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Antibiotic principles


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Antibiotic principles

  1. 1. Principles of Antibiotic Therapy1
  2. 2. Definition -Antibiotic An antibiotic is a substance produced by various species of living microorganisms (e.g. bacteria and fungi) Inhibit pathogens by interfering with intracellular processes Term antibiotic includes synthetic antimicrobial agents i.e. sulphonamides Antibiotics do not kill viruses -not effective in treating viral infections.2
  3. 3. Selection of Antimicrobial Agent Empiric therapy - prior to identification of organism – critically ill patients Organism’s susceptibility to the antibiotic Patient factors - immune system, renal/hepatic function Effect of site of infection on therapy –blood brain barrier Safety of the agent Cost of therapy3
  4. 4. Properties Influencing Frequency of Dosing Concentration dependent killing – antimicrobials including aminoglycosides = significant increase in rate of bacterial killing as the drug concentration increases Time-dependent killing – β-lactams, glycopeptides, macrolides, clindamycin & linezoid – dependent on the % of time that blood concentrations remain above minimum inhibitory concentration (MIC)4
  5. 5. 5
  6. 6. Properties Influencing Frequency of Dosing Post-antibiotic effect (PAE)– persistent suppression of microbial growth after levels of antibiotic have fallen below MIC Antibiotics with a long PAE – aminoglycosides and fluroquinolines Minimum bacterial concentration (MBC) is the lowest concentration of antibiotic that kills 99.9% of bacteria6
  7. 7. MIC INHIBITSFigure 30.2 (part 2) 7Chapter 30 MENU >
  8. 8. MBC KILLSFigure 30.2 (part 3) 8Chapter 30 MENU >
  9. 9. Chemotherapeutic Spectra Narrow-spectrum Antibiotics: Act on a single / limited group of micro-organisms; e.g., isoniazid given for mycobacterium Extended-spectrum Antibiotics: Effective against gram-positive organisms and a significant number of gram-negative organisms; e.g., ampicillin Broad-spectrum Antibiotics: Effective against a wide variety of microbial species; e.g., tetracycline & chloramphenicol. Can alter the nature of intestinal flora = super infection9
  10. 10. Combinations of Antimicrobial Drugs Advantages Synergism; the combination is more effective than either drug used separately; β-lactams and aminoglycosides Infections of unknown origin Disadvantages Bacteriostatic (tetracycline) drugs may interfere with bactericidal ( penicillin and cephalosporin) drugs10
  11. 11. Complications of Antibiotic Therapy Resistance – inappropriate use of antibiotics Hypersensitivity – penicillin Direct toxicity – aminoglycosides = ototoxicity Super infections – broad spectrum antimicrobials cause alteration of the normal flora; often difficult to treat11
  12. 12. Drug Resistance 1. Alteration of the target site of the antibiotic One of the most problematic antibiotic resistances worldwide, methicillin resistance among Staphylococcus aureus. 2. Enzyme inactivation of the antibiotic β-lactam antibiotics (penicillins & cephalosporins) can be inactivated by β-lactamases. 3. Active transport of the antibiotic out of the bacterial cell (efflux pumps) Removal of some antibiotics (i.e. tetracyclines, macrolides, & quinolones) 4. Decreased permeability of the bacterial cell wall to the antibiotic Alteration in the porin proteins that form channels in the cell membrane – Resistance of Pseudomonas aeruginosa to a variety of penicillins and cephalosporins12
  13. 13. AntibioticResistance 4. 2.1. 3.13
  14. 14. Resistance - β-lactamase Some bacteria secrete an enzyme called β- lactamase which destroys the beta lactam ring, rendering beta-lactam antibiotics ineffective. Solution - add clavulanic acid - a β- lactamase inhibitor - i.e. co-amoxiclav (Augmentin) or the combination of piperacillin and tazobactam (Tazocin).14
