principals and therapeutics of antimicrobials

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principals and therapeutics of antimicrobials

  1. 1. Dr. V.K. GUPTA Division of Medicine Principles and therapeutics of antimicrobialsPrinciples and therapeutics of antimicrobials
  2. 2.  Antibiotic Is a chemical substance produced by a microorganism that inhibits the growth or kills other microorganisms  Antimicrobial agent Is a chemical substance derived from a biological source or produced by chemical synthesis that kills or inhibits the growth of microorganisms Antibiotic
  3. 3. Sources of Antibiotics • Natural - Mainly fungal sources Benzylpenicillin and Gentamicin are natural antibiotics • Semi-synthetic - Chemically-altered natural compound Ampicillin and Amikacin are semi-synthetic antibiotics • Synthetic - Chemically designed in the lab Moxifloxacin and Norfloxacin are synthetic antibiotics • There is an inverse relationship between toxicity and effectiveness as you move from natural to synthetic antibiotics
  4. 4. Role of Antibiotics  To inhibit multiplication  Antibiotics have bactericidal / bacteriostatic effect  Minimal Inhibitory Concentration = MIC  MIC = lowest concentration of antibiotic that inhibits growth (Riviere 2009)
  5. 5. Role of Antibiotics • To destroy the bacterial population • Minimal Bactericidal Concentration = MBC • MBC = lowest concentration of antibiotic that kills bacteria • Antibiotics have a bactericidal effect (Riviere 2009)
  6. 6.  Mechanisms of Action Antibiotics operate by inhibiting crucial life sustaining processes in the organism: the synthesis of cell wall material ,DNA, RNA, ribosome's and proteins.  Target The target of the antibiotic should be selective to minimize toxicity for host but all antibiotics are toxic to some degree (Riviere 2009)
  7. 7. Ideal Antibiotics  Selective target – target unique  Narrow spectrum – does not kill normal flora  High therapeutic index – ratio of toxic level to therapeutic level  Few adverse reactions – toxicity, allergy  Various routes of administration – IV, IM, oral  Good absorption from site of injection  Good distribution to site of infection  Emergence of resistance is slow ( Goodman & Gilman's 2006)
  8. 8. (A) Based on spectrum of activity  Narrow spectrum  Active against either gram-negative or gram- positive bacteria e.g. penicillin, streptomycin, erythromycin  Broad-spectrum  Active against both gram-positive and gram- negative bacteria e.g. tetracycline & chloramphenicol (Riviere 2009) Classification of antibiotics
  9. 9. (B)Based on effects of AB (a)Bacteriostatics  inhibit bacterial growth.  The body requires an effective innate and acquired immune system in the case of bacteriostatic antibiotics.  For immuno-compromised patients bacteriostatic antibiotics usually not effective.  Antimetabolites and inhibitors of protein synthesis (except aminoglycoside antibiotics) are usually bacteriostatic (Riviere 2009)
  10. 10. (b) Bactericidal Antibiotic kills bacteria. Inhibitors of cell wall synthesis and agents affecting cell membrane permeability are bactericidal (Riviere 2009)
  11. 11. (C) Based on mode of action A. Antibacterial agents that inhibit the cell wall synthesis B. Antibacterial agents that alter the function of the cytoplasmic membrane C. Antibacterial agents that inhibit the protein synthesis D. Antibacterials that inhibit the nucleic acid synthesis ( Goodman & Gilman's 2006)
