3. Cell Wall Synthesis-Inhibiting Antibacterial Agents

What are the beta-lactams?

P
C
C
M

• penicillins (penems)

• cehpalosporins (cephems)

• carbapenems

• monobactams

What are the relevant examples of penicillin and penicillin derivatives (penems)?

A
A
T
C

• amoxicillin

• ampicillin

• ticarcillin

• clavulanate (potentiator)

What is the mechanism of action for all the beta-lactams?

inhibit cell wall synthesis

Beta-Lactam MOA:

• inhibits the ________-________ of peptidoglycans in the cell wall

• ________ binds to and thus weakens the ________ of this cross-link

• the cell wall then becomes very sensitive to ________ stress

• the process/binding is mostly ________

• this tends to be ________

• cross-linking

• permanently; integrity

• osmotic

• irreversible

• bactericidal

Are the beta-lactams bacteriostatic or bactericidal? Why?

bactericidal; causes irreversible inhibition

What is the bacterial spectra of the beta-lactams? Why?

broad spectrum; most bacteria have a peptidoglycan layer

What Gram status bacteria should be more susceptible to beta-lactams?

Gram positive

Why are Gram positive bacteria more susceptible to beta-lactams?

they have a larger PTDG complex

Why are Gram negative bacteria less susceptible to beta-lactams?

they have two extra layers for the beta-lactam to transverse (the outer layer and the lipoprotein layer)

True or false: There are many newer beta-lactams that are still able to kill Gram negative bacteria, and some newer beta-lactams only kill Gram-negative bacteria.

true

What are the extended spectrum penems? What does this mean?

A
A
H

• amoxicillin

• ampicillin

• hetacillin

they have a broader spectrum than penicillin and includes Gram negative

Which penems are anti-pseudomonas? What is significant about their activity?

P
T

• piperacillin

• ticarcillin

they have little Gram positive activity

How does resistance to beta-lactams primarily occur?

via bacterial enzymes that cleave and inactivate the drug

What are the enzymes that are responsible for the resistance to beta-lactams? What do they do?

beta-lactamases; they cleave the beta-lactam ring

True or false: Genes encoding these beta-lactamases have been present in bacteria prior to the therapeutic use of penicillin by humans.

true

What is a much less common resistance mechanism toward beta-lactams?

some bacteria lack PBPs (mycoplasma)

True or false: Beta-lactams are probably one of the safest antibiotics available for use in animals.

true

What is the therapeutic index for beta-lactams?

high

What are the anaphylactic reactions associated with beta-lactams?

typically mild

With beta-lactams, there is a massive ________ release from the dead Gram ________ bacteria. 

endotoxin; negative

Beta-lactams have the ________ rate of bacterial killing of all bactericidal antibiotics.

slowest

Which beta-lactams have the possible side effect of bleeding disorders?

T
P

• ticarcillin

• procaine penicillin in horses

Why are beta-lactams safer than all other antibiotics?

C
R

• cell wall is biochemically unique to bacteri

• ribosomes and other antibiotic targets are not unique to bacteria

In what way are beta-lactams well-absorbed?

orally

What is the pKa of the beta-lactams? How are they in the stomach?

~2.5; non-ionized

Beta-lactams are a ________-________ antibiotic because of the slow rate of bacterial killing.

time-dependent

When will beta-lactams work better?

if the plasma concentration remains above the MIC for a longer period of time

With beta-lactams, the plasma concentration should be ________ than the MIC for ____-____ of the dosing interval. ____ when treating Gram positive and ____ when treating Gram negative.

greater; 50-100%; 50%; 100%

How should beta-lactams be administered? Rather than what?

often, rather than giving an infrequent large dose

What is the V_d for beta-lactams?

tends to be low

How are the beta-lactams present in the plasma?

ionized

What tissues can beta-lactams reach? How?

B
P
A

• brain

• prostate

• abscesses

inflammatory processes remove some of the barriers, allowing penems and other beta-lactams access

How are beta-lactams excreted by the kidney?

rapidly eliminated since it is ionized/polar in plasma

What is renal excretion of beta-lactams blocked by?

probenecid

What are the sustained release formulations of beta-lactams that are available in the injectable formulations? What is their purpose? These only exist for what?

P
B

• procaine

• benzathine

slow the release from the injection site; penicillin and no other beta-lactams

There is precaution for use of sustained release formulations of procaine penicillin in what species? What are those precautions?

M
C
C

horses

• must not use procaine penicillin within 30 days of a race since procaine is a banned substance in racehorses

• can cause CNS excitement in horses

• can cause Coombs positive hemolytic anemia

What type of procaine penicillin should never be given?

procaine penicillin IV

Procaine penicillin should not be used in what species? Specifically what species?

small exotics and pocket pets; guinea pigs

What drugs can be used in guinea pigs instead?

E
S
D

• enrofloxacin

• SMZ-TMP

• doxycycline

non-antibacterial drug that enhances the efficacy of an antibiotic

potentiator

For penems, how do potentiators act? When can a potentiator only potentiate? What are they structurally similar to?

by inhibiting beta-lactamases present in bacteria; only if the targeted bacteria has this enzyme; beta-lactam antibiotics

competitive inhibitor of bacterial beta-lactamases

clavulanic acid (aka clavulanate)

Clavulanic acid works very well in conjunction with what drug?

amoxicillin

True or false: Some beta-lactams have been optimally paired with a potentiator.

true

What is ampicillin paired with?

sulbactam

What is ticarcillin paired with?

clavulanic acid

What is pipercillin paired with?

tazobactam

What are potentiators sometimes called?

antibiotic adjuvants

What composes clavamox?

amoxicillin plus clavulanate

What is clavamox commonly used for?