  15. 15. Resistance – Decreased Permeability of the Drug Prevents the drug reaching the target penicillin binding proteins (PBPs) Presence of an Efflux pump also reduces the amount of the intracellular drug15
  16. 16. Classifying Antimicrobial Agents Mode of action BACTERICIDAL (kills the bug) BACTERIOSTATIC (stops the bug multiplying) Spectrum of activity BROAD (e.g. effective a variety of gram-neg & gram-pos bacteria) NARROW (e.g. effective only against gram-neg or gram-pos Mechanism of action / site of action; Inhibitors of cell metabolism; (Sulfonamides, Trimethoprim) Cell wall inhibitors; (β-Lactam, Vancomycin) Protein synthesis inhibitors; (Tetrecyclines, Aminiglycosides, Macrolides, Clindamycin, Chloramphenicol) Nucleic acid inhibitors; (Floroquinolones, Rifampin) Cell membrane inhibitors; (Isoniazid, Amphotericin B)16
  17. 17. Classification of Antimicrobials by Site of ActionFigure 30.13 (still) 17Chapter 30 MENU > Wolters Kluver
  18. 18. 1. CELL WALL INHIBITORS Interfere with the synthesis of the bacterial cell wall Little or no effect on bacteria that are not growing and dividing β-lactam group Other antibiotics Penicillins Vancomycin Cephalosporins Bacitracin Carbapenems Daptomycin Monobactams Telavancin β-lactam inhibitors + antibiotic combinations18
  19. 19. Antimicrobial Agents Affecting Cell Wall SynthesisFigure 31.1 (still) 19Chapter 31 MENU >
  20. 20. PENICILLINS (bactericidal) Most widely effective and least toxic Limited use - increased resistance Mechanism of action Inactivates various proteins on bacterial cell wall20
  21. 21. Administration and Fate of PENICILLIN Routes of Administration • Oral only –Pen V, Amoxicillin & amoxicillin combined with clavulanic acid • IV / IM- Tiracillin, piperacillin, ampicillin with sulbactam, tiracillin with clavulanic acid and piperacillin with tozobactam • Others oral, IV or IMI Absorption • Decreases by food in the stomach – administer before meals 30-60min Distribution to bone and CSF insufficient Excretion - KidneysFigure 31.7 (still) 21Chapter 31 MENU >
  22. 22. Adverse Effects of PenicillinFigure 31.9 (still) 22Chapter 31 MENU >
  23. 23. CEPHALOSPORINS (bactericidal) Semi-synthetic antibiotics β-lactam antibiotics closely related functionally and structurally to penicillins Mode of action - inhibit the synthesis of the cell wall More resistant than penicillins to certain β – lactamases Classified as 1st, 2nd, 3rd and 4th generation – based on spectrum of antimicrobial activity23
  24. 24. Mechanism of Action Bactericidal, inhibit cell wall synthesis. Cephalosporins are also beta-lactams so can be degraded by beta-lactamase secreting bacteria. Good to know: Classified by generation, based on general features pertaining to activity; The higher the generation, the broader the spectrum. E.g. ceftriaxone (3rd generation) is effective against more gram negative bacteria than cephalexin (1st generation).24
  25. 25. • Gram +ve and moderate Gram –ve activity • Act as penicillin G substitutes • Resistant to staph penicillinaseFigure 31.10 (part 1) 25Chapter 31 MENU >
  26. 26. Greater activity against Gram -ve organisms; • H influenza • Enterobacter aerogenes • Neisseria species Activity against gram +ve organisms is weaker Some agents with activity against anaerobesFigure 31.10 (part 2) 26Chapter 31 MENU >
  27. 27. • Activity against Gram +ve organisms • Increased activity against Enterobacteriaceae and pseudomonas aeruginosa • Important in the treatment of infectious diseases • Inferior to 1st generations in activity against MSSA (meticillin-sensitive S. Aureus)Figure 31.10 (part 3) 27Chapter 31 MENU >
  28. 28. 4th Generation Cephalosporins Spectrum similar to 3rd Generation Have increased stability Cefepime ;28
