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41 terms

Macrolides & Lincosamides

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Macrolide 1st generation
Erythromycin

Many salt forms! (IV, PO, Topical)
Tablets are usually enteric-coated to protect from gastric acid
Macrolide 2nd generation
Clarithromycin (Biaxin) (PO)
Azithromycin (Zithromax, Z-pak, Tri-pak) (IV, PO)

As efficacious, but much better tolerated
Better absorption, longer T ½, fewer GI side effects
Macrolide 2nd generation-preggo and kids:
Pregnancy Category B
Clarithromycin = C
Children, used commonly
Ketolide
Ketolide: Telithromycin (Ketek), PO
Enhanced activity against macrolide-resistance
FDA Approved 2004, then 2007 'black-box warning'
Removed previously-approved indications
Warned against use in myasthenia gravis
No longer used clinicially due to severe cases of hepatoxicity
Macrolides-time vs conc. dept/ static vs cidal
Debate over time- vs. concentration-dependent
Mostly bacteriostatic (Stopped for a big Mac)
Macrolides-MOA
Protein Synthesis Inhibitor
Inhibit RNA-dependent protein synthesis by binding the 50S ribosomal subunit
Prevents chain elongation
Macrolide-bonus function
Anti-inflammatory properties
Decreases neutrophils in CF pts
(good for little mac's CF)
Macrolide-Absorption
Erythromycin- poor
Clarithromycin- 50%
Azithromycin - 35-40%
Macrolide-Distribution
Body fluids and tissues, bile.
Large distribution throughout the body (Azith >> Clarith > Eryth)
Macrolide-Metabolism
Erythromycin-Hepatic, CYP450
Clarithromycin-Hepatic, CYP450 to active metabilite
-saturable
Azithromycin-Minimal metabolism
Macrolide-Excretion
Erythromycin- Urine: 5-15%
Clarithromycin-Urine: 20-30%
Azithromycin-Bile: 90%, unchanged Urine: 6%
No Renal Adjust needed for any of these
Macrolide-T1/2
Erythromycin- 1.5h
Clarithromycin- 3-4h
Azithromycin - 68h!!! all have ^ Protein binding
Take this Macrolide suspension on an empty stomach, also Antacids: decrease absorption of:
Azithromycin
CYP450 Inhibitor, 3A4, 1A2
Eryth > Clarith
Macrolide- Adverse Rx's
GI: N/V, diarrhea, abdominal pain, metallic taste
Erythromycin is the worst, stimulates GI smooth muscle
Can progress to pseudomembranous colitis (C dif)
Dose-related with azithromycin
^ QT interval
Cholestatic hepatitis, ^ transaminases (Erythromycin)
Acute renal failure (Azithromycin IV formulation)
Can be used to clean out for a colonoscopy
Erythromycin
Erythromycin-Antimicrobial Spectrum
Primarily Streptococci, most closely resembles natural penicillin
^ resistance to S. pneumoniae today, all macrolides
Atypicals
Very limited activity against Gram (-) organisms, H. influenzae
Other: Pasteurella, Brucella, Bordatella
Relatively NO coverage for Enterococci, Staphylococci
Clarithromycin-Antimicrobial Spectrum
Same as erythromycin, plus more Gram (-) coverage
Mycobacterium, some anaerobes
Azithromycin-Antimicrobial Spectrum
Same as clarithromycin
Better Gram (-) H. influenza and M. catarrhalis
Less activity against anaerobes and Mycobacterium
Macrolide Resistance
Cross-resistance within macrolide class and with other classes
Gram ( +): If Eryth 'R', then Clarith and Azith 'R'
Lincosamides, chloramphenicol, stretogramins
Mechanisms of resistance-macrolides
Efflux pumps
Bacterial methylation of ribosomal target, 50S
Plasmid-mediated, MLSb: S. aureus = erm gene
Bacterial enzymatic degradation of drug
Erythromycin-uses
Topical: Acne vulgaris, bacterial conjunctivitis
Topical: Ophthalmic prevention of neonatal gonococcal and chlamydial conjunctivitis
PO: Pre-surgical Gut Decontamination
Used more for its adverse reaction, diarrahea, than its antibacterial properties
IV: alternative in PCN allergy
Clarithromycin-uses
Respiratory tract infections, esp pediatrics
Mycobacterium, MAC, combination therapy treatment and prophylaxis
H. pylori, combination therapy
