Antimicrobial

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Antimicrobial

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Antimicrobial

  1. 1. Antimicrobial Therapy
  2. 2. Now, more DRUGS <ul><li>Major classes </li></ul>
  3. 3. The Drugs <ul><li>Penicillins </li></ul><ul><li>Cephalosporins </li></ul><ul><li>Tetracyclines </li></ul><ul><li>Macrolides </li></ul><ul><li>Fluroquinolones </li></ul>
  4. 4. Penicillins <ul><li>Natural Penicillins </li></ul><ul><ul><li>Penicillin G (Crysticillin AS) </li></ul></ul><ul><ul><li>Penicillin VK (Veetids, Pen-Vee K) </li></ul></ul><ul><li>Penicillinase-resistant penicillins </li></ul><ul><ul><li>Cloxacillin (Tegopen, Cloxapen) </li></ul></ul><ul><ul><li>Dicloxacillin (Dynapen, Dicloxacil) </li></ul></ul><ul><ul><li>Nafcillin (Unipen, Nafcil) </li></ul></ul><ul><ul><li>Oxacillin (Prostaphlin, Bactocill) </li></ul></ul>
  5. 5. Penicillins <ul><li>Aminopenicillins </li></ul><ul><ul><li>Ampicillin (Omnipen, Ampican, Polycillin) </li></ul></ul><ul><ul><li>Amoxicillin (Amoxil, Polymox, Trimox) </li></ul></ul><ul><ul><li>Bacampicillin (Spectrobid) </li></ul></ul><ul><ul><li>Amoxicillin + potassium clavenulate (Augmentin) </li></ul></ul><ul><ul><li>Ampicillin sulbactam (Unasyn) </li></ul></ul><ul><li>Extended Spectrum </li></ul><ul><ul><li>Carbenicillin (Geocillin) </li></ul></ul><ul><ul><li>Mezlocillin (Mezlin) </li></ul></ul><ul><ul><li>Piperacillin (Pipracil) </li></ul></ul><ul><ul><li>Piperacillin sodium + tazobactam sodium (Zosyn) </li></ul></ul><ul><ul><li>Ticarcillin (Ticar) </li></ul></ul><ul><ul><li>Ticarcillin + potassium clavenulate (Timentin) </li></ul></ul>
  6. 6. Indications: Penicillins <ul><li>Non-penicillinase producing staphylococci & streptococci and MOST G(+) organisms </li></ul><ul><li>Some G(-) and MOST anaerobic </li></ul><ul><li>Beta-lactam   activity against G(+), G(-) & anaerobic organisms </li></ul><ul><ul><li>Amoxicillin + clavenulate   spectrum </li></ul></ul><ul><ul><li>Ampicillin + sulbactam  widest spectrum </li></ul></ul>Staphylococcus sp.
  7. 7. Susceptible Organisms <ul><li>Streptococcal pneumonia </li></ul><ul><li>Group A beta-hemolytic </li></ul><ul><li>Neisseria meningitidis </li></ul><ul><li>Neisseria gonorrhea </li></ul><ul><li>Non-penicillinase producing Staphylococcus aureus </li></ul><ul><li>Clostridium tetani </li></ul><ul><li>Clostridium perfringens </li></ul><ul><li>Corynebacterium diptheriae </li></ul><ul><li>Actinomycetes </li></ul><ul><li>Treponema pallidum </li></ul>
  8. 8. Indications <ul><li>Otitis media </li></ul><ul><li>Streptococcal pharyngitis </li></ul><ul><li>Sinusitis </li></ul><ul><li>Pneumococcal pneumonia </li></ul><ul><li>Animal bite </li></ul><ul><li>Impetigo </li></ul><ul><li>Syphilis </li></ul><ul><li>Gonorrhea </li></ul><ul><li>Bacterial endocarditis prophylaxis </li></ul>
  9. 9. Drug Action & Effect: Penicillins <ul><li>Disrupt synthesis of the bacterial cell wall </li></ul><ul><li>Compete for & bind to specific enzyme proteins (PBPs) responsible for building & reshaping the bacterial wall </li></ul><ul><li>Bacteria can no longer lay protein cross links across cell wall </li></ul><ul><li>Activates autolytic enzymes that cause progressive bacterial lysis </li></ul>Penicillin G
  10. 10. Mechanisms of Resistance <ul><li>Formation of Beta-lactamases (penicillinases) </li></ul><ul><ul><li>EXAMPLE: S. aureus resistance to PCN-G </li></ul></ul><ul><li>Diminished permeability of the drug through the bacterial outer cell membrane </li></ul><ul><li>Decreased binding of the drug at its target sites on the inner bacterial membrane </li></ul><ul><li>Inhibitors of beta-lactamases (clavulanic acid, sulbactam, tazobactam) used in combination with PCNs to prevent their inactivation </li></ul>
