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Antibacterial 3


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Antibacterial 3

  1. 1. Common Bacteria by Site of Infection Mouth Peptococcus Peptostreptococcus Actinomyces Skin/Soft Tissue S. aureus S. pyogenes S. epidermidis Pasteurella Bone and Joint S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods Abdomen E. coli, Proteus Klebsiella Enterococcus Bacteroides sp. Urinary Tract E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus Upper Respiratory S. pneumoniae H. influenzae M. catarrhalis S. pyogenes Lower Respiratory Community S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia Lower Respiratory Hospital K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus Meningitis S. pneumoniae N. meningitidis H. influenza Group B Strep E. coli Listeria
  2. 2. Protein Synthesis Inhibitors Tetracyclines Macrolides Chloramphenicol Aminoglycosides Clindamycin Streptogramins
  3. 3. Tetracyclines - Structure Excretion R1 R2 R3 R4 mg/hr tetracycline (Achromycin) H OH CH3 H 65 chlortetracycline (Aureomycin) H OH CH3 Cl 32 oxytetracycline (Terramycin) OH OH CH3 H 90 demethylchlortetracycline (Declomycin) H OH H Cl 35 doxycycline (Vibramycin) OH CH3 H H 16 minocycline (Minocin) H H H N(CH3) 9
  4. 4. Tetracyclines - Uses Gram- Bacteria • Helicobacter pylori (duodenal ulcer) • Borrelia recurrentis (Lyme disease, relapsing fever) Other Organisms • Mycoplasma pneumoniae • acne
  5. 5. Tetracycline - Mechanism • Inhibits protein synthesis • Static • Chelates divalent cations -- Ca++ , Mg++
  6. 6. Tetracycline - Adverse Effects • headache, nausea, vomiting • discoloration of bones and teeth • photosensitivity • liver damage • superinfection
  7. 7. Superinfection A new infection appearing during treatment for a primary infection The organism will be resistant to the antibiotic used for the primary infection Organisms causing superinfection Staphylococcus aureus - enterocolitis Candida albicans - vagina, mouth Clostridium difficile - pseudomembranous colitis Risk factors in hospital > 6 days 6 > age > 60 broad spectrum antibiotic
  8. 8. Tetracylines • Administration Oral administration but interference by food, Ca++ , Mg++ • Excretion renal, fecal enterohepatic
  9. 9. Chloramphenicol - structure/features Features • Broad Spectrum • Inexpensive • Oral administration • Virtually non-toxic
  10. 10. Chloramphenicol - uses/toxicity Uses • Haemophilus influenzae (meningitis) • Typhus • Rocky Mountain Spotted Fever • Eye infections Adverse Effects • superinfection • aplastic anemia
  11. 11. Chloramphenicol - mechanism • Inhibits protein synthesis • Static
  12. 12. Macrolides • Erythromycin is a naturally-occurring macrolide derived from Streptomyces erythreus – problems with acid lability, narrow spectrum, poor GI intolerance, short elimination half-life • Structural derivatives include clarithromycin and azithromycin:  Broader spectrum of activity  Improved Pharmacokinetic properties – better bioavailability, better tissue penetration, prolonged half- lives  Improved tolerability
  13. 13. Macrolides Mechanism of Action Inhibits protein synthesis by reversibly binding to the 50S ribosomal subunit  Suppression of RNA-dependent protein synthesis Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms Time-dependent activity
  14. 14. QUICK REVIEW - Protein Synthesis
  15. 15. Macrolide Spectrum of Activity Gram-Positive Aerobes – erythromycin and clarithromycin display the best activity (Clarithro>Erythro>Azithro) • Methicillin-susceptible Staphylococcus aureus • Streptococcus pneumoniae (only PSSP) – resistance is developing • Group A/B/C/G and viridans streptococci • Bacillus sp., Corynebacterium sp.
