(01) Antibiotic Classes Flashcards
What are the 4 ways that antimicrobial agents can act through?
- Inhibition of Cell Wall synthesis
- Inhibition of Protein Synthesis
- Inhibition of Folic Acid biosynthetic pathways
- Inhibition of DNA/RNA synthesis
What type of bacteria is most sensitive to ß-lactams?
- why?
Gram + bacteria because they have a thick peptidoglycan cell wall
What protects gram - bacteria from ß-lactams?
Only have a thin cell wall that is protected by a LIPOPOLYSACCHARIDE layer
Why would you use a ß-lactimase inhibitor with penicillin?
- how does it work?
- what combinations are used?
- Resistant bacteria may have ß-lactimase present
- Bind to ß-lactimase to prevent them from cleaving ß-lactams
Combos:
- Clavulanic Acid + Amoxicillin
- Tazobactam + Pipercillin
Narrow-Spectrum Penicillins
- structural and functional difference?
Structural:
- Large side chains prevent ß-lactamases from twisting the penicillin into different stereoisomers
Functional:
- Side chains limit their spectrum of activity
Broad Spectrum Penicillin
- derivatives of…
- purpose
- administered with?
- Example?
Broad Spectrum Penicillins are derived from Aminopenicillins (extra amino group to cross LPS layer on gram - bacteria)
Purpose:
- kill more types of bacteria
Administered with:
- ß-lactamase inhibitors, because they are especially sensitive
E.g. Pip/Tazo
Imipenem
- what is it
- activity
- what is it administered with
- why?
Imipenem = ß-lactam
Activity:
- Broad Spectrum
Administered with Cilastin (not and antimicrobial)
Cilastin inhibits Dehydropeptidase-1 (DHP-1) in kidney brush boarder than breaks down Imipenem
**Results in increased urinary concentrations of imipenem
Describe the structural differences between penicillins and cephalosporins
Penicillin:
- Thiazolidine attached to ß-lactam ring
Cephalosporins:
- 6 membered ring attached to ß-lactam ring
What do ß-lactams inhibit?
Inhibit Penicillin-Binding Proteins
- This leads to breakdown of the cell wall because transpeptidases can’t do their job
What makes cephalosporins more user friendly?
- They can be taken with or without food
- They are more acid stable
What is the trend as you move from the 1st generation of cephalosporins to the 4th?
Gram + activity is lost as Gram - activity is gained
What is generally treated using 1st generation cephalosporins?
- 2 examples when specific types are used
Treats:
- streptococcus or staphylococcus
When:
- Cefazolin - surgical prophylaxis
- Cephalexin - most commonly perscribed Cephalosporin for outpatient use
What is generally treated using 2nd generation cephalosporins?
- when are these used?
Mild Gram - Bacteroides infections (anaerobic)
- intraabdominal infections
Would you use a second generation cephalosporin to treat a severe infection?
why or why not?
NO, because 3rd generation cephalosporins are more efficacious
When are 3rd generation cephalosporins typically used and how?
- 2 specific examples
Treat severe infections in combination with a drug of a different class (with a different MOA)
- Ceftriaxone - Treats STIs and Pediatric Meningitis
- Cefepime - treats pseudomonal infections
When are 4th generation cephalosporins used?
Nosocomial (hospital acquired) infections
- These have a tendency to be antibiotic resistant, more severe, or caused by gram - organisms
What is the mechanism of action (MOA) of Vancomycin?
- Attach to the ends of peptidoglycan precursor units (pentapeptides)
- Transglycosylase binds and can’t let go
- This prevents peptidoglycan synthesis
What kind of bacteria is Vancomycin effective against?
- why?
Gram + bacteria.
Effective because gram + bacteria have very thick cell walls and no new cell wall synthesis can occur
Compare the MOA of ß-lactam agents to Vancomycin.
ß-lactam:
- inhibits transpeptidases
Vancomycin:
- inhibits transglycosylases
When would you administer vancomycin orally vs. IV?
- why do you have to do this?
- Vancomycin is poorly absorbed by the digestive tract
Orally:
- Will kill things like C-Diff Colitis in the Colon
IV:
- Can work in blood, soft tissues, brain, heart, etc.
What is the mechanism of action for cephalosporins?
Inhibit Transpeptidases in the same way that penicillin does via the ß-lactam ring
What is the mechanism of action of fosfomycin?
- why is this significant
- Epoxide group irreversibly inhibits enolpyruvyl transferase by binding in place of PEP
- Blocks condensation of Uridine Diphosphate-N-acetyleglucosamine with p-enolpyruvate
**Key 1st step in bacterial cell wall synthesis
Aminoglycosides
- polarity
- consequences of polarity
- Toxicity?
Aminoglycosides are polar
Consequence:
- Poor Penetration of Biological Membranes
- NOT GIVEN ORALLY, NOT ABSORBED IN GI TRACT
Toxicity:
- Proximal Tubule is the only place Aminoglycosides are absorbed.
- Aminoglycosides accumulate in kidney cells and cause Nephrotoxicity
What is the mechanism of action of Aminoglycosides?
- what kind of infections do they treat?
- Irreversibly bind to 30s Ribosomal subunit of bacteria
Low Concentration:
- cause misreading of mRNA by ribosomes
High Concentration:
- Halt Protein Synthesis, trapping Ribosomes at the AUG start codon
- Cationic Antibiotic molecules create fissures in outer membrane allowing contents to leak
* Gram - bacterial infections
Why are aminolgycosides less effective against anaerobes?
Polar aminoglycosides must enter via active transport.
Anaerobes have less energy and are less likely to absorb the drug
What does bacteriostatic mean?
a drug that inhibits replication but does not actively kill existing bacteria is bacteriostatic
T or F: aminoglycosides are bacteriostatic like most other protein synthesis inhibitors
False, Aminoglycosides are bactericidal because they cause leaks in the membrane in addition to halting protein synthesis
What are the classes of protein synthesis inhibitors?
