Pharm 11: Beta-Lactams: Bacterial Cell Wall Inhibitors

95%

What percentage of a dose of penicillin is eliminated from the kidney unchanged?

Inhibition of transpeptidase activity

Basis of penicillin mechanism of action

Transpeptidases, peptidoglycan

Beta-lactam containing antibiotics bind to ___ (i.e. penicillin-binding proteins (PBPs)) and inhibit ___ synthesis

Amidases, lactamases

Penicillins are susceptible to bacterial metabolism and inactivation by ___ and ___.

Carbapenems, monobactam

___ and ___ are resistant to most common Beta-lactamases.

25%

Time above MIC for carbapenems

50-70%

Time above MIC for extended spectrum penicillins

100%

Time above MIC for aminopenicillins and penicillins

T>MIC (time above MIC)

Percentage of a 24 hour period that the drug concentration exceeds MIC

Bactericidal

Is penicillin bacteriostatic or bactericidal?

Time-dependent

Is penicillin concentration or time-dependent?

Variable

Penicillin has a ___ post-antibiotic effect (PAE).

Gram +ve

Is penicillin more potent against Gram +ve or -ve bacteria?

GI amidases, Beta-lactamases, stomach acid, alkalinity (milk and urine)

What are some penicillins degraded by?

Extracellular, poor

Penicillin distribution is ___ (weak acid), so there is [good/poor] distribution into deep tissues and certain sanctuary sites, but penetration is enhanced by inflammation.

Yes

Is penicillin safe for pregnant mothers?

Methicillin

What was the original version of anti-staphylococcal (semisynthetic) penicillin?

Dicloxacillin

Oral version of anti-staphylococcal (semisynthetic) penicillin which can also be used IM in dogs to prevent staph infections during surgery

Penicillin-binding proteins (PBPs) / transpeptidases

Methicillin resistance is due to mutations in ___, not Beta-lactamases.

Piperacillin

Most important extended-spectrum/anti-pseudomonal penicillin to remember

Piperacillin

Extends the spectrum of ampicillin to include pseudomonas, klebsiella, and many other gram -ve bacteria

May lose activity against enterococcus

Resistance may develop quickly with monotherapy

An aminoglycoside

For pseudomonas, what is piperacillin often paired with to suppress resistance?

Methicillin-resistant Staphylococcus aureus

What does MRSA stand for?

1. Inactivation of antibiotic by Beta-lactamase (1000+ of different forms exist) (plasmid-mediated)

2. Mutations of target PBPs (basis of MRSA and responsible for Pen-resistant pneumococci and enterococci)

3. Impaired penetration of drug to target PBPs

   1. Due to impermeability of an outer cell wall or membrane seen only in Gram-ve bacteria (change in porin channel)

   2. Usually not sufficient by itself to cause resistance; may be paired with a beta-lactamase

4. Appearance of new efflux pump

   1. Seen in some Gram-ve bacteria

Mechanisms of Beta-lactam drug resistance

High

On the whole penicillins are relatively safe with a [low/high] margin of safety index

GI disturbance

Most common side effect of penicillins

Herbivores

Antibiotic-associated severe colitis/dysbiosis is especially severe in ___ like guinea pigs.

Penicillins, cephalosporins

A potential risk for cross-reactivity is seen between ___ and with ___.

Beta-lactamase inhibitors, aminoglycosides

Drug combinations commonly seen with penicillins

Beta-lactamase inhibitors

More accurately, these are competitors for Beta-lactamase activity, as they contain a Beta-lactam ring. But they do not compete for penicillin-binding proteins (PBPs), just for the Beta-lactamases.

Aminoglycosides

Penicillins increase access of ___ to the site of action, ribosomes, to produce additive and sometimes synergistic interaction.

