resp pharm 5
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- Initiation of protein synthesis
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– 30S and 50S do their thing w/ mRNA -> 70S
– Aminoglycosides block during initiation - Elongation and translocation of protein synthesis
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- requires hydrolysis of GTP
- tRNA binding to the “A†site is inhibited by Chloramphenicol, Tetracycline, and Clindamycin - Translocation of protein synthesis
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- requires hydrolysis of GTP
- blocked by erythromycin and spectinomycin - Aminoglycosides Mechanism of Action
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- bactericidal
– go into cyto via O2, so they only get aerobes
– once inside, they inhibit protein synthesis by binding 30S and makes initaion complex break down - Aminoglycosides administration
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– parenteral admin
– distribution good except to CSF
– [] dependent w/ a long post-antibiotic effect so single daily dosing to ↑ []’s is good
– excreted unchanged in urine
– 2.5 hr half life - Aminoglycosides Side effects
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- Ototoxicity, nephrotoxicity, which limit usefulness
– neuromuscular blocaid also noted - Gentamicin
- Aminoglycoside
- Aminoglycosides Anitmicrobial activity
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– aerobic (-) infections (Enterobacter, Klebsiella, E. coli, Proteus, Pseudomonas, Serratia)
– usually combo w/ B-lactam - Amikacin
- Aminoglycoside
- Aminoglycosides Resistance
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1) producing enzymes that that phosphorylate, adenylate, or acetylate it – 2) a ↓ in uptake
3) alteration of 30S binding site - Streptomycin
- Aminoglycoside
- Tobramycin
- Aminoglycoside
- Chloramphenicol Mechanism
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- binds to the 50S subunit of the 70S ribosome and inhibits peptidyl transferase
– static - Chloramphenicol Antimicrobial activity
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- for meningitis infections by H. ful or N. meningitidis if a ß-lactam is contraindicated or ineffective
– alternative to the tetracyclines in rockey mountain spotted fever - Chloramphenicol Administration
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– rapdily absorved from GI and distributes everwhere
– inactivated by glucuronyl transferase, so little is excreted unchanged
– liver disease can ↑ ½ life from 3 to 10 hrs - Chloramphenicol Toxic effects
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– Aplastic anemia with pancytopenia is rare but bad
– BM toxicity also seen
– grey-baby syndrome from circulatory collapse
– inhibits P450, so it can slow metabolism of P450 drugs (coumadin) - Chloramphenicol Resistance
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– production of CAT which acetylates and inactivates the drug
– plasmid mediated - Doxycycline
- Tetracyclines
- Minocycline
- Tetracyclines
- Tetracyclines Mechanism
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– static
- binds to the acceptor site on the 30S of 70S to block binding of the A-tRNA - Tetracyclines Antimicrobial activity
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– 1st choice or alternative for M pneumoniae, rickettsial Chlamydiae, V. cholera
- Brucella (w/ an aminoglycoside or rifampin)
- Borrelia infections - Tetracyclines Administration
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- oral (impaired by milk, antacids, or iron) or IV
– Distribution good except for CSF
– removed by liver then circulate in enterohepatic route
– eliminated in feces and urine
– 6-15 hr ½ life - Tetracyclines Side Effects
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- GI irritation most common
– Photosensitivity w/ doxy
– hepatotoxicity if OD
– it will deposit in bones and teeth, so avoided in pregnant women and children under 8
- renal toxicity if given with potentially nephrotoxic drugs or if patient already has impaired renal function - Tetracyclines Resistance
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1) ↑ efflux by an active transport pump
2) production of proteins that interfere w/ binding - Azithromycin
- Erythromycin
- Clarithromycin
- Erythromycin
- Erythromycin Mechanism
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- static
– binds 50S of 70S and blocks translocation from the A to P site - Erythromycin Antimicrobial activity
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- 1st choice for Legionnaire's disease, M. pneumoniae, and C. trachomatis
– alternative for various strep and Anthrax - Erythromycin Admin
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- given orally
– C and E better absorbed than A
– well distributed except CSF
– excreted in bile - Erythromycin Toxcity
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- GI effects occasionally and sometimes intolerance requires discontinuation
- Hepatotoxicity, fever, eosinophilia, and rashes also seen
– E and C inhibit P450
– don’t use > 1 b/c they are antagonistic - Clindamycin Mechanism
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– static
– binds 50S of the 70S ribosomal to block peptidyl transferase - Clindamycin Antimicrobial activity
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- for anaerobic infections Bacteroides, C. perfringens, Strep. anaerobic (peptostreptococcus) and Staph aureus
– C + primaquine is alternative to trimethoprim/sulfamethoxazole for PCP in AIDS patients
– also w/ pyrimethamine for AIDS-related toxoplasmosis - Clindamycin Admin
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- orally or parenterally
– widely distributed except CSF
- 10% excreted unchanged b/c it is metabolized in liver and excreted in the bile
- Small quantities found in feces for up to 2 weeks (GI) - Clindamycin Toxicity
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– GI irritation, skin rashes, and hepatotoxicity common
- Severe diarrhea due to outgrowth of C. difficile, which produces a necrotizing toxin - Clindamycin Resistance
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1) Mutation of the ribosomal binding site
2) Production of a methylase
3) Inactivation - Dalfopristin
- Streptogramins
- Quinupristin
- Streptogramins
- Streptogramins Mechanism
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- binds 50S of 70S, constricting the exit channel of the nascent peptide
- cidal - Streptogramins Antimicrobial activity
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- for vancomycin-resistant E. faecium (but not E. faecalis!)
– other potential uses for MRSA, penR-S. pneumoniae, and GAS, GBS - Streptogramins Administration
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- 70:30 (dalfopristin : quinupristin)
- oral or parenterally
– liver elimination
- t1/2 ~ 1.5 hr - Streptogramins Toxicity
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- well tolerated
- Hepatotoxicity in 1%
- also hypersensitivity, rash, diarrhea, NandV, & myalgia - Linezolid
- Oxazolidinones
- Oxazolidinones Mechanism
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- synthetic
– binds to the 50S and prevents 70S fromation
– usually static but can be cidal - Oxazolidinones Antimicrobial activity
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– to treat MRSA, vancomycin-resistant E. faecium and E. faecalis (VRE), penR-S. pneumoniae, and GAS and GBS
- Resistance recently noted (mutations in 23S rRNA) - Oxazolidinones Administration
- – IV and oral
- Oxazolidinones Toxicity
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– reversible MAO inhibitor, so don’t give w/ MAOIs, tricyclic antidepressants, etc
– avoid tyramine – can ↑ brady in patients taking B-blockers
– thrombocytopenia and superinfections also seen - Metronidazole Mechanism
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– only taken up anaerobes – converted to active metabolite
– disrupts DNA and cidal - Metronidazole Antimicrobial activity
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– 1st choice for C. difficile and Bacteroides fragilis
- has been used for acute dental infections like Vincent's gingivostomatitis
– best one for trichomonias, giardia, and amebia - Metronidazole Administration
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– IV but can be given oral
- Widely distributed
– extensively metabolized & inactivated in the liver
– metabolites and unchanged drug excreted by the kidneys - Metronidazole Toxicity
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– Nausea, headache, dry mouth are common
– Diarrhea, epigastric distress and insomnia more rare
– disulfiram-like action after alcohol
- Carcinogenic and teratogenic in animals and mutagenic to bacteria
– don’t take in pregnancy