More 50S inhibitors

Question 1

Clindamycin: MoA? - Static or cidal?

Answer 1

Bind and inhibit 50S subunit. - Static (cidal at high conc.) Binds in close proximity to macrolides and Quinupristin/Daltopristin (Synercid)– may cause competitive inhibition

Question 2

Clindamycin: mech of resistance?

Answer 2

• Altered target sites – encoded by the erm gene, which alters 50S ribosomal binding site; confers high level resistance to macrolides, clindamycin and Synercid (MLSb resistance) - Active efflux – mef gene encodes for an efflux pump that pumps antibiotic out of the cell - Drug inactivation

Question 3

Describe the spectrum of activity of clindamycin.

Answer 3

Gram positive aerobes: - *MSSA and some CA-MRSA - PSSP: PCN-susc. strep pneumo - Group + viridians strep Anaerobes: * Some bacteriodes spp. - Peptostreptococcus, actinomyces, prevotella spp, propionibacterium, fusobacterium, clostridium spp. (not C. difficile) Other bacteria: - Pneumocystis carinii, Toxoplasmosis gondii, Malaria

Question 4

How is clindamycin administrated? What is the % absorption?

Answer 4

IV, PO (90% absorption, can switch b/w IV and PO)

Question 5

Does clindamycin penetrate the CSF?

Answer 5

Not really

Question 6

Clindamycin primarily metabolized by the ___________. - Does it need adjustments during renal failure? - Is it removed during hemodialysis?

Answer 6

• Liver - Doesn’t need adjustments during renal failure - No

Question 7

What are the clinical uses of clindamycin?

Answer 7

• Anaerobic Infections OUTSIDE of the CNS: Pulmonary, intraabdominal, pelvic, diabetic foot and decubitus ulcer infections - Skin & Soft Tissue Infections: Good option for PCN-allergic patients and infections due to CA-MRSA - Alternative therapy: C. perfringens, PCP, Toxoplasmosis, malaria, bacterial vaginosis

Question 8

What are the 2 main side-effects for clindamycin?

Answer 8

• GI - *C-diff colitis (one of the main inducers)

Question 9

What category of drug does clindamycin belong?

Answer 9

Lincosamide

Question 10

What are the 3 macrolides we should know?

Answer 10

• Azithromycin - Clarithromycin - Erythromycin

Question 11

Which 2 macrolides are derivatives of the other?

Answer 11

Azithromycin and clarithromycin derivatives of erythromycin

Question 12

How do azithro and clarithromycin improve upon erythromycin?

Answer 12

• Broader spectrum of activity - Improved PK properties: better bioavailability, better tissue penetration, prolonged half-lives - Improved tolerability

Question 13

Macrolides: MoA? - Cidal or static?

Answer 13

• Reversibly binding to the 50S ribosomal subunit - Static (cidal at high conc)

Question 14

Which of the macrolides and time-dependent, and which are conc.-dependent?

Answer 14

• Erythromycin and clarithromycin are time-dependent - Azithromycin is conc-dependent

Question 15

Macrolides: mech of resistance?

Answer 15

• Active efflux pump (mef gene) - Altered target sites (erm gene)

Question 16

What is the spectrum of activity for macrolides? (groups are targets)

Answer 16

• Gram-pos aerobes (*MSSA) - Gram-neg aerobes - Anaerobes (esp. upper airway) - Atypical bacteria (*Legionella, DOC) - Other bacteria

Question 17

What bacterium do macrolides importantly NOT have activity against?

Answer 17

Enterobacteriacea (gram-neg aerobe class)

Question 18

What are the relative levels of activity for the 3 macrolides against gram-positive aerobes?

Answer 18

CEA Clarithro > Erythro > Azithro (ACE for gram-neg)

Question 19

What are the relative levels of activity for the 3 macrolides against gram-negative aerobes?

Answer 19

ACE Azithro > Clarithro > Erythro (CEA for gram-pos)

Question 20

Discuss the bioavailabilities of each of the of the 3 macrolides. - Which are acid stable?

Answer 20

• Erythromycin: variable absorption (15 to 45%) - Clarithromycin: well-absorbed (55%) - Azithromycin: 37% bioavail. regardless of food Acid stable: Clarithromycin and azithromycin

Question 21

Do macrolides penetrate the CSF?

Answer 21

Not really

Question 22

Describe the elimination routes of each of the 3 macrolides. * Which are metabolized by CYP450 enzymes?

Answer 22

• Erythromycin: excreted in bile, metabolized by *CYP450 - Clarithromycin: also metabolized (*CYP450) and partially eliminated by the kidney - Azithromycin: liver, NO CYP450

Question 23

Name the clinical uses of macrolides.

Answer 23

Respiratory Tract Infections - Pharyngitis/ Tonsillitis: PCN-allergic pts - Sinusitis, COPD exacerbation, OM - CA-PNA: monotherapy in outpatients; with ceftriaxone for inpatients Uncomplicated Skin Infections STDs MAC Alternative for PCN-Allergic pts: - Group A Strep upper respiratory infections - Prophylaxis of bacterial endocarditis - Syphilis and gonorrhea - RF prophylaxis

Question 24

Which macrolide is best when H. influenzae is suspected?

Answer 24

Azithromycin

Question 25

Which macrolide is best for STDs?

Answer 25

Azithromycin

Question 26

How are macrolides used to treat MAC (mycobacterium avium complex)? I hope to god this doesn’t come up

Answer 26

• Azithromycin for prophylaxis - Clarithromycin/ Azithromycin for tx

Question 27

What are the adverse effects of macrolides? (there is 1 common group and the others are rare)

Answer 27

• GI (only ones that are common) - Cholestatic hepatitis (rare) - Thrombophlebitis - Prolonged QTc - Ototoxicity (tinnitus/deafness)

Question 28

*Erythromycin and clarithromycin– are inhibitors of cytochrome p450 system in the liver and may increase concentrations of: (just read)

Answer 28

Theophylline Digoxin, Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine, Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids