Anti infectives fall 2011


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  • An 81-year-old woman with rheumatoid arthritis, Sjogren's syndrome, and hypertension presented with swelling and pain in the area of the left heel, which had developed suddenly a week after a short course of levofloxacin for acute bronchitis. She reported neither trauma to the area nor any excessive physical activity before the pain began. Examination revealed an ecchymotic area around the left posterior heel and a moderately swollen calf. A defect was palpable in the lateral side of the Achilles' tendon; the medial side was still intact. Movement of the ankle was limited by severe pain. Magnetic resonance imaging (MRI) of the ankle revealed a near-full-thickness rupture of the Achilles' tendon (Panel A, arrows). The patient's ankle was immobilized in a short leg cast for 2 months. After removal of the cast, a repeat MRI scan showed nearly complete healing of the ruptured tendon (Panel B, arrows), and since then, the patient has been walking without limitation. Quinolones may facilitate the enhanced expression of matrix metalloproteinases in tissue, which in turn causes tendon injury and is most common in the elderly and in persons taking corticosteroids.
  • Anti infectives fall 2011

    1. 1. Pharmacology of Antimicrobials
    2. 2. ANTIMICROBIALS--PART I: <ul><li>I. Therapeutics </li></ul><ul><li>II. Classification by Organism </li></ul><ul><li>III. Classification by Mechanisms of Action </li></ul><ul><li>IV. Important Antimicrobial Concepts </li></ul><ul><li>V. Antimicrobial Resistance </li></ul><ul><li>VI. Principles of Selection & Administration </li></ul><ul><li>VII. Adverse Effects of Antibiotic Therapy </li></ul><ul><li>VIII. Nursing Implications </li></ul>
    3. 3. Therapeutic Goal: Clear Tissue of Infecting Organisms <ul><li>Requirements </li></ul><ul><ul><li>Organism be susceptible to concentrations of drug at infected site </li></ul></ul><ul><ul><li>Dose and route of administration result in adequate levels of drug at infected site for sufficient time </li></ul></ul><ul><ul><li>Local factors do not interfere with drug activity </li></ul></ul><ul><ul><li>Host defenses facilitate microbial clearance </li></ul></ul><ul><ul><li>Adjunctive therapies such as drainage or relief of obstruction be used when necessary </li></ul></ul>
    4. 4. Classification of Drug by Microorganism Affected <ul><li>A. Antibacterial Drugs </li></ul><ul><li> 1. Narrow spectrum: target few types </li></ul><ul><li> 2. Broad spectrum: target many types </li></ul><ul><li>3. Anti-mycobacterial drugs </li></ul><ul><li>B. Antifungal drugs </li></ul><ul><li>C. Antiviral drugs </li></ul><ul><li> 1. Other antivirals </li></ul><ul><li> 2. Antiretroviral </li></ul>
    5. 5. Classification of Antibiotics by Mechanism of Action <ul><li>Inhibits bacterial cell wall synthesis </li></ul><ul><li>Inhibits protein synthesis </li></ul><ul><li>Inhibits nucleic acid synthesis </li></ul><ul><li>Interrupts metabolic pathways </li></ul><ul><li>Disrupts cell membrane permeability </li></ul><ul><li>Inhibits enzymes important in microorganism’s function </li></ul>
    6. 6. Important Antimicrobial Drug Concepts: <ul><li>I. Bacteriocidal vs. Bacteriostatic Effects </li></ul><ul><li>A. Bacteriocidal: drug actually kills bacteria </li></ul><ul><li>B. Bacteriostatic: drug inhibits bacterial reproduction so host defenses can kill </li></ul><ul><li>II. Selective toxicity : Drug is toxic to the </li></ul><ul><li>microorganism but not to human host. </li></ul><ul><li>III. Organism Sensitivity : drug is toxic to the microorganism causing the infection. A laboratory test will determine this. </li></ul>
    7. 7. Antimicrobial Resistance <ul><li>Definition: </li></ul><ul><li>The microorganism is no longer affected by a particular antimicrobial that was once effective. </li></ul>
    8. 8. Antimicrobial Resistance: Culture and Sensitivity Testing of Bacteria <ul><li>Bacteria isolated from the site of infection are cultured on a plate. </li></ul><ul><li>Paper discs soaked with various antibiotics are applied to the plate. </li></ul><ul><li>If the bacteria is affected by the antibiotic (is sensitive to it), a clear area will develop around the antibiotic-soaked disc. </li></ul><ul><li>The extent of the clear area is a measure of how well the antibiotic works against that particular bacterium. </li></ul>
    9. 9.
    10. 10. Mechanisms of Antimicrobial Resistance <ul><li>Production of a drug-inactivating enzyme </li></ul><ul><li>Change in receptor structure </li></ul><ul><li>Change in structural features of the microorganism that effects drug permeability </li></ul><ul><li>Development of alternative metabolic pathways </li></ul><ul><li>* These abilities can be conferred on a particular bacterium by a spontaneous mutation or conjugation (a sort of bacterial sex). </li></ul>
    11. 11. Factors Promoting Development of Antimicrobial Resistance <ul><li>I. Administration of antimicrobials when not needed. </li></ul><ul><li>II. Lack of /improper adherence to regimens. </li></ul><ul><li>III. Dosing that does not maintain adequate drug levels. </li></ul>
    12. 12. Common Resistant Microbes <ul><li>Methicillin-resistant Staphylococcus aureus ( MRSA ) </li></ul><ul><li>Penicillin-resistant Streptococcus pneumoniae </li></ul><ul><li>Vancomycin-resistant Enterococci (VRE) </li></ul><ul><li>Multi-drug resistant tuberculosis </li></ul><ul><li>HIV </li></ul>
    13. 13. Principles of Antimicrobial Selection and Administration <ul><li>I. Match “drug with bug” principle </li></ul><ul><ul><li>A. Identify pathogen: culture, gram stain (positive vs. negative), common cause </li></ul></ul><ul><ul><li>B. Determine microbial susceptibility to drug: culture and sensitivity, genotype and phenotype, literature </li></ul></ul><ul><ul><li>C. Role of infectious disease consultant </li></ul></ul><ul><ul><li>1. Suggest appropriate therapy </li></ul></ul><ul><ul><li>2. Prevent overuse or inappropriate use of antimicrobials </li></ul></ul>
    14. 14. Principles of Antimicrobial Selection and Administration <ul><li>II. Consider Drug Spectrum: </li></ul><ul><li>Narrow vs. Broad Spectrum drug </li></ul><ul><li>III. Consider: </li></ul><ul><li>Combination therapy </li></ul><ul><li>IV. Consider Site of Infection: </li></ul><ul><li>Skin </li></ul><ul><li>Lung </li></ul><ul><li>Meninges/brain </li></ul><ul><li>Abscess </li></ul>
    15. 15. Abscess
    16. 16. Principles of Antimicrobial Selection and Administration <ul><li>V. Maintain Adequate Blood Levels </li></ul><ul><li>Many antibiotics should be administered around-the-clock, i.e. every six hours for 4 times per day, every eight hours for 3 times per day, etc. </li></ul><ul><li>Oral antibiotics should be administered on an empty stomach and should not be co-administered with other oral medications. </li></ul>
    17. 17. Principles of Antimicrobial Selection and Administration: <ul><li>VI. Antibiotic Combinations: </li></ul><ul><li>Combinations of antibiotics that work by different mechanisms may be synergistic or they may work against each other. </li></ul><ul><li>In the case of mixed infections with more than one bacterial species, a combination may be required. </li></ul><ul><li>In some instances, antibiotic resistance is discouraged by combinations. </li></ul><ul><li>Combinations should be used only when indicated. </li></ul>
    18. 18. Which of the following promote antimicrobial resistance? <ul><li>Administering antimicrobials when needed </li></ul><ul><li>Maintaining adequate drug levels </li></ul><ul><li>Non-adherence to regimen </li></ul><ul><li>Using antimicrobial to which the organism is sensitive </li></ul>
    19. 19. Patient Variables in Administering Antimicrobials <ul><li>Health status: comorbidities, immunosuppressive therapy, etc. </li></ul><ul><li>B. Life span and gender: appropriateness of dose & agent </li></ul><ul><li>C. Ethnicity/culture: belief about medications may hinder compliance </li></ul><ul><li>D. Environment: access to refrigeration, running water, etc. </li></ul>
    20. 20. Adverse Effects of Antibiotic Therapy <ul><li>Normal gut flora are killed which produces diarrhea and can pave the way for colonization with pathogenic bacteria. </li></ul><ul><li>Suprainfection – infection with a second (antibiotic resistant) organism that occurs during antibiotic therapy. In pseudomembranous colitis, the bowel is colonized with Clostridium difficile , producing a severe diarrhea that is sometimes fatal. </li></ul><ul><li>Allergy – most common with the penicillins. </li></ul>
    21. 21. Pseudomembranous colitis
    22. 22. Nursing Implications for Antimicrobial Therapy <ul><ul><li>I. Assess history carefully for hypersensitivity (allergic) reactions, possible pregnancy and lactation </li></ul></ul><ul><ul><li>II. Assess kidney and/or liver function, especially in hypertensives, diabetics and elderly. </li></ul></ul><ul><ul><li>III. Review culture and sensitivity reports. </li></ul></ul><ul><ul><li>IV. Monitor for response to therapy. </li></ul></ul>
    23. 23. Nursing Implications for Antimicrobial Therapy <ul><ul><li>V . Patient Education: </li></ul></ul><ul><ul><li>Patient should complete full course of antibiotics </li></ul></ul><ul><ul><li>Take missed doses as soon as remembered </li></ul></ul><ul><ul><li>Teach signs and symptoms of hypersensitivity reaction. Can develop hypersensitivity AT ANY TIME. (See following photos) </li></ul></ul><ul><ul><li>May need a backup method of birth control </li></ul></ul>
    24. 24. Stevens Johnsons Syndrome <ul><ul><li>Note extensive sloughing of epidermis from Stevens-Johnson syndrome. Courtesy of David F. Butler, MD. </li></ul></ul>
    25. 25. Nursing Implications: VI. Intravenous Administration of Antibiotics <ul><li>Many antibiotics are easy to give IV – they can be given in small volumes of fluid over short infusion times. </li></ul><ul><li>A few antibiotics have stringent requirements for IV administration – they require large volumes of fluid and lines in large veins, and/or they must be administered slowly. </li></ul><ul><li>Erythromycin and other macrolides – large volumes and large veins. </li></ul><ul><li>Vancomycin and clindamycin – administer slowly. </li></ul><ul><li>If you don’t know – LOOK IT UP! </li></ul>
    26. 26. Antimicrobials: PART II <ul><li>CATEGORIES </li></ul><ul><li>OF </li></ul><ul><li>ANTIMICROBIALS </li></ul>
    27. 27. I. Antibiotics Affecting the Bacterial Cell Wall: Beta-Lactam Antibiotics <ul><li>Beta-lactam antibiotics penetrate the cell wall and bind to targets on cytoplasmic membrane </li></ul><ul><li>Disrupt synthesis/maintenance of the cell wall: bacterium is killed by osmotic pressure. </li></ul><ul><li>Can be inactivated by beta-lactamases: enzymes that degrade the drug. </li></ul><ul><li>Gram-negative organisms have an additional component to their cell wall that most beta-lactam antibiotics cannot penetrate. Therefore, most of these agents are not effective against gram-negative bacteria. </li></ul>
    28. 28. Types of Beta-Lactam Antibiotics: <ul><li>Penicillins </li></ul><ul><li>Cephalosporins </li></ul><ul><li>Carbapenems </li></ul><ul><li>Azetronam </li></ul>Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 963
    29. 29. 1. Penicillins <ul><li>Pharmacotherapeutics : </li></ul><ul><ul><li>Therapeutic: used for gram-positive bacteria such as Strep and Staph & a few gram-negatives such as Neisseria, and syphilis ( Treponema ). Some will cover anaerobes such as Enterobacter & also Pseudomonas , and Klebsiella . </li></ul></ul><ul><ul><li>Prophylactic: used to prevent bacteremia in selected populations at risk for endocarditis, such as people with artificial or damaged heart valves. </li></ul></ul><ul><ul><li>Individual penicillins have varying resistance to beta-lactamases (bacterial enzymes that break apart the beta-lactam ring). </li></ul></ul>
    30. 30. Pharmacokinetics of Penicillins <ul><ul><li>Different penicillins are orally active or not. </li></ul></ul><ul><ul><li>Most have a short half-life. </li></ul></ul><ul><ul><li>Depot forms: benzathine penicillin G and procaine penicillin G are administered by deep IM injection and released over a long time. </li></ul></ul><ul><ul><li>Distribution: bound to plasma proteins and do not cross blood-brain barrier well except when it is compromised as in infection. </li></ul></ul><ul><ul><li>Excretion: kidneys </li></ul></ul>
    31. 31. Blood Levels of Different Formulations of Penicillin G Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 966
    32. 32. Penicillin Allergy <ul><ul><li>As with any drug allergy, penicillin allergy involves the immune system and antibodies that bind to the drug or its degradation products. </li></ul></ul><ul><ul><li>Can be as mild as rash or severe as anaphylaxis. </li></ul></ul><ul><ul><li>Can occur with first or repeated exposure. </li></ul></ul><ul><ul><li>Cross-allergy to other beta-lactam antibiotics. </li></ul></ul><ul><ul><li>Skin testing may not be dependable and may cause an anaphylactic reaction in sensitive individuals. </li></ul></ul>
    33. 33. Adverse Effects & Drug Interactions of Penicillins <ul><li>Adverse effects include gastrointestinal symptoms and suprainfections related to loss of normal flora. </li></ul><ul><li>Overdose can cause neurologic problems, including seizures. </li></ul><ul><li>Synergistic with aminoglycoside antibiotics, but can’t be administered in the same IV line. </li></ul>
    34. 34. Beta-Lactamases (Penicillinases) <ul><li>Enzymes that cut the beta-lactam ring, inactivating beta lactam antibiotics </li></ul><ul><li>Bacteria that manufacture beta-lactamases may be resistant to all or most beta lactam antibiotics. </li></ul>Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 964
    35. 35. Beta-Lactamase Inhibitors <ul><li>Drugs that bind to the active site of beta-lactamases, preventing these enzymes from cutting the beta-lactam ring. This prevents resistance of the bacteria to these antibiotics. </li></ul><ul><li>Many beta-lactamase inhibitors are irreversible. </li></ul><ul><li>Beta-lactam antibiotics can be administered along with beta-lactamase inhibitors. </li></ul>
    36. 36. Penicillin-Beta-Lactamase Inhibitor Combinations <ul><ul><li>Drugs that combine a penicillin drug and the inhibitor: </li></ul></ul><ul><ul><ul><li>Amoxicillin + clavulanic acid = Augmentin </li></ul></ul></ul><ul><ul><ul><li>Ampicillin + sulbactam = Unasyn </li></ul></ul></ul><ul><ul><ul><li>Ticarcillin + clavulanic acid = Timentin </li></ul></ul></ul><ul><ul><ul><li>Piperacillin + tazobactam = Zosyn </li></ul></ul></ul>
    37. 37. Penicillin works by: <ul><li>Affecting the bacterial cell wall </li></ul><ul><li>Inhibiting protein synthesis </li></ul><ul><li>Altering protein synthesis </li></ul><ul><li>Inhibiting an enzyme in bacterial DNA replication </li></ul>
    38. 38. 2. Cephalosporins <ul><li>Similar to penicillins in structure and activity. </li></ul><ul><li>Four generations, each with its own spectrum of </li></ul><ul><li>activity, susceptibility to beta-lactamases, and uses. </li></ul><ul><li>Pharmacokinetics: </li></ul><ul><li>Widely distributed to body fluids including bone </li></ul><ul><li>1 st and 2 nd generations do not cross blood-brain barrier. </li></ul><ul><li>Most eliminated by the kidney: may need decreased dose with decreased renal function </li></ul>
    39. 39. Major Differences between Cephalosporin Generations Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 973 Generation Activity against Gram Negative Resistance to Beta-Lactamases Distribution to CSF 1 st (e.g., cephalothin) Low Low Poor 2 nd (e.g., cefamandole) Higher Higher Poor 3 rd (e.g. cefotaxime) Higher Higher Good 4 th (e.g. cefepime) Highest Highest Good
    40. 40. Possible Problems with Cephalosporins <ul><li>Chance of increased bleeding with warfarin because of interference with Vitamin K metabolism – cefmetazole, cefoperazone, & cefotetan. </li></ul><ul><li>The same three can trigger a disulfiram-like reaction if used with alcohol (Lehne, p. 411). </li></ul><ul><li>To avoid the development of resistant populations of bacteria, third and fourth generations should be reserved for serious infections! </li></ul>
    41. 41. 3. Carbapenems: (imipenem, meropenem & ertapenem) <ul><li>Beta-lactam antibiotics with extremely broad spectrum </li></ul><ul><ul><li>Gram positive cocci </li></ul></ul><ul><ul><li>Gram negative cocci and bacilli </li></ul></ul><ul><ul><li>Anaerobes </li></ul></ul><ul><li>Not absorbed from the GI tract (IV administration) </li></ul><ul><li>Cross allergy with penicillins </li></ul><ul><li>Suprainfection is a problem </li></ul><ul><li>Especially valuable in mixed infections </li></ul>
    42. 42. II. Non-Beta-Lactam Antibiotic Affecting the Bacterial Cell Wall: Vancomycin <ul><li>A potentially toxic antibiotic used to treat serious infections. </li></ul><ul><li>Not a beta-lactam, but interferes with cell wall synthesis. </li></ul><ul><li>Can be used in treating gram + infections in penicillin-allergic patients </li></ul><ul><li>Synergism with aminoglycosides </li></ul><ul><li>Poor penetration into CSF </li></ul><ul><li>Oral preparation can be used for bowel infections, particularly Clostridium difficile (a suprainfection). In this use, the drug isn’t absorbed into the bloodstream. </li></ul>
    43. 43. Adverse Effects of Vancomycin <ul><li>Ototoxicity and nephrotoxicity. </li></ul><ul><li>Multiple drug interactions with hyperlipidemic drugs, muscle relaxants, and ototoxic drugs </li></ul><ul><li>Rapid infusion causes a severe reaction of flushing, tachycardia, and hypotension which can be fatal (infuse over 60 minutes). </li></ul><ul><li>Irritating to the vein, causing thrombophlebitis (use large vein and change IV site often). </li></ul>
    44. 44. III. Bacteriostatic Inhibitors of Protein Synthesis: <ul><li>Tetracyclines </li></ul><ul><li>Macrolides </li></ul><ul><li>Clindamycin </li></ul><ul><li>Chloramphenicol </li></ul><ul><li>5. Others </li></ul>
    45. 45. Porth, Pathophysi-ology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 123. Protein Synthesis
    46. 46. 1.Tetracyclines <ul><li>Tetracycline, doxycycline, minoclycline and others </li></ul><ul><li>Bind to the 30S ribosomal subunit and prevent elongation of the peptide chain. </li></ul><ul><li>Broad spectrum but resistance has developed in many bacterial species, limiting their use. </li></ul><ul><li>Agents of choice for rickettsial diseases (Rocky Mountain spotted fever) and for Chlamydia . </li></ul><ul><li>Used in acne, periodontal disease. </li></ul><ul><li>Mainly oral use, rare IV. </li></ul><ul><li>Poor CSF penetration </li></ul>
    47. 47. Problems with Tetracyclines <ul><li>Poor absorption of some: all form insoluble compounds with calcium, iron, magnesium, aluminum and zinc. So don’t give with antacids/laxatives, milk/dairy, iron. </li></ul><ul><li>Bind to calcium in developing teeth and form a discolored area. So don’t give to pregnant women (will only affect baby teeth) or children below 8 years. </li></ul><ul><li>Suprainfection with bowel organisms or Candida </li></ul>
    48. 48. Tetracycline-Stained Teeth The patient was treated with tetracycline while the permanent teeth were developing. Dark staining is present in the parts of the teeth that were forming during treatment.
    49. 49.
