquinolones

Depends on the drug → long half life

Adverse effects of Fluoroquinolones

1. Cartilage damage → young animals are highly sensitive → do not give to puppies and foals

2. Retinal degeneration in cats → high doses

3. Can trigger seizures in epileptics → FQ inhibit NT GABA

Resistance to Fluoroquinolones

• sudden & stable due to mutations in bacterial DNA gyrase/topoisomerase

• some bacteria can be resistance to one or all FQ

• plasmid born mechanisms

What can Chloramphenicol cause in humans?

Fatal idiosyncratic aplastic anemia in humans

• not dose related

• genetic predisposition

• can develop weeks after therapy

• Banned in food animals

What category should we not use in vet med?

Category 1

What drugs does health canada say to use?

Tetracyclines

What antibiotics should we avoid using when possible?

Fluoroquinolones, Potentiated Penicillins, 3rd gen Cephalosporins

What are some examples of AMDs use in general practice?