Azithromycin-uses
Respiratory infections, STDs, MAC prophylaxis (HIV), OB/GYN, pediatrics
'Drug of choice' for chlamydia infections (STD)
Group B Streptococci mothers with PCN allergy
+/- Ceftriaxone for community-acquired pneumonia
Lincosamides-types
Lincomycin
-1962, Streptomyces lincolnensis, Lincoln, Nebraska
-IV only, Rarely used clinically
Clindamycin (Cleocin, Clindacin, Benzaclin, etc.)
-Derived from lincomycin
-^ oral absorption and antibacterial potency
-Equal therapeutically to lincomycin
-Many dosage forms: IV, IM, Oral capsules and suspension,
-Topical (cream, gel, solution, pads), Vaginal suppository
Lincosamides-preggo and kids
Pregnancy Category B
Children, used frequently, esp S. aureus
Clindamycin-(time vs conc. / static vs cidal)
Debate over time- vs. concentration-dependent
Bacteriostatic and/or bactericidal
Mainly time and static
Clindamycin-MOA
MOA = Protein Synthesis Inhibitor
Inhibit RNA-dependent protein synthesis by binding the 50S ribosomal subunit
Prevents chain elongation
Clindamycin-bonus
Anti-inflammatory properties
Toxin reduction ("down-regulation")
Clindamycin-PK
A-Oral 90%
D-Excellent: tissues, especially deep tissues, abscesses, bone, bile (active metabolites), macrophages (LARGE distribution!) Poor: CSF
M-Hepatic, active and inactive metabolites
E-Feces, activity persists for up to 5 days! (disrupts flora!)
Urine low, no renal adjustment needed
Clindamycin- Drug Interactions
Few: ^ effect of NMBlockers, lowers effect of cyclosporine
Clindamycin -Adverse Reactions
Diarrhea, especially Clostridium difficile-Associated Diarrhea
-20-30% of patients, worse with oral administration
-Pseudomembranous colitis
Allergic=Rashes, fever
Rare=Hepatoxicity, erythema multiforme, ^ LFTs
Lincomycin: CV/ECG changes, hypotension
Clindamycin- Antimicrobial Spectrum
Gram (+)=Staphylococci, Streptococci
Poor activity against Enterococci
Anaerobes, Gram (+) and (-)
-B. fragilis, more potent than erythromycin
-Clostridium, (no C. diff) Fusobacterium, Prevotella, Peptostrep
No activity against aerobic Gram (-) organisms or atypicals
Clindamycin -Resistance Mechanisms
Intrinsic Resistance
Enterobacteriaceae, Pseudomonas, Acinetobacter
Acquired Resistance
Cross-resistance with macrolides
D-Test for Erythromycin
Clindamycin- Clinical Uses
SSTI, abscess
-Community-acquired Staphylococci, outpatient therapy, especially pediatrics (make sure a D-Test is performed)
-Necrotizing faciitis, gangrenous skin infections Group A Streptococci (S. pyogenes) and C. perfringens
-Acne vulgaris, Proprionibacterium acne: topical creams, gels
Anaerobic infections
-Intrabdominal (bowel perforation, fecal abscess), esp B. fragilis
-Aspiration pneumonia
-Gynecologic: Bacterial Vaginosis (BV), topical
Clindamycin-more uses
Tonsillitis, Group A Streptococci pharyngitis
Alternative Gram (+) agent in penicillin-allergic patients
Clindamycin-use w/ other 50S products
Should not be given in combination with macrolides, streptogramins, or chloramphenicol
Competition for the 50S ribosome
Clindamycin-renal adjust?
No adjustment in renal or hepatic failure
Not removed by hemodialysis or peritoneal
Clindamycin & C. Diff.
Clostridium difficile infection and colitis is serious and life-threatening!
-Common Symptoms: watery, profuse, foul-smelling diarrhea; leukocytosis, fever, abdominal pain & cramping
> 3 episodes of diarrhea per day, due to toxins produced by overgrowth of C. difficile in the colon
-Caution: vaginal and topical clindamycin products, even a small amount of drug can trigger changes in colonic flora
-Associated with antibiotic use
Clindamycin is the most causative antimicobial
All antibiotics have been associated, primarily broad spectrum agents such as fluoroquinolones and Cephalosporins
Drug of choice for chlamydia
Azithro (CA)
Can be used for Mycobacterium
Clar & Azithro (CA 4 TB)