  12. 12. 1. Cause misreading of mRNA code and affect permeability e.g. streptomycin & gentamicin 2. Inhibit DNA gyrase e.g. fluoroquinolones 3. Interfere with DNA function e.g. Rifampin 4. Interfere with DNA synthesis e.g. acyclovir
  13. 13. (D) Uses of antibiotics Antibacterial A. Gram positive bacteria Penicillin, Erythromycin B. Gram negative bacteria Streptomycin, Gentamicin C. Broad spectrum Chloramphenicol, Tetracycline,fluroquinalones D. Antitubercular Streptomycin, rifampicin kanamycin capriomycin (Riviere 2009)
  14. 14. Prophylactic – prior to surgical procedure best time half an hr prior to surgery e.g. Penicillin Use a growth promoter – use in adult ruminants monencin & salinomycin Antifungal -systemic antifungal agent amphotericin-B -topical antifungal agent Griseofulvin, (Riviere 2009)
  15. 15.  Antiviral antibiotics- inhibit viral mRNA polymerase and interfere viral protein and maturation e.g. Rifampin interfere viral protein synthesis e.g. Mytomycin, Puromycin  Antineoplastic – prevent RNA transcription and protein synthesis e.g. actinomycin-D inhibition of RNA & DNA synthesis e.g. Doxorubincin, Daunorubicin ( Riviere 2009)
  16. 16. Uses of antibiotics (contd.) • Potentiation of inhibitory neurotransmitters in nematodes and ectoparasite e.g. Ivermectin,doramectin Milbemycin-D & Milbemycin oxime active against HWP in dog Moxidectin active against nematodes and ectoparasite in cattle ( Riviere 2009)
  17. 17. Uses Anticoccidial  inhibit coccidial protein synthesis e.g. Oxytetracycline (curative) and chlortetracycline (prophylactic)  Use as preventive e.g. Monencin Antianaplasmic  Tetracycline Antitheilerial  Oxytetracycline & rolitetracycline ( Riviere 2009)
  18. 18. Advantages  Easily available, cheap and least toxic  Easily distributed in body tissues and fluids  least untoward reaction  If used properly drugs resistant does not developed    Antibiotics have saved countless lives  Broad-spectrum antibiotics which work equally well on bacteria and fungus  Each antibiotic is effective only for some types of disease  Right antibiotic cures the disease in the shortest span of time
  19. 19. Disadvantages Toxicity  Pain, abscess formation on I/M injection  Thrombophlebitis on I/V injection Tetracycline, erythromycin & chloramphenicol  Ototoxic & nephrotoxic Aminoglycoside  Hepatotoxic & nephrotoxic Tetracycline  Bone marrow depression and aplastic anemia Chloramphenicol (Adams 2001)
  20. 20. Disadvantages  Allergic reaction -hypersensitivity reaction Penicillins, aminoglycosides & cephalosporin  Superinfection - Tetracycline, Chloramphenicol  Microbial resistance- Staphylococcus to penicillin Enterococci to streptomycin  Vitamin deficiencies- vitamin-B & vitamin-K  Production of residues in animal products ( Adams 2001)
  21. 21.  Disadvantages of combination  Increase chance of toxicity  Increase intensity of toxicity of a drug by another drug  Increase in nephrotoxicity (gentamycin + cephaloridine)  Chance of Superinfection increase  Increase cost of therapy ( Adams 2001)
  22. 22. Do’s and don’t antibiotics Newborn can not metabolized and excreted because lack of metabolizing enzyme e.g. Chloramphenicol & tetracycline Young animal accumulate in developing teeth and bone e.g. tetracycline Old animal poor renal function slow excretion e.g. aminoglycoside
