6a – Beta-Lactams Flashcards
Beta-lactams structure
- All have beta-lactam ring
- *bacteria ‘break the ring’ to have resistance
- Side chain R: bacteria can ‘break’ them off
What are the different Penicillin G (benzyl penicillin) formulations in vet med? (short and long acting)
- Short acting
o Crystalline penicillin G (Na+ or K+)
o Procaine penicillin G - Long acting
o Benzathine penicillin G
o Procaine penicillin G in oil
Crystalline penicillin G
- Sterile formulations added to sterile saline or lactated ringer for injection (human drugs)
- Soluble powder for drinking water (vet drugs) (NON-sterile drinking water)
- **IV
Procaine penicillin G
- ‘white’ injectable penicillin
- *daily injections
- Oral feed premixes
- *for IM or (SC) injection only
- *procaine slows penicillin absorption
- BAD if IV!
Procaine penicillin G in oil
- Long acting
- *IM or SC injection
Procaine + Benzathine penicillin G
- Long acting in injectable penicillin
- *IM or SC injection only
Penicillin V vs. penicillin G
- Penicillin V is acid stable=can give orally
What are the penicillin G mechanisms of action?
- Inhibit the PENICILLIN BINDING PROTEINS found outside of bacterial cell membrane
- Interferes with enzymes (transpeptidase) needed for peptidoglycan synthesis
- *causes lysis of growing bacterial cells
Penicillin G disrupts synthesis of bacterial cell wall: gram +
- Lots of peptidoglycan in cell wall
- High affinity of PBPS for beta-lactams
- *susceptible to penicillin
Penicillin G disrupts synthesis of bacterial cell wall: gram –
- Less peptidoglycan
- Lower affinity of PBPs for beta-lactams
- *not susceptible to penicillin=harder to get through
What are 2 possible resistance mechanisms to penicillin G?
- **Penicillinase or beta-lactamase enzymes
o Exogenous producers (ex. Staph Aureus)
o Endogenous producers (ex. between cell membrane and cell wall in gram-negatives) - Inability of beta-lactam to penetrate bacterial cell wall (ex. gram negative bacteria: ‘tougher’ cell wall)
- *if PBP change=will not be able to bind=really rapid resistance
Staph aureus (and many Staphs.) and penicillin
- Not susceptible
- Exogenous beta-lactamase (penicillinase) producer
- *penicillin doesn’t even make it to the cell wall
- Ex. maybe try and cephalosporin (can’t be broken down by penicillinase)
Beta-lactamases can be
- Inherent (constitutive chromosomal expression)
- Transferable (plasmid-mediated)
MIC values to determine if it works
*if low MIC value=likely going to work for that bacterial species
Penicillin G spectrum of activity: bacteria that is typically susceptible
- Many gram positives
o Actinomyces spp.
