Macrolides, clindamycin, and chloramphenicol Lecture 19

Question 1

Structure and chemistry of erythromycin, clarithromycin, and azithromycin

Answer 1

clarithromycin is a 6 methoxy erythromycin

azithrymycin has a nitrogen group added to the 14 member macrolide ring

Question 2

MoA of erythromycin, clarithromycin, and azithromycin

Answer 2

reversibly binds to the 50s ribosomal subunit of bacteria to decrease protein synthesis

bacteriostatic

Question 3

absorption of erythromycin, clarithromycin, and azithromycin

Answer 3

Erythromycin: base, stearate, and ethylsuccinate are more completly absorbed in the fasting state. Erythromycin estolate is not affected by food.

Question 4

Distribution erythromycin, clarithromycin, and azithromycin

Answer 4

distributes in tissues longer than in blood

hgh concentrations in alveolar macrophages and leukocytes compared to those in extracellular fluid

azithromycin tissue concentrations exceeds serub by 10-100 fold: allows for 5 day course of therapy

Question 5

Metabolism/excretion erythromycin, clarithromycin, and azithromycin

Answer 5

erythromycin/clarithromycin: hepatic metabolism. 1.4 h half life

clarithromycin: metabolized in the liver by oxidation and hydrolysis. 20-30% of drug excreted into the urine unchanged.
azithrymycin: major route of elimination in feces via biliary excretion. 68 hr half life, consistent witha slow release of drug from tissues. Aids in allowing 5 day regimen

Question 6

AE: erythromycin,

Answer 6

Erythromycin: Gi abdominal crambs, N/V/D, stimulates the motolin receptor in the gut and hormone that stimulates gastric motility.

Thromophelbitis (IV).

Allergic reactions.

Cholestatic hepatitis (rare) Estolate prep; chiefly in adults and pregnant paitnets (avoid estolate form in pregnancy).

N/V, abdominal pain followed by jaundice, fever, LFT changes, Hypsersensitivity reaction to the structure of the estolate compound

generally clears up within days to a few weeks of d/c

Question 7

AE: clarithromycin, and azithromycin

Answer 7

Gi- not as severe as erythromycin

HA, Dizziness

allergic reactions

Question 8

Drug interactions erythromycin, clarithromycin, and azithromycin

Answer 8

erythromycin/clarithromycin: Erythromycin: generally by interfering with cytochorme p450 enzymes. Metabolites form inactive complexes with p450. Decreased matbaolism of theophylline, warfarin, carbamazepine, cyclosporine

azithrymycin: does not inactivate p450

Question 9

SoA: erythromycin, clarithromycin, and azithromycin

Answer 9

G+, Atypicals (all three)

H. Flu, M.Cat (clarithro, azithro)

clarithro: h pylori

Question 10

uses: erythromycin, clarithromycin, and azithromycin

Answer 10

penicillin allergic patients

mycoplasma pneumoniae

legionnaire’s disease

chlamydia trachomatis nongonococcal urethrtisis and cervicities: single i gm dose of azithromycin= 7 days of doxycycline

C. trachomatis during pregnancy (but not the estolate form)

Question 11

Clindamycin Chemistry

Answer 11

derived from lincymycin

chemical modification allowed clindamycin more potency and absorption

Question 12

MoA clinda

Answer 12

Binding of 50 S ribosome resulting in inhibition of protein synthesis

Question 13

pharmacokinetics Clinda

Answer 13

Bioavailability= 90%; food delays absorption but does not affect extent

good tissue penetration

metabolized by the liver

Question 14

SoA: Clinda

Answer 14

G+ and anaerobic coverage.

Strep, Staph (limited bactericidal rate compared to b lactams), anaerobes: bacteroids, including B fragilis, clostridium perfringens, peptostreptococci, peptococci, toxoplasmosis (allergic to sulfonamides)

Question 15

AE: clinda

Answer 15

allergic reactions

diarrhea: 20% of patients; more common with oral form

clostridium difficile (pseudomembranous colitis)- big culprit

hepatotoxicitiy (mild to severe)

Question 16

MoA Chloramphenicol

Answer 16

reversibly binds to the larger 50 S subunit of the 70 S ribosome

Question 17

pharmacokinetics: Chloramphenicol

Answer 17

suspension: must be hydrolyzed in the intestines for active chloramphenicol

IV form has incomplete hydrolysis; therefore, serum concentrations after IV therapy are only about 70% of those after oral administration

excellent CSF concentrations, 30-50% without inflamed meninges

metabolism via glucuronidation in the liver

wide variations in metabolism and excretion in children: must monitor serum levels

Question 18

SoA: Chloramphenicol

Answer 18

wide variety of G+, G-, aerobic and anaerobic organisms.

Rickettsia, chlamydia

Question 19

AE: Chloramphenicol

Answer 19

Hematologic: reversible bone marrow depression due to direct pharacologic effect on inhibition of mitochondrial protein synthesis. Anemia, leukopenia, thrombocytopenia.

Idiosyncratic aplastic anemia: majority of cases occur weeks to months after completion of therapy and is not necessairly dose related

childhood leukemia: increased incidence

Gray baby syndrome: abdominal distention, vomiting, cyanosis, circulatory collapse. DIminished ability of neonates to conjugate chloramphenicol and to excrete the active form in the urine. Generally associated with concentrations > 50mcg/ml

Question 20

Uses: chloramphenicol

Answer 20

bacterial meningitis (h. flu, strep pneumo, neiseria meningitidis). Penicillin/cephalosporin allergic. Oral alternative when IV cannot be used.

Rickettsial infections.