Mid Beta-Lactam Antibiotics And Vancomycin I

Front 1

What are the beta-lactam antibiotics?

Back 1

Penicillins
Cephalosporins
Carbapenems
Monobactams

Front 2

What is "selective toxicity"?

Back 2

The property of anti-bacterial drugs which says that they interact with a target present on the bacterial cell, the prokaryote, that is not present in the mammalian host, the eukaryote.

Front 3

What is the target of the beta lactam drugs?

Back 3

The cell wall

Front 4

What are the properties of an antibiotic that determine its activity against specific bacteria?

Back 4

1. Affinity of the drug for the target
2. The permeability of the drug - how well it can get to its target
3. Stability to bacterial enzymes that inactivate or destroy the drug

Front 5

What are PBPs?

Back 5

Penicillin Binding Proteins - the proteins that are directly bound by penicillin G. These are the enzymes needed for peptidoglycan (cell wall) synthesis.

Front 6

What are the two groups of PBPs? What do they do?

Back 6

Carboxy-peptidases - cleave the terminal D-ala from the pentapeptide releasing ATP and exposing the amino acid to be cross linked

Transpeptidases - which perform the cross-linking reaction

Front 7

To which organisms are beta-lactam antibiotics cidal?

Back 7

Growing organisms

Front 8

What determines the potency of a beta-lactam drug?

Back 8

The affinity to a particular PBP and the permeability properties of the drug

Front 9

What is the general permeability issue in gram negative antibiotics?

Back 9

Gram negatives have an outer cell wall with protein channels and porins. Charged antibiotics such as beta lactamas must get through the porin proteins to reach their targets, the PBPs which are on hte inside of the outer lipoprotein cell wall. A potential space, the periplasmic space occupies the region between the outer cell wall and the peptidoglycan. Bacteria actively regulate what goes through these pores.

Front 10

Describe the defenses of opportunistic gram negatives against beta lactam antibiotics

Back 10

Opportunistic gram negative bacteria (Pseudomonas, Enterobacter and many others) can synthesize whatever they need from small sized components. Their porins are highly regulated, relatively small, and pose a major barrier for the entry of beta-lactams to the periplasmic space and access to the PBPs.

These organisms have efflux pumps which can be activated to pump the antibiotics back out the porins, even if they do get to the site of peptidoglycan synthesis.

Front 11

What do beta-lactamases do?

Back 11

Cleave the beta-lactam ring and destroy the ability of the beta-lactam drug to bind to the target PBP.

Front 12

Describe the chromosomal beta lactamases

Back 12

These are subject to the same regulatory mechanisms as other bacterial operons. There is a two component sensing sytem that responds to the presence of beta-lactam structures. There is a sensor, a response regulator, and a transcriptional activator

Front 13

Describe inducible beta-lactamase expression

Back 13

This is chromosomally mediated and turns on and off depending upon the presence of an inducer.

Front 14

Describe plasma encoded beta lactamases

Back 14

These are constitutively expressed and can be readily transferred from one organism to another.

Front 15

What are extended spectrum beta lactamases?

Back 15

Plasma mediated beta lactamases with large spectrums

Front 16

Where are beta-lactamases located on gram negative bacteria?

Back 16

In the periplasmic space

Front 17

Where are beta-lactamases located on gram positive bacteria?

Back 17

They are secreted into a "cloud" surrounding the organism

Front 18

What is done to prevent beta-lactamase degradation of beta lactam antibiotics for use in gram positive bacteria?

Back 18

Bulky side chains that sterically inhibit beta lactamase activity can be added to the penicillins which are targeting gram positive organisms such as staphylococci that produce beta-lactamases

Front 19

Describe Penicillin B. Its uses, its stability, and how it is administered.

Back 19

It is not ß-lactamase stable but nonetheless is highly active against streptococci, spirochetes (cause syphilis and Lyme disease) and meningococci. Pen G is not acid stable so it is given parenterally: either intravenously or in a repository form(procaine pen G or benzathine pen G) which is given intramuscularly.

Front 20

Describe the structure of the penicillins

Back 20

Beta-lactam ring + thiazolidine ring + R group = which are the side chains that influnence pharmacologic properties.

Front 21

Describe the side chain of ampicillin

Back 21

There is a NH2 group attached to the carbon before the aromatic ring

Front 22

Describe the side chain of amoxicillin

Back 22

There is a NH2 group attached to the carbon before the aromatic ring and an OH group at the the far side of the aromatic group.

Front 23

What does the NH2 group of ampicillin and amoxicillin do?

Back 23

The addition of a charged NH3 group improves the penetration of the penicillin nucleus through Gram negative porins while retaining excellent activity against Streptococci.