  16. 16. Macrolide Spectrum of Activity Gram-Negative Aerobes – newer macrolides with enhanced activity (Azithro>Clarithro>Erythro) • H. influenzae (not erythro), M. catarrhalis, Neisseria sp., Campylobacter jejuni, Bordetella pertussis • Do NOT have activity against any Enterobacteriaceae or Pseudomonas
  17. 17. Macrolide Spectrum of Activity Anaerobes – activity against upper airway anaerobes Atypical Bacteria – all macrolides have excellent activity against atypical bacteria including: • Legionella pneumophila - DOC • Chlamydia sp. • Mycoplasma sp. • Ureaplasma urealyticum Other Bacteria – Mycobacterium avium complex (MAC – only A and C), Treponema pallidum, Campylobacter, Borrelia, Bordetella, Brucella. Pasteurella
  18. 18. Macrolides Pharmacology Absorption  Erythromycin – variable absorption (15-45%); food may decrease the absorption • Base: destroyed by gastric acid; enteric coated • Esters and ester salts: more acid stable  Clarithromycin – acid stable and well-absorbed, 55% bioavailable regardless of presence of food  Azithromycin –acid stable; 38% bioavailable; food decreases absorption of capsules
  19. 19. Macrolides Pharmacology Distribution  Extensive tissue and cellular distribution – clarithromycin and azithromycin with extensive penetration  Minimal CSF penetration Elimination  Clarithromycin is the only macrolide partially eliminated by the kidney (18% of parent and all metabolites); requires dose adjustment when CrCl < 30 ml/min  Hepatically eliminated: ALL  NONE of the macrolides are removed during hemodialysis!  Variable elimination half-lives (1.4 hours for erythro; 3 to 7 hours for clarithro; 68 hours for azithro)
  20. 20. Macrolides Adverse Effects • Gastrointestinal – up to 33 %  Nausea, vomiting, diarrhea, dyspepsia  Most common with erythro; less with new agents • Cholestatic hepatitis - rare  > 1 to 2 weeks of erythromycin estolate • Thrombophlebitis – IV Erythro and Azithro  Dilution of dose; slow administration • Other: ototoxicity (high dose erythro in patients with RI); QTc prolongation; allergy
  21. 21. Macrolides Drug Interactions Erythromycin and Clarithromycin ONLY– are inhibitors of cytochrome p450 system in the liver; may increase concentrations of: Theophylline Digoxin, Disopyramide Carbamazepine Valproic acid Cyclosporine Terfenadine, Astemizole Phenytoin Cisapride Warfarin Ergot alkaloids
  22. 22. Vancomycin Mechanism of Action • Inhibits bacterial cell wall synthesis at a site different than beta-lactams • Inhibits synthesis and assembly of the second stage of peptidoglycan polymers • Binds firmly to D-alanyl-D-alanine portion of cell wall precursors • Bactericidal (except for Enterococcus)
  23. 23. Vancomycin Spectrum of Activity Gram-positive bacteria – Methicillin-Susceptible AND Methicillin-Resistant S. aureus and coagulase-negative staphylococci – Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group A/B/C/G streptococcus – Enterococcus sp. – Corynebacterium, Bacillus. Listeria, Actinomyces – Clostridium sp. (including C. difficile), Peptococcus, Peptostreptococcus No activity against gram-negative aerobes or anaerobes
  24. 24. Vancomycin Pharmacology • Absorption – absorption from GI tract is negligible after oral administration except in patients with intense colitis – Use IV therapy for treatment of systemic infection • Distribution – widely distributed into body tissues and fluids, including adipose tissue; use TBW for dosing – inconsistent penetration into CSF, even with inflamed meninges • Elimination – primarily eliminated unchanged by the kidney via glomerular filtration – elimination half-life depends on renal function
  25. 25. Vancomycin Clinical Uses • Infections due to methicillin-resistant staph including bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis • Serious gram-positive infections in β-lactam allergic patients • Infections caused by multidrug resistant bacteria • Endocarditis or surgical prophylaxis in select cases • Oral vancomycin for refractory C. difficile colitis
  26. 26. Vancomycin Adverse Effects Red-Man Syndrome – flushing, pruritus, erythematous rash on face and upper torso – related to RATE of intravenous infusion; should be infused over at least 60 minutes – resolves spontaneously after discontinuation – may lengthen infusion (over 2 to 3 hours) or pretreat with antihistamines in some cases
