Antimicrobial Use in Lung Infections: Part 1 (Week 3, Mod 9)

REMEMBER: Not every antimicrobial is an antibiotic!!

• Antimicrobial = synthetic

• Antibiotic = naturally produced

What are the 5 different bacterial characteristics that antimicrobials target?

1) Cell Wall

• Beta lactams and glycopeptides

2) Plasma membrane

• Polymyxins

3) Ribosomes

• Aminoglycosides and tetracyclines

  • 30S subunit

• Macrolides, lincosamides, chloramphenicol

  • 50S subunit

4) Metabolic pathways

• Sulfonamides

  • Folic acid synthesis

• Mycolic acid synthesis

  • Izoniazid

5) DNA Synthesis

• Fluoroquinolones

What are the 4 main antimicrobial classes that disrupt protein synthesis in bacteria? What exactly is the target for each class?

• Tetracyclines - bind to the 30S ribosomal subunit; blocks the binding of tRNAs, inhibiting protein synthesis

• Aminoglycosides - bind to the 30S ribosomal subunit; impairs PROOFREADING of mRNA, resulting in the production of faulty proteins

• Chloramphenicol - Binds to the 50S subunit, preventing peptide bond formation and stopping protein synthesis

• Lincosamides and Macrolides - Same ^

**act on the bacterial ribosome which is different from that of vertebrates (selective toxicity)

Describe tetracyclines… in what animal are they most commonly used? What about their structure makes them good “chelating agents”?

Tetracyclines are the MOST common antimicrobial

• Used mainly for large animals (namely cows)

Are great chelating agents due to their structure (for aromatic rings)

• Chelating = binds to metallic ions (i.e. calcium, magnesium, etc.)

  • 4 - ringed structure wraps around these ions and prevents them from being available for bacteria

What 3 types of tetracyclines are “short acting”?

Tetracycline

Chlortetracycline

Oxytetracycline

Can be modified to be long acting…

What two types of tetracyclines are long acting?

DOXYCYCLINE

Minocycline

Are tetracyclines bactericidal, or bacteriostatic?

BacterioSTATIC… binds reversibly to bacterial ribosomes, inhibiting bacterial protein synthesis

• Because of this, more effective against actively multiplying bacteria (not dormant)

Initially diffuse across the outer cell membrane, and are taken up by susceptible bacteria

Describe tetracycline’s spectrum of activity… what kinds of bacteria can they target?

BROAD spectrum of activity

• Against both aerobic and anaerobic Gram-negative

  • Pasteurella multocida and Mannheimia haemolytica - BRD; Bordetella bronchiseptica

• AND Gram-positive

  • Streptococcus, Staphylococcus, Enterococcus spp., and intracellular (Rhodococcus equi) bacteria

  • Mycoplasma

  • Chlamydia spp., rickettsiae

May also bind to mammalian ribosome and cause adverse effects

• Not great selective toxicity

Describe the mode of action of tetracyclines… what subunit of the ribosome does it bind to? What effect does this have?

Binds REVERSIBLY to the 30S subunit on its Acceptor (A) Site (see image)

• Blocks the binding of aminoacyl - tRNA to the mRNA-ribosome complex, preventing elongation of the peptide chain

• Prevents it from growing / multiplying = bacteriostatic

Describe the pharmacokinetics of the tetracyclines… how is it usually administered, and why? Which tetracyclines are the exception?

Is usually given IV or IM

• Oral absorption and bioavailability is low, ESPECIALLY in horses and ruminants

  • SHOULD NOT be given to ruminants… can suppress ruminal microflora

• Oral absorption is further lowered by food due to chelating nature of the med

EXCEPTION!!!!

• Doxycycline and minocycline

  • Are more lipid soluble; absorb in the small intestine and reach effective blood conc. within 2-4 hrs

  • Easily absorbed into tissues and bodily fluids

    • CAN penetrate the BBB and get into CSF

    • Can also cross placenta and be secreted in milk, so milk-producing patients need to have a withdrawal period before selling products again

How are chlortetracyclines and oxytetracyclines metabolized in the body? What does this mean in terms of dosing?

Metabolism is MINIMAL

• Excreted unchanged in urine (mostly) and bile

Undergo SOME enterohepatic recirculation (concentrated in liver and excreted in bile, some reabsorbed from there)

• Increases the half life → PO administration q 8-12 hrs

How are doxycyclines and minocyclines metabolized and excreted from the body? What does this mean in terms of dosing?

Are more lipid soluble and have good absorption after oral administration… calls for less frequent dosing

• q 12-24 hrs

Minocycline: some metabolism and excreted in bile / feces

Doxycycline: NO RENAL EXCRETION

• Good for patients with renal impairment

• Eliminated mainly through feces

Which classes of tetracyclines should not be given to HORSES, and why?

Doxycyclines and Minocyclines

• Enter the intestine via bile and direct diffusion; may cause severe problems in horses

  • PO → severe diarrhea - broad spectrum, so can get rid of good gut flora

  • Rapid IV inj → hypotension → sudden collapse

    • Tetracyclines can chelate calcium, which can cause a rapid drop in available calcium that the heart needs to beat

    • Can be mitigated by slow IV injection

  • Slow constant IV infusion of DOXY → cardiovascular issues

    • Tachycardia, arrhythmia, systemic arterial hypertension

    • All leads to collapse and death in the horse

What are some things you could see in cases of tetracycline toxicity? (hint: some have already been covered)

GI disturbances and broad-spectrum suppression of ruminant intestinal flora

• Can lead to super-infection with resistant bacteria (and fungi and yeasts), and stasis

• In horses (after oral administration) - severe and sometimes fatal diarrhoea

Idiosyncratic liver damage in some animals if there is renal impairment

Renal tubular damage (storage)

Occasional sudden collapse when given rapidly via IV

• Give very slowly, > 5 min or pretreat with calcium gloconate, due to chelation of ionised calcium

Tetracyclines chelate Ca²⁺ ions → they are irreversibly deposited at active sites of ossification in the growing bones and in teeth (dentin and enamel of unerupted teeth)

Photosensitivity

Hepatotoxic due to large doses, especially in pregnant animals

What are 6 main clinical benefits to utilizing tetracyclines?

