Clindamycin: MoA? - Static or cidal?
Bind and inhibit 50S subunit. - Static (cidal at high conc.) Binds in close proximity to macrolides and Quinupristin/Daltopristin (Synercid)– may cause competitive inhibition
Clindamycin: mech of resistance?
- 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
Describe the spectrum of activity of clindamycin.
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
How is clindamycin administrated? What is the % absorption?
IV, PO (90% absorption, can switch b/w IV and PO)
Does clindamycin penetrate the CSF?
Clindamycin primarily metabolized by the ___________. - Does it need adjustments during renal failure? - Is it removed during hemodialysis?
- Liver - Doesn't need adjustments during renal failure - No
What are the clinical uses of clindamycin?
- 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
What are the 2 main side-effects for clindamycin?
- GI - *C-diff colitis (one of the main inducers)
What category of drug does clindamycin belong?
What are the 3 macrolides we should know?
- Azithromycin - Clarithromycin - Erythromycin
Which 2 macrolides are derivatives of the other?
Azithromycin and clarithromycin derivatives of erythromycin
How do azithro and clarithromycin improve upon erythromycin?
- Broader spectrum of activity - Improved PK properties: better bioavailability, better tissue penetration, prolonged half-lives - Improved tolerability
Macrolides: MoA? - Cidal or static?
- Reversibly binding to the 50S ribosomal subunit - Static (cidal at high conc)
Which of the macrolides and time-dependent, and which are conc.-dependent?
- Erythromycin and clarithromycin are time-dependent - Azithromycin is conc-dependent
Macrolides: mech of resistance?
- Active efflux pump (mef gene) - Altered target sites (erm gene)
What is the spectrum of activity for macrolides? (groups are targets)
- Gram-pos aerobes (*MSSA) - Gram-neg aerobes - Anaerobes (esp. upper airway) - Atypical bacteria (*Legionella, DOC) - Other bacteria
What bacterium do macrolides importantly NOT have activity against?
Enterobacteriacea (gram-neg aerobe class)
What are the relative levels of activity for the 3 macrolides against gram-positive aerobes?
CEA Clarithro > Erythro > Azithro (ACE for gram-neg)
What are the relative levels of activity for the 3 macrolides against gram-negative aerobes?
ACE Azithro > Clarithro > Erythro (CEA for gram-pos)
Discuss the bioavailabilities of each of the of the 3 macrolides. - Which are acid stable?
- Erythromycin: variable absorption (15 to 45%) - Clarithromycin: well-absorbed (55%) - Azithromycin: 37% bioavail. regardless of food Acid stable: Clarithromycin and azithromycin
Do macrolides penetrate the CSF?
Describe the elimination routes of each of the 3 macrolides. * Which are metabolized by CYP450 enzymes?
- Erythromycin: excreted in bile, metabolized by *CYP450 - Clarithromycin: also metabolized (*CYP450) and partially eliminated by the kidney - Azithromycin: liver, NO CYP450
Name the clinical uses of macrolides.
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
Which macrolide is best when H. influenzae is suspected?
Which macrolide is best for STDs?
How are macrolides used to treat MAC (mycobacterium avium complex)? I hope to god this doesn't come up
- Azithromycin for prophylaxis - Clarithromycin/ Azithromycin for tx
What are the adverse effects of macrolides? (there is 1 common group and the others are rare)
- GI (only ones that are common) - Cholestatic hepatitis (rare) - Thrombophlebitis - Prolonged QTc - Ototoxicity (tinnitus/deafness)
*Erythromycin and clarithromycin– are inhibitors of cytochrome p450 system in the liver and may increase concentrations of: (just read)
Theophylline Digoxin, Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine, Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids