30S Ribosomal Subunit Inhibitors

Question 1

Name the 3 classes of 30S ribosomal subunit protein synthesis inhibitors and their agents

Answer 1

Tetracyclines - Tetracycline, Doxycycline, Minocycline

Glycylcycline - Tigecycline

Aminoglycosides - Gentamicin, Amikacin, Tobramycin, Streptomycin, Neomycin

Question 2

Mechanism of Action of Tetracyclines

Answer 2

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

Question 3

Tetracyclines are administered ______

Answer 3

Orally best on empty stomach

Question 4

Counselling point on tetracycline administration

Answer 4

Avoid dairy products , antacids and supplements containing divalent and trivalent cations

Formation of non-absorbable chelates

Question 5

Tetracycline distribution, binding and CSF penetration?

Answer 5

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)

Question 6

Spectrum activity of tetracyclines

Answer 6

Gram positive/negative, atypicals, spirochetes

Question 7

Tetracyclines do not cover ________ and ___________

Answer 7

Proteus and Pseudomonas

Question 8

Tetracyclines are eliminated by what route?

Answer 8

Tetracycline - Kidney

Doxycycline - Bile and Urine Unchanged

Minocycline - Extensive metabolism before excretion

Question 9

Contraindications of Tetracycline in ________

Answer 9

Pregnancy

Question 10

Indications of each tetracycline drug

Answer 10

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)

Question 11

Why are glycylcyclines designed for? What is it structurally similar to?

Answer 11

To overcome tetracycline resistance (Efflux pump, Ribosomal protection)

Minocycline structurally related

Question 12

Tigecycline is administered __

Answer 12

IV (Poor oral bioavailability)

Question 13

Tigecycline distribution

Answer 13

Penetrates well into tissues

Low plasma concentrations (Poor option for bloodstream infections)

CSF concentrations about 10% of that in serum (uninflamed meningitis)

Question 14

Tigecycline is eliminated by _____

Answer 14

Biliary fecal route

Question 15

Dose reduction tigecycline is recommended in ________________

Answer 15

Severe hepatic dysfunction

Question 16

Tigecycline is contraindicated in _________

Answer 16

Pregnancy

Question 17

Tigecycline has broad spectrum activity including which resistant strains?

Answer 17

1. MRSA
2. VRE
3. Carbapenem resistant ESBL Gram negatives
4. Multi-drug resistant streptococci
5. Complicated skin/skin-structure infections (except DM foot), intra-abdominal infections, CAP

Question 18

What are the 7 ADRs of tigecycline and tetracycline?

Answer 18

1. Gastric discomfort (Esophageal irritation) - Do not take immediately before sleep
2. Calcified tissue discoloration and hypoplasia from deposition e.g. Gray teeth
3. Hepatotoxicity
4. Phototoxicity
5. Vestibular dysfunction (Dizziness, vertigo, tinnitus)
6. Renal side effects in renal impaired patient
7. Superinfection CDAD

Question 19

Tetracyclines and tigecycline are contraindicated in which population?

Answer 19

Pregnancy, breastfeeding, Children < 8 years old

Caution in myasthenia gravis

Question 20

Aminoglycoside mechanism of action

Answer 20

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

Question 21

Why are aminoglycosides rapidly bactericidal?

Answer 21

Cationic nature affects cell membrane causing fissures to form. Destruction of cell membranes destroy the bacteria

Question 22

Administration route of Aminoglycosides by ______________ except for _________

Answer 22

Parenteral route, Neomycin (Oral)

Question 23

Aminoglycoside distribution and consequence on dosing? How about CSF penetration?

Answer 23

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

Question 24

Aminoglycosides are cleared by what route? Dose adjustment needed?

Answer 24

Renal clearance; Yes for renal impairment

Question 25

Aminoglycoside spectrum activity and why?

Answer 25

Broad-spectrum (Gram positive and negative) - Effective against aerobes only due to the need for energy-dependent active transport into the cell

Question 26

Aminoglycoside usual indications and type of therapeutic regimen

Answer 26

1. Gram negative infections (Enterobacterales, Klebsiella, E coli, Pseudomonas and multi-drug resistant microbes like MDR tuberculosis) 2. Empiric therapy for serious infections (septicemia, complicated UTI, nosocomial RTI) followed by discontinuation upon microbe identification (e.g. by culture)

Question 27

Aminoglycosides are used in combination with _______ in order to ______

Answer 27

Cell wall active agent Beta Lactams; Expand empiric spectrum, synergistic killing and prevent emergence of resistance

Question 28

When is prolonged use of AGs allowed?

Answer 28

Restricted to life-threatening infections

Question 29

Aminoglycosides are cleared ______ except for Neomycin which is cleared _____

Answer 29

renally unchanged; unchanged in the feces

Question 30

Which AG is the preferred choice against Pseudomonas?

Answer 30

Tobramycin

Question 31

Which AG is the widest antimicrobial spectrum AG?

Answer 31

Amikacin

Question 32

Which AG is more active against Gram-positive cocci than other AGs when used synergistically with Beta Lactams?

Answer 32

Gentamicin

Question 33

Which AG is primarily used in combination with tuberculosis agents?

Answer 33

Streptomycin

Question 34

Which AG is the most toxic and is used for bowel prep?

Answer 34

Neomycin

Question 35

Neomycin is contraindicated in ?

Answer 35

1. The presence of intestinal obstruction 2. History of hypersensitivity to Neomycin and other AG 3. Ulcerative GI disease

Question 36

Why is Neomycin not given parenterally?

Answer 36

Due to severe nephrotoxicity risk

Question 37

4 ADRs of Aminoglycosides

Answer 37

1. Ototoxicity (Deafness may be irreversible) 2. Nephrotoxicity (Disrupt calcium mediated transport in proximal tubules) 3. Neuromuscular paralysis (With concurrent neuromuscular blockers administered) 4. Hypersensitivity (Skin rash, contact dermatitis)

Question 38

What to monitor in patients taking Aminoglycosides?

Answer 38

1. Caution when using in renal impairment, hearing defects, myasthenia gravis 2. Limit usage of other nephrotoxic drugs (Amphotericin B, Vancomycin, NSAID, neuromuscular blocking agents) 3. TDM - Peak and trough levels 4. Renal function - Urea, creatinine, electrolytes

Question 39

4 types of resistance mechanisms against aminoglycosides

Answer 39

1. Efflux pump increase 2. Inactivating enzymes produced (e.g. to acetylate AGs) 3. 30S ribosomal subunit alteration 4. Uptake inhibition