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Penicillin : Dr Rahul Kunkulol's Power point Presentations

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Dr Rahul Kunkulol's Power point Presentations

Dr Rahul Kunkulol's Power point Presentations

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  • 1. 1
  • 2. 2
  • 3. 3 Monobactams All of the drugs in this group contain a β-lactam ring in their structure Penicillins N O S Carbapenems N O N O N O S Cephalosporins share similar • features of chemistry, • mechanism of action, • pharmacologic and clinical effects.
  • 4.  Same Mechanism of Action : Inhibit cell wall synthesis  Bactericidal (except against Enterococcussp.); time-dependent killers  Short elimination half-life  Primarily renally eliminated  Cross-allergenicity - except aztreonam 4
  • 5.  All penicillin derivatives produce their bacteriocidal effects by inhibition of bacterial cell wall synthesis. Specifically, the cross linking of peptides on the mucopolysaccharide chains is prevented. If cell walls are improperly made cell walls allow water to flow into the cell causing it to burst. 5
  • 6. 6 It is the last step in peptidoglycan synthesis that is inhibited by the beta-lactam antibiotics. Penicillin binds at the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands. It does this by mimicking the D-alanyl-D- alanine residues that would normally bind to this site. Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a serine residue in the transpeptidase.
  • 7. 7  Binding to PBPs results in: › Inhibition of transpeptidase: transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide. The fifth reside (also D-Ala) is released during this reaction. Spheroblasts are formed. › Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects.
  • 8. 8 Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is inhibited by penicillins and cephalosporins.
  • 9. 9
  • 10.  Production of β-lactamase enzymes  Trapping mechanism  Modification of target PBPs  Impaired penetration of drug to target PBPs  The shortage of antolytic enzyme  The presence of an efflux pump. 10
  • 11.  Penicillins › Natural penicillins  PenG, PenVK, Benzathine Pen, Procaine Pen › Aminopenicillins  Ampicillin, Amoxicillin › Anti-Staph penicillins  Oxacillin, Dicloxacillin › Anti-Pseudomonal  [Carboxy] Ticarcillin  [Ureido] Piperacillin 11
  • 12.  Natural Penicillins  Penicillin G  Penicillin VK  Semisynthetic penicillins:  Acid-stable penicillins (Penicillin V);  Penicillinase-Resistant Penicillins (Nafcillin, Oxacillin, Methicillin)  Extended-spectrum penicillins (Ampicillin and Amoxycillin);  Antipseudomonal (Carbenicillin, Ticarcillin) 12
  • 13.  Natural Penicillins: extracted from the cultural solution of penicillia. › Prototype is penicillin G › Is pH sensitive. Therefore not given orally. › Effective against Gram-positive cells › Susceptible to penicillinase  Semisynthetic Penicillins:  Have broader spectrum. Are effective against Gram-negative cells, too.  Are not resistant to penicillinases 13
  • 14. Gram-positive Gram-negative pen-susc S. aureus Neisseria sp. pen-susc S. pneumoniae Group streptococci Anaerobes viridans streptococci Above the diaphragm Enterococcus Clostridium sp. Other : Treponema pallidum (syphilis) 14
  • 15. Pharmacokinetics  It is relatively unstable in acid, thus the bioavailability is low.  There is poor penetration into the cerebrospinal (CSF), unless inflammation is present.  Active renal tubular secretion results in a short half-life. 15
  • 16.  Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions.  Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal tract of older individuals 16
  • 17.  After intramuscular injection, peak concentrations in plasma are reached within 15 to 30 minutes. This value declines rapidly, since the half-life of penicillin G is 30 minutes.  Repository preparations of penicillin G are employed. The two such compounds currently favored are penicillin G procaine  penicillin G benzathine. Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood.17
  • 18.  Long acting (every 12 h ) .  Acid unstable  Penicillinase sensitive  Used to prevent subacute bacterial endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease . 18
  • 19.  Long acting (every 3-4 weeks )  Acid unstable  Penicillinase sensitive  Treatment of β-hemolytic streptococcal pharyngitis.  Used as prophylaxis against reinfection with β- hemolytic streptococci so prevent rheumatic fever .  Once a week for 1-3 weeks for treatment of syphilis (2.4 million units I.M.) 19
  • 20. Therapeutic uses  It is the drug of first choice for treating the infections of the above mentioned pathogens.  The simultaneous administration of the relevant antitoxin is often necessary for the treatment of diphtheria and tetanus.  The combination of an aminoglycoside is also necessary for bactericidal effects in enterococcal endocarditis. 20
  • 21.  Penicillin G, Penicillin V 21
  • 22.  Pneumococcal Infections › Pneumococcal Meningitis › Pneumococcal Pneumonia  Streptococcal Infections › Streptococcal Pharyngitis (including Scarlet Fever) › Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis  Staphylococcal Infections  Meningococcal Infections  Gonococcal Infections  Syphilis  Actinomycosis  Diphtheria  Anthrax  Clostridial Infections  Fusospirochetal Infections  Rat-Bite Fever  Listeria Infections  Lyme Disease  Erysipeloid  Surgical Procedures in Patients with Valvular Heart Disease 22
  • 23.  Available PO, IM, IV (dosed in units)  Drug of Choice (DoC) [2-4 MU IV q4h] › T. pallidum, N. meningitidis, Group A Strep, and Actinomycosis  Long-acting forms › Procaine PenG (12 hrs) › Benzathine Pen (5 days) [2.4 MU IM for syphilis]  Adverse Reactions – other than skin rash › Penicillin “serum sickness”/drug fever › Jarisch-Herxheimer reaction (1° and 2° syphilis) › Hemolytic anemia, pancytopenia, neutropenia 23
