Antimicrobials 2 Flashcards
definining molecular structure of the ‘penicillins’
beta lactam ring
* Confers activity B
* Destroyed by enzymes secreted by some bacteria: “penicillinases” or “beta-lactamases”
* Temperature labile; warming or freezing can destroy the BL ring
penicillins are only effective against what kind of bacteria?
growing
mechanism of action of penicillins?
inhibit cell wall synthesis
Beta lactams covalently bind to & inactivate the transpeptidase enzyme
Defective cell wall > as cells divide, they lyse & die
what kind of bacteria do penicillins work best against and why?
Penicillins tend to work best against Gram-positive bacteria, which have a thick, unprotected peptidoglycan layer
In Gram-negative bacteria:
* Binding sites are different on transpeptidases
* External bilayer can be difficult to penetrate
* Some bacteria secrete penicillinases into the periplasm
penicillins pharmacokinetics
- Distribute well to extracellular fluids everywhere except CNS & prostate (unless inflamed), poor penetration into cells > low Vd
- Acid stability varies; some cannot be given orally due to acid hydrolysis
- Short half-lives (≤ 2 h)
- Elimination: No metabolism; renal excretion of unaltered drug
Main Adverse Effects of penicillins
1) Hypersensitivity
* Mild allergy to anaphylactic reaction
2) Colitis in hindgut fermenters
* Oral penicillins can disturb gut flora
3) Breakthrough seizures in epileptics
* Beta-lactams inhibit GABAa receptors in the brain > increases neuronal excitability
penicillins resistance profile and reasons
Fairly common
- Poor penetration of complex Gram-neg. cell wall
- Acquired bacterial penicillinases
- Plasmid-encoded > can be transferred to other bacteria
Penicillin G: spectrum, excellent against what type of bacteria, half-life, administration strategies, stability
Narrow spectrum Excellent against:
* Gram-positive aerobes
* Anaerobes
- Sodium salt has 30 min half-life > admin. frequently, or use a depot formulation
- Depot formulation consists of penicillin bound to a molecule such as procaine or benzathine > penicillin gradually dissociates from procaine at IM or SC injection site > longer duration of action
- Penicillin G is not acid stable, must be administered parenterally
amoxicillin: spectrum, what bacteria it is effective against
Example of an extended spectrum penicillin
- Gram-pos. aerobes, anaerobes, plus a variety of Gram-neg. aerobes, especially Enterobacteriaceae
- Activity against Gram-pos. aerobes & anaerobes is generally less than that of penicillin G
- Oral bioavailability exceeds 90%
what is ampicillin and its uses?
similar drug to amoxicillin but mainly used parenterally because of poorer oral bioavailability
>but this means more remains in GI tract > GI upset more likley
what is potentiated penicillin
Bacterial penicillinases can be inactivated with penicillinase inhibitors such as clavulanic acid
> called a “potentiated penicillin”
Penicillins Flash Card: mechanism of action
Inhibition of cell wall synthesis
Penicillins Flash Card: Main adverse effects
- Hypersensitivity
- Contact dermatitis risk > not used topically
- Potentially fatal colitis in hindgut fermenters (oral admin.)
- Reduction of seizure threshold
Penicillins Flash Card: general spectrum
- Penicillin G: Gram-pos. aerobes, anaerobes
- Amoxicillin: Same as pen G, plus several Gram-neg. aerobes
Penicillins Flash Card: Health Canada prudent use stats
First line: Penicillin G, amoxicillin Second line: Potentiated penicillins
Penicillins Flash Card: PK features
Excreted intact in the urine
Penicillin G is not acid-stable
Oral bioavailability of amoxicillin is ~90%
what drug class are the cephalosporins similar to? in what ways?
Similar to penicillins:
* Mech. of action
* Distribution
* Elimination
* Main adverse effects
what route of administration is not good for cephalosporins and why?
- Most are not acid stable > cannot be given orally
if an animal has a penicillin allergy will cephalosporins be safe?
About 5% of humans with a penicillin allergy are also allergic to cephalosporins > avoid in an animal with a penicillin allergy to be safe
3rd gen cephalosporins enter what hard to reach tissue reasonably well?
CNS
1st gen cephalosporins spectrum of activity
1st generation: Similar to amoxicillin
>Mainly Gram-pos. aerobes, + anaerobes, plus some medically important Gram-neg. aerobes
3rd gen cephalosporins spectrum of activity
- Less activity against Gram-pos. & anaerobic bacteria but better against Gram-neg. aerobes
cephalexin is what type of drug? usaed mainly in what animals?
1st gen cephalosporin, used mainly in small animals
ceftiofur is what type of antibiotic? mainly used for what?
3rd gen cephalosporin
resp. infections in livestock & horses; foot rot & metritis in cattle; UTI in dogs, etc.
Cefovecin is what type of drug? what is a drawback?
