Macrolides and Clindamycin Flashcards
Macrolides
Erythromycin
Clarithromycin (Biaxin)
Azithromycin (Zithromax)
Dirithromycin (Dynabat)
Macrolides Chemistry
Agents consist of many membered Lactone ring to which deoxy sugar(s) attach, Clarithromycin differs from Erythromycin (14 Member) by methylation of OH group at position 6, Azithromycin (15 Member) differs by having methyl-substituted N in lactone ring; Modifications increase acid stability, tissue penetration and broaden coverage
Macrolides Spectrum of Action
Strept, Corynebacterium, Campylobacter, Helicobacter, Legionella, Mycobacterium, Chlamydia, Mycoplasma, Ureaplasma and Bordetella; Bacteriostatic - Cidal at high conc., Erythromycin - Most effective VS aerobic Gram + cocci and bacilli (Accumulate 100X), Active VS Gram - including N. meningitidis, N. gonorrhoeae; Clarithromycin -More potent vs Streptococci and Staphylococci, Good activity VS Gram -; Azithromycin Less active VS Gram + but more active VS H.influenzae, Campylobacter
Erythromycin
(14 Member)
Erythromycin - Most effective VS aerobic Gram + cocci and bacilli (Accumulate 100X), Active VS Gram - including N. meningitidis, N. gonorrhoeae
MIC - 0.04-.2
MBC - .2-2
Pharmacokinetics: Oral but parenteral available, Unstable to stomach acid (Protect with enteric coat or forms - sterate, EES, estolate) Instructions vary by dose, Administer free base 1hr before/2hr after meals, Esters may be given with food, Erythromycin best absorbed under alkaline condition (non-ionized), T1/2 = 1.5hrs, q6h
Pregnancy Category B
Clarithromycin
Biaxin
Clarithromycin differs from Erythromycin (14 Member) by methylation of OH group at position 6
More potent vs Streptococci and Staphylococci, Good activity VS Gram -
Pharmacokinetics: Acid stable, Longer t1/2 (6hr BID), Better absorbed, Twice daily dosing/Once daily dosing of extended release formulation, Advantage over erythromycin extended spectrum - lower incidence of GI disturbance and less frequent dosing, Good tissue penetration, Metabolized in liver and eliminated in urine (Undergoes rapid first-pass metabolism to active metabolite 14-hydroxyclarithromycin)
Pregnancy Category C
Azithromycin
Zithromax
Azithromycin (15 Member) differs by having methyl-substituted N in lactone ring
Less active VS Gram + but more active VS H.influenzae, Campylobacter
Pharmacokinetics: (15 member ring); Penetrates tissue well with conc. 10-100 serum, Slowly released from tissue w/t1/2 2-4days, Once daily dosing and shorter treatment, Does not interfere with P450 enzymes so fewer drug interactions
Pregnancy Category B
Dirithromycin
Dynabat
Streptococcal Infections
Macrolides for patients allergic to penicillin
S. pyogenes - Scarlet fever, pharyngitis
S. pneumoniae - Pneumonia
Helicobacter Pylori
Causes peptic ulcer disease
Treat - Clarithromycin (500mg) + Omeprazole (20mg) + Amoxicillin
Macrolides Mechanism of Action
Primarily bacteriostatic, but may be cidal; Inhibit translocation step of protein synthesis by binding to 23S rRNA of 50S ribosomal subunits of sensitive organisms, Binding of macrocodes to 23S rRNA blocks exit tunnel from which newly formed peptides emerge
Azithromycin Properties
Delivered to site of infection - 1. Direct uptake into tissues (Fibroblasts) 2. Phagocytes deliver drug to sites of infection where is released in response to phagocytosis to deliver effective, locally high conc. of drug by biological targeted delivery mechanism - Prefer uptake by phagocytosis leads to conc. in infected tissues which are much higher than in similar non-infected
Azithromycin Pharm Properties for Dentistry
Stable in acid pH, Well absorbed, Absorption not seriously effected by food, Sustained high tissue conc., Extensive penetration of cells, Rapid uptake by phagocytes, Deliver high conc. to site of infection, Once daily delivery, Shorter duration of admin, Less GI side effects than erythromycin
GOOD CANDIDATE FOR SUBACUTE BACTERIAL ENDOCARDITIS (SBE) - Rapid tissue penetration w/low serum levels
Azithromycin in Perio
