Protein Synthesis Inhibitors Flashcards
Examples of Tetracyclines?
- Tetracycline
- Doxycycline
- Minocycline
Mechanism of Action of Tetracyclines?
- enter organism by passive diffusion or energy-dependent transport protein
- bind reversibly to 30S subunit of bacterial ribosome, preventing binding of tRNA to A site of mRNA-ribosome complex – inhibiting bacterial protein synthesis
How should tetracyclines be administered?
Absorbed after oral ingestion, best on empty stomach
avoid administration with dairy products (contains calcium) or substances with divalent or trivalent cations - decreases absorption due to formation of non-absorbable chelates
Can tetracyclines cross CSF?
moderately, more for minocycline and doxycycline
For Tetracyclines:
a) route of administration
b) target organisms
c) elimination
d) pregnancy use. why or why not.
a) all oral
b) tetracycline: rickettsia, chlamydia, mycoplasma pneumoniae, vibrio cholerae, yersnia pestis; doxycycline: those covered by tetracycline, acne vulgaris, bacillus anthracis, s. pneumoniae, h. influenzae (CAP), MRSA (soft tissue infections), borrelia burgdorferi (Lyme disease); minocycline: those covered by tetracycline, h. influenzae, klebsiella
c) tetracycline by kidney; doxycycline by bile and urine; minocycline: liver
d) Category D (NO)
What drug was designed to overcome tetracycline resistance? What two mechanisms of resistance does it overcome? Mechanism of Action?
Tigecycline
- Efflux pumps + Ribosomal Protection
same mechanism of action as tetracyclines
For Tigecycline,
a) Route of Administration
b) Penetration into tissues + CSF?
c) Elimination?
d) Pregnancy use?
e) Target Organisms?
a) IV
b) Well into tissues, low plasma concentration (pls dont use in bloodstream infection); reaches CSF concentrations of 10% of that found in serum with uninflamed meninges
c) Biliary or Fecal
d) Cat D (NO)
e) MRSA, Multidrug resistant Strep, VRE, ESBL, CAP
Adverse effects of tetracycline and tigecycline?
- Gastric Discomfort
- Effects on Calcified Tissues (gives grey teeth) (NO use on oregnant or breast-feeding women or in children <8)
- Hepatotoxicity
- Phototoxicity
- Vestibular Dysfunction
- Renal
- Superinfection = CDAD
What are drug-drug interactions of tetracyclines and tigecyclines?
- Enhance oral sulfonylureas, digoxin, lithium, theophylline
- Reduce efficiacy of oral contraceptives, warfarin
- NO to together with beta lactams
What is the mechanism of action of aminoglycosides?
- diffuse thru porin channels in outer membrane of gram-neg bacteria, transported across inner membrane via active transport
1. Block formation of initiation complex
2. Cause misreading of codons
3. Inhibit translocation
How to enhance entry of aminoglycosides into bacteria?
Cell wall synthesis inhibitors like beta lactams (synergism)
How to inhibit the energy-dependent phase of aminoglycosides entry into bacteria
anaerobic conditions, drop in pH, hyperosmolarity
Names of aminoglycoside antibiotics?
Gentamicin
Tobramycin
Amikacin
Streptomycin
Neomycin
For aminoglycosides,
a) absorption
b) distribution
c) CSF
d) elimination
a) mainly parenteral, except neomycin (oral for bowel prep)
b) variable penetration into most body fluids - dosed based on lean body mass, not actual weight
c) inadequate CSF, even with inflamed meninges
d) renal, neomycin is 97% thru feces
effect of aminoglycosides on pregnant women?
can cross placental barrier and accumulate in fetal plasma and amniotic fluid
for central nervous system infections, how can aminoglycosides be administered. which aminoglycoside?
gentamicin intraventricularly
aminoglycosides are usually used in combination with ____. Why?
Cell Wall active agents.
1. Expand empiric spectrum activity
2. Synergistic Bacterial Killing
3. Prevent emergence of resistance to individual agents
for gentamicin, what are the main organisms is targets?
- proteus, pseudomonas, klebsiella and other MDR gram negs
- combination with penicillin for enterococcal endocarditis (gram pos)
for tobramycin, what are the main organisms is targets?
pseudomonas aeruginosa, alongside anti pseudomonal antibiotics
NO vs enterococci
for amikacin, what are the main organisms is targets?
proteus, p. aeruginosa, klebsiella (2nd line), enterobacter, e coli
m. tb
enterococci (2nd line)
NO vs most other gram pos anaerobic
for streptomycin, what are the main organisms is targets?
yersinia pestis
enterococcal endocarditis (with penicillin) (2nd line)
tb
not so good as other aminoglycosides as aerobic gram negs
for neomycin, what are the main organisms is targets?
e. coli, klebsiella
s. aureus, e. faecalis
bowel prep
What are adverse effects of aminoglycosides?
