Pharmacology 4: Antibacterial agents for systemic therapy Flashcards
What do beta-lactam antibiotics include?
Penicillins
Cephalosporins
Carabapenems
-imipenem and meropenum
Monobactams
-aztreonam
What is beta-latam antibiotics mechanism of action?
Penerate the OUTER cell wall
Bind to and INHIBIT penicillin binding proteins (PBPs)
- Transpeptidase enzymes required for cross-linking of cell wall precursors
INHIBITION of cross-linking
- opens channels through the cell wall to create pores
- Allows fluid into the cell, causing cell swelling and DEATH
BACTERICIDAL
What are the general pharmacokinetics in beta-lactam antibiotics?
Low plasma protein binding
- distribute well to the EXTRAcellular fluid in most tissues
- EXCEPTIONS: cefovecin, ceftiofur
Hydrophilic
- minimalINTRAcellular concentrations
- do NOT distribute well to protected sites (CNS, eye, prostate)
Metabolism
- minimal
- EXPCEPTIONS: ceftiofur
Elimination
- glomerular filtration & tubular secretion
- VERY HIGH CONCENTRATIONS IN URINE!!! 1000X HIGHER THAN PLASMA!!!!
Short half-life and require frequent dosin
- EXCEPTIONS: cefovecin, ceftiofur crystalline free acid
Some PAE against gram + bacteria
- penicillin and streptococci
What are the pharmodynamics of beta-lactam antibiotics?
Time-dependent
-T>MIC 50% of the dosing interval
- minimum
- some people say 80%
– gram -
If immunosupprssed
-T> MIC 90-99%
-constant rate infusions
Benzylpenicillins 4 different kinds are?
Penicillin G
First beta-lactam
First penicillin
First antibiotic
What is Benzylpenicillin still effective against?
Streptococcus species
anaerobes (clostridia)
Gram - bacteria usually:
-e.coli, klebsiella, pseudomonas
What is Benzylpenicillin inactivated by beta-lactamases like?
Staphylococci +/-
Bacteroides fragilis (anaerobe)
What is the spectrum of Benzylpenicillins?
Gram +
streptococci ANAEROBES
Penicillin G routes and forms of drug?
Oral absorption limited
- degraded in gastric acid
IV formulations
-potassium or sodium salt
-human products expensive
IM/SQ formulations
-complexed with procaine or benzathine
-longer half-lives and be dosed less frequently
-veterinary products INEXPENSIVE
Penicillin G effect of formulation is on what?
we do NOT like this
PK
Efficacy
What species do we use Aminopenicillins FREQUENTLY?
CATS
dogs
Describe Aminopenicillins?
Drugs in class
- ampicillin
-amoxicillin
Good oral absorption in small animals
-BETTER amoxicillin
-ampicillin more IV/IM/SQ
Limited to NO oral absorption in large animals
INCREASED SPECTRUM AGAINST GRAM- BACTERIA
-LOWER UNIARY TRACT
-still maintain activity against gram+ and anaerobes
Extended spectrum penicillins
AKA carboxypenicillins
Drugs:
Ticarcillin
PIPERACILLIN
Carbenicillin
Reserved for highly resistant gram- bacteria and anaerobes
- Pseudomonas
Describe Anti-staphylococcal penicillins?
Drugs:
Methicillin
oxacillin
Little activity against gram- or anaerobic organisms
Methicillin (oxacillin) resistant staph. (MRSA/MRSP)
-bacteria reported resistant to oxacillin should be considered to be resistant to all other beta-lactam antibiotics
Are Anti-staphylococcal penicillins used clinically?
NO
What are the classifications for Cephalosporins?
1st generation
2nd generation
3rd generation
4th generation
Describe 1st generation cephalosporins?
Active against gram + bacteria, including some beta-lactamase + staphylococci
Includes:
- cefazolin
- has MOST activity against gram- bacteria
-cefadroxil
-cephalexin
- VERY commonly described to DOGS
Describe 2nd generation cephalosporins?
Greater activity against gram- bacteria
-in general
Activity against gram+ bacteria is similar
Includes
-cefoxitin
-cefotetan
-cefaclor
Describe 3rd generation cephalosporins?
MOST activity against gram- bacteria
Still retain activity against gram+
-lesser
-NOT used clinically - injudicious
Includes:
-ceftiofur
-cefovecin
-cefpodoxime proxetil
- human drugs
–> Ceftazidime and cefotaxime- Pseudomonas, CNS infections
Describe 4th generation cephalosporins?
Includes:
-cefepime
-cefquinome
- Broad spectrum
- Cefquinome is currently unavailable in Europe and UK for veterinary use
- Approval for BRD denied by FDA
RARELY USED IN VETERINARY MEDICINE (US) IN ANY SPECIES
What are the drugs to know Cephalosporins?
1st generation:
-CephAlexin
-CefAzolin
3rd generation:
-Ceftiofur
-Cefpodoxime proxetil
-Cefovecin
What are the 1st generation you need to know for Cephalosporins?
Cephalexin
Cefazolin
What are the 3rd generation you need to know for Cephalosporins?
Ceftiofur
Cefpodozime proxetil
Cefovecin
What species use Cephalexin?
dogs and cats
ORAL
How is Cephalexin used?