o T. pyogenes
o Some B. anthracis, Corynebacterium, Erysipelothrix r., Listeria - Some gram negative (some Histophilus and Pasteurella)
- Many anaerobes (ex. Fusobacterium, some Clostridium)
Penicillin G spectrum of activity: bacteria that is typically resistant
- Most Staph spp. (produce beta-lactamase)
- Most gram negative
o Produce beta-lactamase
o Can’t penetrate cell wall
o Low affinity PBP
Penicillin G absorption: oral
- Poor due to RAPID HYDROLYSIS in stomach acid
- (Exception: penicillin V=acid-stable)
- **what about the feed premix or drinking water formulations: getting in locally but not much systemically (not going for plasma concentrations)
Penicillin absorption: parenteral for crystalline pen G
- Only dosage form that can be IV
- (Rapid absorption after IM or SC injection)
*Penicillin absorption: parenteral for procaine pen G
- Procaine salt more SLOWLY ABOSORBED from IM injection site than crystalline forms
- Results in LOWER but more SUSTAINED, PLASMA CONCENTRATIONS
- **Injections in necks absorbed more rapidly and consistent than in hindquarters (LESS CARCASS DAMAGE)
- **NEVER USE FOR IV INJECTION (if milky=do not give IV)
Penicillin absorption: parenteral for benzathine pen G
- Benzathine salt is poorly soluble=very SLOWLY absorbed
- Produces SUSTAINED (**but often sub-therapeutic) Pen G plasma concentrations
o Can’t reach MIC
o Sits there forever=long residues in milk or meat
Penicillin G distribution
- Weak acid (pKa=2.7)
- *highly ionized at physiological pH (7.4) in plasma
***Penicillin G (and family as a whole) volume of distribution
- **Generally low
- Good concentration in plasma and ECF
o Where most of our infections we are treating are - May not reach therapeutic concentration in SOME tissues
- **Increased distribution to tissues with inflammation
Penicillin elimination
- Metabolism: VERY LITTLE
- Excretion: RENAL
- *short half life: 1-2 hours
o EXCEPT procaine/benzathine forms
o Longer half-life absorption DRIVES the half-life elimination (FLIP-FLOP KINETICS)
o Not that it is excreted slower, but there is just none for it to be excreted as it is not absorbed yet
Penicillin elimination: excretion (renal)
- Some via glomerular filtration
- Most via secretion into renal tubule
o Drug competition for tubular secretion possible, but unlikely - *change dose in animals with renal failure (but so safe, likely don’t need to)
Penicillin PK-PD
- TIME-DEPENDENT ANTIMICROBIALS
o Efficacy not based on reaching Cmax
o *penicillin concentration OVER MIC for as long as possible - Crystalline penicillin: may require TID/QID
- Procaine Pen G: once daily dosing
- Large animal procaine/benzathine pen G: days between doses (prolonged absorption)
o ONLY IF PLASMA CONCENTRATIONS ACTUALLY REACH PATHOGEN MIC
Penicillin dosing
- Uses “units” (IU)
- 1U=0.6 microgram pen G
What are the penicillin adverse reactions?
- Hypersensitivity
- **GI flora changes (diarrhea)
- Drug residues in food animals
Hypersensitivity to penicillin
- Due to R1 side chain, NOT the beta-lactam ring
- Anaphylaxis/local inflammation: Type I
- Autoimmune hemolytic anemia: Type II
- Vasculitis (Type III)
In which animals is GI flora changes (diarrhea) due to penicillin prominent in?
- Hindgut fermenters (colon+cecum)
o Horses, rodents, rabbits - *especially if drug given ORALLY
- Ex. diarrhea
Drug interactions of penicillin G: synergism?
- Beta-lactam disrupts the bacterial cell wall, so may increase aminoglycoside entry into bacterial cell
- PROBABLY NOT ACTUALLY SYNERGISM: no clinical evidence of better outcomes because of synergism
- *but does make sense to use them together=COMPLIMENTARY spectrums of activities (BROAD)
Anti-staphylococcal penicillins
- Different side chain
- Ex. Cloxacillin (Dry-Clox: intramammary suspension) and methicillin
- Not as potent as Pen G
- *can work against S. aureus penicillinase=use for staphylococcus mastitis
- *don’t use them much but need to know what it means to be ‘methicillin-resistant’
“Methicillin-resistant” Staph auereus and pseudintermedius
- Resistant because of a different penicillin binding protein
- megA gene
- we don’t really use methicillin, BUT NOW RESISTANT TO ALL BETA-LACTAMS
What does anti-staphylococcal penicillins work for?
- many gram + (including most Staph.)
- anaerobes
What are 2 examples of aminopenicillins?