  11. 11. Drug Treatment Principles <ul><li>Oral  mild to moderately severe infections </li></ul><ul><li>Parenteral  severe infections </li></ul><ul><li>Broad Spectrum Penicillins  may be used empirically while awaiting culture results </li></ul><ul><li>Penicillin V  group A beta-hemolytic streptococci </li></ul><ul><li>Penicillin G (IM)  drug of choice for syphilis </li></ul><ul><li>Amoxicillin  first line for otitis media </li></ul>
  12. 12. Monitoring: Penicillins <ul><li>Parenteral </li></ul><ul><ul><li> monitor x 30 min for allergic anaphylaxis </li></ul></ul><ul><ul><li> Renal fxn, lytes, cardiac </li></ul></ul><ul><li>Penicillinase-resistant penicillin </li></ul><ul><ul><li> check UA, BUN, creat </li></ul></ul><ul><li>Penicillin G  hyperkalemia-rare </li></ul><ul><li>Parenteral ticarcillin or penicillin G </li></ul><ul><ul><li> sodium loading </li></ul></ul>
  13. 13. Patient Variables <ul><li>Geriatrics </li></ul><ul><ul><li>High sodium content  danger for cardiac/renal </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>< 3 months old  check maternal allergy </li></ul></ul><ul><ul><li> clearance at birth   significantly in 1 st year </li></ul></ul><ul><ul><li>S&E NOT established for carbenicillin, piperacillin, &  -lactamase </li></ul></ul><ul><ul><li>Penapar VK contains aspartame  NOT for PKU </li></ul></ul><ul><li>Gender </li></ul><ul><ul><li> effectiveness of OC  use backup method </li></ul></ul><ul><ul><li>Crosses placenta & excreted in breast milk </li></ul></ul>
  14. 14. Education: Penicillins <ul><li>Take on empty stomach 1 hr before or 2 hr after meals with full glass of water </li></ul><ul><li>Notify provider: rash, itching, hives, severe diarrhea, SOB, urticaria, black tongue, sore throat, vomiting, fever, swollen joints, unusual bleeding or bruising </li></ul><ul><li>Patients with PCN allergy should wear MedicAlert bracelet </li></ul><ul><li>Reconstituted solutions stable x 14 days if refrigerated </li></ul>
  15. 15. Contraindications/Precautions <ul><li>Do NOT use if Hx hypersensitivity to: penicillins, cephalosporins, or imipenem </li></ul><ul><li>Do NOT treat severe infections with PO during acute stage </li></ul><ul><li>Risk of cross-sensitivity with cephalosporins </li></ul><ul><li>Ticarcillin, mezlocillin, piperacillin  hemorrhagic manifestations </li></ul><ul><li>Synergism with: aminoglycosides </li></ul><ul><li>Probenecid   serum concentrations of PCN </li></ul><ul><li>CF  higher incidence of side effects </li></ul><ul><li>Streptococcal  Tx must be sufficient to prevent endocarditis/rheumatic heart disease </li></ul><ul><li>Resistance & superinfection </li></ul><ul><li>Pseudomembranous colitis </li></ul><ul><li>Some products contain tartrazine or sulfites  hypersensitivity </li></ul>
  16. 16. Pharmacokinetics <ul><li>Absorption  variable </li></ul><ul><li>Onset of Action  0.5-2 hr </li></ul><ul><li>Time to Peak  0.5-2 hr </li></ul><ul><li>Protein Binding  20% (ampicillin & amoxicillin) to > 90% (nafcillin, oxacillin, cloxacillin, dicloxacillin) </li></ul><ul><li>Distribution  wide body fluids, pleural/pericardial cavity, joints, bile, placenta, breast milk, CSF </li></ul><ul><li>Elimination  renal rapid (85-90% tubular) </li></ul><ul><ul><li>Half-life=0.4-1.7 hrs (up to 20 hr if anuric) </li></ul></ul><ul><ul><li>Nafcillin & oxacillin   liver metabolism </li></ul></ul>
  17. 17. Common Adverse Reactions <ul><li>Skin </li></ul><ul><ul><li>Maculopapular and erythematous rashes </li></ul></ul><ul><ul><li>Photosensitivity (not with PCNs) </li></ul></ul><ul><ul><li>Onycholysis and discoloration of nails </li></ul></ul><ul><li>GI </li></ul><ul><ul><li>Anorexia, nausea, vomiting, diarrhea, epigastric distress, bulky loose stools </li></ul></ul><ul><ul><li>Sore throat, glossitis, hoarseness, black hairy tongue </li></ul></ul><ul><li>CNS </li></ul><ul><ul><li>Headache </li></ul></ul>
