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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
Q

Penicillin PK-PD

A
  • 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
Q

Penicillin dosing

A
  • Uses “units” (IU)
  • 1U=0.6 microgram pen G
27
Q

What are the penicillin adverse reactions?

A
  • Hypersensitivity
  • **GI flora changes (diarrhea)
  • Drug residues in food animals
28
Q

Hypersensitivity to penicillin

A
  • Due to R1 side chain, NOT the beta-lactam ring
  • Anaphylaxis/local inflammation: Type I
  • Autoimmune hemolytic anemia: Type II
  • Vasculitis (Type III)
29
Q

In which animals is GI flora changes (diarrhea) due to penicillin prominent in?

A
  • Hindgut fermenters (colon+cecum)
    o Horses, rodents, rabbits
  • *especially if drug given ORALLY
  • Ex. diarrhea
30
Q

Drug interactions of penicillin G: synergism?

A
  • 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
Q

Anti-staphylococcal penicillins

A
  • 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
Q

“Methicillin-resistant” Staph auereus and pseudintermedius

A
  • Resistant because of a different penicillin binding protein
  • megA gene
  • we don’t really use methicillin, BUT NOW RESISTANT TO ALL BETA-LACTAMS
33
Q

What does anti-staphylococcal penicillins work for?

A
  • many gram + (including most Staph.)
  • anaerobes
34
Q

What are 2 examples of aminopenicillins?

A
  • Ampicillin
  • Amoxicillin
35
Q

Ampicillin (Polyflex)

A
  • 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
Q

Amoxicillin

A
  • 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
Q

Aminopenicillins vs. ‘regular’ Pen G: spectrum of activity

A
  • 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
Q

What does aminopenicillins work for?

A
  • Many gram + (but not most Staph)
  • Anaerobes
  • **Some gram negatives
39
Q

Aminopenicillin absorption: oral

A
  • 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
Q

Aminopenicillin absorption: injectable

A
  • Ampicillin trihydrate: SLOWLY absorbed (SC, IM)
    o Comparable to Pen G
  • Ampicillin sodium: RAPID, can be given IV
41
Q

Aminopenicillin distribution, metabolism, excretion

A
  • Comparable to Pen G
  • Short half-life
42
Q

Aminopenicillin PK: short half-life

A
  • 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
Q

Aminopenicillin drug interactions

A
  • Comparable to Pen G
  • Give with aminoglycosides: but it’s not SYNERGY
44
Q

Aminopenicillin adverse drug events

A
  • 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
Q

Anti-pseudomonal penicillins

A
  • Piperacillin
  • All HUMAN formulations (expensive and IV with beta-lactamase inhibitor: tazobactam)
46
Q

Anti-pseudomonal penicillins: spectrum of activity

A
  • Active against gram –
  • *active against Pseudomonas
    o Can penetrate its cell wall
  • Active against anaerobes
  • *BUT decreased activity against Gram (+)
47
Q

What is the main beta-lactamase inhibitor in vet med?

A
  • 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
Q

Beta-lactamase inhibitors: mechanism of action

A
  • Little antimicrobial activity on their own
  • IRREVERSIBLY BINDS TO & INACTIVATES beta-lactamase enzymes
49
Q

Beta-lactamases when included with amoxicillin: spectrum of activity

A
  • Most gram +
    o Including beta-lactamase producing Staph (unless methicillin-resistant)
  • Many gram –
  • Many anaerobes
50
Q

Beta-lactamase inhibitors PK

A
  • 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
Q

Extended-spectrum penicillins (carbapenems): main example

A
  • Imipenem
  • *should ONLY BE USED RARELY IN VET MED! (important in HUMAN medicine)
52
Q

Extended-spectrum penicillins (carbapenems): spectrum of activity

A
  • Gram +
  • Gram –
  • Anaerobes
  • Impervious to beta-lactamase enzymes
53
Q

(Imipenem formulation)

A
  • 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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