1) Broad spectrum (aerobic / anaerobic, G+ / G-, local / systemic)

2) Low cost

3) Easy administration

4) Treats unknown causative microorganisms

• Due to broad spectrum nature, if you are unable to narrow down the exact bacteria causing an infection, tetracyclines are a good umbrella treatment

5) Useful in mixed bacterial infections

6) Dox and Min → anti-inflammatory properties

What are the 5 indications of use for tetracyclines in cattle?

• Respiratory infections in calves

• Bovine pneumonia (in feedlots; in feed)

• Anaplasmosis

• Infectious keratoconjunctivitis

• Parenteral administration for serious udder infection 

What are the 4 indications of use for tetracyclines in sheep?

• Q fever (Brucella)

• enzootic abortion (Chlamydophilla abortus)

• prevents Pasteurella haemolytica pneumonia

• Can also be given with streptomycin for Brucella ovis.  

What are the indications of use for tetracyclines in pigs?

Prevent and treat atrophic rhinitis and lower respiratory tract disease,

eradicate leptospirosis. 

What are the 4 indications of use for tetracyclines in cats and dogs?

• Urinary tract infections 

• Ehrlichia canis, Rickettsia rickettsii infections

• Otitis externa

• Chlamydial infection in cats: upper respiratory tract and conjunctiva 

What are the indications of use for tetracyclines in poultry?

Prevention and treatment of enteric and respiratory infection

• Largely administered in feed

Describe the structure of macrolides… what 3 different classifications  come from the different variations of this structure?

Macro = large macrocyclic lactone

Classifications are according to the size of the macrocyclic lactone ring

• 14 membered ring → Erythromycin

• 15 membered ring → Azithromycin, clarithromycin

• 16 membered ring → Ketolides (spiramycin, tylosin, tilmicosin)

What is the mechanism of action of macrolides?

Reversibly bind to the 50S subunit of the ribosomes

• Bind to the donor site, blocking the translocation step

• Leads to inhibition of peptide elongation

• DOES NOT BIND to mammalian ribosomes

What are the 3 different resistance mechanisms that bacteria can implement to resist macrolides?

1) RNA methylation

2) Efflux of the medication

3) Enzymatic inactivation (ex: enzyme esterases)

Describe the spectrum of activity of macrolides… are they bactericidal or bacteriostatic?

Moderate spectrum

• Mainly G+ and some G- (Pasteurella spp.)

  • Most G - are INHERENTLY RESISTANT due to the reduced permeability of their outer membrane

• Mycoplasms

• Some rickettsiae

• *** Useful in the treatment of respiratory infections (Pseudomonas aeruginosa)

Are bacterioSTATIC

Describe the pharmacokinetics of macrolides… how do they distribute through the body?

HIGH PPB (90%) and broad diffusion into bodily fluids

• Does NOT cross BBB, and diffuses poorly into synovial fluid

Actually enters and concentrates in WBC phagocytes - advantageous

• Ensures the antimicrobial is transported directly to the site of infection

Concentrates in the liver

In particular, what are the pharmacokinetics behind erythromycin? How readily is it absorbed, and why?

Is well absorbed orally, but is unstable in gastric acid

• Due to being a weak base; can be ion-trapped in acidic fluids

Food lowers oral absorption, but does prevent GI side effects

Is readily absorbed from the GI tract and has high lipid solubility

• Is well distributed through tissues; crosses the placenta and can enter milk

Is erythromycin toxic? If so, what are some of its side effects?

Erythromycin is one of the SAFEST antimicrobial drugs

• Administered IM in cats and dogs

• PO in poultry

• Intramammary in cattle

Can be an irritant based on how its administered

• PO or IV → thrombophlebitis, periphlebitis

• IM → severe pain

• Intramammary → inflammatory reaction

• GI disturbances

Tilmicosin is a class of macrolide… what is one thing that needs to be taken into consideration before using this medication for treatment?

Concentrates in tissues, PARTICULARLY in the lungs

• Can cause rapid depletion of calcium and lead to heart problems if given too quickly / accidentally injected into yourself

• Can be FATAL

Commercial name - Micotil

What are the clinical uses of the common macrolides? (Erythromycin, Micotil, Spiramicin)

Macrolides are often used as an alternative to penicillin in allergic patients

• Erythromycin is the drug of choice for Campylobacter jejuni and Mycoplasma infections

  • Chronic respiratory disease (CRD) due to Mycoplasma in birds (chickens)

• Micotil used for respiratory diseases in pigs, cattle, and poultry

• Spiramicin used synergistically with metronidazole for periodontal infections in dogs and cats

In general, though, macrolides are used for respiratory infections, skin / wound infections, and GI infections in companion animals

• Mastitis in cows

• Pneumonia and dysentery in pigs, cattle, and poultry

What is an example of an ADVANCED generation macrolide? What are its benefits?

Use: bovine and porcine respiratory disease

• Details: semisynthetic macrolide, a triamilide

Given SC (cattle), IM (pigs); high distribution within 30 min with slow elimination

• Improved Gram-negative spectrum

• High concentrations in lung tissue; in neutrophils and alveolar macrophages. Lung elimination time in cattle and swine is 6-7 days

• Withdrawal times 22 days (cattle), 13 days (pigs), 16 days (sheep)