    50. 50. 2. Macrolides: <ul><li>Erythromycin, clarithromycin, azithromycin. </li></ul><ul><li>Inhibit 50 S ribosomal subunit. </li></ul><ul><li>Erythromycin is commonly used for gram-positive and some gram-negative bacteria. </li></ul><ul><li>Drug of choice for Legionella and Chlamydia </li></ul><ul><li>An alternative to penicillin in allergic patients. </li></ul><ul><li>Poor CSF penetration </li></ul>
    51. 51. 2. Macrolides <ul><li>Some forms of erythromycin are corrosive to the GI tract and can cause erosive esophagitis. Other formulations have fewer problems and can be taken with food. </li></ul><ul><li>IV erythromycin is corrosive to veins and must be diluted in large quantities of fluid and infused slowly into a large vein. </li></ul><ul><li>Hepatotoxicity is a concern. </li></ul>
    52. 52. WARNING! <ul><li>Erythromycin and clarithromycin are strong inhibitors of cytochrome P450 – administer with caution in patients taking drugs metabolized by these enzymes. </li></ul>
    53. 53. 3 . Clindamycin <ul><li>Inhibits 50S ribosomal subunit: shouldn’t be used with a macrolide. </li></ul><ul><li>Good for anaerobes and gram-positive aerobes. </li></ul><ul><li>Poor penetration of the brain. </li></ul><ul><li>Suprainfection with Clostridium difficile . </li></ul><ul><li>IV infusion must be SLOW . </li></ul><ul><li>Reserve for serious infections </li></ul>
    54. 54. IV. Bacteriocidal Antibiotics that Alter Protein Synthesis: Aminoglycosides <ul><li>Tobramycin, gentamycin, amakacin and others </li></ul><ul><li>Bind to the 30S ribosomal subunit. They are bacteriocidal because they promote the formation of abnormal proteins whose abnormal functioning kills the cell. </li></ul><ul><li>No activity against anaerobes. </li></ul><ul><li>Good coverage of gram-negative bacteria including Pseudomonas, Klebsiella, and Serratia . </li></ul><ul><li>Charged drugs that are not absorbed— used IV. </li></ul><ul><li>Can be used topically to sterilize the gut or on the skin (neomycin) or eye. </li></ul><ul><li>Ototoxic and nephrotoxic— adjust for renal impairment </li></ul>
    55. 55. Aminoglycoside Administration <ul><li>For many patients, once daily infusion is as good as divided doses because it produces very high levels that kill bacteria even after the blood level declines. </li></ul><ul><li>Low levels in between the daily dose allows washout from body cells in between doses and lowers the risk of toxicity. </li></ul>
    56. 56. Aminoglycoside: Gentamicin Levels Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 922
    57. 57. V. Sulfamethoxazole-trimethroprim (Bactrim) <ul><li>Bactrim blocks bacterial enzymes that are important for the synthesis of the building blocks of DNA, RNA and proteins. </li></ul><ul><li>This is a combination of a sulfa drug (sulfamethoxazole) and an inhibitor of a bacterial enzyme called dihydrofolate reductase (trimethoprim). </li></ul><ul><li>The two drugs block different steps in the pathway and therefore are synergistic in their activity. Broad spectrum, including many gram negative and gram positive </li></ul><ul><li>Used extensively for UTI and for Pneumocystis carinii pneumonia of AIDS </li></ul>Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 927
    58. 58. Sulfamethoxazole-trimethroprim (Bactrim) <ul><li>Hypersensitivity reactions are most concerning </li></ul><ul><li>Rash, including rare Stevens-Johnson syndrome. </li></ul><ul><li>The trimethoprim component can cause blood dyscrasias. </li></ul><ul><li>Crystalluria (kidney/bladder stones) – patient should remain well-hydrated. </li></ul><ul><li>CNS effects – headache, psychosis </li></ul>
    59. 59. VI. Fluoroquinones <ul><li>Ciprofloxacin, levofloxacin, oxofloxacin and others </li></ul><ul><li>Inhibit an enzyme (DNA gyrase) important in bacterial DNA replication </li></ul><ul><li>Active against aerobic organisms, most gram negative and some gram positive. </li></ul><ul><li>Shouldn’t be taken with aluminum, iron, calcium, iron or zinc supplements. </li></ul><ul><li>Can increase plasma levels of theophylline and warfarin. </li></ul>
    60. 60. Adverse Effects of Fluoroquinones <ul><li>Can cause irreversible joint disease in children <18. </li></ul><ul><li>Rarely, tendon rupture in adults. </li></ul><ul><li>Photosensitivity. </li></ul><ul><li>Candida suprainfections, especially of the oropharynx. </li></ul><ul><li>Infrequent but serious CNS effects. </li></ul>
    61. 61. Vyas H and Krishnaswamy G. N Engl J Med 2007;357:2067 An 81-year-old woman with rheumatoid arthritis, Sjogren's syndrome, and hypertension presented with swelling and pain in the area of the left heel, which had developed suddenly a week after a short course of levofloxacin for acute bronchitis
    62. 62. VII. Metronidazole (Flagyl) <ul><li>Targets anaerobic organisms, including parasites and bacteria </li></ul><ul><li>C. difficile, Bacteroides, Entameba histolytica </li></ul><ul><li>A prodrug that is activated only in anaerobic cells. </li></ul><ul><li>Darkening of the urine </li></ul><ul><li>CNS adverse effects </li></ul><ul><li>Caution during pregnancy, avoid during lactation </li></ul><ul><li>Cytochrome P450 interactions </li></ul>
    63. 63. VIII. Antibiotics for Tuberculosis Target Mycobacteria <ul><li>TB is always treated with 2 or more drugs to avoid the emergence of resistant strains. </li></ul><ul><li>Treatment is prolonged (6-10 months) because the bacteria grow very slowly. Compliance is a huge issue. </li></ul><ul><li>The sensitivity of the bacterium to the proposed regimen must be determined ahead of time. </li></ul><ul><li>Treatment is evaluated for efficacy. </li></ul>
