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Antibiotics inhibiting cell wall synthesis- All you need to know, by RxVichuZ!

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This is my 52nd powerpoint...deals with various drugs that inhibit cell-wall synthesis, their spectrum of activity, ADRs & important applications in infections. Newer molecules have also been elucidated here.

HAPPY READING!!

Published in: Health & Medicine
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Antibiotics inhibiting cell wall synthesis- All you need to know, by RxVichuZ!

  1. 1. PRESENTED BY, VISHNU.R.NAIR, 5TH YER PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).
  2. 2. GENERAL INTRODUCTION
  3. 3. - Here, primarily, important catchpoints on the following will be made: A. BETA-LACTAM ANTIBIOTICS B. BETA-LACTAMASES C. OTHER CELL-WALL SYNTHESIS INHIBITORS. - Very precise insight into individual drugs, their do’s and dont’s & special information has been elucidated - For extensive insight, substantial referring of textbooks is advised!!! HAPPY READING!!!
  4. 4. BETA-LACTAM ANTIBIOTICS
  5. 5. Consist of drugs, that contain BETA-LACTAM RING in their structure Act, by inhibiting cell-wall synthesis Include: A. PENICILLINS B. CEPHALOSPORINS C. MONOBACTAMS D. CARBAPENEMS
  6. 6.  All BETA-LACTAM antibiotics are BACTERICIDAL in nature  Drugs  bind to specific receptors on bacterial cell membrane(Penicillin Binding Proteins, PBPs)  inhibit TRANSPEPTIDASE enzyme  prevents CROSS- LINKING of PEPTIDOGLYCAN chains  Bacteria formed in the presence of beta-lactams  lack CELL-WALL  Since cell-wall is vital for providing rigidity to the cell  lack of cell-wall in susceptible bacteriae causes IMBIBITION of water  causes death of susceptible organisms!  Bacteria like MYCOPLASMA  lack CELL-WALL  thus, INTRINSICALLY RESISTANT TO BETA-LACTAMS & VANCOMYCIN!!
  7. 7. PENICILLINS
  8. 8.  PENICILLIN G  commercially obtained from Penicillium chrysogenum  PENICILLIN G  only NATURAL OCCURRING PENICILLIN!!!  Important limitations of clinical use of Penicillin G include: 1. Drug  undergoes rapid breakdown by acid inside stomach  hence, NOT EFFECTIVE ORALLY! 2. Drug  rapidly excreted from kidney, via TUBULAR SECRETION  thus, has SHORT DURATION OF ACTION! 3. Drug  covers mainly GRAM-POSITIVE BACTERIA  has NARROW SPECTRUM OF ACTIVITY! 4. Most of the Gram-positive bacteria have become resistant to Penicillin G, due to the following reasons: a. Development of BETA-LACTAMASE(penicillinase) b. Development of altered PBPs!! 5. Penicillin G  can cause severe hypersensitivity reactions!!
  9. 9.  To overcome above shortcomings of Penicillin G  newer penicillins have been designed!  STRATEGIES to overcome Penicillin G shortcomings: a. Development of ACID-RESISTANT PENICILLINS: - Pn G(Penicillin G) is not effective orally due to high acid lability - Newer penicillins have been developed that are ACID-RESISTANT  thus can be given orally! - Include OXACILLIN, PENICILLIN V, DICLOXACILLIN, CLOXACILLIN, AMOXICILLIN, AMPICILLIN, etc b. Pn G is SHORT-ACTING. Strategies to overcome this problem include: - Addition of BENZATHINE/ PROCAINE group to Pn G  can make it long-acting - BENZATHINE PN G  longest-acting penicillin! - PROBENECID  if given with Penicillin G  tubular secretion of latter will be inhibited!
