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Antibiotics affecting cell wall synthesis
- 1. Antibiotics Affecting CellWall Synthesis 1 PRESENTED BY : DR ANWESHA DR DEBOSMITAA SANYAL DR MANVI AGARWAL
- 2. Cell Wall Inhibitors •Some antimicrobial drugs selectively interfere with synthesis of the bacterial cell wall-a structure that mammalian cells do not possess. • The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. 2
- 3. Cell Wall Inhibitors •To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. • The most important members of this group of drugs are the beta-lactam antibiotics (named after the beta-lactam ring that is essential to their activity) and vancomycin. 3
- 4. Classification of cellwall Inhibitors 4
- 5.
- 6. Penicillin Learning Objectives: History Classification (Natural Penicillins) Structure and Properties Mechanism of Action Antibacterial Spectrum Uses Adverse Effects 6
- 7. History Who discoveredPenicillin? 7 Alexander Fleming (1881-1955)
- 8. History Scottish biologistand pharmacologist After World War I elected Professor of Bacteriology at the University of London in 1928 Accidentally discovered Penicillin while studying properties of Staphylococci Penicillin- first antibiotic to be used clinically Mass production of the new drug for use in World War II 8
- 9. Semisynthetic Penicillins Acid Labile • Penicillin- G (Benzyl Penicillin) •Procaine penicillin-G •Benzathine penicillin- G • Penicillin- V (Phenoxymethyl penicillin) Acid Resistant Penicillinase Resistant Natural Extended Spectrum • Originally obtained from fungus Penicillium nonatum • Present source from Penicillium chrysogenum 9
- 10. Side chaincan be split off by amidase Other side chains can be attached Beta-lactamases breakdown β– lactam ring 10
- 11. Mechanism of Action Interferes with bacterial cell wall synthesis 11 PEPTIDOGLYCAN LAYER N- ACETYL MURAMIC ACID (NAM) N- ACETYL GLUCOSAMINE (NAG) AMINO ACID CHAINS
- 12. β- Lactam Antibiotic (Penicillin) TRANSPEPTIDASE CROSS-LINKING PENICILLINBINDING PROTEINS (PBPs) (ANIMATION) 12
- 13. β- Lactam Antibiotic (Penicillin) PENICILLINBINDING PROTEINS (PBPs) X - Inhibition of cross-linking 13
- 14. Mechanism of Action Cross-linking is blocked by: X- cleavage of terminal D-alanine X- transpeptidation of 5- glycine chain residues Inhibiting cell wall synthesis DAMAGES cell High osmotic pressure inside cell and low osmotic pressure outside causes cell to BURST due to a weak and unstable cell wall Bactericidal Autolysins released from penicillin-PBP complex to digest remaining cell wall remnants 14
- 15. Antibacterial Spectrum Narrowspectrum Gram positive bacteria Cocci- Streptococci, Pneumococci Bacilli- B. anthracis, C. diphtheriae Limited gram negative bacteria Cocci- Gonocci, Meningococci Actinomyces Spirochetes Treponema Leptospira 15
- 16. Uses Streptococcal Infections: Pharyngitis, Otitis Media, Scarlet Fever Rheumatic Fever Subacute Bacterial Endocarditis Pneumococcal Infections: Lobar Pneumonia Meningococcal Infections: Meningitis Gonococcal Infections: Ophthalmia Neonatorum Syphilis Leptospirosis 16
- 17. Diphtheria Tetanus Actinomycosis Prophylaxis Rheumatic Fever Bacterial Endocarditis Agranulocytosis 17
- 18. Uses Penicillin G- DRUGOF CHOICE IN: Subacute Bacterial Endocarditis Sodium PnG 10-20 MU i.v daily + Gentamicin for 2-6 weeks Ophthalmia Neonatorum Saline irrigation Sodium PnG 10,000-20,000 U/mL 1 drop in each eye every 1-3hours 18
- 19. Syphilis Early/LatentSyphilis Procaine Pn 1.2 MU i.m. daily for 10 days OR Benzathine Pn 2.4 MU i.m. weekly for 4 weeks Late Syphilis Benzathine Pn 2.4 MU weekly for 4 weeks Cardiovascular/Neurosyphilis Sodium PnG 5 MU i.m. 6 hourly for 2 weeks Leptospirosis Sodium PnG 1.5 MU i.v. 6 hourly for 7 days 19
- 20. Diphtheria Tetanusand Gas gangrene Prophylaxis Rheumatic Fever Benzathine Pn 1.2 MU every 4 weeks until 18 years of age or 5 years after attack (whichever is more) 20