C
C
K
T
U

• canine (not large dogs) and feline pyoderma and other dermatopathies

• cat bite abscesses (liquid is good)

• kitten upper respiratory infections

• treatment of wounds

• urinary tract infections

What is amoxicillin used for?

treating bovine mastitis

What is hetacillin and cloxacillin used for? Which is used in both lactating and dry cow preparations?

mastitis treatments; cloxacillin

What is ampicillin commonly used for?

B
C
M

• bovine respiratory disease

• clostridia

• mastitis

What is penicillin G plus streptomycin used for?

cry cow mastitis prep

What is a ticarcillin/clavulanate injectable used topically for?

pseudomonas otitis

penem that has a variety of uses in companion animals

amoxicillin ± clavulanate

penem commonly used in bovine

ampicillin

penem used for pseudomonas otitis

ticarcillin + clavulanate

What is the only feed grade beta-lactam, but is restricted?

penicillin

Summary of Penems:

1. ________ because ________ inhibitors but ________ killers

2. inhibit ________ ________ ________

3. ________ spectrum although it varies from drug to drug

4. resistance is importantly related to the bacterial enzymes that degrade the drug called ____-________

5. circumvention of these enzymes can be done using ________ drugs that inhibit the enzyme

6. side effects are predominantly related to ________

7. pharmacokinetics are ________-dependent

8. can penetrate normally ________ sites if inflammed

9. penicillin G is problematic in ________, ________ ________, and ________ ________

1. bactericidal; irreversible; slow

2. cell wall synthesis

3. broad

4. beta-lactamases

5. potentiating

6. anaphylaxis

7. time

8. privileged

9. horses; small exotics; pocket pets

Penicillin G and V do not work against what bacteria?

Gram negative aerobes

What penem only works against S. aureus?

cloxacillin

What type of bacteria do amoxicillin, ampicillin, and hetacillin work against?

Gram negative aerobes

What penems are the only ones that work against pseudomonas?

ticarcillin and pipercillin

Potentiated penicillin work about what bacterial type only?

aerobes

What is the most important potentiating drug when it comes to penems, and is commonly paired with either amoxicillin or ticarcillin?

clavulanate

What are clinically relevant examples of cephalosporins (cephems)?

C
C
C
C
C
C

• cephalexin

• cephadroxil

• cefazolin

• cefpodoxime

• cefovecin

• ceftiofur

True or false: All are natural or synthetic derivatives of cephalothin derived from cephalosporium acremonium.

true

What are the first generation cephalosporins?

cephalexin, cefadroxil, cephapirin, and cefazolin

What is the route of administration of cephalexin (Keflex)?

oral

What is the route of administration of cefadroxil (Cefa-drops)?

oral

What is the route of administration of cephapirin (Cefa-dry)?

intramammary

What is the route of administration of cefazolin?

IV

What are the second generation cephalopsorins?

none currently relevant to veterinary clinical practice

What are the third generation cephalosporins?

cefpodoxime, ceftiofur, and cefovecin

What is the route of administration of cefpodoxime (Simplicef)?

oral

What is the route of administration of ceftiofur (Excede, Excenel, Naxcel)?

parenteral, intramammary

What is the route of administration of cefovecin (Convenia)?

parenteral

What are the fourth generation cephalosporins?

cefepime and cefquinome injectables

cephalosporin that is pending FDA-CVM approval

cefquinome (Cobactin)

cephalosporin that is an IV anti-pseudomonas drug for humans

cefepime (Maxipime)

What is a fifth generation cephalosporin?

ceftobiprole

What is the method of action for the cephems, carbapenems, and monobactams?

inhibit cell wall synthesis (third step in PTDG synthesis)

Are the cephems, carbapenems, and monobactams, bacteriostatic or bactericidal?

bactericidal

What spectrum does first generation cephalosporins cover?

mostly Gram positive

What spectrum does second generation cephalosporins cover?

both Gram positive and negative

What spectrum does third generation cephalosporins cover?

both Gram positive and negative

What generation of cephalosporins is best at crossing the BBB?

third generation

What spectrum does fourth generation cephalosporins cover?

most Gram negative

What is the main purpose of fourth generation cephalosporins? Specifically which ones?

used on bacteria resistant to third generation; pseudomonas and proteus

What spectrum does fifth generation cephalosporins cover?

human MRSA (close to being approved)

What is the main cause of resistance to cephalosporins? What are they called?

primarily via bacterial enzymes that cleave and inactivate the drug; beta-lactamases but are slightly different than the penicillinase/beta-lactamase discussed previously and are sometimes called cephalosporinases

The enzymes involved in resistance to cephems are not usually sensitive to what? What are they sometimes susceptible to?

clavulanic acid, sulbactam, or tazobactam; advanced potentiators like avibactam

True or false: The side effects of cephalosporins is essentially the same side effects as the penems. Howeverl there is not much cross-reactivity between the two groups. Hypersensitivity to penicillins does not always lead to cephalosporin hypersensitivity and vice versa.

true

What does this tell us about the beta-lactam epitopes for the IgE?

the epitope is not usually the beta-lactam ring and is more likely a side chain + BLR

True or false: Do not assume that newer generation drugs are less immunoreactive.

true

Cephalosporins are well absorbed ________.

orally

What is the pKa of cephalosporins? What does this mean about their presence in the gut?

~4-5; non-ionized in the gut

Cephalosporins are ________ ionized in plasma when compared to penems and have a ________ V_d. They are a ________-dependent antibiotic because of a ________ rate of bacterial killing. Increasing the dosing ________ is of benefit.

less; higher; time; slow; frequency

True or false: The cephalosporins have the same renal elimination characteristics as penems.

true