  10. 10. - Since Pn G has WIDE THERAPEUTIC INDEX  HIGH INITIAL doses of drug can be used!! c. Strategy, to overcome narrow-spectrum activity of Pn G: - Several new penicillins, with extended-spectrum have been developed - Include AMINOPENICILLINS, CARBOXYPENICILLINS, UREIDOPENICILLINS d. Strategy to overcome resistance issues with Penicillin G: - Beta-lactamase inhibitors  if added to Penicillin G  causes inhibition of bacterial enzyme  penicillins escape degradation! - Administration of PENICILLINASE-RESISTANT PENICILLINS, like CLOXACILLIN OXACILLIN, NAFCILLIN, DICLOXACILLIN & METHICILLIN.
  11. 11. e. Strategies, to prevent risk of hypersensitivity with Pn G: - Hypersensitivity reactions can occur with ANY PENICILLIN - PENICILLINS  most common drugs responsible for ANAPHYLACTIC SHOCK - If a person is severely allergic to any penicillin  NO BETA-LACTAM ANTIBIOTIC SHOULD BE ADMINISTERED TO THAT PERSON!!(Except AZTREONAM) - To prevent severe allergic reactions  INTRA-DERMMAL SKIN TESTING can be opted!
  12. 12. HOW TO REMEMBER NAMES OF ACID-RESISTANT PENICILLINS??? USE THE CODE “VODKA”!! “V”: Penicillin V “O”: Oxacillin “D”: Dicloxacillin “K”: Cloxacillin “A”: Amoxicillin, ampicillin!!
  13. 13. HOW TO REMEMBER THE NAMES OF PENICILLINASE- RESISTANT PENICILLINS?? USE THE CODE: “CONDOM”!! “C”: Cloxacillin “O”: Oxacillin “N: Nafcillin “DO”: Dicloxacillin “M”: Methicillin!!
  14. 14. HOW TO REMEMBER NAMES OF EXTENDED- SPECTRUM PENICILLINS?? USE THE CODE: “ACT MAP”!! 1. AMINOPENICILLINS: “A”: Ampicillin, amoxicillin 2. CARBOXYPENICILLINS: “C”: Carbenicillin “T” : Ticarcillin 3. UREIDOPENICILLINS: “M”: Mezlocillin “A”: Azlocillin “P”: Piperacillin!!
  15. 15. All extended-spectrum penicillins  effective against Gram- negative bacteria like E.coli, salmonella, shigella(except AMOXICILLIN!!) CT-MAP Penicillins  effective against PSEUDOMONAS!! MAP-penicillins  effective against KLEBSIELLA!!
  16. 16. PHARMACOKINETICS: - 1 gram of PENICILLIN  equivalent to 1.6 million units - Gastric acid  breaks down penicillins  results in reduced oral bioavailability - Pn G  used ORALLY only for those infections, in which clinical experience has proven efficacy! - AMPICILLIN & NAFCILLIN  excreted partly in bile - Benzyl penicillin is given by i.m injection - Drug  has short t1/2 thus given 6-12 hourly - Procaine & benzathine penicillin are LONG-ACTING(due to slow release)
  17. 17. CLINICAL USES OF DIFFERENT PENICILLINS: A. PENICILLIN G: - DOC for SYPHILIS - Role of BENZATHINE PENICILLIN in SYPHILIS: i. For PRIMARY, SECONDARY & EARLY LATENT SYPHILIS : 2.4 million units i.m, as single dose ii. For LATE LATENT & TERTIARY SYPHILIS: Duration of treatment is 3 weeks(once weekly!) - DOC for NEUROSYPHILIS: Aq. Pn G(Since benzathine Pn has little CNS permeability) - Given also, for GRAM(+) cocci, MENINGOCOCCI, etc - Most staphylococci & gonococci are now resistant - Effective against ANAEROBES (except Bacteroides)!
  18. 18. B. METHICILLIN, NAFCILLIN, OXACILLIN & CLOXACILLIN: - Although mainly given for S.aureus infections  resistant organisms have been isolated - MRSA  developed, due to formation of ALTERNATIVE PBPs  possess less affinity for drugs - In cases of MRSA  treatment of choice is VANCOMYCIN/ TEICOPLANIN - In case of VANCOMYCIN resistance(VRSA)  treatment of choice is LINEZOLID/ STREPTOGRAMINS.