  18. 18. Serious Adverse Reactions <ul><li>Skin </li></ul><ul><ul><li>Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) </li></ul></ul><ul><li>Hypersensitivity </li></ul><ul><ul><li>Rash, fever, anaphylaxis, urticaria, laryngeal edema, serum sickness </li></ul></ul><ul><li>GI </li></ul><ul><ul><li>Dysphagia, enterocolitis, inflammatory lesions in anogenital region </li></ul></ul><ul><li>Hematologic </li></ul><ul><ul><li>Neutropenia, eosinophilia, thrombocytopenia </li></ul></ul><ul><li>Hepatic </li></ul><ul><ul><li>Elevated liver function tests </li></ul></ul><ul><li>CNS </li></ul><ul><ul><li>Transient myopathy, confusion </li></ul></ul>
  19. 19. Drug Interactions <ul><li>PCNs decrease activity of oral contraceptives  must use barrier method to avoid unintended pregnancy </li></ul><ul><li>Ampicillin may reduce bioavailability of atenolol </li></ul>
  20. 20. Drug Interactions <ul><li>Beta blockers may potentiate anaphylactic reactions to PCN </li></ul><ul><li>Tetracycline decreases effectiveness of PCNs </li></ul><ul><li>Probenecid inhibits renal tubular secretion of PCNs </li></ul><ul><li>Allopurinol increases risk of ampicillin-induced rash </li></ul>
  21. 21. Adverse Effects & Drug Interactions <ul><li>You should be familiar with side effects & interactions </li></ul><ul><li>You are NOT expected to memorize dosages </li></ul><ul><li>You should look at comparative pharmacokinetics among drugs in the same class </li></ul>
  22. 22. Cephalosporins <ul><li>1 st Generation </li></ul><ul><ul><li>Cephalexin (Keflex) </li></ul></ul><ul><ul><li>Cefadroxil (Duricef) </li></ul></ul><ul><li>2 nd Generation </li></ul><ul><ul><li>Cefaclor (Ceclor) </li></ul></ul><ul><ul><li>Cefpodoxime (Vantin) </li></ul></ul><ul><ul><li>Cefprozil (Cefzil) </li></ul></ul><ul><ul><li>Cefuroxime (Ceftin) </li></ul></ul><ul><ul><li>Loracarbef (Lorabid) </li></ul></ul><ul><li>3 rd Generation </li></ul><ul><ul><li>Cefixime (Suprax) </li></ul></ul><ul><ul><li>Ceftriaxone (Rocephin) </li></ul></ul><ul><ul><li>Cefdinir (Omnicef) </li></ul></ul><ul><ul><li>Cefditoren (Spectracef) </li></ul></ul>MOST commonly prescribed antibiotics in US !
  23. 23. Indications: Cephalosporins <ul><li>1 st generation  UTI, skin & soft tissue </li></ul><ul><ul><li> most active against G(+) </li></ul></ul><ul><ul><li> moderate activity against some G(-) & no activity against others </li></ul></ul><ul><li>2 nd & 3 rd generation   G(-) activity across generations at expense of G(+) also  $$$ </li></ul><ul><ul><li>2 nd generation  good activity against E. coli  second line Tx for OM & sinusitis </li></ul></ul><ul><ul><li>3 rd generation  broadest spectrum  very effective against G(-) but G(+) sharply reduced </li></ul></ul><ul><li>Minimal toxicity even at high doses  wide therapeutic window does not require monitoring </li></ul><ul><li>Penetrates CSF </li></ul>
  24. 24. Susceptible Organisms <ul><li> -hemolytic streptococci </li></ul><ul><li>Streptococcus pneumoniae </li></ul><ul><li>Escherichia coli </li></ul><ul><li>Proteus </li></ul>
  25. 25. Action & Effect: Cephalosporins <ul><li> -lactam antibiotics  resist bacterial enzymes (esp.  -lactamase)  interfere with synthesis of peptidoglycan in the cell wall  makes the cell wall osmotically unstable </li></ul><ul><li>Are bacteriCIDAL  more effective against RAPIDLY growing organisms </li></ul><ul><li>RESISTANCE: occurs by hydrolysis of the beta-lactam ring by beta-lactamases </li></ul>Cephtriaxone
  26. 26. Drug Treatment Principles <ul><li>Oral  mild to moderately severe infections </li></ul><ul><li>Parenteral  severe infections </li></ul><ul><li>1 st generation: </li></ul><ul><ul><li>Keflex Q6 hr vs Duricef BID (Q12) </li></ul></ul><ul><li>2 nd generation: </li></ul><ul><ul><li>Manufacturers suggest BID dosing . . .  BUT literature does NOT support! </li></ul></ul><ul><li>3 rd generation: </li></ul><ul><ul><li>Rocephin IM or IV only  used for Tx of STDs  Tx of pneumonia in elderly residing in SNFs </li></ul></ul>
  27. 27. Education: Cephalosporins <ul><li>Take with food or milk to prevent GI upset </li></ul><ul><li>Notify provider: nausea, vomiting, or diarrhea or s/s of allergic reaction </li></ul>Lactobacillus sp. A cup of yogurt a day . . . Keeps the diarrhea away !
