Erdman Macrolides & ketolides

Question 1

chemical difference between erythromycin and clarithromycin

Answer 1

clarithromycin is a derivative of erythromycin that substitutes a methoxy group for the C-6 hydroxyl group

• improves bioavailability (increases acid stability), enhances antibacterial activity, enhances tissue penetration and prolongs half life

Question 2

chemical difference between erythromycin and azithromycin

Answer 2

azithromycin is a derivative of erythromycin that has an amino group inserted into the ring at position 9a. 15 membered ring - technically an “azalide”

• improves bioavailabilty, antibacterial activity (especially against H. influenzae), tissue penetration and increased half life

Question 3

MOA of macrolides

Answer 3

interfere with microbial protein synthesis (translocation step)

reversibly bind to 50s ribosomal subunit so that protein synthesis is supressed and growth is inhibited

Question 4

T/F: macrolides display bactericidal activity

Answer 4

False: they typically display bacteriostatic activity

at very susceptible organisms and at high concentrations they MAY have some bactericidal

Question 5

What are the MOR for macrolides

Answer 5

Active efflux

Alteration in the binding site

Question 6

How do bacteria develop the active efflux machanism of resistance

Answer 6

mef gene encodes for pumps - confers LOW-LEVEL resistance to macrolides

macrolides may still be used

Question 7

How do bacteria develop the alteration in binding site mechanism of resistance

Answer 7

erm gene causes a methylation of the macrolide 50S binding site leading to low affinity binding - confers HIGH-LEVEL resistance to ALL macrolides and other Abx that bind to 50S (clinda & synercid)

Sucks - common in Europe

Question 8

T/F: cross resistance is NOT usually observed

Answer 8

False

Question 9

When bactericidal, macrolides display _______ activity

Answer 9

time-dependent

azithromycin may display concentration-dependent in “some cases”

Question 10

Gram (+) aerobe bacteria covered?

Answer 10

S. pneumoniae (65-70% of strains, primarily PSSP)

MSSA (mild-moderate only)

Question 11

Which macrolide has the best gram (+) aerobe coverage

Answer 11

Clarithromycin

Clarithromycin > Erythromycin > Azithromycin

Question 12

Which macrolide has the best gram (-) aerobe coverage

Answer 12

Azithromycin

Azithromycin > Clarithromycin > Erythromycin

Question 13

Gram (-) aerobes covered

Answer 13

NOT THE ENTEROBACTERIACEAE

H. influenzae (not erythromycin)
M. catarrhalis
Neisseria

Question 14

Atypical coverage?

Answer 14

Legionella pneumophila – a DOC*
Chlamydophila and Chlamydia spp.
Mycoplasma pneumoniae
Ureaplasma urealyticum

Question 15

Absorption characteristics of erythromycin

Answer 15

variable bioavailability (15-45%)

• base is acid labile and subject to destruction in stomach
• ester and salt derivatives more stable in acid
• food delays absorption

Question 16

Absorption characteristics of clarithromycin

Answer 16

acid stable and well absorbed fro stomach regardless of food (F= 52-55%)
- peak concentration at about 3 hours

Question 17

Absorption characteristics of azithromycin

Answer 17

acid stable, F= 37%

• peak at 2-3 hours
• food does not affect absorption

Question 18

distribution of macrolides

Answer 18

• all distribute well into all tissues (EXCEPT CSF) and cells
• obtain high tissue concentrations but minimal serum concentrations
  - may be ineffective against bacteremia*****

Question 19

Which macrolide must be adjusted for renal insufficiency

Answer 19

Clarithromycin

Question 20

How is erythromycin eliminated

Answer 20

biliary and hepatic (CYP450 enzymes)

Question 21

How is clarithromycin eliminated

Answer 21

extensively by hepatic (CYP450) and renal

dose adjust in CrCl <30

Question 22

How is azithromycin eliminated

Answer 22

biliary excretion

Question 23

Half lives of macrolides

Answer 23

Azithromycin (68 hrs) > Clarithromycin (3-7 hrs) > Erythromycin (1.4 hrs)

