Cell Wall Antibiotics

Question 1

Concept behind structure of beta lactam rings and side chains

Answer 1

Conformational/stereochemical changes in the beta-lactam ring can combat bacterial resistance!

The side chains determine spectrum, meaning whether they can be used in gram negative or gram positive bacteria

Side chains can also improve performance against some types of bacterial resistance

The side chains also determine allergies to specific drugs

Question 2

Penicillin abbreviation

Answer 2

PCN

Question 3

MOA for PCN

Answer 3

Covalent binding to PBP

Can’t cross-link wall

Induction of autolytic enzymes

Bacterial cell ruptures due to high intracellular osmotic pressures

Question 4

What is most common mechanism of resistance to PCN

Answer 4

Destruction of antibiotic by β-lactamase

Also: Failure of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets

Question 5

Most common mech of resistance in mrsa and strep pneumoniae, and gene mutation is carried on

Answer 5

Low-affinity binding of antibiotic to target PBP - carried on mecA gene

Question 6

Unique structural change for antistaphylococcal PCN

Answer 6

These drugs have a bulky side chain that protects them from beta-lactamase, this same molecular structure limits their spectrum to gram + only due to porin size issues.

Question 7

Examples of antistaphylococcal PCN

Answer 7

nafcillin and oxacillin

Question 8

How do beta-lactamase scavengers work

Answer 8

Beta-lactamase scavengers act as competitive inhibitors for the beta-lactamase enzymes

Question 9

Examples of B lactamase scavengers

Answer 9

clavulanic acid or sulbactam

Question 10

Use of extended spectrum PCN

Answer 10

have increased gram – coverage due to smaller size of molecule. These can also be complexed with beta-lactamase scavengers

Question 11

Examples of extended coverage PCN

Answer 11

Ampicillin and amoxicillin

Question 12

only penicillins that cover Pseudomonas

Answer 12

Ticarcillin and piperacillin

Question 13

Dosing and administration of PCN

Answer 13

All of the penicillins except PCN V and Amoxicilin are IV only. PCN G can be given IM in a suspension in oil;effective levels for 7 days, but it is really viscous and has to be given in a harpoon-sized needle

Question 14

Adverse rxns for all antibiotics

Answer 14

• All antibiotics can cause all four types of hypersensitivity reactions
• Almost all antibiotics are excreted renally, can cause renal failure in overdose and have to be dose adjusted in patients with renal failure due to a decreased ability to excrete the drug and risk of elevated/toxic levels.
• All antibiotics kill normal flora as well as the targeted infection and increase the risk of future resistance as well as opportunistic infections due to the disruption in the normal regulatory balance between the body’s immune system, non-pathogenic flora, and pathogens.

Question 15

PCN adverse rxns

Answer 15

Antistaphylococcal penicillins: neutropenia, displace bilirubin from albumin, increasing risk of kernicterus in neonates, Hepatitis (inflammation of the liver with jaundice and elevated transaminases)

Allergy: penicillin allergy is a very big deal, we will discuss that on the next page

Question 16

What immune response to PCN is an allergy

Answer 16

An IgE repsonse - anaphylaxis would occur

IgM and IgG can be made to the breakdown products of PCN and cause reactions

Question 17

What is the actual risk of giving cephalosporins to patients with a confirmed or reported PCN allergy

Answer 17

It is considered safe to administer a cephalosporin with a side chain that is structurally dissimilar to that of the penicillin, or to administer a third- or fourth- generation cephalosporin.

Question 18

MOA of cephalosporins

Answer 18

Cephalosporins have increased gram – coverage as the generations get higher. Their MOA and causes of resistance are similar to penicillins, however their molecular structure is intrinsically more stable to many bacterial β-lactamases, and thus they have a broader spectrum of activity.

Question 19

Important bacteria cephalosporins do not work well against

Answer 19

Enterococci and Listeria monocytogenes. Fifth generation cephalosporins are again an exception to this rule.

Question 20

First gen cephalosporins are most active against:

Answer 20

Gram-positive cocci

Question 21

Coverage for second gen cephalosporins and common examples

Answer 21

Compared to the first generations, these retain good gram + coverage and begin to have some gram - coverage related to size of the molecule and their ability to fit through the porins

Cefaclor is a drug in this generation causes a serum sickness-like reaction that is common enough that it is very rarely used in the USA

Cefotetan is a drug in this generation also causes hypoprothrombinemia and abnormal bleeding and can also cause “disulfuram-like reaction” aka “antabuse-like reaction” when taken with alcohol

Question 22

Third gen cephalosporins coverage and examples

Answer 22

Again, as the generations advance, there is increased gram – coverage.