  28. 28. Pharmacokinetics, Dosages & Administration Information <ul><li>CONTRAINDICATIONS: allergic reaction </li></ul><ul><li>WARNINGS/PRECAUTIONS: </li></ul><ul><ul><li>Cross-sensitivity with penicillins </li></ul></ul><ul><ul><li>Serum sickness-like reactions, seizures, coagulation abnormalities </li></ul></ul><ul><ul><li>Superinfection </li></ul></ul><ul><ul><li>Give IM deep into muscle </li></ul></ul><ul><li>PHARMACOKINETICS: </li></ul><ul><ul><li>Renal excretion  use with caution/adjust dosage for renal impairment </li></ul></ul><ul><li>DRUG INTERACTIONS: </li></ul><ul><ul><li>Disulfuram-like reaction if parenteral taken with alcohol </li></ul></ul><ul><ul><li>May potentiate aminoglycoside nephrotoxicity </li></ul></ul><ul><ul><li>Probenecid  may increase & prolong serum levels </li></ul></ul>
  29. 29. Tetracyclines <ul><li>Tetracycline (Sumycin) </li></ul><ul><li>Demeclocycline </li></ul><ul><li>Doxycycline (Vibramycin) </li></ul><ul><li>Methscycline </li></ul><ul><li>Minocycline </li></ul><ul><li>Oxytetracycline </li></ul>Sumycin Doxycycline Minocycline
  30. 30. Indications: Tetracyclines <ul><li>Active against wide range of organisms </li></ul><ul><li>1 st drug of choice in Tx of rickettsial infections, vibrio cholera & chlamydia trachomatis </li></ul><ul><li>Used in combination with metronidazole and bismuth subsalicylate for PUD associated with Helicobacter pylori </li></ul><ul><li>Also used to treat acne, PID, UTI </li></ul><ul><li>Doxycycline  prevent malaria </li></ul><ul><li>Appropriate as first line therapy for patients with true allergy to other first line therapies </li></ul><ul><li>NOT active against fungi or viruses </li></ul><ul><li>G(-) activity limited d/t development of resistant strains </li></ul><ul><li>Doxycycline & minocycline  more activity against Bacteroides fragilis & Clostridia </li></ul>
  31. 31. Susceptible Organisms <ul><li>G(+) bacilli </li></ul><ul><ul><li>Actinomyces </li></ul></ul><ul><ul><li>Clostridium </li></ul></ul><ul><ul><li>Listeria </li></ul></ul><ul><ul><li>Nocardia </li></ul></ul><ul><li>G(-) bacilli </li></ul><ul><ul><li>Acinetobacter </li></ul></ul><ul><ul><li>Bacteroides sp. </li></ul></ul><ul><ul><li>Campylobacter </li></ul></ul><ul><ul><li>Escherichia coli </li></ul></ul><ul><ul><li>Enterobacter </li></ul></ul><ul><ul><li>Haemophilus </li></ul></ul><ul><ul><li>Shigella </li></ul></ul><ul><ul><li>Vibrio </li></ul></ul><ul><ul><li>Klebsiella </li></ul></ul><ul><ul><li>Mycoplasma </li></ul></ul><ul><ul><li>Chlamydia </li></ul></ul><ul><ul><li>Spirochetes </li></ul></ul><ul><ul><li>Protozoa </li></ul></ul>
  32. 32. Action & Effect: Tetracyclines <ul><li>All have similar structure & antimicrobial activity </li></ul><ul><li>Cross-resistance is common </li></ul><ul><li>Minor structural differences affect lipid solubility, half-life, & effect of food on bioavailability </li></ul><ul><li>Prohibits protein synthesis by binding to 30S ribosome  leakage of cytosolic nucleotides </li></ul><ul><li>May also reversibly bind to 50S </li></ul><ul><li>Requires microbial growth for effect  Drugs are bacterio STATIC ! </li></ul>Minocycline Doxycycline Tetracycline
  33. 33. Drug Treatment Principles <ul><li>Wide spectrum  good for empiric therapy </li></ul><ul><li>1 st choice for rickettsial infections </li></ul><ul><li>2 nd consideration for many other infections </li></ul><ul><li>Appropriate for patients with allergy to other antibiotics </li></ul><ul><li>Except for doxycycline & minocycline, tetracyclines chelate with Ca, Mg, Zn & Fe  take on empty stomach 1 hr before or 2 hrs after meals – do NOT take with milk or antacids </li></ul><ul><li>Doxycycline & minocycline are highly lipid soluble  readily penetrate CSF, brain, eye & prostate </li></ul><ul><li>Excreted unchanged in urine & feces </li></ul><ul><li>Reduce dose/interval for renal impairment (doxycycline & minocycline do not require dose adjustment) </li></ul><ul><li>Doxycycline MOST useful tetracycline in primary care ! </li></ul>
  34. 34. Patient Variables <ul><li>Geriatrics </li></ul><ul><ul><li>Well absorbed </li></ul></ul><ul><ul><li> serum levels with renal impairment BUT for doxy- and minocycline primary route of excretion is biliary  so impaired renal function does not affect drug half-life  GOOD choice for elderly especially if renal fxn a concern ! </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>Should NOT be given to children < age 8  drugs will cause permanent damage to teeth & bones </li></ul></ul><ul><li>Pregnancy & Lactation </li></ul><ul><ul><li>Readily crosses to placenta & into breast milk  will affect fetal tooth & bone development  NEVER give to pregnant or lactating women !!! </li></ul></ul>
  35. 35. Monitoring & Education: Tetracyclines <ul><li>Baseline renal & hepatic fxn repeat Q3 mo for chronic therapy </li></ul><ul><li>Loss of appetite, jaundice or abdominal pain  may indicate hepatotoxicity  promptly report any changes </li></ul><ul><li>Change in mental status  may indicate intracranial hypertension  promptly report any changes </li></ul><ul><li>Take with full glass of water to prevent ulceration </li></ul><ul><li>Take all tetracyclines except for doxy- & minocycline on an emptying stomach & do NOT take with milk or antacids </li></ul><ul><li>Photosensitivity  use sunscreen </li></ul>
  36. 36. Warnings/Precautions: Tetracyclines <ul><li>Photosensitivity  use sunscreen </li></ul><ul><li>Long-term Democycline Tx  diabetes insipidus syndrome </li></ul><ul><li>Minocycline  light-headedness, dizziness, vertigo, tinnitus  use caution during hazardous tasks </li></ul><ul><li>For individuals with renal impairment  potential for accumulation & hepatotoxicity </li></ul><ul><li>Tetracyclines (except doxycycline) may  BUN </li></ul><ul><li>Headaches, blurred vision  intracranial hypertension </li></ul><ul><li>Use of old/degraded medication  renal toxicity  discard any old/unused medication </li></ul><ul><li>Superinfection (yeast/fungal) </li></ul><ul><li>Some products may contain sulfites  reaction in sensitive individuals </li></ul>
  37. 37. Pharmacokinetics & Adverse Effects: Tetracyclines <ul><li>Excreted unchanged in the urine via glomerular filtration  reduction in dose/interval required in renal impairment </li></ul><ul><li>Secondary biliary excretion route </li></ul><ul><li>Associated with GI intolerance: anorexia, nausea, vomiting, diarrhea, esophagitis, & esophageal ulceraton </li></ul><ul><li>Doxycycline associated with less nephrotoxicity </li></ul><ul><li>IRREVERSIBLE hyperpigmentation of deciduous and permanent teeth & inhibition of bone growth </li></ul><ul><li> ICP  bulging fontanels & pseudotumor cerebri </li></ul><ul><li>Dizzines, tinnitus, visual disturbances </li></ul><ul><li>Hypersensitivity mild rash  urticaria  exfoliative dermatitis  angioedema & systemic anaphylaxis </li></ul><ul><li>Hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia, pseudomembranous colitis, phlebitis </li></ul>
  38. 38. Drug Interactions: Tetracyclines <ul><li>Barbiturates, phenytoin, & carbamazepine do NOT increase the half-life of tetracycline as they do with doxycycline </li></ul><ul><li>Do NOT take with food or milk </li></ul><ul><li>Tetracycline may potentiate the effects of oral anticoagulants via impairing PT activity or by  vitamin K production by intestinal flora  monitor PT carefully </li></ul><ul><li>Medication is not removed with dialysis  if overdosed drink milk + take antacids to impair absorption. </li></ul>
  39. 39. Drug Class: Macrolides <ul><li>Erythromycin </li></ul><ul><ul><li>Erythromycin Base </li></ul></ul><ul><ul><li>Erythromycin Estolate </li></ul></ul><ul><ul><li>Erythromycin Stearate </li></ul></ul><ul><ul><li>Erythromycin Ethylsuccinate </li></ul></ul><ul><li>Newer macrolides </li></ul><ul><ul><li>Azithromycin (Zithromax) </li></ul></ul><ul><ul><li>Clarithromycin (Biaxin) </li></ul></ul><ul><ul><li>Dirithromycin (Dynabac) </li></ul></ul><ul><ul><li>Troleandomycin (TAO) </li></ul></ul>
  40. 40. Indications: Macrolides <ul><li>Otitis media </li></ul><ul><li>Gonorrhea </li></ul><ul><li>Acute bronchitis or pneumonia in COPD </li></ul><ul><li>Community-acquired pneumonia </li></ul><ul><li>Pharyngitis </li></ul><ul><li>Sinusitis </li></ul><ul><li>Erysipelas (S. pyogenes) </li></ul><ul><li>Impetigo (strept or staph) </li></ul><ul><li>Lyme disease (Borellia burgdorferi) </li></ul>