- 21. Adverse Effects Hypersensitivity- rash, itching, urticaria, fever wheezing, angioneurotic edema, serum sickness, exfoliative dermatitis (less common) Anaphylaxis (rare, but fatal) 21
- 22. Adverse Effects Hypersensitivity- *Commonlyseen after PARENTERAL administration *Incidence highest with PROCAINE pn *History of penicillin allergy should be elicited *Scratch test or Intradermal Test dose - negative test does not rule out delayed hypersensitivity reactions 22
- 23. Adverse Effects Superinfections Rare with PnG Bowel, respiratory and cutaneous microflora can undergo changes Jarisch- Herxheimer Reaction Shivering, fever, myalgia, exacerbation of lesions, vascular collapse Seen in syphilitic patients injected with Penicillin Due to sudden release of spirochetal lytic products Symptomatic treatment with aspirin and sedation 23
- 24. Adverse Effects Localirritation Pain at injection site Thrombophlebitis Neurotoxicity Mental confusion, muscular twitching, convulsions, coma Bleeding Due to interference of platelet function Accidental IV procaine penicillin injection CNS stimulation, hallucinations, convulsions 24
- 25. Phenoxymethyl Penicillin PenicillinV Acid stable Given orally Plasma t½ = 30-60 min Antibacterial spectrum- same as PnG Not used for serious infections (preferred only when oral drug is to be selected) Dose- 250-500mg 6 hourly 25
- 26.
- 27. Why Semisynthetics? 27 Penicillin Ghas… 1. Poor oral efficacy 2. Susceptibility to penicillinase 3. Not stable in gastric acid; rapidly broken down in stomach 4. Narrow spectrum of activity 5. Hypersensitivity reactions
- 28. Semisynthetic Penicillins Penicillinase Resistant Extended Spectrum • Methicillin •Cloxacillin • Dicloxacillin • Ampicillin • Bacampicillin • Amoxicillin • Carbenicillin • Piperacillin • Mezlocillin Aminopenicillins Carboxypenicillins Ureidopenicillins 28
- 29. Structural Difference 29 SemisyntheticPns - produced by chemically combining specific side chains to 6-aminopenicillanic acid 6- aminopenicillanic acid
- 30. Penicillinase Resistant: Methicillin Cloxacillin Dicloxacillin 30 • Side chains protect β– Lactam ring from penicillinase (staphylococcal) • Partially protects bacteria from β– Lactam ring. Oxacillin Flucloxacillin Nafcillin
- 31. Methicillin: Highly penicillinaseresistant Acid Labile… should be administered parenterally Narrow spectrum- was used to treat certain Gram positive bacteria Induces penicillinase production Adverse effects- interstitial nephritis, hematuria, albuminuria Not in use due to resistance Replaced by other drugs in same group 31
- 32. MRSA: Methicillin Resistant StaphylococcusAureus Insensitive to penicillinase- resistant penicillins, other β–lactams as well as other antibiotics Evolved from horizontal gene transfer altered PBPs do not bind to penicillins Drugs to be used in MRSA: Vancomycin Linezolid Ciprofloxacin 32
- 33. Cloxacillin/Dicloxacillin Highly penicillinaseresistant Acid stable… can be given orally Used against staphylococcal infection EXCEPT MRSA Mostly binds to plasma proteins Dose: 0.25 – 0.5g every 6 hours 33 Oxacillin/Floxacillin Similar to cloxacillin Nafcillin Given parenterally Other side effects- oral thrush, agranulocytosis, neutropenia
- 34. Extended Spectrum: AMINO- Ampicillin Bacampacillin Amoxicillin CARBOXY- Carbenicillin UREIDO- Piperacillin Mezlocillin 34 Amino substitution in side chain Carboxylic acid group in side chain Cyclic ureas in side chain
- 35. AMPICILLIN AMOXICILLIN • AcidStable • Incomplete oral absorption -Food interference • t½ = 1 hour • Spectrum similar to PnG + S. viridans, enterococci and Listeria • Partially excreted in bile and reabsorbed -Enterohepatic circulation -Primary excretion via kidney • Acid Stable • Better oral absorption -No food interference • t½ = 1 hour • Spectrum similar to ampicillin + more active against penicillin resistant S. pneumoniae • Similar to ampicillin 35
