Antibiotics-Protein synthesis inhibitors Flashcards
What is the coverage spectrum of Penicillin?
Some gram negative bacteria and all gram positives
What is the coverage spectrum of Cephalosporins?
Gram negatives and gram positive bacteria
What are the major differences between eurkaryotes and prokaryotes?
1) Prokaryotes have cell walls whereas eukaryotes do NOT
2) Prokaryotes use 30s/50s ribosomes whereas eukaryotes use 40s/60s ribosomes
3) Prokarytoes DON’T need preformed folate for RNA/DNA synthesis
- remember that both prokaryotes and eukaryotes use topoisomerase but drugs are often more sensitive to bacterial topoisomerase
What are the general features of antibiotics that inhibit protein synthesis?
1) Selective to bacterial ribosomes
2) Have broader spectrum than ß-lactams - all bacteria need protein synthesis to grow
3) Bacteriostatic (with the exception of one group): affect reproduction > integrity (allows the immune system to take over)
Which antibacterial acts by inhibiting action at 30S and 50S subunit of the ribosome?
Aminoglycosides
Which antibacterial acts by inhibiting action at the 30S subunit of the ribosome?
Tetracyclines
Which antibacterials act by inhibiting the action of the 50S subunit of the ribosome?
(i) Macrolides
(ii) Clindamycin
(iii) Linezolid
What are the mechanisms of aminoglycosides?
1) Binds to two receptor sites => 16S RNA, 23S RNA and other ribosomal proteins
2) Leads to wrong base incorporation and misreading of mRNA
3) Translocation (30S binding) and recycling blocked (50S binding)
What additional mechanism does streptomycin have over other aminoglycosides?
Streptomycin can block initiation
Are aminoglycosides bacteriostatic or bactericidal?
Aminoglycosides are bactericidal unlike most other protein synthesis inhibitors
- however at low concentrations it is bacteriostatic
Why are aminoglycosides bactericidal?
Aminoglycosides transport easily into bacterial cells:
- Passive diffusion through the porin channels of the outer membrane
- Energy-dependent, rate-limiting transport through the plasma membrane (inhibited under anaerobic conditions)
Cytotoxicity:
- Drug-induced mutated proteins inserted into the plasma membranes enhance uptake of the drug
What is the most common cause of aminoglycoside resistance?
Inactivating enzymes (acetylases, adenylases )
What are other methods of aminoglycoside resistance?
1) Membrane impermeability
2) Mutation of the binding site
3) Methylation of rRNA
What is the historic use of streptomycin?
Mycobacterium TB (not used in US any more)
What is the coverage of gentamicin and tobramycin?
1) Aerobic gram negative rods
2) Gram positive if synergy with beta lactams
What group of bacteria are resistant to aminoglycosides?
Anaerobes are resistant
What is the best way to administer aminoglycosides?
- Poor oral absorption (poorly distributed to tissues)
- IV and IM
What is the post antibiotic effect of aminoglycosides for gram negative aerobes?
Significant post-antibiotic effect (GN aerobes only):
-Drug keeps acting although the microbe is no longer exposed to it
What are the major side effects of aminoglycosides?
1) Nephrotoxicity (acute tubular necrosis)
2) Ototoxic (auditory and vestibular)
- high-pitched sounds affected first, irreversible
3) Bone marrow suppression
4) Muscle weakness
5) Allergic reactions - rashes
What is concentration dependent killing?
Concentration dependent killing -exposure to higher concentration of the drug is more efficient (even if it is short); there is no benefit of longer exposure
What drugs exhibit concentration dependent killing?
1) Aminoglycosides
2) Fluoroquinolones
3) Metronidazole
What is time dosing dependent killing?
TDK - you need longer exposure (e.g., frequent dosing)
What are dosing considerations for aminoglycosides?
Extended (EID, once daily) interval dosing to reduce toxicity.
