30S Ribosomal Subunit Inhibitors Flashcards
Name the 3 classes of 30S ribosomal subunit protein synthesis inhibitors and their agents
Tetracyclines - Tetracycline, Doxycycline, Minocycline
Glycylcycline - Tigecycline
Aminoglycosides - Gentamicin, Amikacin, Tobramycin, Streptomycin, Neomycin
Mechanism of Action of Tetracyclines
Enter the bacterial cell through passive diffusion and active transport
Concentrate intracellularly and bind reversibly to 30S subunit to prevent tRNA binding to A site of mRNA-ribosome complex
Tetracyclines are administered ______
Orally best on empty stomach
Counselling point on tetracycline administration
Avoid dairy products , antacids and supplements containing divalent and trivalent cations
Formation of non-absorbable chelates
Tetracycline distribution, binding and CSF penetration?
Concentrate in bile, liver, kidney, gingival fluid, skin
Bind to tissue undergoing calcification (teeth and bone)
Cross placental barrier and concentrate in fetal bones and dentition
Moderate CSF penetration (Doxy and Mino)
Spectrum activity of tetracyclines
Gram positive/negative, atypicals, spirochetes
Tetracyclines do not cover ________ and ___________
Proteus and Pseudomonas
Tetracyclines are eliminated by what route?
Tetracycline - Kidney
Doxycycline - Bile and Urine Unchanged
Minocycline - Extensive metabolism before excretion
Contraindications of Tetracycline in ________
Pregnancy
Indications of each tetracycline drug
Tetracycline - Atypicals (Chlamydia, Mycoplasma pneumoniae), Vibrio cholerae, Yersinia pestis (Causing Plague)
Doxycycline - Above, Acne vulgaris, Anthrax, CAP, MRSA skin/soft tissue infection, Rickettsial disease
Minocycline - Tetracycline resistant strains (Some), Severe Acne, RTI, Yersinia (Plague)
Why are glycylcyclines designed for? What is it structurally similar to?
To overcome tetracycline resistance (Efflux pump, Ribosomal protection)
Minocycline structurally related
Tigecycline is administered __
IV (Poor oral bioavailability)
Tigecycline distribution
Penetrates well into tissues
Low plasma concentrations (Poor option for bloodstream infections)
CSF concentrations about 10% of that in serum (uninflamed meningitis)
Tigecycline is eliminated by _____
Biliary fecal route
Dose reduction tigecycline is recommended in ________________
Severe hepatic dysfunction
Tigecycline is contraindicated in _________
Pregnancy
Tigecycline has broad spectrum activity including which resistant strains?
- MRSA
- VRE
- Carbapenem resistant ESBL Gram negatives
- Multi-drug resistant streptococci
- Complicated skin/skin-structure infections (except DM foot), intra-abdominal infections, CAP
What are the 7 ADRs of tigecycline and tetracycline?
- Gastric discomfort (Esophageal irritation) - Do not take immediately before sleep
- Calcified tissue discoloration and hypoplasia from deposition e.g. Gray teeth
- Hepatotoxicity
- Phototoxicity
- Vestibular dysfunction (Dizziness, vertigo, tinnitus)
- Renal side effects in renal impaired patient
- Superinfection CDAD
Tetracyclines and tigecycline are contraindicated in which population?
Pregnancy, breastfeeding, Children < 8 years old
Caution in myasthenia gravis
Aminoglycoside mechanism of action
Diffuse through aqueous porin channels of Gram negatives’ outer membrane
Active transport energy-dependent phase
Block formation of initiation complex and cause misreading of codons. Wrong aminoacyl tRNAs bind to A site without matching the codon present in mRNA at the position. This inhibits translocation
Why are aminoglycosides rapidly bactericidal?
Cationic nature affects cell membrane causing fissures to form. Destruction of cell membranes destroy the bacteria
Administration route of Aminoglycosides by ______________ except for _________
Parenteral route, Neomycin (Oral)
Aminoglycoside distribution and consequence on dosing? How about CSF penetration?
Penetration into body fluids vary (Due to low distribution to fatty tissue, they dosed based on lean body mass, not actual body weight)
Poor CSF penetration
Cross placenta barrier and may accumulate in fetal plasma and amniotic fluid
Aminoglycosides are cleared by what route? Dose adjustment needed?
Renal clearance; Yes for renal impairment
Aminoglycoside spectrum activity and why?
Broad-spectrum (Gram positive and negative) - Effective against aerobes only due to the need for energy-dependent active transport into the cell
Aminoglycoside usual indications and type of therapeutic regimen
- Gram negative infections (Enterobacterales, Klebsiella, E coli, Pseudomonas and multi-drug resistant microbes like MDR tuberculosis)
- Empiric therapy for serious infections (septicemia, complicated UTI, nosocomial RTI) followed by discontinuation upon microbe identification (e.g. by culture)
Aminoglycosides are used in combination with _______ in order to ______
Cell wall active agent Beta Lactams;
Expand empiric spectrum, synergistic killing and prevent emergence of resistance
When is prolonged use of AGs allowed?
Restricted to life-threatening infections
Aminoglycosides are cleared ______ except for Neomycin which is cleared _____
renally unchanged; unchanged in the feces
Which AG is the preferred choice against Pseudomonas?
Tobramycin
Which AG is the widest antimicrobial spectrum AG?
Amikacin
Which AG is more active against Gram-positive cocci than other AGs when used synergistically with Beta Lactams?
Gentamicin
Which AG is primarily used in combination with tuberculosis agents?
Streptomycin
Which AG is the most toxic and is used for bowel prep?
Neomycin
Neomycin is contraindicated in ?
- The presence of intestinal obstruction
- History of hypersensitivity to Neomycin and other AG
- Ulcerative GI disease
Why is Neomycin not given parenterally?
Due to severe nephrotoxicity risk
4 ADRs of Aminoglycosides
- Ototoxicity (Deafness may be irreversible)
- Nephrotoxicity (Disrupt calcium mediated transport in proximal tubules)
- Neuromuscular paralysis (With concurrent neuromuscular blockers administered)
- Hypersensitivity (Skin rash, contact dermatitis)
What to monitor in patients taking Aminoglycosides?
- Caution when using in renal impairment, hearing defects, myasthenia gravis
- Limit usage of other nephrotoxic drugs (Amphotericin B, Vancomycin, NSAID, neuromuscular blocking agents)
- TDM - Peak and trough levels
- Renal function - Urea, creatinine, electrolytes
4 types of resistance mechanisms against aminoglycosides
- Efflux pump increase
- Inactivating enzymes produced (e.g. to acetylate AGs)
- 30S ribosomal subunit alteration
- Uptake inhibition