- 36. AMPICILLIN AMOXICILLIN Uses: • UTI •Respiratory tract -Bronchitis -Otitis media -Sinusitis • Meningitis • Gonorrhea (Single dose 3.5g + 1g of probenecid) • Cholecystitis • SABE (2g i.v. 6th hourly with gentamicin) • H. pylori • Septicemia • ANUG Uses same as ampicillin • Preferred over ampicillin in many cases - Bronchitis - UTI - SABE - Gonorrhea 36
- 37. AMPICILLIN AMOXICILLIN Ampicillin +Cloxacillin • Post operative infections • Not synergistic • Irrational and harmful Adverse Effects: • Diarrhea • Rashes - HIV - EB virus infection - Lymphatic leukemia Dose • 0.5 - 2g 6th hourly (oral/i.m/i.v) Coamoxiclav • Lower incidence of diarrhea • 0.25 – 1g TID (oral/i.m/slow i.v) 37
- 38. Carbenicillin: Has activityagainst Pseudomonas and Proteus Acid Labile… should be administered parenterally t½= 1 hour Excreted rapidly in urine Uses- serious Pseudomonas or Proteus infections Can be combined with Gentamicin BUT SHOULD NOT BE MIXED IN THE SAME SYRINGE Dose- 1-2g i.m or 1-5g i.v every 4-6 hours Adverse effects- fluid retention & CHF in patients with borderline renal and cardiac function, bleeding 38
- 39. Piperacillin: Has moreactivity against Pseudomonas and Klebsiella, Enterobacteriaceae and Bacteroides Acid Labile… should be administered parenterally t½= 1 hour Excreted rapidly in urine Uses- serious Pseudomonas or Klebsiella infections like UTI Concurrent use of Gentamicin or tobramycin is advised Dose- 100-150mg/kg/day i.m/i.v in 3 divided doses Adverse effects- diarrhea, nausea, headache 39
- 40.
- 41. MECHANISM FOR ACQUIRINGRESISTANCE Reistance to penicillins and other beta lactams are due to one of four general mechanism : • Inactivation of the antibiotic by beta lactamase • Modification of target PBP’S • Impaired penetration of drugs to target PBP’S • The presence of an efflux pump. 41
- 42. CEPHALOSPORINS • Cephalosporins, closelyakin to penicillins structurally and functionally, are beta-lactam antibiotics. • Most are synthesized semi-synthetically by attaching side chains to 7-aminocephalosporanic acid. • They share the same mode of action and resistance mechanisms with penicillins but exhibit greater resistance to certain beta-lactamases. 42
- 43. A. Antibacterial spectrum •Cephalosporins have been classified as first, second, third, fourth, and fifth generation, based largely on their bacterial susceptibility patterns and resistance to beta-lactamases. 43
- 44. First generation cephalosporins •The first-generation cephalosporins act as penicillin G substitutes. • They are resistant to the staphylococcal penicillinase and also have activity against Proteus mirabilis, E. coli, and Klebsiella pneumoniae. 44
- 45. Second generation cephalosporins- •The second-generation cephalosporins display greater activity against three additional gram-negative organisms: • H. influenzae, • Enterobacter aerogenes, and • some Neisseria species, • whereas activity against gram-positive organisms is weaker 45
- 46. Third generation cephalosporins- •These cephalosporins have assumed an important role in the treatment of infectious diseases. • Although inferior to first-generation cephalosporins regarding their activity against gram-positive cocci, the third-generation cephalosporins have enhanced activity against gram-negative bacilli, as well as most other enteric organisms plus Serratia marcescens. • Ceftriaxone or cefotaxime have become agents of choice in the treatment of meningitis. 46
- 47. • Klebsiella pneumonia •Proteus mirabilis • Pseudomonas aeruginosa 47
- 48. Fourth generation cephalosporins •Cefepime is classified as a fourth-generation cephalosporin and must be administered parenterally. • Cefepime has a wide antibacterial spectrum, being active against streptococci and staphylococci. • Cefepime is also effective against aerobic gram- negative organisms, such as enterobacter, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. 48