    64. 64. Mycobacteria infection <ul><li>Patients with HIV infection are very susceptible to TB and other mycobacteria and are treated differently than other patients. </li></ul><ul><li>A reactive skin test in a previously negative patient indicates a new exposure. The patient should be treated. </li></ul><ul><li>TB infection can be followed by a latent phase where the disease is inactive. Persons in the latent phase should be treated to avoid the re-emergence of active disease. </li></ul><ul><li>Patients with newly reactive skin tests & patients in the latent phase can be treated with monotherapy, frequently isoniazid but sometimes rifampin. </li></ul>
    65. 65. VIII. Tuberculosis Drug: Isoniazid <ul><li>Inhibits the formation of the mycobacterial cell wall – highly specific for TB. </li></ul><ul><li>Pharmacokinetics- distributed to all body tissues and fluids, crosses blood-brain barrier to achieve therapeutic levels. </li></ul><ul><li>Used alone to treat latent TB and with at least one other drug for active TB. </li></ul><ul><li>Risk of peripheral neuropathy is decreased by giving with pyridoxine (vitamin B 6 ). </li></ul><ul><li>Hepatotoxic, especially in older people. Contraindicated for people with pre-existing liver disease. Monitor liver enzymes. </li></ul><ul><li>Alcohol consumption increases the risk of hepatotoxicity. </li></ul><ul><li>Increases levels of phenytoin – draw phenytoin levels and decrease the dose if necessary. </li></ul>
    66. 66. VIII. Tuberculosis Drug: Rifampin <ul><li>Used with at least one other drug for active TB </li></ul><ul><li>Distributed to the CSF. </li></ul><ul><li>Hepatic metabolism. </li></ul><ul><li>Hepatotoxic and increases the hepatotoxicity of isoniazid and pyrazinamide. </li></ul><ul><li>Induces cytochrome P450 enzymes – decreases levels of birth control pills, seizures meds, and others. </li></ul><ul><li>Turns body fluids red! (Warn the patient) </li></ul>
    67. 67. VIII. Tuberculosis Drug: Pyrazinamide <ul><li>Often combined with isoniazid, rifampin, and ethambutol. </li></ul><ul><li>Hepatotoxic – follow liver enzymes. </li></ul>
    68. 68. VIII. Tuberculosis Drug: Ethambutol <ul><li>Distributed widely but doesn’t penetrate the brain </li></ul><ul><li>Can cause optic neuritis. Need eye exam by ophthalmologist </li></ul><ul><li>Allergic reactions </li></ul><ul><li>NOT hepatotoxic! </li></ul>
    69. 69. Antifungals: Amphotericin B <ul><li>Nickname – Amphoterrible! </li></ul><ul><li>Binds to sterols in the fungal membrane and increases permeability – the fungal cell swells and bursts </li></ul><ul><li>Toxic to mammalian cells (human) because of the cholesterol in cell membranes. </li></ul><ul><li>Used for systemic fungal infections. </li></ul><ul><li>Infusion reactions – phlebitis and systemic symptoms (fever, chills, rigors, nausea and headache). </li></ul><ul><li>Nephrotoxic – use with caution with other nephrotoxic drugs (aminoglycosides) </li></ul><ul><li>Dose reduction when used with flucytosine – a highly synergistic combination. </li></ul>
    70. 70. Antifungals: Ketoconazole <ul><li>Inhibits the synthesis of a sterol component of the fungal cell membrane. </li></ul><ul><li>Oral alternative to amphotericin B for systemic fungal infections. </li></ul><ul><li>Can be used topically for fungal skin infections. </li></ul><ul><li>Strong inhibitor of cytochrome P450 enzymes – use with extreme caution in hepatically metabolized drugs – Table 91-3 Lehne. </li></ul><ul><li>Rare hepatic necrosis. </li></ul>
    71. 71. Antivirals: Acyclovir <ul><li>Active against all herpes viruses: herpes simplex, herpes zoster, and cytomegalovirus (CMV)— although most strains of CMV are resistant. </li></ul><ul><li>Suppresses synthesis of viral DNA – but must be activated by a viral enzyme, thymidine kinase. </li></ul><ul><li>Resistance is commonly due to thymidine kinase deficiency. </li></ul><ul><li>Topical, oral, and IV. </li></ul><ul><li>Nephrotoxic – maintain high hydration to dilute drug in renal tubules. </li></ul><ul><li>Valacyclovir (Valtrex) is a prodrug of acyclovir – but it is more bioavailable. </li></ul><ul><li>NOTE – immunization for chicken pox and shingles (both are manifestations of herpes zoster) is available </li></ul>
    72. 72. Herpes Zoster (Shingles)
    73. 73. Antivirals: Ganciclovir <ul><li>Active against all herpes viruses, including CMV – but has serious toxicities. </li></ul><ul><li>Reserved for treatment of CMV in immunocompromised patients, including HIV-infected and transplant patients. </li></ul><ul><li>Poor oral bioavailability is slightly increased by food. </li></ul><ul><li>Excreted unchanged in the urine – decrease dose for patients with renal impairment. </li></ul><ul><li>Granulocytopenia and thrombocytopenia are prominent adverse effects – monitor blood counts. </li></ul><ul><li>Teratogenic and embryotoxic – birth control should be in place. </li></ul>
    74. 74. Antivirals: Drugs for Influenza <ul><li>First line of defense is immunization ! (practically everyone should be immunized). </li></ul><ul><ul><li>Traditional injected vaccine is approved for everyone </li></ul></ul><ul><ul><li>Live inhaled vaccine (Flu-Mist) is approved for people 2-49 years old </li></ul></ul><ul><li>The seasonal flu vaccine for this season (2010-2011) will include H1N1. </li></ul>
    75. 75. Drugs for Influenza <ul><li>Amantadine and rimantadine – work as prophylaxis during epidemics and as treatment. </li></ul><ul><ul><li>Only effective against influenza A </li></ul></ul><ul><li>Neuraminidase inhibitors </li></ul><ul><ul><li>Oseltamivir (Tamiflu) is an oral drug that can be used as prophylaxis or to shorten the duration of flu </li></ul></ul><ul><ul><li>Zanamivir (Relenza) is inhaled but works similarly to oseltamivir – not approved for prophylaxis. </li></ul></ul><ul><ul><li>Both must be taken very soon after the first flu symptoms appear to be effective in shortening the duration of the flu. </li></ul></ul>
    76. 76. Amphotericin B is an: <ul><li>Antibacterial </li></ul><ul><li>Antifungal </li></ul><ul><li>Antiviral </li></ul><ul><li>Antiseptic </li></ul><ul><li>Antimycobacterial </li></ul>
