Protein Synthesis Inhibitors Flashcards
In general, what are the possible ways antibiotics can interfere with protein synthesis?
Interact with ribosomes
Block initiation
Inhibit tRNA synthesis
Affect multiple mechanisms leading to RNA processing disruption
Which protein synthesis inhibitors affect the 50S subunit and which affect the 30S subunit?
50S subunit = Chloramphenicol, Ketolides (blocks aminoacyl tRNA to acceptor site)… Macrolides, Clindamycin, Streptogramins (blocks peptidyl tRNA translocation from acceptor to donor site)
30S Subunit = Tetracyclines (blocks amino acid tRNA to acceptor site) and Aminoglycosides (block initiation complex formation, misread mRNA, translocation of mRNA)
Can antibiotics move from -static to -cidal?
Yes
Can increase concentration, also depends on site of infection and infecting organism i.e. Linezolid is -static for enterococci and staph…but cidal for strep
How do Aminoglycosides work?
All have an aminocyclitol ring
Mechanism: displaces cations that link phospholipids together which causes membrane leak, irreversibly disprupts protein synthesis (blocking initiation or translocation, misreading mRNA), access membrane through porin channels via active oxygen dependent process (decreased activity with in acidic/anaerobic conditions like in abscesses, synergistic with cell-wall antibiotics like PCN and cephalosporins)
How do bacteria develop resistance against Aminoglycosides? How is this dealt with?
Resistance: modify the aminoglycoside so it can’t bind ribosome, alter binding of aminoglycosides on rRNA, reduce aminoglycoside uptake
To combat this, combine cell-wall inhibitors with aminoglycosides
What is the spectrum of Aminoglycosides?
Aerobic gram-negative bacilli (but not really anaerobes and gram-positive)
i.e. Klebsiella, Enterobacter, Pseudamonas aeruginosa and treating things like UTI, respiratory tract, skin and soft-tissue infections
Usually used in combination to broaden ability to cover serious illness like bacteriemia/sepsis, pseudomonal infection, and endocarditis (synergizing with Vancomycin or PCN)
What are the ADRs of Aminoglycosides and how should dosing be monitored?
Aminoglycosides have concentration-dependent killing (so need to monitor peaks AND troughs to keep in therapeutic range but avoid toxicity)… also have pronounced post-antibiotic effect
ADR: ototoxicity (possibly irreversible) and nephrotoxicity (usually reversible), risk is increased with increased therapy duration, other oto/nephrotoxic drugs, elderly and elevated serum levels… may also have NMJ blockade with curare-like effect in patients with myasthenia gravis or Parkinson’s (respiratory paralysis)
- Streptomycin most ototoxic (not reported with Gentamycin), and also should not use with sulfite-allergic because contains metabisulfite
- Tobramycin inhaled form can cause bronchospasm and hoarseness
- Rare Reactions: Hypersensitivity, optic nerve dysfunction, peripheral neuritis, encephalopathy, pancytopenia, exfoliative dermatitis, amblyopia
What are the most widely used Aminoglycosides? What are some other ones and their limitations?
Most widely used = Gentamycin, Tobramycin, Amikacin (these have cross-resistance)
Streptomycin for enterococcal infections
Neomycin and Kanamycin oral or topical use only due to toxicity
*Spectinomycin has structural similarities to aminoglycosides (used for treating gonorrhea in PCN-allergic patients
What are the pharmacokinetics of Aminoglycosides?
Not orally absorbed (but although Neomycin is too toxic for IV, can use to clean bowel)
Distributes widely in extracellular fluid, insoluble in lipid so volume of distribution is lower in obese… also poor distribution in bile, aqueous humor, bronchial secretions, sputum and CSF
Clearance is proportional to CrCl so need to adjust for renal insufficiency to avoid accumulation
What is the two dosing options/strategies for Gentamycin?
“Once daily”: recommended for most clinical situations since allows for very high concentration-dose killing and can monitor for toxicity…but NOT recommended for gram-positive, if CrCl is less than 30, CF, spinal cord infection or burn patients
Multiple daily: use synergy load then maintenance
What are the potential drug interactions from using Aminoglycosides?
Loop diuretics (increased nephrotoxicity)
Non-depolarizing muscle relaxants (respiratory depression)
Digoxin levels altered by Neomycin (which alters GI flora responsible for metabolism)
What should be known about giving Aminoglycosides to pregnant women?
Amikacin, Streptomycin, Tobramycin, Kanamycin = Category D and 8th Cranial Nerve toxicity in fetus
Gentamycin, Neomycin (minimal absorption of PO dose) = Category C
Breastfeeding = AAP (american academy of pediatrics?) compatible
What is the spectrum of Tetracyclines and what are some conditions they can treat?
Broad spectrum: Gram-positive, gram-negative, aerobic and anaerobic
- Mycoplasma pneumoniae
- Chlamydia pneumoniae/trachomatis (for cervicitis, urethritis, PID, prostatitis if under 35, partners)
- Rickettsia for RMSF
- Borrelia burgdorferi for Lyme’s
- Inhalation Anthrax for when combined with doxycyline in multidrug regimen
- Inflammatory acne
- Sinusitis
- Malabsorption syndrome from overgrowth
- Rickettsia and Borrelia burgdorferi harder targets for tetracyclines
What is the mechanism of Tetracyclines and the 3 groups based on pharmacokinetics?