  19. 19. C. AMPICILLIN, AMOXICILLIN: - Wide-spectrum, penicillinase-sensitive antibiotics - In addition to Gram (+) organisms  they are also effective against: i. Enterococci ii. Listeria iii. Hemophilus organisms! - Activity of above drugs  enhanced, when used in combination with BETA- LACTAMASE INHIBITORS(sulbactam, clavulanic acid). - Special uses of AMPICILLIN: i. DOC for Listeria meningitis(cephalosporins are ineffective here!) ii. DOC for UTI caused by E.faecalis.
  20. 20. D. PIPERACILLIN, TICARCILLIN, CARBENICILLIN, AZLOCILLIN, MEZLOCILLIN: - Possess activity against GRAM-NEGATIVE RODS (including Pseudomonas species!) - Used along with BETA-LACTAMASE INHIBITORS & along with AMINOGLYCOSIDES - UREIDOPENICILLINS  highly effective against KLESIELLA species!!
  21. 21. HOW TO REMEMBER IMPORTANT USES OF PENICILLIN G(DOC)??? USE THE CODE : “LAST MAN”!!! “L” : Leptospira “A”: Actinomyces “S”: Streptococcus, staphylococcus(non-penicillinase producing) “T”: Treponema, Tetanus(also gas gangrene!) “M”: Meningococcus “AN”: Anthrax(Ciprofloxacin is also 1st line agent!)
  22. 22. TOXICITY ISSUES WITH PENICILLINS: 1. HYPERSENSITIVITY REACTIONS: - Serum sickness - Anaphylaxis - It is MANDATORY to conduct INTRA-DERMAL SENSITIVITY TESTING before giving PENICILLINS! - If a patient develops hypersensitivity reaction to Penicillins  ALL OTHER BETA-LACTAM ANTIBIOTICS are CONTRAINDICATED(except AZTREONAM!!!) 2. AMPICILLIN  if used in patients with viral diseases like “infectious mononucleosis”  can cause development of MACULOPAPULAR SKIN RASHES! 3. METHICILLIN  can cause ACUTE INTERSTITIAL NEPHRITIS 4. NAUSEA & DIARRHEA with oral drugs like AMOXICILLIN & AMPICILLIN
  23. 23. 5. AMPICILLIN  incompletely absorbed  causes increased suppression of normal microbial flora  can cause higher incidence of DIARRHEA! 6. AMPICILLIN  can also cause PSEUDOMEMBRANOUS COLITIS 7. PROCAINE PENICILLIN  given in high doses  can cause SEIZURES & CNS ABNORMALITIES 8. OXACILLIN  can cause HEPATITIS 9. NAFCILLIN  can cause NEUTROPENIA 10. CARBENICILLIN  given in high dose  can cause BLEEDING!
  24. 24. CEPHALOSPORINS
  25. 25. BETA-LACTAM antibiotics, having 7- AMINOCEPHALOSPORANIC ACID nucleus Classified into 5 generations.
  26. 26. CEPHALOSPORIN GENERATION ORAL PARENTERAL FIRST Cephalexin, cefadroxil, cephradine Cefazolin SECOND Cefaclor, cefuroxime axetil, loracarbef, cefprozil Cefuroxime, cefotetan, cefoxitin, cefmetazole THIRD Cefixime, cefopodoxime, ceftibuten, cefditoren, cefdinir Ceftriaxone, cefoperazone, ceftizoxime, cefotaxime, ceftazidime, moxalactam FOURTH Cefepime, cefpirome FIFTH Ceftaroline fosamil, ceftobiprole, ceftolozane.
  27. 27. PHARMACOKINETICS: - Most cephalosporins  excreted via kidney through TUBULAR SECRETION - CEFOPERAZONE & CEFTRIAXONE  secreted in the BILE - Nephrotoxicity of cephalosporins  enhanced with concurrent use of LOOP DIURETICS!
