Antibacterials - Clindamycin and Tetracycline

Question 1

Clindamycin is synthesized from …

Answer 1

the naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile

Question 2

What is the mechanisms of action of clindamycin

Answer 2

Similar to that of macrolide antibiotics like erythromycin

inhibits protein synthesis by binding to the bacterial 50S ribosome

Question 3

Antagonism and cross-reactivity between clindamycin and ____ have been reported

Answer 3

erythromycin

Question 4

clindamycin is most effective against

Answer 4

1. Aerobic gram+ cocci
   
   • –strep
   • –staph
2. Anaerobic gram- bacilli
   
   • –bacteroides
   • –fusobacterium

Question 5

Clindamycin can be used for …

Answer 5

1. bone infections with s. aureus
2. severe acne
3. bacterial vaginosis
4. lung abscesses and anaerobic lung and pleural space infections
5. MRSA

Question 6

Clindamycin is administered ____ with ___ and ___ to treat AIDS patients with ____

Answer 6

Clindamycin is administered IV with pyrimethamine and leucovorin to treat AIDS patients with Toxoplasma gondii

Question 7

What do we see a lot with clindamycin treatment?

Answer 7

C. diff

Clindamycin knocks out all other organisms in colon except C. diff and then we get an overgrowth

C. diff is inherently resistant to clindamycin

Question 8

Metabolism of clindamycin

Answer 8

1. oxidative N-demethylation
2. react with cytochrome P450 to oxide drug to sulfide

Both of these are inactive

Question 9

Pharmacokinetics of clindamycin

Answer 9

Very readily absorbed from GI tract

Widely distributed among tissues - this is why it is useful for AIDS with CNS infection

Excreted in urine and bile

Elimination half life of 1.5-5 hours

Question 10

Accumulation of clindamycin can occur in pts with …

Answer 10

hepatic failure … may need to adjust the dose

Question 11

Tetracycline is a …

Answer 11

broad-spectrum antibiotic produced by streptomyces bacteria

Question 12

Tetracyclines for stable …

consequences?

Answer 12

chelates with polyvalent metal ions such as Ca++, Al+++, Cu++, Mg++

consequences
1. should not be admin with calcium rich foods b/c insoluble chelates are not absorbed from GI tract; should not be admin with antacids that contain multivalent metals (TUMS)

2. should not be admin to children when they are forming their permanent teeth, b/c chelate calcium during formation of teeth resulting in permanently brown or grey teeth
3. pain on injection is caused by formation of insoluble calcium complexes (minimize pain by injection with EDTA which chelates the calcium)

Question 13

WRT tetracycline, the hydrogen on the amine-bearing carbon atom is …, resulting in …

Answer 13

acidic, resulting in enolization and epimerization

this is an inactive product

Question 14

Dehydration

Answer 14

tertiary, benzylic hydroxyl group at C6 has an antiperiplanar relationship with the proton at C5a and is set up for elimination

Question 15

Epianhydrotetracycline is toxic to the … and can produce a ….. like syndrome, meaning

Answer 15

Toxic to the kidneys

Fanconi like syndrome

meaning that there is a failure of reabsorption in the renal tubules (PCT)

Question 16

What forms of tetracycline are completely free of potential toxicity to the kidneys?

Answer 16

minocycline and doxycycline

b/c they lack a C-6 hydroxyl group

Question 17

Cleavage in base - Tetracyclines

Answer 17

undergo cleavage in base at pH values of 8.5 or above

the lactone product is inactive

Question 18

Mechanism of action of tetracycline

Answer 18

bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome resulting in termination of peptide chain growth

Question 19

Therapeutic use of tetraclines

Answer 19

Broad-spectrum antibiotics

• Most common use is for treatment of acne
• Drug of choice for chlamydia, rickettsia, brucellosis, and spirochetal infections

Also used for

• anthrax
• plague
• tularemia
• Legionnaries’ disease

Question 20

What are specific agents within the tetracycline class?

Answer 20

1. Tetracycline
2. Demeclocycline
3. Meinocycline
4. Oxytetracycline
5. Doxycycline

Question 21

tetracycline

Answer 21

1. generic and relatively inexpensive

2. food and milk lower oral absorption by about 50%

Question 22

demeclocycline - how is it different than tetracycline?

how is it similar?

Answer 22

it has a secondary hydroxyl group at C6 instead of the tertiary hydroxyl group, therefore, it dehydrates more slowly than tetracycline

food and milk lower oral absorption by about 50%

Question 23

minocycline - how is minocycline different than the rest?

oral bioavailability?

Answer 23

lacks C6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration – so no potential for 4-epianhydrotetracycline mediated toxicity

oral bioavailability is 90-100%
absorption is lowered by ~20% when taken with food or milk

Question 24

minocycline is the only tetracycline that causes

Answer 24

vestibular toxicity (vertigo, ataxia, nausea)

Question 25

oxytetracycline - what is notable about its properties?

oral bioavailability?

Answer 25

most hydrophilic tetracycline

oral bioavailability is ~60%
– reduced by 50% when taken with food or milk

Question 26

doxycycline - synthesized from?
structural differences from other tetracyclines?
oral bioavailability?
half life?

Answer 26

synthesized from oxytetracycline

lacks C6 hydroxyl - does not undergo acid-catalyzed dehydration - no potential for 4-epianhydroxtetracycline-mediated toxicity

oral bioavailability 90-100%
– reduced by 20% when taken with food or milk

half life 18-22 hr which permits once a day dosing

Question 27

what is considered to be the tetracycline of choice? why?

Answer 27

doxycycline

no potential for 4-epianhydrotetracycline mediated toxicity and it produces fever GI symptoms than other tetracyclines