Cell Wall Antibiotics Flashcards
Concept behind structure of beta lactam rings and side chains
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
Penicillin abbreviation
PCN
MOA for PCN
Covalent binding to PBP
Can’t cross-link wall
Induction of autolytic enzymes
Bacterial cell ruptures due to high intracellular osmotic pressures
What is most common mechanism of resistance to PCN
Destruction of antibiotic by β-lactamase
Also: Failure of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets
Most common mech of resistance in mrsa and strep pneumoniae, and gene mutation is carried on
Low-affinity binding of antibiotic to target PBP - carried on mecA gene
Unique structural change for antistaphylococcal PCN
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.
Examples of antistaphylococcal PCN
nafcillin and oxacillin
How do beta-lactamase scavengers work
Beta-lactamase scavengers act as competitive inhibitors for the beta-lactamase enzymes
Examples of B lactamase scavengers
clavulanic acid or sulbactam
Use of extended spectrum PCN
have increased gram – coverage due to smaller size of molecule. These can also be complexed with beta-lactamase scavengers
Examples of extended coverage PCN
Ampicillin and amoxicillin
only penicillins that cover Pseudomonas
Ticarcillin and piperacillin
Dosing and administration of PCN
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
Adverse rxns for all antibiotics
- 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.
PCN adverse rxns
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
What immune response to PCN is an allergy
An IgE repsonse - anaphylaxis would occur
IgM and IgG can be made to the breakdown products of PCN and cause reactions
What is the actual risk of giving cephalosporins to patients with a confirmed or reported PCN allergy
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.
MOA of cephalosporins
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.
Important bacteria cephalosporins do not work well against
Enterococci and Listeria monocytogenes. Fifth generation cephalosporins are again an exception to this rule.
First gen cephalosporins are most active against:
Gram-positive cocci
Coverage for second gen cephalosporins and common examples
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
Third gen cephalosporins coverage and examples
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.
Example of fourth gen cephalosporin
cefepime and it is used frequently for neutropenic fever patients to cover a broad spectrum of resistant bacteria
What makes 5th gen cephalosporins unique
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.
Examples of 5th gen cephalosporins
ceftaroline and ceftolozane (only cephalosporine coupled with a B lactamase scavenger)
Example of monobactams and clinical use
Aztreonam is the only drug, and is only active against aerobic gram – rods, which include Pseudomonas aeruginosa. No activity against anaerobes.
What are carbapenems
Beta-lactam drugs. Carbenapenems have a conformational change around the beta-lactam ring that makes them intrinsically resistant to regular beta-lactamases.
Example and use of carbapenems
imipenem, and it is paired with cilistatin, a drug that prevents renal tubular inactivation by the dehydropeptidase-1 enzyme to prolong the half life.
Toxicities for carbapenems
Toxicity seen in this class includes decreased mental status and seizures.
MOA of vancomycin
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.)
Spectrum of vancomycin
Only gram positive
Cause of vancomycin resistance
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.
Can vancomycin be given orally?
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
Toxicity of vancomycin
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.
MOA of daptomycin
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
Toxicity for daptomycin
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
MOA of fosfomycin
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.
MOA of bacitracin
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.
Bacitracin toxicity and what its used for
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.
Toxicity shared by vancomycin and gentomycin
ototoxicity - both can cause deafness, especially in combo