  41. 41. Activity: Macrolides <ul><li>Similar antibacterial spectrum across agents </li></ul><ul><li>Newer macrolides </li></ul><ul><ul><li>added effectiveness against G(-) bacteria & anaerobes </li></ul></ul><ul><li>Valued for unique ability to treat atypical pathogens seen in community-acquired pneumonia </li></ul><ul><li>Clarithromycin </li></ul><ul><ul><li>Increased potency against G(-) bacteria & anaerobes </li></ul></ul><ul><li>Azithromycin </li></ul><ul><ul><li>Less active than erythromycin against most staphylococci & streptococci BUT more potent against other organisms </li></ul></ul><ul><li>Azithromycin & Clarithromycin </li></ul><ul><ul><li>Used for more complicated infections </li></ul></ul>
  42. 42. Action & Effect: Macrolides <ul><li>May be bactericidal or bacteriostatic </li></ul><ul><li>Characterized by similar antibacterial spectrum </li></ul><ul><li>Coverage varies according to specific drug b </li></ul><ul><li>Inhibit protein synthesis by stimulating dissociation of RNA from the ribosome </li></ul>
  43. 43. Drug Treatment Principles: Macrolides <ul><li>Good first-line choice for uncomplicated infections </li></ul><ul><li>Erythromycin </li></ul><ul><ul><li>Inexpensive & good substitute for cephalosporin or penicillin </li></ul></ul><ul><ul><li>Strength of erythromycin products expressed as erythromycin base equivalents </li></ul></ul><ul><li>Azithromycin </li></ul><ul><ul><li>Extended half-life & QD dosing, free of many drug interactions </li></ul></ul>
  44. 44. Drug Treatment Principles: Macrolides <ul><li>Cause several changes in P450  inhibits metabolism of: </li></ul><ul><ul><li>Theophylline, phenytoin (dilantin), carbamazepine (tegretol) </li></ul></ul><ul><li>Use with caution in presence of severe renal or hepatic impairment </li></ul><ul><li>Dirithromycin </li></ul><ul><ul><li>Does NOT alter P450  no clinically significant adverse drug interactions </li></ul></ul><ul><li>Erythromycin estolate </li></ul><ul><ul><li>Most commonly associated with hepatotoxicity </li></ul></ul>
  45. 45. Pharmacokinetics: Macrolides <ul><li>Pharmacokinetics </li></ul><ul><ul><li>May be affected by alterations in bioavailability, protein binding, rate of metabolism or excretion </li></ul></ul><ul><ul><li>Depend on P450 3A4 as major route of metabolism  toxicity may occur when route blocked </li></ul></ul><ul><ul><li>Key differences in pharmacokinetics (see table 63-2 p. 677 Edmunds) </li></ul></ul>
  46. 46. Patient Variables: Macrolides <ul><li>Geriatrics </li></ul><ul><ul><li>Lower dose generally NOT necessary UNLESS renal or hepatic impairment </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>Key factors: age, weight, severity of illness </li></ul></ul><ul><ul><li>Dirithromycin </li></ul></ul><ul><ul><ul><li>Safety & efficacy in children < 12 NOT established </li></ul></ul></ul>
  47. 47. Patient Variables: Macrolides <ul><li>Pregnancy </li></ul><ul><ul><li>Category B: Erythromycin, Azithromycin </li></ul></ul><ul><ul><ul><li>Erythromycin estolate associated with  LFTs </li></ul></ul></ul><ul><ul><li>Category C: Clarithromycin, Dirithromycin </li></ul></ul><ul><ul><ul><li>Do NOT use in pregnancy unless no other alternative </li></ul></ul></ul><ul><ul><li>Troleandomycin </li></ul></ul><ul><ul><ul><li>Safety NOT established </li></ul></ul></ul><ul><li>Lactation </li></ul><ul><ul><li>Erythromycin </li></ul></ul><ul><ul><ul><li>Compatible with breast feeding BUT does transfer </li></ul></ul></ul><ul><ul><li>Azithromycin, Clarithromycin, Dirithromycin & Troleandomycin </li></ul></ul><ul><ul><ul><li>May be excreted in breast milk  use with CAUTION </li></ul></ul></ul>
  48. 48. Monitoring & Education: Macrolides <ul><li>Monitor </li></ul><ul><ul><li>Hepatic function with long-term use especially erythromycin estolate </li></ul></ul><ul><li>Patient Education </li></ul><ul><ul><li>Azithromycin </li></ul></ul><ul><ul><ul><li>Take on empty stomach </li></ul></ul></ul><ul><ul><li>Clarithromycin </li></ul></ul><ul><ul><ul><li>Take with/without food </li></ul></ul></ul><ul><ul><ul><li>Suspension should NOT be refrigerated, shake well before use </li></ul></ul></ul><ul><ul><li>Dirithromycin </li></ul></ul><ul><ul><ul><li>Take with food or within 1 hour of eating </li></ul></ul></ul><ul><ul><li> OC efficacy  use backup method of contraception </li></ul></ul>