    77. 77. Human Immunodeficiency Virus Photo: Hardin MD/University of Iowa and CDC
    78. 78. Warning! <ul><li>HIV drugs have many overlapping toxicities and many interactions with each other and other drugs. </li></ul><ul><li>When administering these drugs – LOOK THEM UP! </li></ul><ul><li>Don’t depend on physicians or other nurses to prevent your mistakes! </li></ul>
    79. 79. Of particular note! <ul><li>HIV is always treated with combinations of drugs. The current combinations are collectively referred to as ART ( A nti- R etroviral T herapy), ARV ( A nti- R etro v irals) or HAART (highly active antiretroviral therapy). To avoid development of viral resistance, it is very important that patients receiving HAART take their medications reliably and on time. </li></ul><ul><li>Skipping doses can have devastating results, both for the individual patient and for society if the patient infects someone else with a resistant strain of virus. </li></ul><ul><li>Because the medications have a variety of side effects that can be very bothersome, it may be tempting to patients to discontinue treatment when they feel better. </li></ul>
    80. 80. HIV drugs <ul><li>Five classes currently on the market: </li></ul><ul><li>Nucleoside reverse transcriptase inhibitors (NRTIs) </li></ul><ul><li>Non-nucleoside reverse transcriptase inhibitors (NNRTIs) </li></ul><ul><li>Protease inhibitors (PIs) </li></ul><ul><li>Attachment inhibitors </li></ul><ul><ul><li>Fusion (subq and costs $2680/month) </li></ul></ul><ul><ul><li>CCR5 antagonist </li></ul></ul><ul><li>5. Integrase inhibitors </li></ul>
    81. 81. HIV Meds (cont’d) <ul><li>ART, ARV or HAART therapy: </li></ul><ul><li>A combination of three or four drugs that target different aspects of the viral life-cycle. </li></ul><ul><li>Can reduce viral load so that it is undetectable in blood, but does not cure HIV infection. </li></ul><ul><li>Controversy: when to begin ART, ARV or HAART? Currently wait until CD4+ cells drop below 500 cells/mm 3 but some recommend earlier treatment. </li></ul>
    82. 82. HIV Drugs Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 1067
    83. 83. Pregnant HIV-Infected Patients <ul><li>Pregnant patients who would otherwise receive treatment should receive it while pregnant, although particular drugs might have to be avoided. </li></ul><ul><li>Treatment of the patient’s infection will reduce viremia and thereby reduce the risk of transmission to the fetus. </li></ul><ul><li>In women who have not received therapy during pregnancy, RT inhibitors can be given during labor, and to both mother and child after delivery. This strategy reduces maternal to fetal transmission dramatically. </li></ul><ul><li>PMTCT programs = Prevention of Mother to Child Transmission. </li></ul>
    84. 84.
    85. 85. I. & II. Reverse Transcriptase Inhibitors <ul><li>Nucleoside Reverse Transcriptase Inhibitors (NRTIs) </li></ul><ul><li>Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) </li></ul><ul><li>Work at same stage in the replication cycle but in different ways </li></ul>NRTIs NNRTIs
    86. 86. I. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) <ul><li>Inhibit viral enzyme, reverse transcriptase, that converts viral RNA into DNA, by terminating the growing DNA strand. This activity can also inhibit human DNA polymerases so these drugs are toxic to dividing cells. </li></ul><ul><li>Zidovudine (AZT), ddi, ddc, 3tc, d4t and others. </li></ul><ul><li>Can cause mitochondrial toxicity in liver (hepatomegaly and fatty liver) and elsewhere leading to lactic acidosis. </li></ul><ul><li>Bone marrow depression, anemia, neutropenia. </li></ul><ul><li>All have GI toxicity – stomatitis, nausea, diarrhea, etc. </li></ul><ul><li>Peripheral lipoatrophy (particularly d4t) </li></ul><ul><li>Peripheral neuropathy </li></ul>
    87. 87. Facial Lipoatrophy
    88. 88. II. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) <ul><li>Bind to the active site of the reverse transcriptase enzyme. </li></ul><ul><li>More specific for the viral reverse transcriptase and do not affect human DNA polymerases the way the nucleoside RT inhibitors do. </li></ul><ul><li>Nevirapine, delavirdine, efavirenz </li></ul><ul><li>All have cytochrome P450 interactions but of different kinds (nevirapine is an inducer, delavirdine and efavirenz can inhibit). </li></ul><ul><li>Many drug interactions. </li></ul><ul><li>Rash can be severe – Stevens-Johnson syndrome. </li></ul><ul><li>Severe hepatotoxicity. </li></ul><ul><li>Avoid St. John’s wort. </li></ul>
    89. 89. III. Protease Inhibitors (PIs) <ul><li>Inhibit viral protease, which is responsible for the final step in maturation of an infective virus. </li></ul><ul><li>Because of the inability to cut the long viral proteins into functional units, the virus remains immature and non-infective. </li></ul>Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 1067 PIs
    90. 90. III. Protease Inhibitors (PIs) <ul><li>Indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, tipranavir and lopinavir </li></ul><ul><li>Several dosage forms and one combination (lopinaver +ritonavir). </li></ul><ul><li>All cause significant adverse effects: </li></ul><ul><li>1. Hyperglycemia/diabetes </li></ul><ul><li>2. Fat redistribution </li></ul><ul><li>3. Hyperlipidemia </li></ul><ul><li>4. Increased bleeding in patients with hemophilia. </li></ul><ul><li>5. Reduced bone mineral density. </li></ul><ul><li>6. Elevation of serum transaminases (liver enzymes). </li></ul><ul><li>7. ECG changes with atazanavir (prolonged QT) </li></ul><ul><li>Despite plethora of bad effects, these drugs are so important in managing HIV infected patients that they are rarely discontinued because of bad effects. </li></ul>
    91. 91. Buffalo Hump
    92. 92. Enlarged Abdomen .