- Aminoglycosides
- Macrolides
- Lincosamides
- Tetracyclines
- Streptogramins
- Mupirocin
Macrolides
- MOA
- Common macrolides
- Bacteriostatic or Bacteriocidal
- Bind 23s RNA molecule of 50s subunit of bacterial ribosome and inhibit PEPTIDYLTRANSFERASE
- Phagocytized by Macrophages which is a WBC and will travel to site of infection and bring drug with it
- Erythromycin
- Azithromycin
- Bacteriostatic (bacteriocidal at high enough conc.)
Lincosamides
- MOA
- example of a lincosamide
- Bacteriostatic or Bacteriocidal
MOA
- bind 23S rRNA molecule of 50S RSU and block transfer of a new Aminoacid onto a growing chain
Clindamycin is a Lincosaminde
Bacteriostatic (bacteriocidal at high enough concentrations)
Why are lincosamides considered beneficial in toxin producing infections?
- Toxins are proteins or are made by proteins within the bacteria
- Since these block protein synthesis, they also block toxin production
Tetracyclines
- MOA
- Bacteriostatic or Bacteriocidal
MOA:
- bind REVERSIBLY to 16S rRNA of 30S RSU
- Weakens the ribosome-tRNA interaction and prevents addition of AA to growing peptide
Bacteriostatic
What are 2 characteristics of Tetracyclines that makes them selective for bacteria over human cells?
- Active transport system by which they are taken up is present only in bacteria
- Like the others, it is specific to prokaryotic Ribosomal subunits (30S)
Streptogramins
- MOA
- Relationship of Quinpristin and Dalfopristin
- Bacteriostatic or bactericidal
MOA:
- Bind to 50S RSU
Synergistic Relationship:
Quinupristin
- binds at same place as macrolides and has similar effect
Dalfopristin
- binds 50S near Quinprisitin causing conformational change that ENHANCES QUINUPRISTIN BINDING
- also directly interferes with chain formation
**Bactericidal
Mupirocin
- MOA
Inhibition of isoleucyl transfer-RNA synthetase
**Applied Topically
Chloramphenicol
- MOA
- Drug-Drug interactions, why?
MOA:
Binds to 50S RSU and at transpeptidyl transferase and inhibits trasnpeptidation reaction
Interferes with:
- Macrolides and Lincosamides because they have Clindamycin because they bind near the same site
Fluroquinolones
- MOA
- Bacteriostatic or Bactricidal?
MOA:
Gram -
- Inhibit DNA gyrase (topoisomerase II)
Gram +
- Inhibit DNA gyrase (topoisomerase IV)
- Prevents separation of replicated DNA into respective daughter cells
*Allows Double Strand break but prevents reattachment
Bactricidal:
- accumulation of DNA fragments leads to cell death
Why do Fluroquinolones not affect humans to any great extent?
we have different forms of Topoisomerase II and Topoisomerase IV
**Note: these are enzymes that relax supercoiled DNA
What is the MOA of Rifamprins?
Bind PROKARYOTIC RNA polymerase, prevents initiation of RNA synthesis
**does NOT affect elongation
What important characteristic of Rifamprin gives it access into many different enviroments?
- what are some examples of environments that it can access?
Rifamprin is lipofilic and can therefore penetrate into many different areas.
- Mycobacterial walls - contain long fatty acids (mycolic acids)
- Biofilms
- CNS - can treat meningitis
- Phagocytic cells - can kill bacteria that can live intracellularly
Cotrimioxazole
- Composition
- MOA
- uses?
Composition:
Trimethoprim and Sulfamethoxazole (sulfonamide)
MOA:
Sulfamethoazole
-prevents PABA from entering Folic Acid
Trimethoprim
- prevents reduction of Dihydrofolate to Tetrahydrofolate by DIHYDROFOLATE REDUCTASE
Uses:
- Uncomplicated UTIs and acute exacerbations of chronic bronchitiits
Why does Trimethorprim not affect human DHF reductase?
The drug is much more selective for the bacterial form.
100,000 times the normal dose is required to inhibit human dihydrofolate reductase
DAPTOMYCIN
- MOA
- Bacteria affected
- Bacteriostatic or Bactricidal?
- what system can it not be used to treat and why?
MOA:
- Lipopeptides bind to membrane and cause rapid depolarization
- Protein, DNA, and RNA synthesis is halted and cell dies
- Affects Gram + bacteria
- Bactricidal
- Doesn’t treat pulmonary infections because drug is deactivated by surfactant in lungs
Fidaxomicin
- MOA
- Cross resistance issues?
MOA:
- Inhibits sigma dependent transcription of Bacterial RNA polymerases
No Cross resistance (even with rifamprin)
Cell wall inhibitors 8 total
5 Penicillins
- Penicillin G
- Ampicillin
- Piperacillin
- Aztreonam
- Imipenem
3 others
- Ceftriaxone
- Vancomycin
- Cephalexin
8 protein synthesis inhibitors
Aminoglycosides:
1. Gentamicin
Macrolides:
- Azithromycin
- Clarithromycin
- Erythromycin
Oxazolidinones:
5. Linezolid
Tetracylines:
- Doxycycline
- Tigecyline
Others:
8. Mupirocin
7 Drugs that affect nucleic acid metabolism.
Fluoroquinolones
1. Ciprofloxacin
Rifamycins
2. Rifampin
Nitroimidazoles
3. Metronidazole
Dihydrofolate Reductase inhibitors
4. Cotrimoxazole
Sulfonamides
5. Cotrimoxazole
Others
- Daptomycin
- Fidaxomicin
