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Beta-lactam antibiotics

Beta-lactam antibiotics. Subat Turdi. Beta-Lactam Structure. PENICILLINS. CATEGORIES OF PENICILLINS: NATURAL PENICILLINS: Penicillin G, Penicillin V (PenVee K) PENICILLINASE-RESISTANT PENICILLINS Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin BROAD SPECTRUM PENICILLINS

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Beta-lactam antibiotics

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  1. Beta-lactam antibiotics Subat Turdi

  2. Beta-Lactam Structure

  3. PENICILLINS • CATEGORIES OF PENICILLINS: • NATURAL PENICILLINS: • Penicillin G, Penicillin V (PenVee K) • PENICILLINASE-RESISTANT PENICILLINS • Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin • BROAD SPECTRUM PENICILLINS • Ampicillin, Amoxicillin, Amoxicillin/Clavulanic acid, Bacampicillin

  4. PENICILLINS • EXTENDED-SPECTRUM PENICILLINS • Carbenicillin, Ticarcillin (Ticarcillin/clavulanic acid • Mezlocillin, Piperacillin, Piperacillin/Tazobactam

  5. PENICILLINS • ACTION: • bind to bacterial cell wall components preventing cross-linking of peptidoglycan - essential for cell wall synthesis • the beta-lactam agents bind to other enzymes, as well, in order to inhibit bacterial cell wall synthesis

  6. PENICILLINS • defective cell wall synthesis leads to cell lysis and destruction of the organism

  7. PENICILLINS PHARMACOKINETICS

  8. PENICILLINS • ORAL ABSORPTION • INTRAMUSCULAR ABSORPTION • DISTRIBUTION • Penicillins do not penetrate cell membranes easily; however, when inflammation is present, membrane permeability is increased. • METABOLISM AND EXCRETION • Excreted by kidneys unchanged.

  9. PENICILLINS • CONTRAINDICATIONS AND PRECAUTIONS • Allergy • Renal Insufficiency • Pregnancy

  10. -LactamsAdverse Effects • Hypersensitivity – 3 to 10 % • Higher incidence with parenteral administration or procaine formulation • Mild to severe allergic reactions – rash to anaphylaxis and death • Antibodies produced against metabolic by-products or penicillin itself • Cross-reactivity exists among all penicillins and even other -lactams • Desensitization is possible

  11. HYPERSENSITIVITY REACTIONS

  12. -LactamsAdverse Effects • Neurologic – especially with penicillins and carbapenems (imipenem) • Especially in patients receiving high doses in the presence of renal insufficiency • Irritability, jerking, confusion, seizures • Hematologic • Leukopenia, neutropenia, thrombocytopenia – prolonged therapy (> 2 weeks)

  13. -LactamsAdverse Effects • Gastrointestinal • Increased LFTs, nausea, vomiting, diarrhea, pseudomembranous colitis (C. difficile diarrhea) • Interstitial Nephritis • Cellular infiltration in renal tubules (Type IV hypersensitivity reaction – characterized by abrupt increase in serum creatinine; can lead to renal failure • Especially with methicillin or nafcillin

  14. -LactamsAdverse Effects • Cephalosporin-specific: MTT side chain - cefamandole, cefotetan, cefmetazole, cefoperazone, moxalactam • Hypoprothrombinemia - due to reduction in vitamin K-producing bacteria in GI tract • Ethanol intolerance • Others: phlebitis, hypokalemia, Na overload

  15. PENICILLINS • Drug Interactions: • Do not administer concurrently with: • Bacteriostatic Antibiotics (decrease Pen activity) • Anticoagulants (increases bleeding potential) • Aminoglycosides (Pen inactivates Aminoglycosides) • Never mix Penicillins with Aminoglycosides - Toxic • Salicylates compete with PenG (prolongs Pen T 1/2 ) • Probenecid inhibits renal tubular secretion of penicillins prolongs concentration and T1/2

  16. ALL -lactams • Mechanism of Action • interfere with cell wall synthesis by binding to penicillin-binding proteins (PBPs) which are located in bacterial cell walls • inhibition of PBPs leads to inhibition of peptidoglycan synthesis • are bactericidal

  17. ALL -lactams • Mechanisms of Resistance • production of beta-lactamase enzymes • most important and most common • hydrolyzes beta-lactam ring causing inactivation • alteration in PBPs leading to decreased binding affinity • alteration of outer membrane leading to decreased penetration

  18. Antimicrobial Spectrum of Activity • General list of bacteria that are killed or inhibited by the antibiotic • are established during early clinical trials of the antibiotic • local, regional and national susceptibility patterns of each bacteria should be evaluated; differences in antibiotic activity may exist • Individualized susceptibilities should be performed on each bacteria if possible

  19. Natural Penicillins(penicillin G) Gram-positiveGram-negative pen-susc S. aureusNeisseria sp. pen-susc S. pneumoniae Group streptococciAnaerobes viridans streptococci Above the diaphragm Enterococcus Clostridium sp. Other Treponema pallidum (syphilis)

  20. Penicillinase-Resistant Penicillins(nafcillin, oxacillin, methicillin) Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins Gram-positive methicillin-susceptible S. aureus Group streptococci viridans streptococci

  21. Aminopenicillins(ampicillin, amoxicillin) Developed to increase activity against gram-negative aerobes Gram-positive Gram-negativepen-susc S. aureus Proteus mirabilis Group streptococci Salmonella, Shigella viridans streptococci some E. coli Enterococcus sp. L- H. influenzae Listeria monocytogenes

  22. Carboxypenicillins(carbenicillin, ticarcillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negativemarginalProteus mirabilis Salmonella, Shigella some E. coli L- H. influenzae Enterobacter sp. Pseudomonas aeruginosa

  23. Ureidopenicillins(piperacillin, azlocillin) Developed to further increase activity against resistant gram-negative aerobes Gram-positiveGram-negative viridans strep Proteus mirabilis Group strep Salmonella, Shigella some Enterococcus E. coli L- H. influenzae Anaerobes Enterobacter sp. Fairly good activity Pseudomonas aeruginosa Serratia marcescens some Klebsiella sp.

  24. -Lactamase Inhibitor Combos(Unasyn, Augmentin, Timentin, Zosyn) Developed to gain or enhance activity against -lactamase producing organisms Gram-positiveGram-negative S. aureusH. influenzae E. coli AnaerobesProteus sp. Bacteroides sp. Klebsiella sp. Neisseria gonorrhoeae Moraxella catarrhalis

  25. β-lactam Antibiotics Cephalosporins • Produced by fungi, Cephalosporium • ring similar to penicillins • so action similar to penicillins • Originally for gram-positive cocci • Used when • infecting bacterial strain is reistant due to penicillinase • when allergy or toxicity to penicillin present • Broader spectrum • few serious side effects • Local irritation at injection site • Nausea, vomiting, diarrhea • Penicillin allergic persons can also be sensitive (~15%)

  26. Classification and Spectrum of Activity of Cephalosporins • Divided into 4 major groups called “Generations” • Are divided into Generations based on • antimicrobial activity • resistance to beta-lactamase

  27. First Generation Cephalosporins Best activity against gram-positive aerobes, with limited activity against a few gram-negative aerobes Gram-positive Gram-negative meth-susc S. aureusE. coli pen-susc S. pneumoniaeK. pneumoniae Group streptococci P. mirabilis viridans streptococci

  28. Second Generation Cephalosporins • Also includes some cephamycins and carbacephems • In general, slightly less active against gram-positive aerobes, but more active against gram-negative aerobes • Several second generation agents have activity against anaerobes

  29. Second Generation CephalosporinsSpectrum of Activity Gram-positive Gram-negative meth-susc S. aureusE. coli pen-susc S. pneumoniaeK. pneumoniae Group streptococci P. mirabilis viridans streptococci H. influenzae M. catarrhalis Neisseria sp.

  30. Second Generation CephalosporinsSpectrum of Activity The cephamycins (cefoxitin, cefotetan, and cefmetazole) are the only 2nd generation cephalosporins that have activity against anaerobes Anaerobes Bacteroides fragilis Bacteroides fragilis group

  31. Third Generation CephalosporinsSpectrum of Activity • In general, are even less active against gram-positive aerobes, but have greater activity against gram-negative aerobes • Ceftriaxone and cefotaxime have the best activity against gram-positive aerobes, including pen-resistant S. pneumoniae • Several agents are strong inducers of extended spectrum beta-lactamases

  32. Third Generation CephalosporinsSpectrum of Activity Gram-negative aerobes E. coli, K. pneumoniae, P. mirabilis H. influenzae, M. catarrhalis, N. gonorrhoeae (including beta-lactamase producing); N. meningitidis Citrobacter sp., Enterobacter sp., Acinetobacter sp. Morganella morganii, Serratia marcescens, Providencia Pseudomonas aeruginosa (ceftazidime and cefoperazone)

  33. Fourth Generation Cephalosporins • 4th generation cephalosporins for 2 reasons • Extended spectrum of activity • gram-positives: similar to ceftriaxone • gram-negatives: similar to ceftazidime, including Pseudomonas aeruginosa; also covers beta-lactamase producing Enterobacter sp. • Stability against -lactamases; poor inducer of extended-spectrum  -lactamases • Only cefepime is currently available

  34. CarbapenemsSpectrum of Activity • Most broad spectrum of activity of all antimicrobials • Have activity against gram-positive and gram-negative aerobes and anaerobes • Bacteria not covered by carbapenems include MRSA, VRE, coagulase-negative staph, C. difficile, S. maltophilia, Nocardia

  35. MonobactamsSpectrum of Activity Aztreonam bind preferentially to PBP 3 of gram-negative aerobes; has little to no activity against gram-positives or anaerobes Gram-negative E. coli, K. pneumoniae, P. mirabilis, S. marcescens H. influenzae, M. catarrhalis Enterobacter, Citrobacter, Providencia, Morganella Salmonella, Shigella Pseudomonas aeruginosa

  36. -lactamsPharmacology • Concentration-independent bacterial killing – Time above MIC correlates with efficacy • Absorption • Many penicillins degraded by gastric acid • Oral -lactams are variably absorbed; food delays rate and extent of absorption • Pen VK absorbed better than oral Pen G • Amoxicillin absorbed better than ampicillin

  37. -lactamsPharmacology • Distribution • Widely distributed into tissues and fluids • Pens only get into CSF in the presence of inflamed meninges; parenteral 3rd and 4th generation cephs, meropenem, and aztreonam penetrate the CSF • Elimination • most eliminated primarily by the kidney, dosage adjustment of these agents is required in the presence of renal insufficiency • Nafcillin, oxacillin, ceftriaxone, and cefoperazoneare eliminated primarily by the liver; piperacillin also undergoes some hepatic elimination • ALL -lactams have short elimination half-lives (< 2º), except for a few cephalosporins (ceftriaxone)

  38. -LactamsSpecial Pharmacologic Considerations • Some preparations of parenterally-administered penicillins contain sodium; must be considered in patients with CHF or renal insufficiency Sodium Penicillin G 2.0 mEq per 1 million units Carbenicillin 4.7 mEq per gram Ticarcillin5.2 mEq per gram Piperacillin 1.85 mEq per gram • Imipenem is combined with cilastatin to prevent hydrolysis by enzymes in the renal brush border

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