Mechanism: Reversible protein synthesis inhibition via 30S RNA subunit binding, blocks addition of amino acids to the growing polypeptide
(Bacteriostatic)
3 Groups:
Short-acting i.e. Tetracycline, Oxytetracycline
Intermediate-acting i.e. Democlocycline for SIADH (no longer used as antibiotic)
Long-acting i.e. Doxycycline, Minocycline
*If short-acting would need frequent dosing QID, if longer-acting can use BID)
What is the most important mechanism of resistance against Tetracyclines? Which tetracycline has the most resistance against this resistance?
Bacterial efflux pump (encoded in multi-drug resistence gene shared via plasmids)
*Minocycline is the most resistant against this
Also resistance via prevention of TCN entering the cell
How are Tetracyclines administered based on pharmacokinetics? ADRs?
Available oral, parenteral and ophthalmic
Metabolism: incomplete GI absorption impaired by concurrent ingestion (dairy, aluminum hydroxide, Ca2+, Mg2+, iron/zinc salts, Bismuth Subsalicylate)… distributed throughout body including meninges and eliminated mostly by kidneys (Doxy-hepatic) so may need to adjust for renal insufficiency
Accumulates in liver, spleen, bone marrow, bone and enamel of unerupted teeth
ADR: N/V/D most common, modified GI flora potential for Candida and C.diff, photosensitization, vestibular and lupus-like reactions (Minocycline), pseudotumor cerebri, and binds to bone and teeth so contraindicated for kids under 8 in US and considered Category D for pregnant/breastfeeding women (only time Doxycycline is indicated is if need to treat Lyme’s)
Name the 3rd Generation Tetracycline and what it was developed for
Tigecycline (Tygacil)
*Developed to overcome bacterial resistance to TCN via efflux and ribosomal mutations
Indications: Broad spectrum including MRSA, reserved for complicated resistant infections (intra-abdominal and skin)
Chloramphenicol
50S inhibitor
Depending on species, can be either bactericidal or bacterostatic
Indications: Broad spectrum for gram-positive and gram-negative, but because of blood dyscrasia is reserved for life-threatening infections (i.e. typhoid fever, RMSF, PCN-allergic meningitis patients)
Mechanism: Reversible binding to 50S to inhibit peptide bond formation, also inhibits mitochondrial protein synthesis in mammalian cells
Distributes broadly including CNS/CSF
ADR: Effects due to inhibition of mitochondrial 70S ribosomes = myelosuppresion, reversible anemia, neutropenia, thrombocytopenia, Gray Baby Syndrome since neonates can’t metabolize Chloramphenicol
*Never give to pregnant women and neonates
How is resistance developed against Chloramphenicol?
Plasmids
Decreased cellular permeability (most common), enzyme modification (acetyltransferases acetylate drug so it can’t bind ribosome), ribosomal insensitivity due to mutation
Macrolides
50S inhibitor
First discovered as Erythromycin, and then derived from that to achieve better tissue penetration, acid stability and broader spectrum = Clarithromycin and Azithromycin
*Erythromycin for most Gram-positive and spirochetes but poor anaerobic coverage
*For Gram-positive and anaerobic bacteria: Clarithromycin (compared to erythro has enhanced cover of atypical mycobacteria) and Azithromycin (less staph and strep cover but more atypical mycobacteria and H. influenzae cover)
Mechanism: Binds to 50S to block translocation and prevent elongation, bacteriostatic but at high concentration is bactericidal
Resistance to macrolides?
If resistant to PCN then also resistant to Erythromycin
H. influenzae is resistant to Erythromycin alone (but susceptible if combine with Sulfonamide i.e. in Pediazole)
Resistance usually plasmid mediated (decrease permeability, decreased 50S affinity, plasma-associated esterase, active efflux)
What are the ADRs Macrolides?
Available PO, IV, and ophthlalmic (IV 5x concentration as PO)
Erythromycin base must be given as enteric coated capsule (since destroyed by acid, Azithro and Clarithro not as destroyed)
Wide distribution including prostate and macrophages (not CNS)
-Erythromycin and Azithromycin excreted unchanged in bile
-Clarithromycin excreted unchanged in bile and urine
Erythro ADR: Most common is N/V/D/cramps since binds to motilin receptor (peristalsis), cholestatic jaundice most commonly with estolate salt form, CV (ventricular arrythmia, palpiatations, dizziness, QT prolongation with IV)
Clarithro ADR: Less GI upset and BID dosing compared to erythro… also N/D, abnormal tastes, dyspepsia, HA, tooth discoloration, transient anxiety and behavioral changes
Azithro ADR: Angioedema, but less GI upset than erythro
*Great tissue penetration and prolonged intracellular half-life
Drug interactions when using Macrolides?
Extensive
Erythro and Clarithro are CYP3A4 substrates and inhibitors, so there are many interactions that increase/decrease effect i.e. statins, ergots, digoxin, carbamazepine, warfarin etc.
*Contraindicated for concurrent use with Cisapride
Azithromycin is NOT metabolized by CYP3A4
In general, how are Ketolides different from Macrolides?
Is a newer generation of Macrolides and derivative of Erythromycin
Binds stronger to 50S subunit, greater potency against Gram-positive, more activity against Macrolide-resistant strains (able to bind to 50S subunit when site is methylated by bacterial methylase)