500mg once daily for 3d, Pentrates biofilm efficiently so used as adjunct therapy, Penetrates and accumulates in neutrophils and macrophages and carried by cells to inflamed tissue, Persists for >28d in neutrophils, Fibroblasts act as reservoir to release drug slowly and transfer to neutrophils, Anti-inflammatory properties by regulating neutrophil and macrophage activity and cytokine production, hence used in diseases such as asthma, COPD, cystic fibrosis; Reduces gingival overgrowth in patients taking cyclosporine A, DHP Ca channel blockers, phenytoin and reduced gingival overgrowth by inhibiting cyclosporin A induced proliferation of fibroblasts and collagen accumulation and by activating MMP2 not MMP1; Antibacterial, Antiinflammatory and Healing
Macrolides Adverse Effects
May activate motilin receptors causing nausea, vomiting and diarrhea, Some forms taken with food but not erythromycin free base, Serious side effect of erythromycin estolate is cholestatic hepatitis - Syndrome is hypersensitivity rxn to estolate; FDA warning for causing QT interval prolongation and therefore risk of arrhythmia and cardiovascular death - Best to avoid use in patients with underlying cardiac states associated with rhythm issues, myocardial dysfunction, myocardial infarction angina, cardiac failure, hypertension, hyperlipidemia, diabetes
Erythromycin Adverse Effects
Metabolites inhibit P450 CYP3A4 enzymes leading to elevated concentration of drugs (statins) - Increase risk of muscle pain and wasting with statin, Drugs interact with Erythromycin and Clarithromycin - Theophylline, Oral anticoagulants, Lanoxin (Digoxin), Methylprednisolone, Phenytoin sodium (Dilantin), Carbamazepine (Tegretol), Cyclosporine (Sandimmune), Ergot Alkaloids, Midazolam, Triazolam, HMG CoA Inhibitors (Statins), AAC
Pravastatin
Not metabolized by CYP3A4
Macrolides Resistance
Serious clinical problem - Efflux of drug by active pump or decrease membrane permeability to agents, Production of methylase enzyme that modify ribosomal targets, leading to decreased drug binding (Most Gram+), Production of esterase’s that hydrolyze macrolides (Enterobacteriaceae)
Clindamycin
Cleocin
Chemistry: Derivative of Lincomycin by Stept. Lincolnensis so Lincosamide
Clindamycin Spectrum of Action
Acts on 50S ribosome, Active VS Gram + cocci and Anaerobes (Not aerobic Gram -), Greater activity VS Anaerobes particularly Bacteroides fragilis, Mainly used to treat serious anaerobic infections caused by Bacteroides and mixed infections caused by other anaerobes
Clindamycin In Dentistry
Refractory periodontal infections (600mg/d * 7d), Premedication prophylaxis in cases of penicillin allergy (600mg PO 1h prior to treat, 600mg IV 30min before procedure), Excellent tissue penetration used to treat bone and joint infections - Effective for endo infections or dental abscesses involving bone and/ soft tissue not responding adequately to penicillin
Clindamycin Spectrum of Action
Use as alternate in dental patients allergic to Penicillin (Treat lung abscesses), Choice for anaerobic lung and pleural space infections, Not predictable for brain abscess as poor penetration into CSF - (Use Metronidazole + Penicillin or 3rd gen Cephalosporin), Available as topical cream or lotion for acne vulgarism and bacterial vaginosis
Clindamycin Mechanism of Action
Bind to 50S subunit of ribosome and inhibit protein synthesis
Clindamycin Pharmacokinetics
Well absorbed oral, Provided as capsules of Clindamycin HCl or as Palmitate ester to prepare flavored suspensions for pediatric use, Well distributed into fluids and tissue (Not CSF), Metabolized by liver and excreted in urine and bile, Reduced dose by 50% with liver disease, No reduction for renal disease
Clindamycin Adverse Effects
GI disturbances, particularly diarrhea, skin rash, severe pseudomembranous colitis (AAC) - (abdominal pain, diarrhea, fever, mucus and blood in stool) due to superinfection with C. difficile, C.diff can be lethal, Treat C. diff with Metronidazole or Oral Vancomycin to stop antibiotic
Telithromycin
Ketek
Semi-synthetic derivative of erythromycin, Binds 23rRNA of 50S ribosomal subunit similar to macrolides but with greater affinity, Used to treat bacteria resistant to macrolides, Involved in drug interactions, Causes hepatic necrosis and liver failure, Inhibits CYP3A4