- Concentration-dependent killing
- Toxicity both time and concentration dependent
- Significant post-antibiotic effect (GN aerobes only)
- Watch out for renal dysfunction
What are the main aminoglycosides?
streptomycin, gentamicin, tobramicin, amikacin
What are the main tetracyclines?
Doxycycline, teracycline, minocycline
What is the mechanism of tetracyclines?
Binds to 30S subunit & blocks amino-acyl-tRNA binding resulting in the elongation block
How does bacterial resistance to tetracyclines develop?
- Reduced cell permeability-efflux pumps
- Reduced binding to ribosomal 30S site
- Inactivation by enzymes
*Rarely used in US because of resistance
Describe the absorption of tetracyclines.
- Well absorbed from the gut
- reduced absorption with food and chelators e.g. Al(OH)3
- Good tissue penetration (fairly large Vd)
- Doxycycline - mainly hepatic metabolism
What are the main side effects of tetracyclines?
- Gastrointestinal intolerance (N/V/D)
- Hepatotoxic
- Skin photosensitivity
- Never use in pregnancy, neonates, children- deposits in enamel of teeth and bone
- Doxycycline is the only tetracycline that can be used in renal failure
What are the primary macrolides?
- Erythromycin
- Azithromycin
- Clarithromycin
What is the mechanism of macrolides?
Binds to and block polypeptide release channel on 50S
How does macrolide resistance develop?
1) Role of 23S rRNA- nucleotide 2058 (a part of 50S)
- Modification of A-2058 (chromosomal mutation or induction of methylase) leads to resistance
2) Efflux or reduced permeability
3) Mutation or modification of the binding site
4) Production of esterase (by Enteriobacteriaceae)
*Strep pneumoniae and Staph aureus are often resistant
What are the principle uses of azithromycin?
- Respiratory tract infections
- Gram positive cocci, Mycoplasma, Legionella, Chlamydia, H. influenzae, Mycobacteria
- Can be used in penicillin-allergic individual
Describe the pharmokinetics of macrolides?
- Well absorbed in the GI tract
- Hepatic metabolism
What toxicity is associated with macrolides?
- Allergy-skin rashes
- Hepatitis 2-5%
- Gastrointestinal upsets (N/V/D)
- Ototoxic-especially in elderly
What is the mechanism of clindamycin?
- Binds to the 50S subunit on a 23S rRNA binding site and interferes with the peptide bond formation
- Binding site partially overlaps with macrolides
How does clindamycin resistance develop?
- Mutual interference if co-prescribed with the macrolides
- Resistance mechanisms same as with macrolides
What is the use/spectrum of clindamycin?
- Used for skin and soft tissue infection + dental
- Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents
- Bacteriostatic
- Gram positive cocci (Staph. and Strep.)
- Oral and bowel anaerobes (50% Bacillus fragilis)
Describe the pharmacokinetics of clindamycin?
- Well absorbed from the gastrointestinal tract
- Good tissue penetration (large Vd) concentrated intracellularly
- Hepatic metabolism
What are the side effects of clindamycin?
- Hypersensitivity reactions: skin rashes
- Gastrointestinal intolerance: N/V/D but also pseudomembranous colitis (C.difficile)
- Hepatotoxic-hepatitis
- Bone marrow suppression - WBC
What is the mechanism of Linezolid?
- Binds to 23S rRNA of 50S at the A site
- Blocks formation of the initiation complex
How does linezolid resistance develop?
- Mutation of 23S rRNA binding site
- No cross-resistance with other drug classes
What is the spectrum of linezolid?
- Used to treat VRE, VRSA and MRSA
- Wide range of gram positive organisms susceptible
- Bacteriostatic against staph and enterococci
- Bacteriocidal for most strep
What are the side effects of linezolid?
- Hematologic : leukopenia/thrombocytopenia & aplastic anemia
- Gastrointestinal intolerance: N/V/D
- Biochemical hepatitis