  29. 29. Administration and fate of cephalosporins • Resistance same as that for penicillinsFigure 31.11 (still) 29Chapter 31 MENU >
  30. 30. Most Common Side Effects –Cephalosporins • Diarrhoea • Individuals • Nausea hypersensitive to • Abdominal pain penicillins may also be • Vomiting hypersensitive to • Headache cephalosporins • Dizziness • Like almost all • Skin rash antibiotics, may cause • Fever mild or severe cases of • Abnormal liver tests pseudomembranous • Vaginitis colitis30
  31. 31. OTHER β-LACTAM ANTIOBIOTICS Carbapenems: Imipenem – broad spectrum of activity against Gram +ve and Gram –ve aerobic and anaerobic bacteria Meropenem – Important for empirical mono therapy of serious infections31
  32. 32. Other β-Lactam Antiobiotics Monobactams Activity restricted to Gram –ve aerobic bacteria Aztreonam32
  33. 33. β-LACTAMASE INHIBITORS β-lactamase inhibitors – clavulanic acid – sulbactam and tazobactam Do not have significant antibacterial activity Bind to and inactivate the β- lactamases – protect the antibiotics Formulated in combination with β-lactamase sensitive antibiotics Clavulanic acid and amoxicillin Growth of E. Coli in presence of33 amoxicillin with and without clavulanic acid
  34. 34. VANCOMYCIN; • Tricyclic glycopeptide • Effective against multiple drug resistant organisms (MRSA) & enterococci • Resistance is becoming a problem • Enterococcus faecium • Enterococcus faecalisFigure 31.17 (still) 34Chapter 31 MENU >
  35. 35. Vancomycin Adverse Effects – Serious problemFigure 31.18 (still) 35Chapter 31 MENU >
  36. 36. DAPTOMYCIN Cyclic lipopeptide – linezolid and quinupristin / dalfopristin Treatment of infections caused by resistant gram +ve MRSA – methicillin S. Aureus MSSA - methillin susceptible S. Aureus VRE - vancomycin- resistant enterococci Daptomycin is bactericidal Concentration dependent Inactivated by surfactant – never used in treatment of pneumonia36
  37. 37. Adverse Effects Constipation Nausea Headache Myalgias Insomnia Increased hepatic transaminases Elevation of creatine phosphokinases37
  38. 38. TELAVANCIN Semi-synthetic lipoglycopeptide antibiotic Synthetic derivative of Vancomycin Treatment of complicated skin and skin structure infections caused by resistant gram +ve organisms including MRSA38
  39. 39. Mechanism of Action • Inhibits bacterial cell wall synthesis • Also involves disruption of bacterial cell membrane • Bactericidal against MRSAFigure 31.20 (still)Chapter 31 MENU >
  40. 40. Cautions & Adverse Effects Telavancin Prolonged QT intervalFigure 31.21 (still)Chapter 31 MENU >
  41. 41. 2. PROTEIN SYNTHESIS INHIBITORS • Target the bacterial ribosome • High levels of drugs i.e. Chloramphenicol or the tetracyclines may cause toxic effect •Interaction with the host mitochondrial ribosomes41
  42. 42. TETRACYCLINES – Antibacterial spectrum Broad-spectrum bacteriostatic antibiotic Effective against: Gram+ve and Gram-ve bacteria Organisms other than bacteria42
  43. 43. Tetracyclines – drug of choice43
  44. 44. Absorption Adequately but incomplete oral absorption Taking with dairy foods decreases absorption Resistance Widespread resistance limits44 clinical use
  45. 45. Administration of Tetracyclines Distribution – • Liver, kidneys, liver and skin • Bind to tissue undergoing calcification; bones and teeth, tumours with high calcium • Penetrate most bodyFigure 32.5 (still) fluidsChapter 32 MENU >
  46. 46. Tetracycline - Adverse EffectsFigure 32.6 (still) 46 Adverse effects have restricted their usefulnessChapter 32 MENU >
  47. 47. GLYCYLCYCLINES (Pronunciation: gli-sil-sī-klēns) Tigecycline – a derivative of minocycline Similar to tetracycline Broad-spectrum activity against Multidrug-resistant Gram +ve pathogens Some Gram –ve organisms Aerobic organisms Treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections Mechanism of action – bacteriostatic47