  23. 23. Pregnancy penicillin and erythromycin can safely given avoid all antibiotic in first trimester period of organogenesis × tetracycline, aminoglycoside Milking animal Iprinomectin nil milk withholding period (radostits 2000) × Chloramphenicol & ivermectin
  24. 24. Renal dysfunction × tetracycline, aminoglycoside, amphotericin-B Hepatic dysfunction Don’t- erythromycin, chloramphenicol, & rifampin Drug allergy  Erythromycin is alternative to penicillin allergy × Penicillin, aminoglycoside, erythromycin & trimethoprim
  25. 25. Presence of blood, pus, CSF penicillin × aminoglycoside Food animal  follow withdrawal time × chloramphenicol
  26. 26. Penicillin, aminoglycoside,& chloramphenicol Do’s- parenterally × Don’t- orally Meningitis  Do’s- chloramphenicol, cefotaxime & rifampin × Don’t- aminoglycoside Pleural& peritoneal membrane Do’s- chlortetracycline × Don’t- penicillin
  27. 27. Toxicity  prefer penicillin, cephalosporin's & erythromycin × Aminoglycoside, tetracycline chloramphenicol, vancomycin Follow directions  Dos- full course of antibiotics × Don’t - stop antibiotics too early Spectrum  narrow spectrum drugs × Broad spectrum drugs Combination  bacteriostatics + bacteriostatics or bactericidal + bactericidal × bacteriostatics + bactericidal
  28. 28. Mechanism by which small doses of an antimicrobial can lead toMechanism by which small doses of an antimicrobial can lead to propagation/selection of resistant strains of bacteriapropagation/selection of resistant strains of bacteria
  29. 29. 1. ß-LACTAM ANTIBIOTICS  Kidneys/bladder/genitourinary tract → exceed MIC (Rock, 2007; Bill, 2006) CNS infections (Vaden , 2001)
  30. 30. PENICILLINS • Penicillin G (natural); ampicillin, amoxycillin (aminopenicillins; broad- spectrum ); cloxacillin (penicillinase-resistant; narrow-spectrum), carbenicillin, ticarcillin (extended-spectrum) • Procaine penicillin G (1 day) and benzathine penicillin G (7 days): not IV → affect cardiac conduction system (Vaden , 2001) • Aminopenicillins: empty stomach (Bill, 2006) Eye/brain/prostate/intracellular bacteria (Bill, 2006; Vaden, 2001) Resistant: Pseudomonas, Staphylococci; cross-resistance
  31. 31.  Cloxacillin: staphylococcal infections (Bill, 2006)  Add clavulanic acid and sulbactam → potentiated compound  Kidneys/liver/lung (Rock, 2007) • Hypersensitivity reactions most common ADR → record; mild skin rash to life-threatening anaphylactic shock; injectable > oral; emergency treatment (epinephrine + corticosteroids); cross-reactivity (Rock, 2007; Bill, 2006) • Hydrolysis → degradation (main) (Vaden , 2001) • Clavulanate packaged individually in foil → absorbs moisture (Bill, 2006)
  32. 32. CEPHALOSPORINS • 4 generations: ↑ → ↓G+; ↑ G- (Bill, 2006) • Cephadroxil, cephalexin, cefpodoxime (PO), cefotaxime & ceftazidime • Stable in solutions for short time, unless frozen • False + reaction: glucosuria and proteinuria (Vaden , 2001) • Reactions: much less (Bill, 2006)
  33. 33. 2. AMINOGLYCOSIDES • Neomycin (topical), amikacin (broadest spectrum) & gentamicin (Riviere, 2001) • ↓ cross-resistance (Bill, 2006) • Usually administered parenterally (Riviere, 2001) • t1/2:2-5 h; post antibiotic effect (PAE) (Bill, 2006) Eye/brain/prostate/respiratory tract (Strausbaugh, 1983) Cellular debris (pus) → flush thoroughly (Bill, 2006) Anaerobic bacteria/conditions (Riviere, 2001) Denuded skin/surgical sites → renal failure (Mealey, 1994)