Cefdinir is an oral agent in this class that is used frequently for outpt respiratory illnesses due to its delicious strawberry flavor and has the predictable side effect of causing red stool!

Ceftriaxone is a 3rd gen that maintains 24 hours of bacteriocidal serum levels after a single IM or IV dose. This is not possible with any other antibiotic in normal patients, so this is given as a single does in ERs very frequently to cover the patient for a broad spectrum of infections as cultures are collected.

Ceftazidime is the earliest generation cephalosporin with coverage for pseudomonas.

Question 23

Example of fourth gen cephalosporin

Answer 23

cefepime and it is used frequently for neutropenic fever patients to cover a broad spectrum of resistant bacteria

Question 24

What makes 5th gen cephalosporins unique

Answer 24

They bind specifically to penicillin-binding protein 2a, which is the mutated PBP from the MecA gene that mediates methicillin resistance in staphylococci and streptococci, resulting in bactericidal activity against these strains of bacteria.

Question 25

Examples of 5th gen cephalosporins

Answer 25

ceftaroline and ceftolozane (only cephalosporine coupled with a B lactamase scavenger)

Question 26

Example of monobactams and clinical use

Answer 26

Aztreonam is the only drug, and is only active against aerobic gram – rods, which include Pseudomonas aeruginosa. No activity against anaerobes.

Question 27

What are carbapenems

Answer 27

Beta-lactam drugs. Carbenapenems have a conformational change around the beta-lactam ring that makes them intrinsically resistant to regular beta-lactamases.

Question 28

Example and use of carbapenems

Answer 28

imipenem, and it is paired with cilistatin, a drug that prevents renal tubular inactivation by the dehydropeptidase-1 enzyme to prolong the half life.

Question 29

Toxicities for carbapenems

Answer 29

Toxicity seen in this class includes decreased mental status and seizures.

Question 30

MOA of vancomycin

Answer 30

Inhibits cell wall synthesis by binding firmly to the d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide.

This inhibits both the transpeptidase enzyme, preventing cross-linking, and the transglycosylase, preventing elongation of peptidoglycan. (Transpeptidase can be called tranglycosylase in some sources, it’s the same enzyme.)

Question 31

Spectrum of vancomycin

Answer 31

Only gram positive

Question 32

Cause of vancomycin resistance

Answer 32

Modification of the d-Ala-d-Ala binding site of the peptidoglycan building block in which the terminal d-Ala is replaced by d-lactate. This results in the loss of a critical binding site.

Question 33

Can vancomycin be given orally?

Answer 33

Vancomycin is 0% bioavailable. It is not absorbed at all when taken orally. Orally would never work for systemic infections. This is a must know fact. It can be used orally only for a serious intestinal infection of the lumen of the gu

Question 34

Toxicity of vancomycin

Answer 34

acute renal failure, due to toxic levels/lack of monitoring

Synergistic ototoxicity with other ototoxic drugs like gentamycin

Red Man Syndrome (see below) due to histamine release when drug is infused quickly in some patients.

Question 35

MOA of daptomycin

Answer 35

Daptomycin has a unique mechanism of action and does not work at the cell wall exactly. It depolarizes the cell MEMBRANE via Ca2+-dependent insertion of its lipophilic tail

With membrane depolarization comes K+ efflux and rapid death of the bacterium

Question 36

Toxicity for daptomycin

Answer 36

Myopathy (muscle breakdown), must check weekly creatine phosphokinase level when on this drug and warn patients about myopathy, if muscle pain develops and/or these enzymes become elevated, stop the drug.

Allergic pneumonitis which is an unique toxicity of the drug and presents with fever, bilateral lung infiltrates, and hypoxia

Question 37

MOA of fosfomycin

Answer 37

Inhibits the cytoplasmic enzyme enolpyruvate transferase, preventing formation of N-acetylmuramic acid,

This is a required component of the peptidoglycan layer and not a reaction used in mammalian cells

So, it does not directly inhibit the building of the cell wall, but rather inhibits creation of a key ingredient required for their creation.

The drug is actively transported into the bacterial cell, and resistance is due to inadequate transport of drug into the cell.

Question 38

MOA of bacitracin

Answer 38

Inhibits cell wall formation by disrupting cycling of bactoprenol lipid carrier that transfers peptidoglycan subunits to the growing cell; thus, the cell wall can’t grow.

Question 39

Bacitracin toxicity and what its used for

Answer 39

Bacitracin is not able to be used systemically due to its nephrotoxicity, but it is a very frequently used topical antibiotic for wounds as it has good gram postive coverage.

Question 40

Toxicity shared by vancomycin and gentomycin

Answer 40

ototoxicity - both can cause deafness, especially in combo