Clindamycin and Tetracycline

Question 1

Which abx bind to 30S?

Answer 1

• AMGs
• Tetracycline

Question 2

• What is the mechanism of clindamycin?
• How does it compare to erythromycin?

Answer 2

• Clindamycin inhibits protein synthesis by binding to the bacterial 50S ribosome.
• This is the same site erythromycin binds to.

• clindamycin inhibits peptide bond formation and elongation
• erythromycin blocks the ribosomal exit tunnel which also inhibits elongation

Question 3

What are the main clinical uses of clindamycin?

Answer 3

• aerobic gram-positive cocci
• anerobic gram-negative bacilli
• bone infections
• severe acne
• bacterial vaginosis

Question 4

What is the main side effects of clindamycin that limits clinical use?

Answer 4

• pseudomembranous colitis
  (and diarrhea)

potentially lethal condition

Question 5

How is clindamycin metabolized?

Answer 5

• Clindamycin is extensively metabolized by CYP 450 enzymes in the liver
• Clindamycin gets metabolized to the sulfoxide and the N-demethylated derivative.
• These metabolites are pharmacologically inactive

Question 6

What is the absorption for clindamycin like?

Answer 6

• 90% of the administered dose is absorbed from the GI tract
• widely distributed
• penetrates CNS in high concentrations

Question 7

How is clindamycin excreted?

Answer 7

• excreted in urine and bile
• half-life 1.5-5 hours

Accumulation of clindamycin can occur in patients with hepatic failure –> dose adjustments may be required

Question 8

What is the significance of pseudomembranous colitis?

Answer 8

• potentially lethal
• overgrowth of C. diff results in production of toxins
• diarrhea, colitis, toxic megacolon

Question 9

How do tetracyclines bind to heavy metals?

Ca, Al, Cu, Mg

Answer 9

Tetracyclines form stable chelates with metal ions via their hydroxyl and carbonyl groups.

Question 10

Why should tetracyclines not be administered with meds/food containing metals?

calcium especially

Answer 10

Insoluble calcium chelates that form are not absorbed from the GI tract. The drug won’t work at all.

When unavoidable, the metals should be administered 1 hour before or 2 hours after the tetracycline.

Question 11

What is the preferred route of administration for tetracyclines?

Answer 11

oral

Question 12

Why shouldn’t children under the age of 8 years not take tetracyclines?

Answer 12

Tetracyclines chelate calcium during the formation of teeth. This results in permanently brown or grey teeth.

Question 13

Why do tetracyclines undergo epimerization?

Answer 13

• The hydrogen on the amine-bearing carbon atoms is acidic.
• Epimerization is slow in the solid state and most rapid in solution at pH 4.

Question 14

What is the effect of epimerization on tetracyclines?

Answer 14

The product is pharmacologically inactive.

Question 15

What structural feature enables a tetracycline to undergo dehydration and what is the result?

Answer 15

• benzylic hydroxyl group at C6
• 4-epianhydrotetracycline

Question 16

What are the toxicities associated with epianhydrotetracycline?

product of dehydration

Answer 16

• toxic to kidneys
• produce Fanconi-like syndrome

failure of the reabsorption mechanism in the proximal convoluted tubules which can be fatal

Question 17

Why do minocycline and doxycycline lack the renal toxicity of tetracycline?

Answer 17

Minocycline and doxycycline lack a C-6 hydroxyl group, so they don’t undergo the dehydration that leads to toxicity

Question 18

How do tetracyclines cleave in basic conditions?

Answer 18

Base-catalyzed cleavage starting at C12 leads to ring opening and loss of activity.

Undergo cleavage in base at pH values of 8.5 or above. The product is inactive

Question 19

What is the mechanism of action of tetracyclines?

Answer 19

• Tetracyclines bind to the 30S ribosomal subunit
• This inhibits bacterial protein synthesis by blocking the attachment of aminoacyl-tRNA to the A site of the ribosome.
• This leads to termination of peptide chain growth.
• Inhibitors of the codon-anticodon interaction

Question 20

Tetracyclines can inhibit protein synthesis in the host. How is come this it is not toxic to the host but it is toxic to bacteria?

Answer 20

• Eukaryotic cells do not have a tetracycline uptake mechanism
• This prevents tetracycline from reaching a high enough concentration for toxicity

Question 21

What are the main therapeutic uses for tetracyclines?

Answer 21

• broad-specrum abx
• treatment of acne
• chlamydia
• Rickettsia
• brucellosis

Question 22

What are the advantages to using tetracycline instead of one of the other abx in the tetracycline class?

Answer 22

• generic and inexpensive

Question 23

How do food and milk impact oral absorption of tetracycline or demeclocycline?

Answer 23

Lower oral absorption by about 50%

Question 24

Why is demeclocycline more stable to dehydration that tetracycline?

Answer 24

Demeclocycline has a secondary hydroxyl group at C6 instead of a tertiary hydroxyl group.

Question 25

How is the absorption of minocycline or doxycycline impacted by food or milk?

Answer 25

The absorption of minocycline or doxycycline is decreased by 20%

Question 26

What are the unique toxicities associated with minocycline?

Answer 26

• vestibular toxicities:
• vertigo
• ataxia
• nausea

Question 27

Why is doxycycline considered the tetracycline of choice?

Answer 27

• no potential for dehydration rxn toxicities
• fewer GI symptoms
• 18-22 hour half life permits once a day dosing

Question 28

What are the toxic effects of tigecycline?

Answer 28

• hepatotoxicity
• pancreatitis
• anaphylactoid

Question 29

What are the main therapeutic uses for sarecycline and omadacycline?

Answer 29

• moderate to severe acne
• penumonia
• skin infections

Question 30

Why should sarecycline and omadacycline not be administered to pregnant women?

Answer 30

• They cross the placenta and could cause fetal harm (teeth/bone malformations)
• excreted in breast milk