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PHARMACOLOGY 3 > 6a – Beta-Lactams > Flashcards

6a – Beta-Lactams Flashcards

1
Q

Beta-lactams structure

A
  • All have beta-lactam ring
  • *bacteria ‘break the ring’ to have resistance
  • Side chain R: bacteria can ‘break’ them off
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2
Q

What are the different Penicillin G (benzyl penicillin) formulations in vet med? (short and long acting)

A
  • 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
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3
Q

Crystalline penicillin G

A
  • 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
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4
Q

Procaine penicillin G

A
  • ‘white’ injectable penicillin
  • *daily injections
  • Oral feed premixes
  • *for IM or (SC) injection only
  • *procaine slows penicillin absorption
  • BAD if IV!
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5
Q

Procaine penicillin G in oil

A
  • Long acting
  • *IM or SC injection
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6
Q

Procaine + Benzathine penicillin G

A
  • Long acting in injectable penicillin
  • *IM or SC injection only
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7
Q

Penicillin V vs. penicillin G

A
  • Penicillin V is acid stable=can give orally
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8
Q

What are the penicillin G mechanisms of action?

A
  • 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
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9
Q

Penicillin G disrupts synthesis of bacterial cell wall: gram +

A
  • Lots of peptidoglycan in cell wall
  • High affinity of PBPS for beta-lactams
  • *susceptible to penicillin
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10
Q

Penicillin G disrupts synthesis of bacterial cell wall: gram –

A
  • Less peptidoglycan
  • Lower affinity of PBPs for beta-lactams
  • *not susceptible to penicillin=harder to get through
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11
Q

What are 2 possible resistance mechanisms to penicillin G?

A
  • **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
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12
Q

Staph aureus (and many Staphs.) and penicillin

A
  • 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)
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13
Q

Beta-lactamases can be

A
  • Inherent (constitutive chromosomal expression)
  • Transferable (plasmid-mediated)
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14
Q

MIC values to determine if it works

A

*if low MIC value=likely going to work for that bacterial species

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15
Q

Penicillin G spectrum of activity: bacteria that is typically susceptible

A
  • 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)
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16
Q

Penicillin G spectrum of activity: bacteria that is typically resistant

A
  • Most Staph spp. (produce beta-lactamase)
  • Most gram negative
    o Produce beta-lactamase
    o Can’t penetrate cell wall
    o Low affinity PBP
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17
Q

Penicillin G absorption: oral

A
  • 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)
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18
Q

Penicillin absorption: parenteral for crystalline pen G

A
  • Only dosage form that can be IV
  • (Rapid absorption after IM or SC injection)
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19
Q

*Penicillin absorption: parenteral for procaine pen G

A
  • 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)
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20
Q

Penicillin absorption: parenteral for benzathine pen G

A
  • 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
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21
Q

Penicillin G distribution

A
  • Weak acid (pKa=2.7)
  • *highly ionized at physiological pH (7.4) in plasma
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22
Q

***Penicillin G (and family as a whole) volume of distribution

A
  • **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
23
Q

Penicillin elimination

A
  • 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
24
Q

Penicillin elimination: excretion (renal)

A
  • 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)
25
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
26
Penicillin dosing
- Uses “units” (IU) - 1U=0.6 microgram pen G
27
What are the penicillin adverse reactions?
- Hypersensitivity - **GI flora changes (diarrhea) - Drug residues in food animals
28
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)
29
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
30
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)
31
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’
32
“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
33
What does anti-staphylococcal penicillins work for?
- many gram + (including most Staph.) - anaerobes
34
What are 2 examples of aminopenicillins?
- Ampicillin - Amoxicillin
35
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
36
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
37
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
38
What does aminopenicillins work for?
- Many gram + (but not most Staph) - Anaerobes - **Some gram negatives
39
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)
40
Aminopenicillin absorption: injectable
- Ampicillin trihydrate: SLOWLY absorbed (SC, IM) o Comparable to Pen G - Ampicillin sodium: RAPID, can be given IV
41
Aminopenicillin distribution, metabolism, excretion
- Comparable to Pen G - Short half-life
42
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)
43
Aminopenicillin drug interactions
- Comparable to Pen G - Give with aminoglycosides: but it’s not SYNERGY
44
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
45
Anti-pseudomonal penicillins
- Piperacillin - All HUMAN formulations (expensive and IV with beta-lactamase inhibitor: tazobactam)
46
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 (+)
47
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
48
Beta-lactamase inhibitors: mechanism of action
- Little antimicrobial activity on their own - IRREVERSIBLY BINDS TO & INACTIVATES beta-lactamase enzymes
49
Beta-lactamases when included with amoxicillin: spectrum of activity
- Most gram + o Including beta-lactamase producing Staph (unless methicillin-resistant) - Many gram – - Many anaerobes
50
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)
51
Extended-spectrum penicillins (carbapenems): main example
- Imipenem - *should ONLY BE USED RARELY IN VET MED! (important in HUMAN medicine)
52
Extended-spectrum penicillins (carbapenems): spectrum of activity
- Gram + - Gram – - Anaerobes - Impervious to beta-lactamase enzymes
53
(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

PHARMACOLOGY 3 (15 decks)

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