  34. 34.  DOC for serious G- infections (Riviere, 2001)  + penicillin (Bill, 2006) • ↑ toxicity potential; accumulate within kidneys (PCT) and inner ear by pinocytosis (active) → nephrotoxicity and ototoxicity (auditory: dogs; vestibular toxicity: cats) (Bill, 2006; Bennett, 1982) • Monitoring renal function: urine sediment (casts or increased protein are early signs) & urine SG (not for cats) (Bill, 2006; Grauer,1995) • Hydrophilic → steep gradient for diffusion; OD → much safer (Freeman, 1997)
  35. 35. 3. FLUOROQUINOLONES • Enrofloxacin, difloxacin, orbifloxacin and marbofloxacin • Broad-spectrum; aerobic bacteria (Papich, 2007) • Well absorbed PO; not affected by food; reduced (90%) with ulcer treatment medication (Bill, 2006; Nix, 1989) First-choice antibiotics (WHO, 1997) Streptococcal infections (Bill, 2006)
  36. 36.  Infections: prostate/skin/soft tissue/wounds/bone/ear/ respiratory & urinary tract (DeManuelle, 1999; Paradis, 1990)  ↑ intracellular concentrations → ↑ concentrations in infected tissue e.g., pyoderma (WHO, 1997; Garaffo, 1991)  Pregnancy (Papich, 2001) • Very safe drugs; but affect developing joint cartilage → not in young • Cats: retinal degeneration → enrofloxacin dose reduced to 5 mg/kg OD • ↑ seizure activity → avoid in epileptics (Papich, 2007; Bill, 2006)
  37. 37. 4. TETRACYCLINES • TC, OTC (hydrophilic) and minocycline/ doxycycline (lipophilic) • Irritating: give PO or IV; slow IV or dilute (Riviere, 2001) • PO preferred: chelation decreases absorption (Bill, 2006; Aronson, 1980) • Distribution ~ lipid solubility (Riviere, 2001) • TC/OTC → not metabolised; enterohepatic circulation; doxycycline largely excreted into the intestine (Bill, 2006; Kunin, 1961) • OTC: light-sensitive drug (Rock, 2007)
  38. 38.  Doxycycline/minocycline → eye/CNS/prostate/ intracellular bacteria/↓ renal function (Bill, 2006; Shaw, 1986) • Yellow, mottled tooth discoloration; slow bone development (first few weeks) (Bill, 2006; Moffit, 1974) • Dogs: irritation of GIT; cats less tolerant; ® doxycycline + food (Rock, 2007) • Expired TC/OTC → nephrotoxic compound → Fanconi’s syndrome (Bill, 2006)
  39. 39. 5. SULPHONAMIDES/SULPHA DRUGS • Sulphasalazine, sulphadiazine, sulphadimethoxine & sulphamethoxazole • Many bacteria resistant (Bill, 2006) • Potentiated sulphonamides → + TMP→ ↓ MIC of both drugs → ↓ SE, ↑ efficacy, bactericidal → OD/ BID (Rock, 2007; Bill, 2006) Necrotic tissue (Rock, 2007) Topical use: except silver sulphadiazine & mafenide (Spoo, 2001)  Serosal/synovial/ocular/CS fluid/prostate/respiratory & urinary tract (Rock, 2007; Bill, 2006)  Sulfasalazine → IBD → 70% in LI → sulfapyridine (sulphonamide) + 5- aminosalycilic acid (local anti-inflammatory effect) (Rock, 2007)
  40. 40. • Dogs: decreased tear production (KCS, or “dry eye”) (Bill, 2006; Collins, 1986) • Dog develops new CS → suspect ADR’s (notorious: 82%); Dobermanns predisposed; dermal reactions (drug eruptions); hypersensitivity: type III (Rock, 2007; Noli, 1995) • Cats: PO: salivation • Sulfasalazine: cautious in cats & aspirin hypersensitive animals • Crystalluria (dehydration or acidic urine) → concern in small animals (Bill, 2006)
  41. 41. Sulfonamide crystals are typically yellow in color
  42. 42. 6. LINCOSAMIDES • Lincomycin and clindamycin (↑ used) • ® G+ infections when penicillin resistance/intolerance (Rock, 2007)  Clindamycin: anaerobic bacteria (Bill, 2006; Noli, 1999)
