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ANTIBIOTICS INHIBITING CELL-WALL SYNTHESIS: ALL YOU NEED TO KNOW

ANTIBIOTICS INHIBITING CELL-WALL SYNTHESIS: ALL YOU NEED TO KNOW. PRESENTED BY, VISHNU.R.NAIR, 5 TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP). GENERAL INTRODUCTION. Here, primarily, important catchpoints on the following will be made: BETA-LACTAM ANTIBIOTICS BETA-LACTAMASES

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ANTIBIOTICS INHIBITING CELL-WALL SYNTHESIS: ALL YOU NEED TO KNOW

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  1. ANTIBIOTICS INHIBITING CELL-WALL SYNTHESIS: ALL YOU NEED TO KNOW PRESENTED BY, VISHNU.R.NAIR, 5TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).

  2. GENERAL INTRODUCTION

  3. Here, primarily, important catchpoints on the following will be made: • BETA-LACTAM ANTIBIOTICS • BETA-LACTAMASES • 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. BETA-LACTAM ANTIBIOTICS

  5. Consist of drugs, that contain BETA-LACTAM RING in their structure • Act, by inhibiting cell-wall synthesis • Include: • PENICILLINS • CEPHALOSPORINS • MONOBACTAMS • CARBAPENEMS

  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. PENICILLINS

  8. PENICILLIN G  commercially obtained from Penicillium chrysogenum • PENICILLIN G  only NATURAL OCCURRING PENICILLIN!!! • Important limitations of clinical use of Penicillin G include: • Drug  undergoes rapid breakdown by acid inside stomach  hence, NOT EFFECTIVE ORALLY! • Drug  rapidly excreted from kidney, via TUBULAR SECRETION  thus, has SHORT DURATION OF ACTION! • Drug  covers mainly GRAM-POSITIVE BACTERIA  has NARROW SPECTRUM OF ACTIVITY! • Most of the Gram-positive bacteria have become resistant to Penicillin G, due to the following reasons: • Development of BETA-LACTAMASE(penicillinase) • Development of altered PBPs!! 5. Penicillin G  can cause severe hypersensitivity reactions!!

  9. To overcome above shortcomings of Penicillin G  newer penicillins have been designed! • STRATEGIES to overcome Penicillin G shortcomings: • 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. 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. 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. 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. HOW TO REMEMBER THE NAMES OF PENICILLINASE-RESISTANT PENICILLINS?? USE THE CODE: “CONDOM”!! “C”: Cloxacillin “O”: Oxacillin “N: Nafcillin “DO”: Dicloxacillin “M”: Methicillin!!

  14. HOW TO REMEMBER NAMES OF EXTENDED-SPECTRUM PENICILLINS?? USE THE CODE: “ACT MAP”!! • AMINOPENICILLINS: “A”: Ampicillin, amoxicillin 2. CARBOXYPENICILLINS: “C”: Carbenicillin “T” : Ticarcillin 3. UREIDOPENICILLINS: “M”: Mezlocillin “A”: Azlocillin “P”: Piperacillin!!

  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. 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. CLINICAL USES OF DIFFERENT PENICILLINS: • PENICILLIN G: • DOC for SYPHILIS • Role of BENZATHINE PENICILLIN in SYPHILIS: • For PRIMARY, SECONDARY & EARLY LATENT SYPHILIS : 2.4 million units i.m, as single dose • 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. 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. C. AMPICILLIN, AMOXICILLIN: • Wide-spectrum, penicillinase-sensitive antibiotics • In addition to Gram (+) organisms  they are also effective against: • Enterococci • Listeria • Hemophilus organisms! • Activity of above drugs  enhanced, when used in combination with BETA-LACTAMASE INHIBITORS(sulbactam, clavulanic acid). • Special uses of AMPICILLIN: • DOC for Listeria meningitis(cephalosporins are ineffective here!) • DOC for UTI caused by E.faecalis.

  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. 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. TOXICITY ISSUES WITH PENICILLINS: • 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. 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. CEPHALOSPORINS

  25. BETA-LACTAM antibiotics, having 7-AMINOCEPHALOSPORANIC ACID nucleus • Classified into 5 generations.

  26. 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!

  27. SPECIAL USES & IMPORTANT FEATURES OF CEPHALOSPORIN GENERATIONS: • FIRST-GENERATION CEPHALOSPORINS: • Active against Gram(+) cocci, including STAPHYLOCOCCI • MRSA is resistant to cephalosporins as well! • DOC for SURGICAL PROPHYLAXIS : CEFAZOLIN!

  28. B. SECOND-GENERATION CEPHALOSPORINS: • Has less activity against Gram(+) organisms(compared to 1st generation) • Extended Gram(-) coverage • Drugs active against BACTEROIDES FRAGILIS(anaerobe): • Cefotetan • Cefmetazole • 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

  29. 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: • Cefoperazone • Ceftazidime(most active, when used along with aminolglycosides!) • CEFTAZIDIME  DOC for MELIOIDOSIS (caused by Burkholderiapseudomallei) • CEFTIZOXIME  has maximum activity against BACTEROIDES! • CEFOTAXIME  metabolized to an active metabolite (desacetyl-cefotaxime)

  30. CEFTRIAXONE: • FIRST-CHOICE DRUG for: • Gonorrhea • Salmonellosis(including typhoid) • E.coli sepsis • Proteus species • Serratia • Hemophilus • Bacterial meningitis(empirical therapy). • Long-term use of > 2g/day of CEFTRIAXONE can result in : • Biliary sludging syndrome • Cholelithiasis(due to drug precipitation in bile).

  31. 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!

  32. E. FIFTH-GENERATION CEPHALOSPORINS: • Indicated for CAP & MRSA infections • Ceftolozane & ceftobiprole  also effective against PSEUDOMONAS!!

  33. TOXICITY ISSUES WITH CEPHALOSPORINS: • Hypersensitivity reactions • 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!

  34. MONOBACTAMS

  35. 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!!)

  36. CARBAPENEMS

  37. Includes: • Imipenem • Meropenem • Doripenem • Ertapenem • Have wide activity against: • Gram (+) cocci • Gram (-) rods • Anaerobes.

  38. 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 : • Enterobacter • Klebsiella • 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!!

  39. 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: • Cilastatin increases t1/2 of imipenem • Cilastatin  prevents formation of nephrotoxic metabolite • Main ADRs of IMIPENEM-CILASTATIN combination: • Seizures • GI distress. • MEROPENEM, DORIPENEM & ERTAPENEM  not metabolized by RENAL DEHYDROPEPTIDASE  less risk of SEIZURES!! • ERTAPENEM  very long-acting!!

  40. BETA-LACTAMASES

  41. Refer to “enzymes, that HYDROLYZE beta-lactam antimicrobials, by acting on BETA-LACTAM ring” • There are 2 basic types of BETA-LACTAMASE classifications: • 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”!

  42. 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

  43. 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: • Can be inhibited by CLAVULANIC ACID/TAZOBACTAM • Can hydrolyze: • Penicillins • Cephalosporins • Monobactams

  44. c. Cannot hydrolyze: • CEFAMYCINS(Cefoxitin, cefotetan, cefmetazole) • CARBAPENEMS d. CARBAPENEMS  DOC for infections caused by bacteria producing ESBL!!

  45. BETA-LACTAMASE INHIBITORS

  46. Include: • Clavulanic acid • Sulbactam • Tazobactam • 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

  47. CEFTAZIDIME-AVIBACTAM combination  FDA-approved for : • Complicated UTI (including PYELONEPHRITIS) • Complicated intra-abdominal infections • MEROPENEM-VABORBACTAM  new combination, approved for COMPLICATED UTI!!!

  48. OTHER CELL-WALL SYNTHESIS INHIBITORS

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