  28. 28. SPECIAL USES & IMPORTANT FEATURES OF CEPHALOSPORIN GENERATIONS: A. FIRST-GENERATION CEPHALOSPORINS: - Active against Gram(+) cocci, including STAPHYLOCOCCI - MRSA is resistant to cephalosporins as well! - DOC for SURGICAL PROPHYLAXIS : CEFAZOLIN!
  29. 29. B. SECOND-GENERATION CEPHALOSPORINS: - Has less activity against Gram(+) organisms(compared to 1st generation) - Extended Gram(-) coverage - Drugs active against BACTEROIDES FRAGILIS(anaerobe): i. Cefotetan ii. Cefmetazole iii. Cefoxitin. - CEFUROXIME  attains higher CSF levels (compared to other 2nd generation drugs)  thus, can be used for BACTERIAL MENINGITIS!(Ceftriaxone is preferred as empirical, though). - LORACARBEF  chemically similar to CEFACLOR
  30. 30. C. THIRD GENERATION CEPHALOSPORINS: - Active against GRAM-NEGATIVE ORGANISMS(resistant to other BETA- LACTAM ANTIBIOTICS) - Penetrate BBB easily (except CEFOPERAZONE & CEFIXIME) - Third-generation drugs, active against PSEUDOMONAS: i. Cefoperazone ii. Ceftazidime(most active, when used along with aminolglycosides!) - CEFTAZIDIME  DOC for MELIOIDOSIS (caused by Burkholderia pseudomallei) - CEFTIZOXIME  has maximum activity against BACTEROIDES! - CEFOTAXIME  metabolized to an active metabolite (desacetyl-cefotaxime)
  31. 31. - CEFTRIAXONE: • FIRST-CHOICE DRUG for: a. Gonorrhea b. Salmonellosis(including typhoid) c. E.coli sepsis d. Proteus species e. Serratia f. Hemophilus g. Bacterial meningitis(empirical therapy). • Long-term use of > 2g/day of CEFTRIAXONE can result in : a. Biliary sludging syndrome b. Cholelithiasis(due to drug precipitation in bile).
  32. 32. D. FOURTH-GENERATION CEPHALOSPORINS: - Possess activity against Gram(-ve) organisms(including PSEUDOMONAS), resistant to 3rd generation ones! - Efficacy against G(+) cocci  similar as that of 3rd generation ones! - Inactive against ANAEROBES!
  33. 33. E. FIFTH-GENERATION CEPHALOSPORINS: - Indicated for CAP & MRSA infections - Ceftolozane & ceftobiprole  also effective against PSEUDOMONAS!!
  34. 34. TOXICITY ISSUES WITH CEPHALOSPORINS: 1. Hypersensitivity reactions 2. Drugs, containing METHYLTHIOTETRAZOLE group can cause HYPOPROTHROMBINEMIA & DISULFIRAM-LIKE REACTION with ALCOHOL, that include: - Cefamandole - Cefoperazone - Moxalactam - Cefotetan 3. CEFTAZIDIME  can cause NEUTROPENIA!! 4. LORACARBEF  in high doses  can cause SEIZURES!
  35. 35. MONOBACTAMS
  36. 36.  Includes AZTREONAM  Active against GRAM-NEGATIVE RODS(including Pseudomonas)  Inactive against Gram-positive organisms/anaerobes  Given i.v  T1/2 prolonged in renal failure  ONLY BETA-LACTAM ANTIBIOTIC, that can be used in patients having SEVERE ALLERGY TO PENICILLINS/ CEPHALOSPORINS(since it is not cross-allergenic!!)
  37. 37. CARBAPENEMS
  38. 38.  Includes: a. Imipenem b. Meropenem c. Doripenem d. Ertapenem • Have wide activity against: a. Gram (+) cocci b. Gram (-) rods c. Anaerobes.
  39. 39.  MEROPENEM  most active against PSEUDOMONAS  ERTAPENEM  least active against PSEUDOMONAS  CARBAPENEMS  BETA-LACTAMASE RESISTANT!!  For activity against Pseudomonas infections  carbapenems should be given in combination with AMINOGLYCOSIDES!!  DOC for : i. Enterobacter ii. Klebsiella iii. Acinobacter species • Since CARBAPENEMS are the ONLY BETA-LACTAM ANTIBIOTICS that are efficacious against ESBL(Extended Spectrum Beta-Lactamases)  they are also DOC for ESBL-producing bacteria!!