  49. 49. Warnings/Precautions: Macrolides <ul><li>Drug interactions: </li></ul><ul><ul><li>warfarin (Coumadin), digoxin, triazolam (Halcion), terfenadine and ergotamine </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Pre-existing liver disease for erythromycin estolate </li></ul></ul><ul><li>Warnings/Precautions </li></ul><ul><ul><li>Superinfection </li></ul></ul>
  50. 50. Adverse Effects: Macrolides <ul><li>Adverse effects </li></ul><ul><ul><li>Most frequent dose-related side effects: </li></ul></ul><ul><ul><ul><li>Abdominal cramping & discomfort, anorexia, nausea, vomiting, diarrhea </li></ul></ul></ul><ul><ul><ul><li>Newer macrolides rarely cause GI side effects </li></ul></ul></ul><ul><ul><li>Mild allergic reactions: rash with/without pruritis, urticaria, bullous fixed eruptions, eczema </li></ul></ul><ul><ul><li>Isolated reports of reversible hearing loss in renal impairment or high doses </li></ul></ul><ul><ul><li>Rare cardiac events: ventricular arrhythmias including V-tach & torsades de pointes in individuals with prolonged QT </li></ul></ul><ul><ul><li>Troleandomycin </li></ul></ul><ul><ul><ul><li>Associated with allergic cholestatic hepatitis </li></ul></ul></ul>
  51. 51. Drug Class: Fluoroquinolones <ul><li>Quinolones </li></ul><ul><ul><li>Cinoxacin </li></ul></ul><ul><ul><li>Nalidixic acid </li></ul></ul><ul><li>Fluoroquinolones </li></ul><ul><ul><li>Ciprofloxacin (Cipro) </li></ul></ul><ul><ul><li>Enoxacin (Penetrex) </li></ul></ul><ul><ul><li>Grepafloxacin (Raxar) </li></ul></ul><ul><ul><li>Levofloxacin (Levaquin) </li></ul></ul><ul><ul><li>Lomefloxacin (Maxaquin) </li></ul></ul><ul><ul><li>Norfloxacin (Noroxin) </li></ul></ul><ul><ul><li>Ofloxacin (Floxin) </li></ul></ul><ul><ul><li>Sparfloxacin (Zagam) </li></ul></ul><ul><ul><li>Trovafloxacin (Trovan) </li></ul></ul>
  52. 52. Indications: Fluoroquinolones <ul><li>Lower respiratory infections </li></ul><ul><li>Skin & skin structure infections </li></ul><ul><li>Bone/joint infections </li></ul><ul><li>Infectious diarrhea </li></ul><ul><li>Typhoid fever </li></ul><ul><li>STDs </li></ul><ul><li>Complicated UTI </li></ul><ul><li>Prostatitis </li></ul><ul><li>Prophylaxis of bacterial infections in neutropenic patients </li></ul>
  53. 53. Activity: Fluoroquinolones <ul><li>Bactericidal </li></ul><ul><li>Broad range of activity against both G(+) and G(-) </li></ul><ul><ul><li>Greater activity against staphylococci & pseudomonas </li></ul></ul><ul><li>Non-fluorinated  use limited to UTIs </li></ul><ul><ul><li>Narrow spectrum of activity  mainly G(-) </li></ul></ul><ul><ul><li>Poor tissue penetration </li></ul></ul><ul><ul><li>Rapid development of resistant strains </li></ul></ul><ul><ul><li>Cardiotoxicity at higher doses required for tissue penetration </li></ul></ul><ul><li>Fluorinated  Greater utility </li></ul><ul><ul><li>Better safety profile </li></ul></ul><ul><ul><li>Broader spectrum of activity </li></ul></ul><ul><ul><li>Less tendency for resistance </li></ul></ul><ul><ul><li>Excellent oral absorption </li></ul></ul>
  54. 54. Action & Effect: Fluoroquinolones <ul><li>Bactericidal </li></ul><ul><li>Interfere with enzyme needed for synthesis of bacterial DNA </li></ul><ul><ul><li>Inhibition of DNA gyrase essential for transcription, replication, & repair of DNA in bacteria </li></ul></ul>
  55. 55. Drug Treatment Principles: Fluoroquinolones <ul><li>NOT considered first line therapy </li></ul><ul><ul><li>Use depends on severity of infection </li></ul></ul><ul><li>Reserved for moderate to severe or complicated infections </li></ul><ul><ul><li>Exacerbation of bronchitis, community acquired pneumonia, skin, bone, genital infections </li></ul></ul><ul><li>NOT for use in </li></ul><ul><ul><li>Simple UTIs, sinusitis, otitis </li></ul></ul><ul><li>Penetration in CNS NOT enough to be effective </li></ul><ul><li>Resistance develops quickly </li></ul><ul><li>Potential for severe adverse effects: </li></ul><ul><ul><li>CNS toxicity & cardiac arrhythmias </li></ul></ul><ul><li>Trovafloxacin </li></ul><ul><ul><li>Significant hepatotoxicity  use limited to acute care </li></ul></ul>