  43. 43. 7. MACROLIDES • Erythromycin, azithromycin, clarithromycin & tylosin (Papich, 2007) • Spectrum ~ penicillin → substitutes (Bill, 2006) • PO: preferred; food affects absorption (Kirst, 1989) CSF (Wilson, 1984) Acidic environment (Sabath, 1968)  Respiratory tract (Papich, 2001)  Well distributed (prostate) (Bill, 2006) • Inhibits cytochrome P-450; erythromycin ~ motilin (Papich, 2001; Lester, 1998) • Vomiting/regurgitation → most common adverse effects (Bill, 2006; Kunkle, 1995)
  44. 44. 8. CHLORAMPHENICOL • Broad spectrum (Papich, 2001; IARC, 1990) Lactating animals (Papich, 2001) Serious CNS infections (Rahal, 1979)  Well distributed (eye/CNS/prostate) → new agents (Bill, 2006; Hird, 1986) • SE: myelosuppression (cats) → ↓ dose than dogs → ↓ liver metabolism + ↓ elimination; neonates (Bill, 2006) • Inhibits cytochrome P-450; ↑ half lives e.g., pentobarbital (Adams, 1970) • Myelosuppression → avoid repeated contact or inhalation (Bill, 2006; Yunis, 1988)
  45. 45. 9. METRONIDAZOLE • Bactericidal • Anaerobic conditions (Bill, 2006) • Neurologic side effects (Longhofer, 1988)
  46. 46. REQUISITES FOR RATIONAL ANTIBACTERIAL THERAPY 1) Lesion management and supportive care (Davis,1985) 2) Following the “five rights” of drug administration: a) Right drug b) Right dose c) Right patient d) Right route e) Right time (Galbraith, 1999) 3) Monitoring of patient 4) Client education 5) Monitoring response to therapy (Rock, 2007)
  47. 47. a. RIGHT DRUG • Necessary conditions:  In vitro susceptibility: by CST/AST (Rock, 2007)  In vivo susceptibility  Host tolerance (Bill, 2006) • Other considerations:  Cost, client compliance, ease of administration & convenient dosage interval (Bill, 2006)  Risks/ interactions: avoid compounding (never mix cationic & anionic drugs) (Papich, 2007; Mir, 1998)  Impact of the disease process on drug pharmacokinetics (e.g., aminoglycosides) and pharmacodynamics (e.g., sulfonamides) (Novotny 1993; Wilcke 1986) • Check name (Rock, 2007)
  48. 48. b. RIGHT DOSE • Optimum concentrations at site of infection (Bill, 2006) • Formula: • Under doing (larger dogs) → more serious • Over dosing (cats) (Barragry, 1994) No diuretics (Mir, 1998)  Check strength (Rock, 2007)
  49. 49. c. RIGHT PATIENT • Neonatal & pediatric patients: Tetracyclines, sulfonamides, and fluoroquinolones (Novotny, 1993)  ↓ hepatic biotransformation → avoid chloramphenicol (Short, 1984)  ↑ Vd → ↑ dose (Novotny, 1993) • Pregnancy:  Basic drugs concentrate in fetal plasma (Novotny, 2001)
  50. 50. • Geriatric patients:  Water-soluble drugs: ↓ Vd  ↓ elimination (Ritschel, 1987) • Liver failure:  ß-lactams Lincosamides, macrolides, sulfonamides, and chloramphenicol (Bunch, 1995; Tams, 1984) • Renal failure:  Aminoglycosides → same dose; ↑ interval (Bill, 2006; Polzin, 2000)  Sulphonamides (prevent crystalluria) (Spoo, 2001)
  51. 51. d. RIGHT ROUTE • PO:  Giving a drink of water before administration  Enteric-coated formulations/capsules : do not break (Rock, 2007)  Empty stomach (Scherer, 1992) Vomiting Suspensions : SC or IM • Severe dehydration: ↓ SC absorption (Novotny, 2001)
  52. 52. e. RIGHT TIME • Frequency: t1/2= 2-3 h: time & concentration dependent (Bill, 2004) • Time dependent drugs: 100% contact time → compromised IS; ≥ 50% contact time → working IS (Aucoin, 2002) • Duration (Novotny, 2001)
  53. 53. Thank you……

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