Antimicrobials Part 1 (Cell Wall Synthesis Inhibitors) Flashcards
What is prophylactic therapy? What groups should you consider for this type of therapy?
Pre-treatment to prevent infection in patients with weakened defenses (immunocompromised states).
Used for individuals on immunosuppressive therapy, cancer patients, and in pre-surgical procedures.
What is empiric therapy? How is an antibiotic selected in this case?
Treatment of known or probably infection.
Agent selected based on rational judgement and experience, not just “broad spectrum”.
What is definitive therapy? How might this be favored in comparison to empiric therapy?
Pathogen’s identity and antibiotic susceptibility is determined.
Compared to empiric therapy, this reduces risk of resistance emerging to broader-spectrum agents.
What are two reasons to choose a narrow-spectrum agent over a broad-spectrum agent?
- Reduces risk of superinfection and opportunistic infections (C. difficile)
- Reduces risk of community resistance development
What are the two ways cell wall synthesis inhibitors weaken the cell wall of bacteria?
- Transpeptidase inhibition: Disrupts transpeptidase, which catalyzes the formation of cross-bridges between peptidoglycan polymer strands
- Autolysin activation: Increases the activity of enzymes critical for breaking down cell wall segments to permit growth and division
Transpeptidase and autolysin are also known as _____.
Penicillin-binding proteins
Penicillins bind to them to produce a lytic effect (bactericidal).
Where are penicillin-binding proteins (PBPs) located?
On the cell membrane of both gram-positive and gram-negative bacteria.
Do penicillins work on bacteria that lack a cell wall?
NO
If bacteria lack a cell wall, they also lack PBPs and therefore, penicillin cannot bind.
What are the three steps in which this class of antibiotics can interfere with peptidoglycan synthesis?
- Inhibition of synthesis of murein monomers (e.g. fosfomycin)
- Inhibition of polymerization of murein monomers into the glycan backbone (e.g. vancomycin)
- Inhibition of glycan polymer cross-linking into peptidoglycan (e.g. beta lactams and “others”)
Cell wall synthesis inhibitors are primarily effective against ______ ______ bacteria.
Gram-positive
Gram-negative bacteria are intrinsically resistant to many drugs from this class.
Some gram-negative species express ______ _______ permeable to some antibiotics (e.g., ampicillin, amoxicillin, but NOT vancomycin)
Porin channels
Note: Some species lack porin channels (Pseudomonas aeruginosa)
What are 3 resistance mechanisms that gram-negative and gram-positive bacteria can acquire/develop?
- Altered PBPs (e.g. MRSA)
- Expression of efflux pumps (e.g. multidrug-resistance protein; Klebsiella pneumoniae)
- Beta-lactamase enzymes that degrade beta-lactam drugs (most S. aureus and an increasing number of Streptococci)
The ______ ______ ______ is the common core structure of all beta-lactam drugs which ______ penicillin-binding proteins at the penicillin binding site.
Beta-lactam ring, acetylates
The acetylation of penicillin-binding proteins at the penicillin-binding site ______ the enzyme.
Inactivates
The spectra and specific properties of beta-lactam drugs vary based on identities of the ______ ______.
R groups
Penicillinase, cephalosporinase, and AmpC-lactamase are examples of ______ ______.
Beta-lactamases
Which subclass of beta-lactams are largely resistant to beta-lactamases?
Carbapenems
Name 4 common beta-lactamase inhibitors
- Clavulanic acid/clavulanate
- Sulbactam
- Tazobactam
- Avibactam
Beta-lactamases can be inhibited by ______ beta-lactam drugs with other agents
Co-administering
Methicillin is an example of how ______ ______ of drug structure can make beta-lactams more resistant to beta-lactamse inactivation
Chemical modification
What is penicillin’s principal adverse drug reaction (ADR)?
Allergic reactions
Osmotic pressure is ______ inside the bacterial cell membrane and cell wall. Disruption of the cell wall makes the cell favor water ______. A functional cell wall ______ the cell from expanding and bursting. Penicillins ______ the cell wall and cause bacteria to ______ ______ water and ______.
High, absorption, prevents, weaken, take up, rupture
What are the three groups of penicillins organized by spectrum of activity?
- Natural penicillins
- Anti-staphylococcal penicillins
- Extended-spectrum agents (aminopenicillins and antipseudomonal penicillins)
Natural penicillins are ______ spectrum.
Narrow
Natural penicillins target gram-______ organisms and are sensitive to penicillinases.
Positive
Clinical uses of natural penicillins (5)
- Pneumococcal infections (S. pneumoniae) - pneumonia and meningitis (can cross the BBB)
- Gonorrhea (Neisseria) - except penicillinase-expressing strains
- Gas gangrene (C. perfringens)
- Syphilis (Treponema pallidum) - single IM dose is curative
- Pharyngitis (beta-hemolytic Streptococcus)
___% of S. aureus strains are resistant to natural penicillins
90%
Penicillin G is administered ____ or ____
IV, IM
Penicillin V can be administered PO, but use in severe infections is discouraged due to ______ ______.
Poor bioavailability
Natural penicillins distribution, half life, and excretion
Distributed throughout the body
t 1/2 = 30 minutes
Renally excreted
Benzathine can ______ penicillin G for IM repository (low but prolonged drug levels).
Stabilize
Natural penicillins DDIs (1)
Anti-gout drug, probenecid, blocks renal transporters and increases penicillin half-life
Natural penicillin considerations
Dose adjustment required for patients with impaired renal function
Pediatric dosage of natural penicillins is determined by the child’s ______ ______.
Body weight
Natural penicillins ADRs (5)
Otherwise, usually well-tolerated
- Hypersensitivity (Type I, immediate due to repeat exposure) - 10% of patients self-report an allergy (rash, angioedema, anaphylaxis) to penicillin (contraindication). All other beta-lactams are contraindicated in patients with a previous allergic reaction to penicillin.
- Diarrhea: disruption of the normal balance of intestinal microorganisms. Can lead to superinfections caused by C. difficile.
- Nephrotoxicity: acute interstitial nephritis
- Neutotoxicity: may provoke seizures. Contraindicated in patients with epilepsy.
- Hematologic toxicities: decreased coagulation, cytopenias; monitor CBCs
Anti-staphylococcal (penicillinase-resistant) Penicillins Drugs (4)
- Methicillin
- Nafcillin
- Oxacillin
- Dicloxacillin