Vancomycin and Macrolides

Question 1

vancomycin and teicoplanin

Answer 1

glycopeptides

-both in clinical use

Question 2

what does vancomycin do?

Answer 2

inhibitor of G(+) cell wall biosynthesis

Question 3

MOA of vancomycin

Answer 3

binding to the peptidyl side chain D-alanyl-D-alanyl terminus in the peptidoglycan precursor -> process of cross-linking
-transpeptidase reaction that is required for cross-linking is inhibited by high affinity binding of vancomycin to the substrate.

Question 4

how have bacteria become resistant to vancomycin?

Answer 4

mutation of the peptidoglycan cell wall precursor from D-A-D-A to D-A-D-Lactate
-vancomycin does not inhibit transpeptidase with this mutation because has 1000 less affinity

Question 5

what are some rare complications from vancomycin?

Answer 5

nephrotoxicity and ototoxicity-> associated with high concentrations of drugs
-red skin rash and potential anaphylaxis

Question 6

erythromycin

Answer 6

mcrocyclic lactones

-14 membered lactone ring

Question 7

what is essential to macrolide antibiotics?

Answer 7

deoxyhexose sugars

Question 8

why is the pKa of erythromycin important?

Answer 8

pKa= 8.8

allows to form stable salts that are more soluble

Question 9

MOA of macrolides

Answer 9

inhibit bacterial protein synthesis by binding reversibly to the P site of the bacterial ribosome-> inhibit translocation of peptidyl-tRNA from A site to P site

Question 10

what ribosome to macrolides bind to?

Answer 10

23S RNA

Question 11

macrolide action is mainly

Answer 11

bacteriostatic

Question 12

how are macrolides transported to site of infection?

Answer 12

accumulate in leukocytes, there transported directly to infection

Question 13

resistance: lactone ester hydrolase

Answer 13

is induced to degrade the macrolides by hydrolysis of the macrocycle.

Question 14

resistance: drug induced production of?

Answer 14

RNA methylase

-methylates an adenine base on the 23 S RNA of the 50S ribosomal subunit-> inhibits binding of macrolides to 50S subunit

Question 15

resistance: mutation of which base?

Answer 15

adenine to guanine at specific A2058 site

-10,000 fold reduction in binding of erythromycin and clarithromycin to 23 S ribosomal RNA

Question 16

resistance: evolved way to get ride of drugs?

Answer 16

efflux pump ejects drugs from the cell by an active transport process

Question 17

how can erythromycin be inactivated?

Answer 17

under acidic conditions by a process involving the 6-OH group
-intramolecular acit-catalyzed ketal-formation

Question 18

the ketal-formation is active or inactive?

Answer 18

inactive

Question 19

how is erythromycin orally administered?

Answer 19

enteric coated tablets or more stable salts or esters

Question 20

how can acid stability be achieved?

Answer 20

with a 6-OCH3 derivative-> enhances oral absorption

Question 21

what does the 6-OCH3 do to erythromycin stability?

Answer 21

blocks ketal formation at low pH

Question 22

what is the name of the antibiotic with a 6-OCH3?

Answer 22

clarithromycin

Question 23

what antibiotic is the amine analog that is more acid stable?

Answer 23

azithromycin

• reliable absorption
• N-methylated methyleneamino moiety replaces C-9 ketone-> no ketal formation

Question 24

how is erythromycin degraded?

Answer 24

demethylation in liver

-elimination route in bile ( small % in urine)

Question 25

erythromycin half life

Answer 25

1.5 hours

Question 26

what do erythromycin and clarithromycin both do?

Answer 26

bind and inhibit CYP3A and related P450 enzymes | -can increase activities of certain drugs due to inhibition of their metabolism

Question 27

what two drugs reduce the activity of erythromycin?

Answer 27

rifampicin and rifabutin

Question 28

what is the common side effects with 14-membered macrolides?

Answer 28

stimulate GI motor activity: V, gastric cramps, abdominal pain

Question 29

what are rare but serious side effects of macrolides?

Answer 29

steven's johnson syndrome and toxic epidermal necrolysis

Question 30

how does erythromycin cause jaundice?

Answer 30

long term use (10-20 days) can induce reversible cholestatic hepatitis which manifests as jaundice with cramping/ nausea and fever -relieved upon termination of drug therapy

Question 31

what is a side effect of a pregnant women or while nursing who take erythromycin?

Answer 31

increased probability of pyloric stenosis in child

Question 32

prodrug of erythromycin?

Answer 32

erythromycin estolate | propionyl ester, lauryl sulfate

Question 33

what does the propionyl ester do for erythromycin estolate?

Answer 33

makes it more lipophilic than erythromycin itself-> increases oral absorption and blood levels of erythromycin after oral administration

Question 34

what can be a complication from erythromycin estolate?

Answer 34

cholestatic jaundice | -bile becomes granular impede bile duct flow> backed up bile salts get into circulation

Question 35

erythromycin estolate is contraindicated in?

Answer 35

people with liver disease or dysfunction

Question 36

what is erythromycin estolate used to treat?

Answer 36

GABH strep syphilis amebic dysentery prophylactically prior to surgery to prevent: endocarditis from alpha-hemolytic strep (viridans group)

Question 37

erythromycin ethyl succinate

Answer 37

- also makes more lipophilic and increases absorption | - used as flavored oral suspension for pediatric use to mask bitter taste, or as coated tablet

Question 38

clarithromycin

Answer 38

ketal formation blocked by C-6 methyl ether

Question 39

what has better antibiotic activity that clarithromycin itself?

Answer 39

its metabolite-> 14-R-hydroxy | -especially against H. influenza

Question 40

why is clarithromycin better to use than erythromycin?

Answer 40

better oral absorption high blood levels produces less GI upset b/c of blocked ketal formation

Question 41

how is azithromycin different from erythromycin and clarithromycin?

Answer 41

15 membered lactone ring-> N-CH3 been inserted between C 9 and 10, carbonyl oxygen removed -prevents cyclic ketal formation

Question 42

is azithromycin stable in acidic conditions?

Answer 42

yes

Question 43

what is azithromycin half life?

Answer 43

terminal half life of 68 hours | -concentration of azithromycin in tissues can be 50 times higher than in plasma

Question 44

why shouldn't antacids be taken with azithromycin?

Answer 44

Mg and Al can form coordination complexes with azithromycin and prevent absorption

Question 45

how is azithromycin predominantly excreted?

Answer 45

biliary excretion

Question 46

what bacteria does azithromycin target?

Answer 46

gram negative

Question 47

most common side effects of azithromycin?

Answer 47

diarrhea, azithromycin N&V, and abdominal pain