  56. 56. Patient Variables: Fluoroquinolones <ul><li>Renal Impairment </li></ul><ul><ul><li>Metabolized in liver but renal excretion  adjust dose </li></ul></ul><ul><li>Pediatrics </li></ul><ul><ul><li>NOT currently approved for use in children </li></ul></ul><ul><ul><li>Use restricted for when there is NO safer alternative </li></ul></ul><ul><ul><li>RISK  arthralgias, joint swelling, permanent articular damage </li></ul></ul>
  57. 57. Patient Variables: Fluoroquinolones <ul><li>Geriatrics </li></ul><ul><ul><li>Adjust dose based on renal function </li></ul></ul><ul><li>Pregnancy </li></ul><ul><ul><li>Category C </li></ul></ul><ul><li>Lactation </li></ul><ul><ul><li>Breast milk concentrations = serum in 2 hours </li></ul></ul><ul><ul><li>NOT recommended for nursing mothers d/t risk of articular damage in children </li></ul></ul>
  58. 58. Monitoring: Fluoroquinolones <ul><li>Coumadin </li></ul><ul><ul><li> PT & INR QD for 1 st week then Q week </li></ul></ul><ul><ul><li>Patient should report any bleeding </li></ul></ul><ul><li>Theophylline </li></ul><ul><ul><li> clearance   levels </li></ul></ul><ul><li>Renal hepatic function </li></ul><ul><ul><li>Baseline & Q6weeks </li></ul></ul><ul><li>Hematology </li></ul><ul><ul><li>Leukopenia, hemolytic anemia, thrombocytopenia </li></ul></ul><ul><li>CNS side effects </li></ul>
  59. 59. Patient Education: Fluoroquinolones <ul><li>Drink fluids </li></ul><ul><li>Norfloxacin, enoxacin, ofloxacin </li></ul><ul><ul><li>Take on empty stomach </li></ul></ul><ul><li>Ciprofloxacin & lomafloxacin </li></ul><ul><ul><li>Can be taken without regard to meals </li></ul></ul><ul><li>Do NOT take with </li></ul><ul><ul><li>Milk, antacids, iron preparations, or products containing aluminum, magnesium, calcium, iron, or zinc including sucralfate </li></ul></ul><ul><li>Use caution when driving, operating heavy machinery, or performing tasks that require attentiveness </li></ul><ul><li>Avoid sun exposure  photosensitivity reaction </li></ul>
  60. 60. Warnings/Precautions: Fluoroquinolones <ul><li>Contraindications </li></ul><ul><ul><li>Hypersensitivity </li></ul></ul><ul><ul><li>Cross sensitivity b/w quinolones & fluoroquinolones </li></ul></ul><ul><li>Warnings/Precautions </li></ul><ul><ul><li>Photosensitivity & cataracts </li></ul></ul><ul><ul><li>Superinfection especially with C. difficile </li></ul></ul><ul><ul><li>CNS effects </li></ul></ul><ul><ul><ul><li>Confusion, restlessness, tremor,  ICP, hallucinations, seizures </li></ul></ul></ul>
  61. 61. Pharmacokinetics: Fluoroquinolones <ul><li>Well absorbed after oral administration </li></ul><ul><li>Widely distributed to most body tissues & fluids </li></ul><ul><li>High tissue concentrations in: </li></ul><ul><ul><li>Kidneys, gall bladder, liver, lungs, cervix, endometrium, prostate, & phagocytes </li></ul></ul><ul><li>High fluid concentrations achieved in </li></ul><ul><ul><li>Urine, sputum, bile </li></ul></ul><ul><li>Ciprofloxacin & ofloxacin distributed to </li></ul><ul><ul><li>Skin, fat, muscle, bone, cartilage, CSF </li></ul></ul><ul><li>NOT removed by peritoneal or hemodialysis </li></ul><ul><li>Key differences in pharmacokinetics [seeTable 64-2 p. 683 Edmunds)] </li></ul>
  62. 62. Adverse Effects: Fluoroquinolones <ul><li>Most common adverse effects </li></ul><ul><ul><li>GI: nausea, vomiting, diarrhea, abdominal pain </li></ul></ul><ul><ul><li>CNS especially with overdosage: headache dizziness, confusion, restlessness, sleep disorders, seizures </li></ul></ul><ul><ul><li>Skin: rash, pruritis </li></ul></ul><ul><li>Other effects: </li></ul><ul><ul><li>Liver:  AST & ALT </li></ul></ul><ul><ul><li>Renal:  BUN & Creatinine, renal failure </li></ul></ul><ul><ul><li>Hematologic: leukopenia, eosinophilia </li></ul></ul><ul><ul><li>Ciprofloxacin & norfloxacin  crystalluria in alkaline media  ensure adequate hydration </li></ul></ul>
  63. 63. Drug Interactions: Fluoroquinolones <ul><li>Reduced absorption  give 2 hr before or 6 hr after </li></ul><ul><ul><li>Antacids, vitamins, enteral formulas, sucralfate & medications containing divalent or trivalent cations (e.g., Mg, Ca, Zn, Al) </li></ul></ul><ul><li>Through P450 inhibition, may reduce metabolism of </li></ul><ul><ul><li>Theophylline and caffeine, especially with enoxacin & ciprofloxacin preferred drug = ofloxacin or lomafloxacin </li></ul></ul><ul><ul><li>Warfarin   PT & INR at beginning of therapy </li></ul></ul>

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