Amoxicillin + Clavulanate (Clavinox)

Ticarcillin + Clavulanate

Ampicillin + Sulbactam (Sultamicillin)

Pipericillin + Tazobactam

Beta-lactamase inhibitor plus penicillin combinations

Beta-lactamase inhibitors

Extend the spectrum of penicillins to include bacteria that express Beta-lactamases

Carbapenems

1. Mechanism of action is similar to penicillins

2. It has the broadest antimicrobial spectra and is remarkably resistant to penicillinases and many cephalosporinases

3. Activity against gram-positive cocci and anaerobes and more than 90% of gram-negative bacteria including those resistant to other Beta-lactam antibiotics and the aminoglycosides

4. Not to be used empirically or as a first-line of drug (mainly seen in human med; expensive)

Imipenem

1. More likely than other Beta-lactam antibiotics to cause seizures

2. Extensively metabolized by the renal tubules to a potentially toxic compound

3. Used in fixed combinations with cilastatin to avoid destruction in the kidneys (extends its half-life and reduces levels of nephrotoxic metabolites)

Monobactams

1. Have a monocyclic Beta-lactam ring

2. Relatively resistant to many Beta-lactamases

3. Active ONLY against aerobic gram negative (GNR)

4. Currently, only aztreonam is available in the U.S.

5. Seems to be tolerated by virtually all patients who are allergic to penicillins

6. Unclear optimal role clinically at this time, but often given in place of an aminoglycoside for narrow coverage of aerobic GNR like E. coli

1st generation cephalosporins

Cefazolin, cephalexin, cephaloridine, cefadroxil, cephalothin, cephapirin, cephacetrile

2nd generation cephalosporins

Cefuroxime, cefotetan, cefaclor, cefoxitin, (cefazolin)

3rd generation cephalosporins

Ceftiodur, ceftazidime, cefovecin, ceftriaxone, cefixime

1. Similar to penicillins in structure, mechanism of action, and some toxicities (bactericidal, time-dependent, post-antibiotic effect, weak acids, extracellular distribution)

2. Have broader spectrum of activity (good and bad)

3. Not active as a class vs. enterococci, Listeria

4. As a general rule 1st generation are more active against Gram +ve organisms (e.g., staph, streptococci), while later drugs (2nd, 3rd, 4th gen) are more active against Gram -ve aerobic organisms (e.g., E. coli, etc.)

General characteristics of cephalosporins

+, -

1st generation cephalosporins are more against against gram [+/-] bacteria, while later generation cephalosporins are more active against gram [+/-] aerobic bacteria.

Less, less, less, resistant

1. Compared to penicillins, cephalosporins are:

   1. [Less/more] sensitive to GI amidases

   2. [Less/more] sensitive to bacterial Beta-lactamases

   3. [Less/more] sensitive to alkalinity

   4. [Sensitive/resistant] to acidity

Less

Allergies with cephalosporins are [less/more] common than with penicillins. There is potential cross-reactivity between cephalosporins and penicillins.

Second generation cephalosporins

1. Most important would be cefuroxime and cefotetan/cefoxitin

2. Similar activity to first generation but a bit more active against Gram -ve rods (GNR), including Klebsiella

3. Not used as much as 1st and 3rd generation drugs

Cefovecin (Convenia)

1. $350 for 1 vial 800 mg

2. 3rd generation for dogs and cats, mainly for skin infections

3. A very long half-life allowing 1 injection every 14 days (up to 4 injections)

4. T1/2 because of high plasma protein binding (>96% in dogs and >99.5% in cats) + very slow renal elimination (elimination half-life of 5.5 days in dogs and 6.9 days in cats)

5. Excellent compliance but resistance concerns with long periods at sub-therapeutic plasma levels

1. Beta-lactamase selection (most transferable)

2. Penicillin binding protein modification (like MRSA)

3. Reduced permeability and increased efflux of drug

Resistance mechanisms against cephalosporins

Overuse, 3rd

1. ___ of cephalosporins (especially __ generation) is thought to have played a significant role in the emergence of resistance to beta-lactam antibiotics

2. Limit their use as first-line empirical options

1. Any extra-label use (for a food animal) of cephalosporins are only approved for humans or companion animals

2. Any change to the dose, frequency, duration, or route on the label of cephalosporins approved for food animals

3. Any use of cephalosporins for disease prevention

1. Relatively new (2012) regulation limiting legal use of cephalosporins in vet med in food animals

2. Limitations include: