Beta lactam & other cell wall- & membrane-active antibiotics

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  • 1. Beta-Lactam & Other Cell Wall &Membrane-Active Antibiotics By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science
  • 2. Beta-Lactam & Other Cell Wall Antibiotics  General Considerations  Introduction to beta lactams  Penicillins  Cephalosporins  Other beta-lactam drugs  Miscellaneous  Drugs of choice based on:  Disease or Pathogen  Site of infection  Drug PicturesM.H.Farjoo
  • 3. Escherichia Coli
  • 4. Staphylococcus_aureus
  • 5. Introduction  β-lactam drugs have a β-lactam ring and consist of:  Penicillins  Cephalosporins  Other beta-lactam drugs  Miscellaneous  They have similar:  Mechanism of action.  Pharmacologic effects.  Mechanism of bacterial resistance.M.H.Farjoo
  • 6. Core structures of four β-Lactam antibiotic families. Thering marked B in eachstructure is the β-lactam ring.The penicillins are susceptibleto bacterial metabolism andinactivation by amidases andlactamases at the pointsshown. Note that thecarbapenems have a differentstereochemical configurationin the lactam ring thatapparently imparts resistanceto β-lactamases.
  • 7. Introduction (Cont’d)  β-lactam antibiotics, inhibit bacterial growth by interfering with bacterial cell wall synthesis.  They covalently bind to the active site of PBPs inhibiting the transpeptidation.  This halts peptidoglycan synthesis, and the cell dies.  Penicillins and cephalosporins kill bacteria only when they are actively growing and synthesizing cell wall.M.H.Farjoo
  • 8. The transpeptidation reaction in Staphylococcusaureus that is inhibited by β-lactam antibiotics. Thecell wall of gram-positive bacteria is made up of longpeptidoglycan polymer chains consisting of thealternating aminohexoses N-acetylglucosamine (G)and N-acetylmuramic acid (M) with pentapeptideside chains linked (in S aureus) by pentaglycinebridges. The exact composition of the side chainsvaries among species. The diagram illustrates smallsegments of two such polymer chains and theiramino acid side chains. These linear polymers mustbe cross-linked by transpeptidation of the sidechains at the points indicated by the asterisk toachieve the strength necessary for cell viability.
  • 9. A highly simplified diagram of the cell envelopeof a gram-negative bacterium. The outermembrane, a lipid bilayer, is present in gram-negative but not gram-positive organisms. It ispenetrated by porins, proteins that formchannels providing hydrophilic access to thecytoplasmic membrane. The peptidoglycanlayer is unique to bacteria and is much thickerin gram-positive organisms than in gram-negative ones. Together, the outer membraneand the peptidoglycan layer constitute the cellwall. Penicillin-binding proteins (PBPs) aremembrane proteins that cross-linkpeptidoglycan. β-Lactamases, if present, residein the periplasmic space or on the outer surfaceof the cytoplasmic membrane, where they maydestroy β-lactam antibiotics that penetrate theouter membrane.
  • 10.    M.H.Farjoo
  • 11. Penicillins  Penicillins are divided into three groups:  Penicillin salts  Extended-spectrum  Antistaphylococcal  In each group gastric acid resistant penicillins for oral use exist.M.H.Farjoo
  • 12. Penicillin Salts  Penicillin G Salts consist of:  Na+ & K+ salts of penicillin G  Benzathine  Procaine  Penicillin V is the oral form of this group.  All of them are hydrolyzed by β-lactamases.  Benzathine and procaine have delayed absorption resulting in prolonged blood concentrations.M.H.Farjoo
  • 13. Penicillin Salts (Cont’d)  An IM injection of benzathine penicillin, 1.2 million units, treats streptococcal pharyngitis for 10 days.  It is enough to prevent streptococcal infection for 3 weeks.  An IM injection of 600,000 unit of procaine penicillin is useful for 12-24 hrs.  Penicillin V is used only in minor infections. Amoxicillin is often used instead.M.H.Farjoo
  • 14. Extended-spectrum Penicillins  Extended-spectrum penicillins consist of:  Aminopenicillins:  Ampicillin  Amoxicillin  Carboxypenicillins:  Ticarcillin  Ureidopenicillins:  Piperacillin  Mezlocillin  Azlocillin  They are relatively susceptible to hydrolysis by β- lactamases.M.H.Farjoo
  • 15. Antistaphylococcal Penicillins  Antistaphylococcal Penicillins consist of:  Methicillin  Nafcillin  Isoxazolyl Penicillins:  Oxacillin  Cloxacillin  Dicloxacillin  They are resistant to β-lactamases produced by staphylococci.M.H.Farjoo
  • 16. Pharmacokinetics of penicillins  Ampicillin, and amoxicillin are acid-stable and well absorbed.  Ampicillin and amoxicillin, have identical activity, but amoxicillin is better absorbed orally.  Anti staphylococcal penicillins are acid-stable and have reasonable bioavailability.  Food impairs absorption of oral penicillins (except amoxicillin) and they should be taken 1-2 hr before or after a meal.M.H.Farjoo
  • 17. Pharmacokinetics of penicillins (Cont’d)  For parenteral use, IV administration is preferred to the IM route because of irritation and pain from large doses.  Penetration into the eye, the prostate, and the central nervous system is poor.  In meninges therapeutic penicillin concentrations can be achieved with a daily parenteral dose of 18-24 million units.  Nafcillin, Oxacillin, cloxacillin, and dicloxacillin are also cleared by biliary excretion.M.H.Farjoo
  • 18. Pharmacokinetics of penicillins (Cont’d)  Blood levels of all penicillins can be raised by simultaneous administration of probenecid.  Probenecid impairs renal secretion of β-lactams.  The half-life of penicillin G is 30 min., in renal failure it increases to 10 hrs.  Depending on the severity of infection, doses range between 4 and 24 million units/day.  Extended-spectrum penicillins are inactivated by β- lactamases.M.H.Farjoo
  • 19. Resistance to penicillins  Resistance is due to one of four mechanisms:  Inactivation by β-lactamase (the most common mechanism).  Modification of target PBPs.  Impaired penetration of drug to target PBPs.  Efflux. Only in gram-negatives because  Some β-lactamases prefer penicillins to of their impermeable outer cell wall membrane cephalosporins others hydrolyze both of them.M.H.Farjoo
  • 20. Adverse Reactions to penicillins  The penicillins are nontoxic. Most adverse effects are due to hypersensitivity.  All penicillins are cross-sensitizing and cross- reacting.  5-8% of people claim a penicillin reaction but it is not true.  < 1% of persons who have received penicillin without incident will have an allergic reaction when given penicillin.  Penicillin should be administered with caution if there is a history of penicillin allergy.M.H.Farjoo
  • 21. Adverse Reactions to penicillins Cont’d  The incidence of allergic reactions in small children is negligible.  Allergic reactions include:  Anaphylactic shock (0.05%)  Serum sickness Urticaria, fever, joint swelling, intense  A variety of skin rashes. pruritus, respiratory embarrassment occurring 7-12 days after exposure  In renal failure, high dose penicillin can cause seizures.M.H.Farjoo
  • 22. Adverse Reactions to penicillins Cont’d  Nafcillin is associated with neutropenia.  Oxacillin can cause hepatitis.  Large doses of oral penicillins may lead to vomiting and diarrhea.  Ampicillin has been associated with vaginal candidiasis and pseudomembranous colitis.  Ampicillin and amoxicillin can cause skin rashes that are not allergic in nature.M.H.Farjoo
  • 23. Penicillin Units  Penicillin G contains 1600 units per mg, 1 million units = 0.6 g).  In dry form, penicillins are stable for years at 4 C.  Solutions lose their activity rapidly (24 hours at 20 C) and must be prepared fresh.M.H.Farjoo
  • 24. Cephalosporins  Cephalosporins are similar to penicillins but:  More stable to bacterial β-lactamases.  Have a broader spectrum of activity.  They are grouped into 4 generations.M.H.Farjoo
  • 25. First-generation Cephalosporins  First-generation include Cephalexin  Probenecid, increases serum levels substantially. Cephalothin  In patients with impaired renalCefazolin dosage must function, be reduced. Cefadroxil Cephapirin  First-generation cephalosporins are rarely the drug of Cephradine choice for any infection.  Oral cephalosporins should not be relied on in serious systemic infections.M.H.Farjoo
  • 26. Second-generation Cephalosporins  Second-generation include Cefaclor Cefamandole  They have extended gram-negative coverage compared to first generation. Cefonicid Cefuroxime Cefprozil  The oral second-generation cephalosporins are Loracarbef active against β-lactamase. Ceforanide Cefoxitin  Because of their activity againstCefmetazole anaerobes Cefotetan (including B fragilis), can be used to treat such infections (peritonitis or diverticulitis).M.H.Farjoo
  • 27. Third-generation Cephalosporins  Third-generation agents include Cefoperazone  They have expanded gram-negative coverage. Cefotaxime Ceftazidime  They can treat infections resistant to most other Ceftizoxime drugs. Ceftriaxone Cefixime  Cefpodoxime Parenteral cephalosporins (except cefoperazone) achieve sufficient levels in the CSF. Proxetil Cefdinir  The excretion of cefoperazone and ceftriaxone ispivoxil Cefditoren mainly through the biliary tract. Ceftibuten Moxalactam  The others are excreted by the kidney.M.H.Farjoo
  • 28. Fourth-generation Cephalosporins  Cefepime is a fourth-generation cephalosporin.  It is useful in the treatment of enterobacter infections.  Otherwise, its clinical role is similar to that of third-generation agents.M.H.Farjoo
  • 29. Adverse Effects of Cephalosporins  Cephalosporins elicit hypersensitivity reactions identical to penicillins.  Some individuals with a history of penicillin allergy may tolerate cephalosporins.  Cephalosporins with methylthiotetrazole group (cefamandole, cefmetazole, cefotetan, cefoperazone) cause two problems:  Bleeding disorders due to hypoprothrombinemia which can be prevented by vitamin K1.  Severe disulfiram-like reactions (alcohol and alcohol- containing medications must be avoided).M.H.Farjoo
  • 30. Other beta-lactam drugs  Other beta-lactam drugs consist of:  Monobactams Aztreonam  Carbapenems Ertapenem Imipenem MeropenemM.H.Farjoo
  • 31. Monobactams  Monobactams: are drugs with a monocyclic β- lactam ring.  They are resistant to β-lactamases and active against gram-negative rods.  They have no activity against gram-positive bacteria or anaerobes.  Penicillin-allergic patients tolerate aztreonam without reaction.M.H.Farjoo
  • 32. Carbapenems  Imipenem has good activity against gram- negative, gram-positive and anaerobe organisms.  Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations.  It is administered with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use.  Meropenem and ertapenem are not degraded by renal dehydropeptidase.M.H.Farjoo
  • 33. Carbapenems (Cont’d)  IM ertapenem is irritating, so it is formulated with 1% lidocaine.  A carbapenem is used for P aeruginosa resistant to other drugs and mixed aerobic and anaerobic infections.M.H.Farjoo
  • 34. Miscellaneous  Miscellaneous drugs related to β-lactams are:  Beta-lactamase inhibitors Clavulanic Acid Sulbactam Tazobactam  Other cell wall or Vancomycin membrane-active agents Daptomycin Fosfomycin Bacitracin CycloserineM.H.Farjoo
  • 35. Beta-lactamase Inhibitors  They are inhibitors of many but not all bacterial β-lactamases.  Penicillin-β-lactamase inhibitor are used in empirical therapy of a wide range of pathogens.M.H.Farjoo
  • 36. Vancomycin  Vancomycin is active against gram-positives bacteria, particularly staphylococci.  β-lactamase producing staphylococci and those resistant to nafcillin and methicillin are killed.  Vancomycin kills staphylococci slowly and only if cells are actively dividing.M.H.Farjoo
  • 37. Vancomycin (Cont’d)  Vancomycin is poorly absorbed from the GI tract.  It is used orally only for antibiotic-associated enterocolitis caused by C difficile.  Metronidazole is preferred as initial therapy and vancomycin is reserved for refractory cases.  Parenteral vancomycin is ised in sepsis caused by methicillin-resistant staphylococci.M.H.Farjoo
  • 38. Vancomycin (Cont’d)  Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection.  A common reaction is "red man" or "red neck" syndrome.  This infusion-related flushing is caused by release of histamine.  It can be largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval.M.H.Farjoo
  • 39. Daptomycin  It is similar to vancomycin but is active against vancomycin-resistant enterococci and S aureus.  it appears to bind to and depolarize the cell membrane, causing potassium efflux and rapid cell death.  It can cause myopathy, and creatine phosphokinase levels should be monitored.M.H.Farjoo
  • 40. Fosfomycin  It inhibits the cytoplasmic enzyme, enolpyruvate transferase.  The drug is transported into the bacterial cell by glycerophosphate or glucose 6-phosphate transport systems.  Resistance is due to inadequate transport of drug into the cell.  Fosfomycin is active against both gram-positive and gram-negative organisms.  Fosfomycin is used for treatment of uncomplicated lower urinary tract infections in women.  The drug appears to be safe for use in pregnancy.M.H.Farjoo
  • 41. Bacitracin  There is no cross-resistance between bacitracin and other antimicrobial drugs.  Systemic bacitracin is highly nephrotoxic and is only used topically.  Bacitracin (with polymyxin or neomycin), is used for mixed bacterial flora in surface lesions of the skin or mucous membranes.M.H.Farjoo
  • 42. Cycloserine  Cycloserine is used only to treat tuberculosis resistant to first-line agents.  Cycloserine causes serious CNS toxicity with headaches, tremors, acute psychosis, and convulsions.M.H.Farjoo
  • 43. Disease or Pathogen First Choice Gram-negative cocci (aerobic) Neisseria meningitidis Penicillin Gram-positive cocci (aerobic) Streptococcus pneumoniae Penicillin Streptococcus pyogenes (group A) Penicillin Streptococcus agalactiae (group B) Penicillin (+ aminoglycoside?) Viridans streptococci Penicillin Staphylococcus aureus Beta-lactamase-negative Penicillin Enterococcus species Penicillin aminoglycoside Anaerobic bacteria Gram-positive (clostridia, Peptococcus, Penicillin Actinomyces, Peptostreptococcus) Spirochetes Leptospira species Penicillin Treponema species PenicillinM.H.Farjoo
  • 44. Disease Or Pathogen First Choice Gram-negative Rods (Aerobic) Antipseudomonal Penicillin + Pseudomonas Aeruginosa Aminoglycoside Gram-positive Cocci (Aerobic) Staphylococcus Aureus Beta-lactamase-positive Penicillinase-resistant Penicillin Gram-positive Rods (Aerobic) Listeria Species Ampicillin ( Aminoglycoside) Spirochetes Borrelia Burgdorferi Early AmoxicillinM.H.Farjoo
  • 45. Disease Or Pathogen First Choice Gram-negative Cocci (Aerobic) Moraxella (Branhamella) Cephalosporin (Second- Or Catarrhalis Third-generation) Neisseria Gonorrhoeae Ceftriaxone, Cefpodoxime Gram-negative Rods (Aerobic) Cephalosporin (First- Or Second- E Coli, Klebsiella, Proteus generation) Salmonella Cephalosporin (Third-generation) Spirochetes Borrelia Burgdorferi Late CeftriaxoneM.H.Farjoo
  • 46. Disease Or Pathogen First Choice Gram-negative Rods (Aerobic) Enterobacter, Citrobacter, Carbapenem Serratia Gram-positive Cocci (Aerobic) Staphylococcus Aureus Methicillin-resistant Vancomycin Gram-positive Rods (Aerobic) Bacillus Species (Non- Vancomycin anthracis)M.H.Farjoo
  • 47. Site Of Infection First Choice Bacterial Endocarditis Acute Vancomycin + Gentamicin Subacute Penicillin + Gentamicin Acute Otitis Media, Amoxicillin Sinusitis Cellulitis Penicillinase-resistant Penicillin Meningitis Ampicillin + Cephalosporin (Third- Neonate generation) Peritonitis Due To Ruptured Piperacillin-tazobactam Viscus Pneumonia Adult (Community-acquired) Outpatient: AmoxicillinM.H.Farjoo
  • 48. Septic arthritis Child Ceftriaxone Adult Cefazolin Cellulitis Cephalosporin (First-generation) Meningitis Ampicillin + Cephalosporin (Third- Neonate generation) Child Ceftriaxone Or Cefotaxime Vancomycin Adult Ceftriaxone, Cefotaxime Peritonitis Due To Ruptured Metronidazole + Cephalosporin (Third- Viscus generation) Pneumonia Child Ceftriaxone, Cefuroxime, Cefotaxime Inpatient: Macrolide + Cephalosporin Adult (Community-acquired) (Third-generation) Vancomycin + Cephalosporin (Third- Septicemia generation)M.H.Farjoo
  • 49. Saayeh khosh formations in Southern Iran
  • 50. Summary In English
  • 51. Thank you Any question?