  • 24.  The oral form of Penicillins,  Indicated only in minor infections because of their relatively poor bioavailability, weaker antimicrobial activity, the need for dosing many times  Narrow antimicrobial spectrum. 24
  • 25.  Hypersensitivity – 5 to 20 %  skin rashes, fever, eosinophilia, angioedema, serum sickness, and anaphylactic shock.  Cross-reactivity exists among all penicillins and even other β-lactams  The most serious hypersensitivity reaction is anaphylactic shock. (very rare, the ratio is about 0.5 to 1 of 10000 patients )  As soon as anaphylactic shock occurs, instantly inject adrenaline to deliver trachea edema and spasm. 25
  • 26. Ask allergic history carefully .  Must make skin test .  The injection of these drugs is made up before it is injected.  As a number of these drugs are replaced, the skin test must be done again.  After every injection, all of patients must be observed, and the drugs for an emergency treatment are prepared at any time 26 How to prevent the occurrence of anaphylactic shock?
  • 27.  Other adverse effects:  Gastrointestinal upset, ( orally administered preparations)  Nephrotoxicity, is very rare.  Superinfections. results from alterations in intestinal flora. A higher incidence occurs with broad- spectrum penicillins. 27 Penicillins : Adverse effects
  • 28. Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins Gram-positive methicillin-susceptible S. aureus Group streptococci viridans streptococci 28
  • 29.  Methicillin  Nafcillin  Oxacillin  Dicloxacillin 29
  • 30. a. Methicillin and isoxazolyl penicillins (e.g. oxacillin, cloxacillin and dicloxacillin) b. They are the drugs of first choice for treating infections of the penicillase- productive aurococcus. But penicillin- susceptible strains of streptococci and pneumococci are also susceptible c. Enterococci and methicillin-resistant strains of staphylococci are resistant to these penicillins 30
  • 31. 31  IV  DoC – MSSA, MSSE [2g IV q4h] › Actually less active against Pen susceptible isolates than Pen › More active than Vanc vs. MSSA  Significant hepatic metabolism › No need to dose adjust for renal impairment  ADRs › Hepatotoxicity (cholestatic hepatitis) › Neutropenia › Kernicterus in neonates
  • 32. 32  Oral  NOT equivalent to IV Ox (therapeutically) › Poor oral absorption › ~50% (better on empty stomach)  Dose: 250-500mg po QID
  • 33. Developed to increase activity against gram- negative aerobes Gram-positive Gram-negative pen- susc S. aureus Proteus mirabilis Group streptococci Salmonella, Shigella viridans streptococci some E. coli Enterococcus sp. βL- H. influenzae Listeria monocytogenes 33
  • 34. 34
  • 35. Ampicillin and amoxicillin a. They are similar to penicillin G in the activity against gram-positive organisms but are weaker than the latter. b. They are more satisfactory for the treatment of enterococci and streptococcus viridians. 35
  • 36. c. They are similar to chloramphenicol in the activity against gram-negative organisms. d. They are acid-resistant but are not penicillase-resistant. e. Pseudomonas aeruginosa are fail to respond to these drugs. f. Amox better tolerated PO and better absorbed (Amp must be taken on empty stomach) 36
  • 37. Developed to further increase activity against resistant gram-negative aerobes Gram-positive Gram-negative marginal Proteus mirabilis Salmonella, Shigella some E. coli βL- H. influenzae Enterobacter sp. Pseudomonas aeruginosa 37
  • 38. 38
  • 39. carbenicillin, ticarcillin a. Extend the ampicillin spectrum of activity to P.aeruginosa and enterobacter species. But their activity to G+ cocci is less than that of ampicillin. b. They are not acid-resistant and penicillase-resistant. c. Ticarcillin is more active than carbenicillin against P.aeruginosa and enterobacter species. 39
  • 40. d. Chiefly used to treat serious infections caused by G- microorganisms, particular P.aeruginosa, indole-positive proteus and enterobacter. e. Generally used in combination with an aminoglycoside for pseudomonal infections. 40
  • 41. Developed to further increase activity against resistant gram-negative aerobes Gram-positive Gram-negative viridans strep Proteus mirabilis Group strep Salmonella, Shigella some Enterococcus E. coli βL- H. influenzae Anaerobes Enterobacter sp. Fairly good activity Pseudomonas aeruginosa Serratia marcescens some Klebsiella sp. 41
  • 42.  IV  DoC: Pseudomonas  Spectrum: most Enterobacteriaceae (E. coli, Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Shigella)  Most active penicillin vs. Pseudomonas  Often used in combination with Aminoglycoside or Cipro/Levofloxacin  ADRs › Bleeding (platelet dysfunction) › Neutropenia/Thrombocytopenia 42
  • 43. clavulanic acid, sulbactam, tazobactam a. Inactivate bacterial beta-lactamases and are used to enhance the antibacterial actions of beta-lactam antibiotics. b. Only have weak antibacterial action. 43
  • 44. c. Inhibitors of many but not all bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by the enzymes. d. Available only in fixed combinations with specific penicillins.  The companion penicillin, not the beta- lactamase inhibitor, determines the antibacterial spectrum of the combination. 44
  • 45.  Augmentin (Amox/Clav) PO  Spectrum: MSSA and upper respiratory infections (S. pneumo, H.Inf, M. catarrhalis) and most anaerobes  Clav is responsible for most of the GI side- effects seen with Amox/Clav  Variable ratios of Amox/Clav in liquids/tabs/chew tabs 45

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