- Ampicillin
- Amoxicillin
Ampicillin (Polyflex)
- Trihydrate salt injectable suspension
o IM/SC (NOT IV) in cattle, swine, dogs, cats - Many human sterile crystalline Na (IV injection) and oral forms
Amoxicillin
- Many vet oral tables/suspensions
o With or w/o clavulanic acid
o Indications: wide variety of infections in dogs/cats - Soluble powder for medicated water
o Swine and poultry - *better oral bioavailability
Aminopenicillins vs. ‘regular’ Pen G: spectrum of activity
- Active against all bacteria that Pen G is (comparable potency)
- **amino group allows better PENETRATION through the outer layer of Gram-negative bacteria than pen G (especially amoxicillin)
- BUT: *still susceptible to degradation by microbial beta-lactamase/penicillinase enzymes
What does aminopenicillins work for?
- Many gram + (but not most Staph)
- Anaerobes
- **Some gram negatives
Aminopenicillin absorption: oral
- Ampicillin and amoxicillin are acid-stable
- Amoxicillin oral F=60-80%
o Ampicillin is about ½ that - Amoxicillin: both fed or fasting state is OK
o Usually give with food, unless a reason not to
o Fed: decrease diarrhea or vomiting)
Aminopenicillin absorption: injectable
- Ampicillin trihydrate: SLOWLY absorbed (SC, IM)
o Comparable to Pen G - Ampicillin sodium: RAPID, can be given IV
Aminopenicillin distribution, metabolism, excretion
- Comparable to Pen G
- Short half-life
Aminopenicillin PK: short half-life
- BID dosing necessary for oral forms (time-dependent, like Pen G)
o TID: would be even better, but not end of world - SID for ampicillin trihydrate (polyflex) after IM injection (like procaine pen G)
Aminopenicillin drug interactions
- Comparable to Pen G
- Give with aminoglycosides: but it’s not SYNERGY
Aminopenicillin adverse drug events
- Slightly less than Pen G
- Cross-reactivity in patients with Pen G hypersensitivity?
o NOT LIKELY DUE TO DIFFERENT SIDE CHAINS - More cross-reactivity with SOME CEPHALOSPORINS
- *Oral adverse events: vomit, diarrhea
o Intestinal flora disruption
o Particularly ampicillin (do NOT give to lab animals)
o Amoxicillin: better oral bioavailability so less making its way to the hind gut
Anti-pseudomonal penicillins
- Piperacillin
- All HUMAN formulations (expensive and IV with beta-lactamase inhibitor: tazobactam)
Anti-pseudomonal penicillins: spectrum of activity
- Active against gram –
- *active against Pseudomonas
o Can penetrate its cell wall - Active against anaerobes
- *BUT decreased activity against Gram (+)
What is the main beta-lactamase inhibitor in vet med?
- Clavulanic acid
o In many oral tablet and suspensions for small animals (often with amoxicillin)
o *ratio of Amox : Clav in human formulations is different! (due to different PKs) - Ex. Clavamox, Clavaseptin
Beta-lactamase inhibitors: mechanism of action
- Little antimicrobial activity on their own
- IRREVERSIBLY BINDS TO & INACTIVATES beta-lactamase enzymes
Beta-lactamases when included with amoxicillin: spectrum of activity
- Most gram +
o Including beta-lactamase producing Staph (unless methicillin-resistant) - Many gram –
- Many anaerobes
Beta-lactamase inhibitors PK
- Almost same as amoxicillin
- Quickly and extensively absorbed after oral administration
- RENAL excretion
- Similar half-life
- Minimal ADE
o If they do occur, it’s likely due to aminopenicillin portion (not the beta-lactamase inhibitor)
Extended-spectrum penicillins (carbapenems): main example
- Imipenem
- *should ONLY BE USED RARELY IN VET MED! (important in HUMAN medicine)
Extended-spectrum penicillins (carbapenems): spectrum of activity
- Gram +
- Gram –
- Anaerobes
- Impervious to beta-lactamase enzymes
(Imipenem formulation)
- Typically given IV (IM or SC is painful)
- Hydrolysed by dihydropeptidase enzymes in kidney, producing toxic metabolites
- *very short half life, RENAL EXCRETION