  40. 40.  IMIPENEM  rapidly inactivated by RENAL DEHYDROPEPTIDASE I  thus given in combination with CILASTATIN(cilastatin inhibits this enzyme)!  Additional benefits of CILASTATIN when given with IMIPENEM: a. Cilastatin  increases t1/2 of imipenem b. Cilastatin  prevents formation of nephrotoxic metabolite • Main ADRs of IMIPENEM-CILASTATIN combination: a. Seizures b. GI distress. • MEROPENEM, DORIPENEM & ERTAPENEM  not metabolized by RENAL DEHYDROPEPTIDASE  less risk of SEIZURES!! • ERTAPENEM  very long-acting!!
  41. 41. BETA-LACTAMASES
  42. 42. Refer to “enzymes, that HYDROLYZE beta-lactam antimicrobials, by acting on BETA-LACTAM ring” There are 2 basic types of BETA-LACTAMASE classifications: A. MOLECULAR CLASSIFICATION(AMBER CLASSIFICATION): - Based on STRUCTURE(amino acid sequence) - Classified into 4 categories: A,B,C & D - Class “A”, “D” & “C” enzymes  require serine residue to hydrolyze beta-lactams - Class “B” enzymes  require ZINC IONS  hence also known as “METALLO-BETA LACTAMASES”!
  43. 43. B. FUNCTIONAL CLASSIFICATION(BUSH CLASSIFICATION): - Based on the type of SUBSTRATE of BETA- LACTAMASE(i.e, which beta-lactam is hydrolyzed) - Also takes into consideration whether THE ENZYME IS INHIBITED BY CLAVULANIC ACID(CA)/ OTHER DRUGS
  44. 44. BETA-LACTAMASE MOLECULAR GROUP INHIBITED BY SUBSTRATES CEPHALOSPORINASE C NONE Cephalosporins, aztreonam SERINE BETA- LACTAMASES A/D CA & TZB PENICILLINASE A CA & TZB Penicillin G & early cephalosporins ESBL A CA & TZB Penicillins, cephalosporins(NOT CARBAPENEMS!) CARBENICILLINASE A CA & TZB Cloxacillin, oxacillin OXACILLINASE A/D CA & TZB Cloxacillin, oxacillin, most cephalosporins(not aztreonam), carbapenems, cefamycins, etc METALLO-BETA LACTAMASES B EDTA Carbapenems
  45. 45. EXTENDED-SPECTRUM BETA-LACTAMASES: A BRIEF INSIGHT: - Enzymes , that offer resistance to MOST BETA-LACTAM antibiotics (Penicillins, cephalosporins, monobactams) - Mainly found in G(-ve) organisms, like KLEBSIELLA & E.coli - Important features include: a. Can be inhibited by CLAVULANIC ACID/TAZOBACTAM b. Can hydrolyze: i. Penicillins ii. Cephalosporins iii. Monobactams
  46. 46. c. Cannot hydrolyze: - CEFAMYCINS(Cefoxitin, cefotetan, cefmetazole) - CARBAPENEMS d. CARBAPENEMS  DOC for infections caused by bacteria producing ESBL!!
  47. 47. BETA-LACTAMASE INHIBITORS
  48. 48.  Include: 1. Clavulanic acid 2. Sulbactam 3. Tazobactam 4. Vaborbactam • More active against PLASMID-ENCODED BETA-LACTAMASES(produced by gonococci & E.Coli), than against INDUCIBLE CHROMOSOMAL BETA- LACTAMASES(produced by PSEUDOMONAS & ENTEROBACTER)! • AMOXICILLIN  combined with clavulanic acid • AMPICILLIN  combined with SULBACTAM • PIPERACILLIN  combined with TAZOBACTAM
  49. 49.  CEFTAZIDIME-AVIBACTAM combination  FDA-approved for : a. Complicated UTI (including PYELONEPHRITIS) b. Complicated intra-abdominal infections • MEROPENEM-VABORBACTAM  new combination, approved for COMPLICATED UTI!!!