Front 24

What does the OH group on amoxicillin do?

Back 24

The OH group in amoxicillin provides stability to stomach acid.

Front 25

What is done to make ampicillin and amoxicillin beta-lactamase stable?

Back 25

Neither ampicillin nor amoxicillin is beta-lactamase stable, so they are often given in combination with a beta-lactamase inhibitor.

Front 26

What beta-lactamase inhibitor is given with ampicillin? How is the combination administed and used?

Back 26

Ampicillin + sulbactam = Unasyn - used parentally for a wide variety of infections including those cause by anaerobic bacteria, gram positive, and gram negative organisms.

Front 27

What beta-lactamase inhibitor is given with amoxicillin? How is the combination administed and used?

Back 27

Amoxicilin + clavulanic acid = augmentin - Respiratory infections; it covers S. aureus also since the clavulanate inhibits the staphylococcal beta-lactamase, as well as beta-lactamase-producing Hemophilus and Moraxellae

Front 28

What are the anti-staphylococcal penicillins?

Back 28

Oxacillin
Methicillin
Nafcillin

Front 29

What are "semi-synthetic" penicillins? Why were they first made? What is special about them?

Back 29

Anti-staphylococcal penicillins. They were first made to deal with the growing problem of Staphylococcal infections due to penicillin-resistant organisms. These penicillins have large buly side chains that protect the beta-lactam bond and do not interfere with penetration to the target PBP's since these gram posive bacteria have no out cell wall.

Front 30

What are the anti-pseudomonas penicillins?

Back 30

Piperacillin
Carbenicillin - no longer used
Ticarcillin - no longer used

Front 31

Describe why anti-pseudomonas penicillins were produced

Back 31

To kill opportunists (the Gram negative bacteria with tightly regulated porin channels and multiple efflux systems), "semi-synthetic" or "broad spectrum" penicillins were developed that have charged R-side chains to improve permeability though the porins and with structural properties that increase affinity for the PBP3 target.

Front 32

Describe the structure of piperacillin

Back 32

Piperacillin has a piperazie ring - a compact charged group that significantly increases the activity of the drug against P. aeruginosa, a common Gram negative opportunist.

Front 33

What beta-lactamase inhibitor is given with piperacillin? Describe its use.

Back 33

Piperacillin + tazobactam = Zosyn - which provides protection against the plasma mediated beta-lactamases, particularly those of the TEM type. Unfortunately the tazobactam does not provide protection against the derepressed chromosomal beta-lactamases of P. aeruginosa (ampC) which has predominantly cephalosporinase activity.

However, the combination Zosyn does provide broad spectum activity against Gram positive bacteria as well as many of the enteric Gram negative and opportunistic pathogens.

Front 34

Describe mutations in PBPs

Back 34

This is a mechanism of resistance to penicillins. S. pneumoniae can accumulate mutations in the PBPs and become relatively or absolutely resistant to penicillin. When these organisms die and lyse, their DNA is taken up by other streptococci and in the presence of antibiotic selective pressure, the now transformed penicillin-resistant organisms are maintained in the population.

Front 35

Describe beta-lactamase production in Gram positives

Back 35

In Gram positives, this is a major problem with S. aureus which classically produces a penicillinase. In some recent outbreaks, staphylococci were found to be producing ß-lactamases with cephalosporinase activity as well. Again, there can be mutations in the ß-lactamase genes that alter the activity of the enzyme, and in the presence of selective pressure, these mutants flourish.

Front 36

Describe beta-lactamase production in Gram negatives

Back 36

Gram negative bacteria can express both chromosomal ß-lactamases as well as plasmid mediated enzymes with a wide variety of activities.

Front 37

Describe efflux pumps

Back 37

The expression of efflux pumps in both Gram negative and in Gram positive bacteria is a major cause of antibiotic resistance. The drugs are rapidly removed from the cell by an inducible pump system. In Gram negative organisms, such as P. aeruginosa, there are >20 different efflux systems that have been identified.

Front 38

Describe the distribution and elimination of penicillins

Back 38

In general, penicillins are charged molecules with distributions limited to the extracellular space. With inflammation, they can achieve bactericidal levels in the CSF and are used to treat meningitis.

They penicillins are handled by the kidneys, primarly by tubular secretion and achieve high levels in the urine of patients with normal renal function. Each drug has somewhat different pharmacokinetic properties. There is some bilitary excretion (significant for nafcillin) and therapeutic levels are achieved in bile.

Front 39

What are the adverse effects associated with penicillins?

Back 39

The adverse effects that are most important include allergy, both immediate IgE-mediated hypersensitivity reactions that include anaphylaxis, and delayed responses such as rash.