- Ototoxcity
- Nephrotoxcity
- Neuromuscular paralysis
- hypersensitivity
- contraindicated in pregnancy
What are precautions in aminoglycosides? think abt the adverse effects
- caution if pt with renal impairment, hearing defect of MG
- avoid use with nephrotoxic drugs
- therapeutic drug monitoring
- renal function tests
6 NOs of aminoglycosides?
- NO protein synthesis
- mainly aerobic gram Negative Organisms
- No in pregnancy
- NO in oral administration
- NO CSF penetration
- Nephro and Oto toxicities
Resistance to aminoglycosides mechanisms?
- Efflux pumps
- Inactivating enzymes
- Alteration of 30S ribosomal subunit
- Inhibition of uptake by bacteria
State the 3 classes of 50S protein synthesis inhibitors
- Macrolides
- Clindamycin
- Linezolid
What are 3 examples of macrolide antibiotics?
- Erythromycin
- Clarithromycin
- Azithromycin
Which macrolide is an alternative to patients with penicillin allergy
erythromycin
What is the mechanism of action of macrolide antibiotics?
- Reversibly binds to 50S ribosomal subunits of sensitive organisms
- Inhibit the translocation step such that the nascent peptide chain residing at the A site of the transferase reaction fails to move to the peptidyl donor (P) site
How are macrolides administered?
Oral and Parenteral
CSF penetration of macrolides?
Poor CNS penetration
What to take note when taking macrolides?
Food interferes with the absorption of erythromycin and azithromycin
What are target organisms of erythromycin? Types of Infection?
Gram Pos + Gram Neg, Atypicals
Community-Acquire Pneumonia
What are target organisms of clarithromycin? Types of Infection?
Gram Pos + Gram Neg, Mycobacteria, Atypicals (Legionella, H. pylori)
What are target organisms of azithromycin?
H. influenzae, Moraxella Catarrhalis
Atypicals
Chlamydia trachomatis
N. gonorrhoae (with ceftriaxone IM)
Enteric pathogens (campylobacter, salmonella, shigella, vibrio cholerae)
Distribution of the 3 macrolides.
E - Diffuses readily into intracellular fluids except CSF. Increased penetration with inflamed meninges
C - Extensive tissue distribution. Greater tissue concentration of drug than in serum
A - Extensive tissue distribution. Greater tissue concentration of drug than in serum
Metabolism + Excretion of the 3 macrolides.
E - Hepatic; bile
C - Hepatic; bile and urine
A - Biliary; feces
Adverse Effects of Macrolides?
- Gastric Distress and Motility
- Hepatotoxicity
- Ototoxicity
- Prolong QT interval
Can macrolides be used in pregnancy?
yes
Drug interactions of macrolides.
- E and C inhibit hepatic metabolism of some drugs
- E potentiates the effects of corticosteroids, digoxin and warfarin (CYP3A4 inhibitor)
Mechanism of resistance of macrolides.
acquisition of erm genes resulting in ribosomal methylation and reduced binding of macrolides to 50S ribosomal subunits
increased expression of efflux pumps
Mechanism of action of clindamycin
binds to 50s subunit and inhibit peptide synthesis
target organisms of clindamycin. types of infection?
gram pos (inc MRSA and strep), anaerobes
toxic shock syndrome, skin/soft tissue infection, alternatives to penicillin allergies
NO aerobic gram neg coverage
for clindamycin,
a) administration
b) distribution
c) metabolism
d) excretion
a) Oral and IV, topical, gel, lotion, vaginal cream
b) Well into body fluids but not into CSF
c) Hepatic
d) bioinactive metabolites
adverse effects of clindamycin
- Esophageal irritation - take with full glass of water
- GI effects (diarrhoae and vomitting)
- Skin Rashes
- CDAD
- cross-reactivity with macrolides
mechanisms of resistance to clindamycin
- alteration of 50s subunit
- alteration in the 23s ribosomal rna subunit by methylation and nucleotidylation of the hydroxyl group of clindamycin
In macrolide resistant strains, what is a 2nd line antibiotic? Why?
Clindamycin. Not a substrate for macrolide efflux pumps, making them a choice of antibiotic in such macrolide resistant strains
Mechanism of action of linezolid?
binds the bacterial 23s ribosomal rna of the 50s subunit and prevents formation of a functional 70s initiation complex, which is an essential component of the bacterial translation process
target organisms of linezolid?
gram pos (inc MRSA, VRE, VRSA)
for linezolid,
a) administration
b) distribution
c) excretion
d) resistance
a) oral and iv
b) widely distributed thruout body inc CSF
c) two inactive metabolites
d) mutations in 23S ribosomal RNA; cfr rRNA methyltransferase
adverse effects of linezolids
- GI effects (nausea, diarrhea, headache, rash)
- Bone marrow suppression: thrombocytopenia (pls monitor blood counts)
- serotonin syndrome (esp if given with serotonin uptake inhibitors or MAO inhibitors) (pls avoid tyramine and histamine rich food like aged cheese, cured or smoked meats, draft beer, fava beans, soy products)
- irreversible peripheral neuropathies and optic neuritis