  50. 50. OTHER CELL-WALL SYNTHESIS INHIBITORS
  51. 51.  Includes: 1. GLYCOPEPTIDES 2. FOSFOMYCIN 3. BACITRACIN 4. CYCLOSERINE
  52. 52. GLYCOPEPTIDES
  53. 53.  Includes: 1. Vancomycin 2. Teicoplanin 3. Oritavancin 4. Telavancin 5. Dalbavancin
  54. 54. A. VANCOMYCIN: - Drug  inhibits “bacterial transglycosylase enzyme”  prevents CHAIN ELONGATION  causes inhibition of bacterial cell-wall synthesis - Narrrow-spectrum antibiotic - Mainly effective against G(+ve) organisms, including MRSA, pneumococci & C.difficile - Generally administered via i.v route - Excreted unchanged in urine - Rapid i.v infusion of high doses of Vancomycin  results in RED MAN SYNDROME(diffuse flushing, due to HISTAMINE release) - Vancomycin  not absorbed from GIT  thus higher concentration of drug can reach the colon  thus it can BE USED ORALLY FOR THE TREATMENT OF PSEUDOMEMBRANOUS COLITIS
  55. 55.  Toxic effects of vancomycin include: 1. Chills 2. Ototoxicity 3. Nephrotoxicity • Dose should be reduced in RENAL FAILURE • In VANCOMYCIN RESISTANCE(to S.aureus & Enterococci) terminal ALANINE-ALANINE is replaced by ALANINE-LACTATE(of peptidoglycan)  this reduces affinity of drug for TRANSGLYCOSYLASE. • Vancomycin is DOC for: 1. MRSA 2. Corynebacterium jeikeium 3. Serious infection in PENICILLIN-ALLERGIC PATIENTS!!
  56. 56. B. TEICOPLANIN: - Similar features as that of vancomycin - Given once daily, due to long half-life(45-70 hours) - Given by either i.v/i.m route - Excreted unchanged in urine - Does not cause RED MAN SYNDROME/NEPHROTOXICITY!! C. ORITAVANCIN: - Newer glycopeptide - Used for MRSA infections!
  57. 57. D. TELAVANCIN: - Approved for COMPLICATED SKIN & SKIN STRUCTURE INFECTIONS - Effective against MRSA - Other than that of vancomycin MOA  it also DISRUPTS MEMBRANE POTENTIAL of susceptible organisms!! E. DALBAVANCIN: - Given as ONCE-WEEKLY DRUG - Same mechanism as vancomycin - Additional benefits: Effective against MRSA & VRSA!!!!
  58. 58. FOSFOMYCIN
  59. 59. - Drug  inhibits ENOLPYRUVATE TRANSFERASE  prevents cell-wall synthesis - Most-common ADR: Diarrhea - DOC(along with NTU) for UNCOMOLICATED UTI!!
  60. 60. BACITRACIN
  61. 61. Potent cell-wall synthesis inhibitor Due to high risk of NEPHROTOXICITY  indicated ONLY FOR TOPICAL USE! Selectively active against G(+ve) bacteria!
  62. 62. CYCLOSERINE
  63. 63. Causes NEUROTOXICITY(tremors, seizures) Can also precipitate NEUROPSYCHIATRIC MANIFESTATIONS One of the second-line agent for treatment of TUBERCULOSIS!
  64. 64. CONCLUSION: - Basically, drugs that inhibit BACTERIAL CELL-WALL SYNTHESIS has been explained here - Summarized names/classes of drugs include: a. BETA-LACTAM ANTIBIOTICS(Penicillins, cephalosporins, monobactams, carbapenems) b. GLYCOPEPTIDE ANTIBIOTICS c. FOSFOMYCIN d. BACITRACIN e. CYCLOSERINE!
  65. 65. THANK YOU!!!!

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