  27. 27. Vancomycin Adverse Effects • Nephrotoxicity and Ototoxicity – rare with monotherapy, more common when administered with other nephro- or ototoxins – risk factors include renal impairment, prolonged therapy, high doses, ? high serum concentrations, other toxic meds • Dermatologic - rash • Hematologic - neutropenia and thrombocytopenia with prolonged therapy • Thrombophlebitis
  28. 28. Linezolid Mechanism of Action • Binds to the 50S ribosomal subunit near to surface interface of 30S subunit – causes inhibition of 70S initiation complex which inhibits protein synthesis • Bacteriostatic (cidal against some bacteria)
  29. 29. Linezolid Spectrum of Activity Gram-Positive Bacteria – Methicillin-Susceptible, Methicillin-Resistant AND Vancomycin-Resistant Staph aureus and coagulase- negative staphylococci – Streptococcus pneumoniae (including PRSP), viridans streptococcus, Group streptococcus – Enterococcus faecium AND faecalis (including VRE) – Bacillus. Listeria, Clostridium sp. (except C. difficile), Peptostreptococcus, P. acnes Gram-Negative Aerobes – relatively inactive Atypical Bacteria – Mycoplasma, Chlamydia, Legionella
  30. 30. Linezolid Pharmacology • Concentration-independent bactericidal activity • Absorption – 100% bioavailable • Distribution – readily distributes into well- perfused tissue; CSF penetration ≈ 70% • Elimination – both renally and nonrenally, but primarily metabolized; t½ is 4.4 to 5.4 hours; no adjustment for RI; not removed by HD
  31. 31. Linezolid Adverse Effects • Gastrointestinal – nausea, vomiting, diarrhea (6 to 8 %) • Headache – 6.5% • Thrombocytopenia – 2 to 4% – Most often with treatment durations of > 2 weeks – Therapy should be discontinued – platelet counts will return to normal
  32. 32. Linezolid (Zyvox®) Drug–Drug/Food interactions Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Tyramine rich foods, adrenergic drugs and serotonergic drugs should be avoided due to the potential drug-food and drug-drug interactions. A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.
  33. 33. Linezolid and Tyramine cont Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air- dried meats such as pepperoni (0.1 to 8 mg tyramine per ounce); sauerkraut (8 mg tyramine per 8 ounces); soy sauce (5 mg tyramine per 1 teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to 6 mg tyramine per 8 ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
  34. 34. Clindamycin Mechanism of Action Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit  Binds in close proximity to macrolides – competitive inhibition Clindamycin typically displays bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms
  35. 35. Clindamycin Spectrum of Activity Gram-Positive Aerobes • Methicillin-susceptible Staphylococcus aureus (MSSA) • Methicillin-resistant Staphylococcus aureus (MRSA) – some isolates • Streptococcus pneumoniae (only PSSP) – resistance is developing • Group and viridans streptococci
  36. 36. Clindamycin Spectrum of Activity Anaerobes – activity against Above the Diaphragm Anaerobes (ADA) Peptostreptococcus some Bacteroides sp Actinomyces Prevotella sp. Propionibacterium Fusobacterium Clostridium sp. (not C. difficile) Other Bacteria – Toxoplasmosis gondii, Malaria
  37. 37. Clindamycin Pharmacology Absorption – available IV and PO  Rapidly and completely absorbed (90%); food with minimal effect on absorption Distribution  Good serum concentrations with PO or IV  Good tissue penetration including bone; minimal CSF penetration Elimination  Clindamycin primarily metabolized by the liver; half- life is 2.5 to 3 hours  Clindamycin is NOT removed during hemodialysis
  38. 38. Clindamycin Adverse Effects • Gastrointestinal – 3 to 4 %  Nausea, vomiting, diarrhea, dyspepsia • C. difficile colitis – one of worst offenders  Mild to severe diarrhea  Requires treatment with metronidazole • Hepatotoxicity - rare  Elevated transaminases • Allergy - rare
  39. 39. New Guys on the Block • Tigecycline (Tygacil®) • Daptomycin (Cubicin®)
  40. 40. Tigecycline Mechanism of Action Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis.