  48. 48. GLYCYLCYCLINES Adverse Effects Associated with nausea and vomiting and other adverse effects similar to tetracyclines Drug interactions Inhibits the clearance of warfarin Oral contraception with Glycylcyclines – less effective48
  49. 49. AMINOGLYCOSIDES Similar antimicrobial spectrum to Macrolides Relatively toxic but still useful in treatment of infections caused by anaerobic Gram –ve bacteria Ototoxicity = main limitation Inhibit bacterial protein synthesis Have a PAE Good to know: Only available IV Not absorbed by gut49
  50. 50. Aminoglycosides Antibacterial spectrum – effective in combination for empirical treatment of aerobic Gram –ve bacilli infections – Pseudomonas aeruinosa Combines with a β-lactam i.e. Vancomycin Aminoglycosides and bactericidal amikacin,gentamycin, tobramycin and streptomycin50
  51. 51. Figure 32.9 (still)Chapter 32 MENU >
  52. 52. Adverse Effects of AminoglycosidesFigure 32.10 (still)Chapter 32 MENU >
  53. 53. MACROLIDES (bacteriostatic) May also be bacteicidal Large group of antibacterials Low toxicity Similar spectrum of activity PAE – antibacterial activity continues after concentrations have dropped Good to know: Take on an empty stomach53
  54. 54. Macrolides – Antibacterial Spectrum Erythromycin – effective against the same organisms as penicillin G Clarithromycin - spectrum of activity similar to erythromycin also Chlamidia, Legionella, Moraxella & Ureaplasma species & Helicobacter pylori54
  55. 55. Macrolides – Antibacterial Spectrum Azithromycin – less active to strep and staph. More active against H. Influenzae, Moraxella catarrhalis. Preferred therapy for urethritis caused by chlamydia trachomatis. Also activity against Mycobacterium avium- intracellularae complex in patients with AIDS Telithromycin (ketolite) – spectrum similar to azithromycin, resistance lower = more55 effective
  56. 56. Therapeutic Applications of Macrolides Most strains of staphylococci in hospitals are resistantFigure 32.12 (still)Chapter 32 MENU >
  57. 57. Macrolides • Absorption • food interferes with absorption • IV = increased thrombophlebitis • Distribution • High in all body fluids & prostatic fluids - except CSF • Elimination • Erythromycin & telithromycin interfere with metabolism of drugs such as theophylline &Figure 32.13 (still) carbamazepineChapter 32 MENU >
  58. 58. Macrolides - Adverse EffectsInteractions –Erythromycin, telithromycin and clarithromycin inhibitmetabolism of a number of drugs = toxic accumulationFigure 32.15 (still)Chapter 32 MENU >
  59. 59. OTHERS Chrolamphenical - Chrolomycetin Clindamycin- Cleocin, Dalacin C Linezolid - Zyvox Quinupristin / dalfopristin - Synercid59
  60. 60. Chloramphenicol Active against a wide range of Gram +ve and Gram –ve organisms High toxicity – bone marrow toxicity Restricted for life-threatening infections where no alternative exists60
  61. 61. Chloramphenicol - Spectrum Broad spectrum antibiotic Active against bacteria, Rickettsia, Mot affected against - Pseudomonas Aeruginosa and chlamydiae Excellent activity against anaerobes Both bactericidal and Bacteriostatic61
  62. 62. Adverse Effects • Clinical use limited to life threatening infections – serious side effects, GI upsets, overgrowth of Candida albicans • Anaemias – haemolytic anaemia • Gray baby syndrome – poor feeding, depressed breathing, cardiovascular collapse, cyanosis and death • Interactions – blocks the metabolism of warfarin, phenytoin, tolbutamide & chlopropamide = increased effects of the drugsFigure 32.18 (still)Chapter 32 MENU > • Bone Marrow depression
  63. 63. CLINDAMYCIN Mechanism of action same as erythromycin Treatment of infections caused by anaerobic bacteria – Bacteriodes fragilis (infections associated with trauma) & MRSA Resistance same as erythromycin63
