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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)

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