  41. 41. Tigecycline Spectrum of Activity Broad spectrum of activity • Treatment of complicated skin and skin structure infections caused by susceptible organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-sensitive Enterococcus faecalis; treatment of complicated intra- abdominal infections
  42. 42. Tigecycline Pharmacokinetics • Metabolism: Hepatic, via glucuronidation, N- acetylation, and epimerization to several metabolites, each <10% of the dose • Half-life elimination: Single dose: 27 hours; following multiple doses: 42 hours • Excretion: Urine (33%; with 22% as unchanged drug); feces (59%; primarily as unchanged drug) – No dose adjustment required in renal dysfunction
  43. 43. Tigecycline Adverse Effects • >10%: Gastrointestinal: Nausea (25% to 30%), diarrhea (13%) • 2% to 10%: • Cardiovascular: Hypertension (5%), peripheral edema (3%), hypotension (2%) • Central nervous system: Fever (7%), headache (6%), dizziness (4%), pain (4%), insomnia (2%) • Dermatologic: Pruritus (3%), rash (2%) • Endocrine: Hypoproteinemia (5%), hyperglycemia (2%), hypokalemia (2%) • Hematologic: Thrombocythemia (6%), anemia (4%), leukocytosis (4%) • Hepatic: SGPT increased (6%), SGOT increased (4%), alkaline phosphatase increased (4%), amylase increased (3%), bili increased (2%), LDH increased (4%) • Neuromuscular & skeletal: Weakness (3%) • Renal: BUN increased (2%) • Respiratory: Cough increased (4%), dyspnea (3%)
  44. 44. Daptomycin Mechanism of Action  Daptomycin binds to components of the cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein.  Daptomycin is bactericidal in a concentration- dependent manner
  45. 45. Daptomycin Spectrum of Activity Gram-Positive Aerobes Treatment of complicated skin and skin structure infections caused by susceptible aerobic Gram-positive organisms; • Staphylococcus aureus bacteremia, including right- sided infective endocarditis caused by MSSA or MRSA
  46. 46. Daptomycin Pharmacokinetics • Absorption – available IV only • Half-life elimination: 8-9 hours (up to 28 hours in renal impairment) • Excretion: Urine (78%; primarily as unchanged drug); feces (6%) • Dosage adjustment in renal impairment: – Clcr <30 mL/minute: Administer dose q48hr
  47. 47. Daptomycin Adverse Effects • Hematologic: Anemia (2% to 13%) • Gastrointestinal: – Diarrhea (5% to 12%) – vomiting (3% to 12%) – constipation (6% to 11%)
  48. 48. FDA Categorization of Antibiotics in Pregnancy • Category A – Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. • Category B – Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). • Category C – Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. • Category D – There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). • Category X – Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
  49. 49. Antibiotics in Pregnancy FDA Category Antibiotics in Category A B Penicillins, Cephalosporins, Carbapenems (except Imipenem), Daptomycin, Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin, Metronidazole (avoid first trimester), Nitrofurantoin, Acyclovir, Amphoterocin B, Ethambutol C Quinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid, Trimethoprim/Sulfa (D if used near term), Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin D Tetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides (some put gentamicin as a category C) X Ribavarin
  50. 50. Antibiotics Penetration into Eucaryotic Cells (esp. Macrophages) Antibiotic Class Intracellular Accumulation Ratio Predominant Subcellular Localization Beta Lactams <1 Cytosol Glycopeptides (Vancomycin) 8 (after 24 hrs) Lysosomes Oxazolidinones (linezolid) 1 Unknown Aminoglycosides 2-4 (after several days) Lysosomes Macrolides 4-300 Lysosomes/cytosol Fluoroquinolones 4-10 Cytosol Clindamycin 5-20 Unknown Tetracyclines 1-4 Unknown Antibiotics in bold print are generally considered most effective for intracellular organisms