Antimicrobials III: Protein Synthesis Inhibitors Flashcards
DNA/RNA Synthesis Inhibitors
Indirect: folate antagonists
Direct: Quinolones and other drugs
What do protein synthesis inhibitors target?
bacterial ribosome–> prevents growth
Most are bacteriostatic
some are bactericidal
What are 3 issues with protein synthesis inhibitors?
- need access to ribosomes
- mode of resistance is antibiotic efflux and reduced uptake by bacteria
- bacterial-produced enzymatic deactivation
Bacterial Protein Synthesis Step 1
charged tRNA unit delivers an amino acid to acceptor site on 70S ribosome
Bacterial Protein Synthesis Step 2
tRNA at the donor site, with an amino acid chain binds the growing chain to a new amino acid
Bacterial Protein Synthesis Step 3
uncharged tRNA left at donor site is released
Bacterial Protein Synthesis Step 4
new amino acid chain w/ tRNA is translocated to peptidyl side
Tetracyclines and Aminoglycosides affect which step in bacterial protein synthesis?
Step 1 - bind the 30S subunit and prevent the binding of incoming charged tRNA unit
Macrolides, Clindamycin, and Chloramphenicol affect which step in bacterial protein synthesis?
Step 2 - bind tot he 50S subunit and block peptide bond formation
Target 30S subunit (2)
- aminoglycosides
- gentamicin, amikacin, tobramycin, neomycin, streptomycin - tetracyclines
- doxycycline, tetracycline, tigecycline(IV), minocycline
Target 50S subunit (5)
- lincosamides
- clindamycin - Macrolides
- azithromycin, clarithromycin, erythromycin - Streptogramins
- quinupristin/dalfopristin(IV) - Oxazolidinones
- linezolid - Amphenicols
- chloramphenicol
Aminoglycosides (ANGST) MOA
ANGST: amikacin, neomycin, gentamicin, streptomycin, tobramycin
- broad-spectrum
- bind to 30S subunit = prevent initiation of protein synthesis–> causing misreading of RNA
- bacteriostatic
Aminoglycosides are primarily used against gram ________
negative bacilli–> E. coli, Klebsiella pneumoniae, P. aeruginosa
Aminoglycosides are toxic to the ______ and ______.
kidney and inner ear - binds to renal tissue and may reach toxic concentrations in kidney and inner ear (neomycin and streptomycin)
How are aminoglycosides administered? Half-life?
parenterally –> IV, IM
2-3hrs
Aminoglycosides: excretion
excreted unchanged in the urine
Aminoglycosides: ADRs
- ototoxicity: balance/vertigo, deafness
- neurotoxicity: blockade of presynaptic release of ACh at NMJ and postsynaptic blockade–> weakness and respiratory depression
- hypersensitivity rxns
Aminoglycosides: Contraindications
myasthenia gravis; also avoid w/ pregnancy
Tetracyclines: Names and MOA
- doxycycline, tigecycline(IV), minocycline, tetracycline
- broad-spectrum against gram +/-
- bind reversibly to 30 S subunit –> preventing tRNA from binding to the mRNA-ribosome complex
How does resistance to tetracyclines occur? (3)
- acquire efflux pathways
- produce protein blocking it from binding to ribosome
- enzymatically inactivate the drug
Tetracyclines: Spectrum
activity MSSA and MRSA
Tetracyclines: Don’t Take With?