Question 24

T/F macrolides are removed during dialysis

Answer 24

False: NONE are removed

Question 25

Used in the treatment of __________ in penicillin allergic patients

Answer 25

``` Group A strep Upper respiratory infections prophylaxis of bacterial endocarditis syphilis and gonorrhea superficial minor staph infections rheumatic fever prophylaxis ```

Question 26

Used in the treatment of....

Answer 26

RTI uncomplicated skin and soft tissue infections STD mycobacterium avium complex infections (MAC)

Question 27

What is the treatment of nongonococcal urethritis or cervicitis due to CHLAMYDIA TRACHOMATIS

Answer 27

a single 1-gram dose of azithromycin

Question 28

T/F - clarithromycin and azithromycin have small volume of distributions

Answer 28

FALSE: very large Vds

Question 29

Other bacterial coverage by macrolides?

Answer 29

Mycobacterium avium complex (MAC – only A and C)

Question 30

macrolide treatment of CAP?

Answer 30

monotherapy in outpatients and in combination with ceftriaxone for inpatients *especially for atypical coverage*

Question 31

macrolide tx of MAC

Answer 31

azithromycin for prophylaxis | clarithromycin for treatment

Question 32

ADE with macrolide use

Answer 32

gastronintestinal, thrombophlebitis/infusion site irritation, QT prolongation

Question 33

when is gastrointestinal SE most common and how can it be minimized

Answer 33

oral administration of erythromycin - give with food if possible

Question 34

How to partially avoid thrombophlebitis

Answer 34

dilute the dose (at least 250mL), infuse slowly, and give into a large vein

Question 35

Ototoxicity is seen...?

Answer 35

rarely - in patients with renal insufficiency and receiving high doses of erythromycin IV

Question 36

Drug interactions of E & C

Answer 36

both inhibitors of CYP450 theophylline, carbamazepine, valproate, cyclosporin, digoxin, phenytoin, warfarin may increase serum concentrations & risk of toxicity

Question 37

Drug interactions for azithromycin

Answer 37

not an inhibitor of CYP450 - no drug-drug interactions however monitor PT/INR on patients stable on warfarin due to cases of hypoprothrombinemia

Question 38

Only approved ketolide is

Answer 38

telithromycin

Question 39

difference in MOA between macrolides and ketolide

Answer 39

ketolide binds to 2 different sites (domain II and V) on the ribosome 10 times tighter binding to domain II -> provides activity against macrolide resistant strains

Question 40

MOR of ketolide

Answer 40

alteration in binding site

Question 41

ketolides display ______ activity

Answer 41

bacteriostatic **concentration-dependent cidal activity against some organisms*

Question 42

Spectrum of activity of ketolide

Answer 42

same as macrolides (A&C) except - covers macrolide-resistant S. pnuemoniae - potentially less active against M. catarrhallis & H. influenzae - 10x better against borrelia burgdorferi

Question 43

T/F: telithromycin is available only IV

Answer 43

false: only oral

Question 44

Pharmacollogy of ketolide

Answer 44

A - F=57%, Tmax in 1-2 hours and NOT affected by food D - penetrates tissues well E - metabolized by CYP450 and feces - No dosage adjustment for renal insufficiency

Question 45

ADE for telithromycin

Answer 45

hepatotoxicity & diarrhea, QTc prolongation (exacerbation of myasthenia), decreased visual acuity and blurred vision

Question 46

Drug interactions of ketolides

Answer 46

CYP450 drugs (similar to C & E macrolides)

Question 47

Only FDA approved use of ketolide

Answer 47

CAP

Question 48

Telithromycin dose for tx of CAP

Answer 48

800 mg QD x7-10 days

Question 49

T/F: telithromycin is approved for the tx of sinusitis and brochitis

Answer 49

FALSE - no longer approved due to adverse effect profile