3. Bacterial Protein Synthesis Inhibitors

Question 1

Types of bacterial protein synthesis inhibitors

Answer 1

30S:

1. Tetracyclines
   - Tetracyclines
   - Doxycyclines
   - Minocyclines
2. Glycylcycline
   - Tigecycline
3. Aminoglycosides
   - Gentamicin
   - Tobramycin
   - Amikacin
   - Streptomycin
   - Neomycin

50S:

1. Macrolides
   - Erythromycin
   - Clarithromycin
   - Azithromycin
2. Clindamycin
3. Linezolid

Question 2

MOA of tetracyclines

Answer 2

1. Enter via passive diffusion and also via an energy-dependent transport protein mechanism
2. Concentrate intracellularly in susceptible organisms
3. Bind reversibly to the 30S subunit of the bacterial ribosome → prevents binding of tRNA to the A site of the mRNA-ribosome complex → inhibiting bacterial protein synthesis
   → bacteriostatic

Question 3

Pharmacokinetics of tetracyclines

Answer 3

1. Absorbed after oral ingestion. Best on empty stomach
2. Avoid administration with dairy products (contain calcium) or other substances that contain divalent and trivalent cations → decreases absorption due to formation of non absorbable chelates
3. Contraindicated in pregnancy → cross the placental barrier and concentrate in fetal bones and dentition

Question 4

MOA of tigecycline

Answer 4

1. Structurally related to minocycline but alterations to molecule → expanded spectrum of activity and decreased susceptibility to development of resistance seen with tetracyclines
2. Overcome 2 common mechanism of tetracycline resistance
   - Resistance mediated by acquired efflux pumps and/or
   - Ribosomal protection
3. Binds to the bacterial 30S ribosome → blocking the entry of transfer RNA

Question 5

Pharmacokinetics of tigecycline

Answer 5

1. IV → poor oral bioavailability

2. Contraindicated in pregnancy

Question 6

Adverse effects of tetracyclines and tigecycline

Answer 6

1. Gastric discomfort
2. Effects on calcified tissues → discolouration and hypoplasia of teeth, and a temporary stunting of growth
3. Hepatotoxicity
4. Phototoxicity
5. Vestibular dysfunction
6. Renal side effects in patients with pre-existing renal disease
7. Superinfection → CDAD, pseudomembranous colitis

Question 7

Contraindications for tetracyclines and tigecycline

Answer 7

1. Should not be used in pregnancy or breast-feeding women or in children less than 8 years of age
2. Last half of pregnancy → affects primary teeth
3. Receiving up to the age of 7/8 years can affect permanent teeth (yellow-gray-brown) discolouration

Question 8

MOA of aminoglycosides

Answer 8

• Distort the structure of ribosomes by binding to them and
  1. Block the formation of the initiation complex
  2. Cause misreading of the codons as wrong amino acyl tRNAs are able to bind to the A site without matching the codon present in mRNA at that position
  3. Inhibit translocation
  → rapidly bactericidal
• Diffuse through the aqueous porin channels in the outer membrane of gram - bacteria and are transported across the inner membrane via active transport
• This energy-dependent phase can be inhibited by anaerobic conditions, drop in pH, and hyperosmolarity
• Entry can be enhanced by cell wall synthesis inhibitors like beta lactams (synergism)

Question 9

Pharmacokinetics of aminoglycosides

Answer 9

Poor oral bioavailability (polar) → mainly parenteral administration

Question 10

Contraindications in neomycin

Answer 10

1. Presence of intestinal obstruction
2. History of hypersensitivity to neomycin and other aminoglycosides
3. Ulcerative gastrointestinal disease
4. Not given parenterally due to severe nephrotoxicity

Question 11

Adverse effects of aminoglycosides

Answer 11

1. Ototoxicity
2. Nephrotoxicity
3. Neuromuscular paralysis
4. Hypersensitivity reactions
5. Contraindicated in pregnancy

Question 12

Resistance to aminoglycosides

Answer 12

1. Increased efflux pumps → reduce the effective intracellular conc.
2. Produce aminoglycoside inactivating enzymes
3. Some bacteria alter the 30S ribosomal subunits → prevent aminoglycosides interference with protein synthesis
4. Low level of resistance may result from inhibition of the aminoglycoside uptake by the bacteria

Question 13

MOA of macrolides

Answer 13

1. Inhibit protein synthesis by reversibly binding to the 50S ribosomal subunits
2. Inhibit the translocation step → nascent peptide chain residing at the A site of the transferase reaction fails to move to the peptidyl donor (P) site
   → bacteriostatic

erythromycin is an alternative to penicillin in individuals with allergy to beta-lactams

Question 14

Adverse effects of macrolides

Answer 14

1. Gastric distress and motility → less with clarithromycin and azithromycin than erythromycin
2. Hepatotoxicity → cholestatic jaundice
3. Ototoxicity
4. Prolong QT interval → cause in patients with pro-arrhythmic conditions

Question 15

Contraindications in macrolides

Answer 15

Hepatic dysfunction → macrolides accumulate in the liver

Question 16

Pregnancy usage with macrolides

Answer 16

1. Azithromycin and Erythromycin → cat B
2. Clarithromycin → cat C

Note that macrolides are used for a wide variety of bacterial infections in pregnancy!

Question 17

Drug interactions in macrolides

Answer 17

1. Erythromycin and clarithromycin inhibit hepatic metabolism → toxic accumulation of drugs
2. Erythromycin potentiates the effects of corticosteroids, digoxin, and warfarin by interfering with CYP-mediated metabolism of these drugs (CYP3A4)

Question 18

Resistance in macrolides

Answer 18

1. Acquisition of 1 of a number of erm (erythromycin methylases) genes → ribosomal methylation and reduce binding of macrolides to 50S ribosomal subunit
2. Increased expression of efflux pumps

Question 19

MOA of clindamycin

Answer 19

Binds exclusively to 50S subunit of bacterial ribosome and inhibit peptide synthesis

Note that clindamycin and erythromycin act at sites of proximity → antagonise each other’s action
Cross resistance between the 2 due to erm methylases can also occur

Question 20

Adverse effects of clindamycin

Answer 20

1. Take full glass of water to reduce esophageal irritation. Do not lie down immediately
2. Skin rashes
3. CDAD → C. difficile is always resistant to clindamycin. Contraindicated in patients with pseudomembranous colitis or ulcerative colitis

Question 21

Resistance in clindamycin

Answer 21

1. Alteration of 50S ribosomal subunit by aa substitution
2. Alteration in the 23S RNA subunit by methylation
3. Nucleotidylation of the hydroxyl group of clindamycin

Not a substrate for macrolide efflux pumps → choice for macrolide resistant strains

Question 22

MOA of linezolid

Answer 22

Bind the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process

Question 23

Resistance against linezolid

Answer 23

1. Mutations in the 23S ribosomal RNA

2. cfr rRNA methyltransferase against lincosamides (clindamycin) and oxazolidiones (linezolid)

Question 24

Adverse effects of linezolid

Answer 24

1. GI effects: nausea, diarrhoea, headaches, rashes
2. Bone marrow suppression: thrombocytopenia
3. Possesses nonselective monoamine oxidase inhibitory activity → lead to serotonin syndrome
4. Irreversible peripheral neuropathies and optic neuritis

Question 25

Contraindications in linezolid

Answer 25

1. Not approved for treatment of catheter-related bloodstream infections or catheter-site infections
2. Do not use within 2 weeks of MAO inhibitors
3. Avoid tyramine-containing foods and serotonergic drugs → precipitate a hypertensive crisis
4. Pregnancy → Cat C