Antacids and dairy–> antibiotics form chelates with divalent metal ions
Tetracyclines: Metabolism and Excretion
- hepatically
- feces and urine
Tetracyclines: DDIs
digoxin, CYP substrates(warfarin) or inducers(carbamazepine, alcohol, barbiturates, etc)
Tetracyclines are ______% bound by serum proteins
40-80%
Tetracyclines: ADRs
- hypersensitivity = rare
- phototoxicity
- GI: nausea, vomiting, diarrhea
- bind to newly formed bone or developing teeth
- hepatotoxicity
- nephrotoxicity
- dizziness, vertigo, tinnitus
Tetracyclines: Contraindications
- children under 8
- pregnancy
- pt with preexisting liver disease
Macrolides: MOA and Names
- azithromycin and erythromycin = PO and IV
- clarithromycin = PO
- bind reversibly to 50S subunit and inhibits translocation of the growing peptide/ may also interfere with transpeptidation
- bacteriostatic
Macrolides: Spectrum
- broad-spectrum
- effective against many gram +/- organisms susceptible to penicillin G
- good alternative if pt has penicillin allergy
Macrolides: Resistance (3)
- efflux pumps
- decreased affinity of 50S subunit for antibiotic = gram+
- enzymatic degradation = gram-
Macrolides: ADR (3)
- ototoxicity
- cardiotoxicity
- many DDIs w/ agents for competing for CYP450 metabolism
Streptogramins: names
quinupristin and dalfopristin
Streptogramins: MOA
- derived from streptomyces pristinaespiralis
- both bind to 50S at different sights
- Q = prevents elongation/release of incomplete peptide chains
- D = disrupts elongation/interferes w/ addition of new peptides onto chain
Streptogramins: Spectrum
- bactericidal = gram + cocci
- bacteriostatic = Enterococcus faecium and VRE strains
- also for atypical pneumonia
Streptogramins: Resistance (2)
- enzymatic deactivation
- efflux pump
Streptogramins: Pharmacokinetics
hepatically metabolized and excreted in feces –> good for those w/ MRSA and renal problems
Streptogramins: ADRs (2)
- hyperbilirubinemia
2. metabolism by CYP3A4 leads to DDIs w/ inducers/inhibitors
Oxazolidinones: name
linezolid
Oxazolidinones: MOA
binds to the 23S ribosomal RNA of the 50S inhibiting the formation of the 70 S complex
- bacteriostatic
- bactericidal against streptococci
Oxazolidinones: Spectrum
- drug-resistant, aerobic, gram +
- alternative to daptomycin for Vancomycin-resistant enterococci (VRE)
Oxazolidinones: Resistance (1)
reduced binding to target site
Oxazolidinones: Pharmacokinetics
excreted by renally and biliary
Oxazolidinones: ADRs/DDIs (3)
- neurotoxicity = irreversible peripheral neuropathy and optic neuritis = blindness
- HTN
- serotonin syndrome
Chloramphenicol: Spectrum
- broad-spectrum
- aerobic and anaerobic EXCEPT P. aeruginosa
Chloramphenicol: Major Toxicity
high circulating chloramphenicol levels can lead to mitochondrial ribosomes to also be affected leading to BONE MARROW TOXICITY
Chloramphenicol: ADRs (2)
- bone marrow depression/aplastic anemia (can be fatal)
2. Gray baby syndrome (often fatal): babies can’t conjugate drug
Lincosamides: name
clindamycin
Lincosamides: Spectrum
- bacteriostatic against gram +
- MRSA, streptococcus, anerobic bacteria
Lincosamides: Pharmacokinetics
100% orally bioavailable
Lincosamides: ADR
high risk of C. difficile superinfection
DNA/RNA Synthesis Inhibitors: 2 Types
Indirect: folate antagonists
Direct: Quinolones and other drugs
Fluoroquinolones: Names
ciprofloxacin, levofloxacin, moxifloxacin
Fluoroquinolones: MOA
inhibit DNA gyrase and topoisomerases in inhibition of DNA replication
Fluoroquinolones: Spectrum
B. anthracis, Mycobacterium sp., Listeria sp., Chlamydia sp., UTIs, anaerobic, resistant respiratory infections, GI infections
Fluoroquinolones: Pharmacokinetics
- well absorbed orally
- divalent cations impair absorption
- renal elimination
Fluoroquinolones: ADRs (4)
- discontinue if: nausea, vomiting, headache, dizziness
- phototoxicity
- cardiotoxicity - prolong QT interval
- inhibit CYP450 - 1A2 and 3A4
Folic Acid/Folate Antagonists: Name
cotrimoxazole
Folic Acid/Folate Antagonists: Spectrum
- broad and bacteriostatic
- gram + cocci and gram - bacilli, actinomycetes, chlamydia and protozoa, UTIs
Folic Acid/Folate Antagonists: MOA
competitive inhibitor of folic acid synthesis
- inhibits dihydrofolate reductase and dihydropteroate synthesis
Sulfonamides: Pharmacokinetics
- well absorbed orally
- bound to serum albumin and widely distribute throughout body tissues including CSF and fetal tissues
Sulfonamides: ADRs (3)
- nephrotoxicity = crystalluria
- hypersensitivity = rashes, angioedema, Stevens-Johnson syndrome
- Kernicterus = hyperbilirubinemia-associated brain damage in newborns
Cotrimoxazole/TMP-SMZ: Spectrum
- fixed dose
- UTIs, prophylactic and resolving certain opportunistic infections in AIDS, S. typhii