Orally for dogs and cats
FDA approved: Rilexene (chewable) $$$
Dermatitis cause by non-methicillin/oxacillin resistant staphylococci
What species use Cefazolin?
IV for dogs, cats, and SOMETIMES horses
How is Cefazolin used?
IV use
Extralabel use
Surgical prophylaxis
-administer within 60minutes of incision
-dose q90-120 minutes until wound closure
What is the species you use Cefpodoxime proxetil for?
Dogs
Cefpodoxime proxetil is prescribed for dogs but has been used safely in what other species?
Cats
Foals
What is Cefpodoxime proxetil used for?
Use in dogs (cats/foals)
-Skin and soft tissue infections
Longer half-life
-once daily dose
-better for owner compliance
PRODRUG
-ester improves oral absorption
What species use Cefovecin?
dogs and CATS
2# antibacterial in cats
What uses does Cefovecin have?
FDA approved treatment for skin infections in dogs and cats (convenia)
single SQ dose
Therapeutic for 2 weeks
Long half-life due to affinity protein binding!
What important to consider about long lasting antibiotics?
Once administered there is NO turning back
Effects persist longer (meaning ADVERSE effects too)
NOT fast acting
What species is Ceftiofur for?
FDA approved for
(dogs)
horses
chickens
turkeys
cattle
goats
sheep
swine
What is Cephalosporins used for?
Main Cephalosporin used systemically in LARGE ANIMALS
respiratory issues and foot rot
How many formulations does Ceftiofur have?
3 formulations:
Ceftiofur sodium (Naxcel)
Ceftiofur hydrochloride (Excenel)
Ceftiofur crystalline free acid (Excede)
How do you use Ceftiofur crystalline free acid?
Cattle
-single SQ dose at the base of ear
Swine
-single IM dose
Horses
-IM does and REPEATED once in 4 days
What is the extralabel use of Cephalosporins in food animals?
Prohibited by FDA in major food producing species
-Cattle
-Swine
-Chickens
-Turkeys
EXCEPTION: Cephaphrin
NOT prohibited in minor food producing species
-Sheep
-Goat
-Honeybees
-Fish
-Wildlife
What are adverse effects of beta-lactam antibiotics?
They are RELATIVELY RARE
-hypersensitivity reactions (anaphylaxis, IMHA)
- cross-reactivity between penicillins and cephalosporins may exist (15% of people)
-VERY high concentrations, can inhibit GABA
- cause CNS excitement and seizures
- can occur with other beta-lactams as well
-procaine reactions (NOT penicillin)
-GI effects
- dogs/cats
–> vomiting oral high dosages
- horses and rabbits
- high incidence of colitis with oral admin
Drug interactions with beta-lactam antibiotics
Aminoglysoides
-SYNERGISM
-INACTIVATION
- chemical inactivation when mixed (do NOT precipitate)
- Does NOT happen in vivo (diluted by plasma)
What are the mechanisms of resistance for beta-lactam antibiotics?
1 ENZYME MEDIATED DEGRADATION
Methicillin-resistance
-mediated via the MecA gene
- encodes for penicillin binding protein 2a (VERY low binding affinity for all beta-lactam antibiotics)
-RESISTANT TO ALL BETA-LACTAMS
- includes carbapenems and monobactams
Reduced penetration of drug into bacteria
-gram- capsule
-altered or reduced number of porins
- channels the antibiotics can use to cross cell membranes
-bet-lactamases
-penicillinases
-cephalosporinases
-carbapenemases (BAD)
-other
What are the beta-lactamase inhibitors?
Clauvulanic acid
Sulbactam
Tazobactam
What is the mechanism of action for beta-lactamase inhibitors?
Combine with beta-lactanmase enzymes to form an inactive coplex
- gram- and gram+ bacteria
Co-administed antibiotics is then able to exert its effect
Also bind to different PBPs
- bactericidal effects
- NOT sufficient to ever administer ALONE
What are formulations combined with a beta-lactamase inhibitor?
Amoxicillin + clavulanic acid (Clavamox)
Ampicillin + sulbactam (NOT absorbed orally) (Unasyn)
Ticarcillin + clavulanic acid (Timentin)
Piperacillin + tazobactam (Zosyn)
KEY CONCEPT
Beta-lactams are what?
Time dependent
Bactericidal
Cell wall inhibitors
RENAL ELIMINATION
Hydrophilic (confined to plasma and ISF)
Synergistic when combined with aminoglycosides
SAFE! Hypersensitivity and mild GI
Some inactivated by beta-lactamases (unless combined with beta-lactamase inhibitors)
ALL INACTIVATED BY
MecA methicillin resistance
KEY CONCEPTS
Penicillin G
Streptococci and anaerobes
Susceptible to beta-lactamases
Inadvertent IV injection of procaine penicillin causes severe procaine reaction
Benazathine formulations do NOT reach therapeutic concentrations
KEY CONCEPTS
Aminopenicillins
Steptococci and anaerobes
Increasing gram- spectrum
Susceptible to beta-lactamases unless combined with a beta-lactamse inhibitor
-amoxicillin + clavulanic acid
- ampicillin + sulbactam
Amoxicillin + clavulanic acid (CLAVAMOX) =
#1 antibiotic to DOGS
#2 antibiotic to CATS