  64. 64. Clindamycin Administration • Well absorbed by oral route • Adequate levels not achieved in the brain • Penetration into bone - good Accumulation of drug in patients with compromised renal function or hepatic failure Side Effects Fatal pseudomembraneousFigure 32.20 (still) colitisChapter 32 MENU >
  65. 65. Quinupristin / Dalfopristin • Reserved for Vancomycin- resistant Enterococcus faecium (VRE) • Active against Gram +ve cocci including those resistant to other antibiotics, including MRSA • Primary use treatment of E.faecium infections + VRE strains Adverse Effects • Venous irritation, Arthralgia & myalgia, Hyperbilirubinaemia, drugFigure 32.21 (still) interactionsChapter 32 MENU >
  66. 66. LINEZOLID Adverse effects • GI upset • Diarrhoea • Headaches • Rash • Thrombocytopenia • Inhibits MAO activity • Precipitate serotonin syndrome in patients taking SSRI’sFigure 32.24 (still)Chapter 32 MENU >
  67. 67. 3. NUCLEIC ACID INHIBITORS -QUINOLONES Not recommended for children May prolong QT interval, not to be used in patients with arrhythmias Limited therapeutic utility and rapid development of resistance Interfere with absorption Antacids containing aluminium or magnesium Dietary substances containing iron or zinc Calcium , milk or yogurt67
  68. 68. Newer compounds, Ciprofloxacin & ofloxacin, • Greater potency • Broader spectrum of antimicrobial activity • Greater efficacy against resistant organisms • Active against Gram–ve bacilli & cocci, mycobacteria, mycoplasmas & rikettsiae • Some cases better safety profile than older quinolones Respiratory quinolones • Levofloxacin, gemifloxacin & moxifloxacin • Active against Gram +ve, typical,Figure 33.5 (still) atypical & anaerobic pathogensChapter 33 MENU >
  69. 69. Therapeutic Applications of FluroquinolonesFigure 33.4 (still)Chapter 33 MENU >
  70. 70. Adverse Reactions to FloroquinolonesFigure 33.7 (still)Chapter 33 MENU >
  71. 71. Sulfonamides –Cell MembraneInhibitors • Seldom prescribed on their own • Resistance limits spectrum of antimicrobial activity • Trimethoprim -similar activity to sulphonamides – in combination with sulphonamides is synergistic Adverse effects: • Nephrotoxicity • Hypersensitivity • Haemopoeitic disturbances • Kernicterus • Displaces warfarin & MethotrexateFigure 33.10 (still) from binding sitesChapter 33 MENU >
  72. 72. Therapeutic application of Cotrimoxazole (sulfamethoxazole plus trimethoprim)Figure 33.14 (still)Chapter 33 MENU >
  73. 73. Adverse Effects CotrimoxazoleFigure 33.16 (still)Chapter 33 MENU >
  74. 74. 4. ANTIMYCOBACTERIALSFigure 34.1 (still)Chapter 34 MENU >
  75. 75. Figure 34.10 (still)Chapter 34 MENU >
  76. 76. 5. ANTIFUNGAL DRUGS Amphotericin B Flucytosine Ketoconazole Flucanozole Itraconazole Variconazole Posaconazole Echinocandins76
  77. 77. Drugs for Cutaneous and Mycotic Infections Terbinafine Neftifine Butenafine Griseofulvin Nystatin Imidazole Ciclopirox Tolnaftate77
  78. 78. The Top Ten Rule 1. All cell wall inhibitors are Beta-lactams (penicllins, cephalosporins etc) except vancomycin. 2. All penicllins are water soluble except nafcillin. 3. All protein synthesis inhibitors are bacteriostatic, except for the aminoglycosides 4. All cocci are gram positive, except Neisseria spp. 5. All bacilli are gram negative, except anthrax, tetanus, botulism and diphtheria bugs 6. All spirochaetes are gram negative78
  79. 79. The Top Ten Rule 7. Tetracylcines and macrolides are used for intracellular bacteria 8. Beware pregnant women and tetracylcines, aminoglycosides, fluoroquinolones and sulfonamides. 9. Antibitoics beginning with C are particularly associated with pseudomembranous colitis i.e. Cephalosporins, Clindamycin and Ciprofloxacin. 10. While the penicillins are the most famous for causing allergies, a significant proportion of people with penicillin allergies may also react to cephalosporins. These should therefore also be avoided.79
  80. 80. 80
  81. 81. 81