3rd gen cephalosporin
o 2-week formulation essentially guarantees inappropriate duration of therapy in most patients
>veterinary surgeons prescribing cefovecin rarely justified its use
Cephalosporins Flash Card: mechanism of action
Inhibition of cell wall synthesis
Cephalosporins Flash Card: main adverse effects
- Hypersensitivity
- Potentially fatal colitis in hindgut fermenters (oral admin.)
- Reduction of seizure threshold
Cephalosporins flash card: general spectrum
- First gen.: Similar to amoxicillin
- Third gen.: A mix, but mainly Gram-neg. aerobes
Cephalosporins flash card: health canada prudent use stats
First line: First generation
Second line: Third generation
cephalosporins flash card: PK features
Only a few are acid-stable (e.g., cephalexin)
Not destroyed by penicillinases, but may be inactivated by some “beta-lactamases”
Some third-gen drugs enter CNS readily
what are the major types of beta-lactams? scope of effect?
Penicillins
-penicillin G: Gram positive aerobes, anaerobes
-amoxicillin: Gram positive aerobes, anaerobes, some gram negative aeroboes
Cephalosporins
-1st gen: Gram positive aerobes, anaerobes, some gram negative aeroboes
-3rd gen: gram negative aerobes, some grame pos aerobes, some anaerobes
two main uses for aminoglycosides
1) Systemic for severe Gram-neg. aerobic infections
2) Topical (e.g., for Staph)
do aminoglycosides cross cell membranes well? why?
limited ability to cross membranes > highly ionized
best route of administration for aminoglycosides
must be given parenterally for systemic treatment
-oral absorption only ~3%
most used drug in the aminoglycosides group
gentamicin
aminoglycosides mechanism of action
Inhibit bacterial protein synthesis by binding to bacterial ribosomes
AGs cause wrong AA to be incorporated into growing protein
> these can form lethal porins
> kill bacterial cell
spectrum of activity for aminoglycosides
Gram-neg. aerobes
+ Staph (including MRSA/MRSP)
+ Mycoplasma
resistance considerations for aminoglycosides:
1) Constitutive: Entry of drug into cell requires oxygen-dependent transport system
> AGs are therefore ineffective against anaerobes
2) Plasmid-acquired: Aminoglycosidase
mechanism of aminoglycosides nephrotoxicity?
1) NEPHROTOXICITY
- AGs are eliminated by filtration into the urine intact
- AGs enhance free-radical formation following accumulation in renal tubular cells > damage some renal tubular epithelial cells in every patient
- Proximal renal tubular epithelium regenerates well > usually not a problem (i.e., as long as cell loss is not extensive)
- Ordinary dose can be very damaging to kidneys of dehydrated patients & patients with renal disease (T1/2 of most AGs doubles in old age)
- Excretion is directly proportional to creatinine clearance > helps in making dosage adjustments
what types of patients have an increased risk of adverse effects from aminoglycosides?
dehydrated and those with renal disease
how can we minimize nephrotoxic adverse effects of aminoglycosides?
AGs enter renal tubular cells via a saturable transporter
> amount entering cells depends on duration of exposure rather than peak concentration
Damage is minimized by allowing a washout period each day
> give single daily dose and allow concentrations to fall for remainder of day
use and considerations for aminoglycosides in food animals
IM use in cattle may result in drug residues detectable for >1 year (e.g., kidney)
Approved only for neonatal colibacillosis in piglets, and for intrauterine infusion (negligible absorption from sites of admin) in dairy and beef cattle and horses (also used in newborn chicks)
use and considerations for aminoglycosides in food animals
IM use in cattle may result in drug residues detectable for >1 year (e.g., kidney)
Approved only for neonatal colibacillosis in piglets, and for intrauterine infusion (negligible absorption from sites of admin) in dairy and beef cattle and horses (also used in newborn chicks)
ototoxicity of aminoglycosides mechanism? how to avoid?
AGs damage CN VIII & hair cells in cochlea & vestibular apparatus
- Can cause permanent, severe, high-frequency hearing loss
- Topical otic prep: ensure tympanum is intact
3 main aminoglycosides and their uses:
Gentamicin:
- Broadest spectrum (Gram-neg. aerobes, Staph, mycoplasma)
- The most commonly used AG
Tobramycin:
* Used second-line for infections resistant to gentamicin
Amikacin
* Used second-line for infections resistant to gentamicin
* Resistant to many aminoglycosidases
Aminoglycosides Flash Card: mechanism of action
Inhibition of protein synthesis (bactericidal effect)
Aminoglycosides Flash Card: main adverse effects
- Nephrotoxicity
- Ototoxicity
Aminoglycosides Flash Card: general spectrum
- Gram-neg. aerobes
- Staph
- Mycoplasma
Aminoglycosides Flash Card: health canada prudent use stats
First line: Topical admin.
Second line: Systemic admin.
Aminoglycosides Flash Card: PK features
- Highly ionized > negligible oral or topical absorption
- Food residues > 1 year with parenteral administration