    93. 93. III. Protease Inhibitors <ul><li>All are metabolized by cytochrome P450 enzymes. Concurrent administration with inducers or inhibitors of cytochrome P450 can affect half-lives and drug levels (recall that the non-nucleoside RT inhibitors have varying effects on the cytochrome P450 enzymes). See table 93-6 in Lehne. </li></ul><ul><li>St. John’s wort and garlic preparations should be avoided. </li></ul><ul><li>Most have GI side effects similar to the nucleoside and non-nucleoside RT inhibitors. </li></ul>
    94. 94. IV. Entry Inhibitors <ul><li>Inhibits entry of HIV into CD4 positive cells. </li></ul><ul><li>Two types: </li></ul><ul><ul><li>Fusion Inhibitors </li></ul></ul><ul><ul><li>Attachment Inhibitors </li></ul></ul>Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 986 Fusion Inhibitor Attachment Inhibitor
    95. 95. Fusion Inhibitor (Enfuvirtide (Fuzeon) <ul><li>The drug binds to gp41, a viral envelope protein. </li></ul><ul><li>Resistance occurs when the viral gene encoding gp41 mutates to alter its shape so the drug can’t bind. </li></ul>
    96. 96. Fusion Inhibitor: Enfuvirtide <ul><li>The only fusion inhibitor currently on the market. </li></ul><ul><li>Must be given by subcutaneous injection twice a day. </li></ul><ul><li>Reserved for patients who have failed more standard HAART with RT inhibitors and protease inhibitors. </li></ul><ul><li>Extremely expensive. </li></ul><ul><li>Injection-site reactions (pain & tenderness) are common and may persistent for days. </li></ul><ul><li>Risk of bacterial pneumonia is increased. </li></ul><ul><li>Hard to manufacture – supply is limited. </li></ul>
    97. 97. Attachment Inhibitors <ul><li>Blocks the CCR5 receptor so HIV does not attach to the CD4 cell </li></ul><ul><ul><li>A.k.a. CCR5 antagonist </li></ul></ul><ul><li>Maraviroc (Selzentry™) only approved CCR5 antagonist </li></ul><ul><li>Need to have tropism testing (only works for CCR5 receptor not other receptor types) </li></ul>
    98. 98. IV. Attachment Inhibitors: Maraviroc <ul><li>Dosage is adjusted depending on whether it is combined with a CYP 450 inducer or inhibitor </li></ul><ul><li>Pregnancy Category B </li></ul><ul><li>Side effects include: </li></ul><ul><ul><li>Cough, fever, rash, muscle & joint pain, stomach pain, dizziness, liver toxicity </li></ul></ul><ul><ul><li>Use with caution in people with cardiovascular disease </li></ul></ul>
    99. 99. V. Integrase Inhibitors <ul><li>A critical step in the HIV life cycle is the integration of viral genetic information into the host cell DNA which then turns into a viral factory. </li></ul><ul><li>The enzyme integrase aids in this task. </li></ul><ul><li>Integrase inhibitors block this enzyme. </li></ul><ul><li>There is one opportunity for this to be effective. If it fails, there is no other opportunity since the genetic information from the virus is already incorporated </li></ul>Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 986 Integrase Inhibitor
    100. 100. V. Integrase Inhibitors: Raltegravir <ul><li>Currently one approved drug –raltegravir (Isentress) </li></ul><ul><li>Given twice daily (a compliance issue) </li></ul><ul><li>Diarrhea, nausea, and headache are possible adverse effects. </li></ul><ul><li>Eliminated by metabolism – plasma concentrations may be reduced by enzyme inducers, particularly rifampin. </li></ul><ul><li>Pregnancy category C </li></ul>
    101. 101. All of the following are classes of HIV medications EXCEPT: <ul><li>Protease Inhibitor </li></ul><ul><li>Integrase Inhibitor </li></ul><ul><li>Beta-Lactamase Inhibitor </li></ul><ul><li>Reverse Transcriptase Inhibitor </li></ul>
    102. 102. Resistance and Adherence <ul><li>Replication rate of HIV is between 1 and 10 billion virions/day </li></ul><ul><li>There is a high probability of introducing base-pair errors by HIV reverse transcriptase </li></ul><ul><li>HIV can mutate into a drug-resistant form very quickly </li></ul><ul><li>Combining antiretroviral drugs that work at different points in the replication cycle minimizes resistance. </li></ul><ul><li>Recommend > 95% adherence to antiretroviral medications to prevent resistance. </li></ul>
    103. 103. Conclusion <ul><li>Therapy for HIV infection is complicated and drugs have significant toxicity and interactions with other drugs. </li></ul><ul><li>Management of HIV-infected patients is best done by health care providers who are very experienced with these drugs and their side effects. </li></ul><ul><li>When HIV-infected patients are hospitalized on general medical or surgical floors, nurses must become knowledgeable about the patient’s regimen and how it might interact with other drugs the patient might be given as part of his/her hospital treatment. </li></ul>