- 49. Fifth generation cephalosporins Ceftaroline is a novel fifth-generation cephalosporin, that exhibits broad-spectrum activity against Gram-positive bacteria, including MRSA and extensively-resistant strains, such as vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and vancomycin-resistant S. aureus (VRSA). 49
- 50. B. Resistance • Mechanismsof bacterial resistance to the cephalosporins are essentially the same as those described for the penicillins. 50
- 51. C. Pharmacokinetics • Administration:Many of the cephalosporins must be administered IV or IM because of their poor oral absorption. • Distribution: All cephalosporins distribute very well into body fluids except CSF. • Fate: Biotransformation of cephalosporins by the host is not clinically important. Elimination occurs through tubular secretion and/or glomerular filtration . 51
- 52. D. Adverse effects •Allergic manifestations: Patients who have had an anaphylactic response to penicillins should not receive cephalosporins. The cephalosporins should be avoided or used with caution in individuals who are allergic to penicillins (about 5- 15 percent show cross-sensitivity). • In contrast, the incidence of allergic reactions to cephalosporins is one to two percent in patients without a history of allergy to penicillins. 52
- 53. • Nephrotoxicity maydevelop with prolonged administration, dosages should be adjusted in the presence of renal diseases. • Alcohol intolerance (a disulfiram-like reaction) has been noted with cephalosporins that contain the methyl-acetaldehyde (MTT) group, including cefamandole (no longer available in the United States), cefotetan, moxalactam, and cefoperazone. • Bleeding is also associated with agents that contain the MTT group because of anti-vitamin k effects. Administration of the vitamin corrects the problem. 53
- 54. CARBAPENEMS • Carbapenems area class of beta‐lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most beta‐lactamases. 54
- 55. • Carbapenems areone of the antibiotics of last resort for many bacterial infections, such as Escherichia coli (E. coli) and Klebsiella pneumoniae. • Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of an enzyme named NDM‐1 (New Delhi metallo‐beta‐lactamase). 55
- 56. Carbapenems The following drugsbelong to the carbapenem class: • Imipenem • Meropenem • Ertapenem • Doripenem • Panipenem/betamipron • Biapenem 56
- 57. • There arecurrently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems 57
- 58. MONOBACTAMS • The monobactams,also disrupt bacterial cell wall synthesis. • Aztreonam, which is the only commercially available monobactam, has antimicrobial activity directed primarily against the enterobacteriaceae, but it also acts against aerobic gram‐negative rods, including P.aeruginosa. • It lacks activity against gram‐positive organisms and anaerobes. This narrow antimicrobial spectrum prevent its use alone in empiric therapy. 58
- 59. • Aztreonam isresistant to the action of betalactamases. • It is administered either IV or IM and is excreted in the urine. It can accumulate in patients with renal failure. • Aztreonam is relatively nontoxic, but it may cause phlebitis. 59
- 60. • this drugmay offer a safe alternative for treating patients who are allergic to penicillins and/or cephalosporins. 60
- 61. BETA‐LACTAMASE INHIBITORS • Hydrolysisof the beta‐lactam ring, either by enzymatic cleavage with a beta‐lactamase or by acid, destroys the antimicrobial activity of a beta‐lactam antibiotic. • Beta‐Lactamase inhibitors, such as clavulanic acid, sulbactam , and tazobactam, contain a beta‐lactam ring but, by themselves, do not have significant antibacterial activity. • Instead, they bind to and inactivate beta‐lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes. 61
- 62. • The beta‐lactamaseinhibitors are therefore formulated in combination with betalactamase sensitive antibiotics. • For example, the effect of clavulanic acid and amoxicillin on the growth of betalactamase producing E. coli. 62
- 63. CLAVULANIC ACID SULBACTAMTAZOBACTAM • Streptomyces clavuligerus • β-Lactam ring present but no antibacterial activity • Inhibits a wide variety of β-Lactamases • Inhibition increases with time “progressive” • “Suicide” inhibitor Pharmacokinetics • Rapid oral absorption • t½= 1 hour • Eiminated by glomerular filtration • Combined with Amox • Related chemically to clavulanic acid • Some antibacterial activity present; too weak • Irreversible β-Lactamase inhibitor • Less potent than clavulanic acid; same inhibition with higher dose • Inconsistent oral absorption • Combined with Ampicillin • Similar to sulbactam • Antipseudomonal • Broadens spectrum of Piperacillin •Combined with Piperacillin 63
- 64. CLAVULANIC ACID SULBACTAMTAZOBACTAM COAMOXICLAV • Combined with Amox •Does not potentiate action of amox Uses: • Skin, intra-abdominal, gynecological, urinary tract, biliary tract and resp tract infections Dose: 250mg + 125mg tab 500mg + 125mg tab 1g + 0.2g vial deep i.m/i.v Adverse Effects: • Poor GI tolerance • Candida infections • Combined with Ampicillin Uses: • PPNG gonorrhea • Intra-abdominal infections •Gynecological •Skin/soft tissue infections Dose: 1g + 0.5g vial (1-2 vials Deep i.m/i.v 6-8th hourly Adverse Effects: • Pain at site of injection • Thrombophlebitis • Diarrhea • Combined with Piperacillin • Combined with ceftriaxone also Dose: 4g + 0.5g iv over 30min, 8th hourly 64
- 65. VI. Vancomycin • Vancomycinis a tricyclic glycopeptide • It has become increasingly important because of its effectiveness against multiple drug‐resistant organisms, such as Methicillin-resistant Staphylococcus aureus(MRSA )and enterococci. 65
- 66. A. Mode ofaction • Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization, • This weakens the cell wall and damages the underlying cell membrane. 66
- 67. B. Antibacterial spectrum •Vancomycin is effective primarily against gram‐positive organisms . • It has been lifesaving in the treatment of MRSA and methicillin‐resistant Staphylococcus epidermidis (MRSE) infections as well as enterococcal infections. 67
- 68. Antibacterial spectrum • Vancomycinacts synergistically with the aminoglycosides, and this combination can be used in the treatment of enterococcal endocarditis. 68
- 69. C. Resistance • Vancomycinresistance can be caused by plasmid‐mediated changes in permeability to the drug or by decreased binding of vancomycin to receptor molecules. 69
- 70. D. Pharmacokinetics • SlowIV infusion is employed for treatment of systemic infections or for prophylaxis. • Metabolism of the drug is minimal, and 90 to 100 percent is excreted by glomerular filtration. • The normal half‐life of vancomycin is 6 to 10 hours 70
- 71. E. Adverse effects •Side effects are a serious problem with vancomycin and include local pain and/or phlebitis at the infusion site. • Flushing(red man syndrome ) results from histamine release associated with a rapid infusion. • Ototoxicity and nephrotoxicity are more common when vancomycin is administered with another drug (for example, an aminoglycoside) that can also produce these effects. 71
- 72. CONCLUSION Antibiotics thattarget cell wall inhibition play a crucial role in the treatment of bacterial infections. These antibiotics exert their effects by interfering with the synthesis or integrity of the bacterial cell wall, which is essential for bacterial survival. The most common class of cell wall inhibitors is the beta-lactam antibiotics, which includes penicillins, cephalosporins, and carbapenems. 72
- 73. These antibioticsare effective against a wide range of bacteria, including both gram-positive and some gram-negative bacteria. They are commonly used to treat infections such as pneumonia, skin infections, and urinary tract infections. However, it is important to note that bacteria can develop resistance to these antibiotics through various mechanisms 73