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Antimicrobials 1
- 1. Antimicrobials-1 (Cell wall inhibitors) Dr. M. Ahsan (MBBS, MD)
- 2. Beta-lactam antibiotics • Antibiotics which contain a beta-lactam ring are called beta-lactam antibiotics • Penicillins • Cephalosporins • Monobactams • Carbapenems
- 3. Penicillins • Penicillin was discovered was Alexander Fleming (1928) • Antibacterial effect was analysed by Florey & Chain (1940) • Used clinically for the first time in 1941 • Initial source: Penicillium notatatum • Commercial source: P. chrysogenum • Penicillin in an extremely effective antibiotic and remarkably non- toxic (safe even in pregnancy)
- 5. Penicillin units • Unitage: • 1 U of crystalline sod. Benzyl penicillin = 0.6 of standard preparation • 1g = 1.6 million units • 1 MU = 0.6 g
- 6. Classification • Natural penicillin: Penicillin G (benzyl Pn) • Acid resistant alternative to Penicillin G: Penicillin V (Phenoxymethyl Pn) • Penicillinase resistant penicillins: Methicillin, Cloxacillin, Flucloxacillin, Dicloxacillin • Extended spectrum penicillins: a. Aminopenicillins : Amoxicillin, Ampicillin, Bacampicillin b. Carboxypenicillins: Carbenicillin, Ticarcillin c. Ureidopenicillins: Piperacillin, Mezlocillin
- 7. Mechanism of action • Beta-lactam antibiotics interfere with cell wall synthesis • In presence of beta-lactam antibiotics, cell wall deficient forms are formed which swell and burst…..Bactericidal • Rapidly multiplying bacteria are more susceptible • Beta-lactam antibiotics inhibit the enzyme transpeptidase so that cross-linking does not take place
- 8. Cell wall inhibitors Drug Mechanism/enzyme inhibited Process inhibited Fosfomycin Enolpyruvate transferase Conversion of UDP-NAG to UDP-NAM Cycloserine Alanine racemase and alanine ligase Formation of pentapeptide Bacitracin Dephosphorylation of bactoprenol Regeneration of bactoprenol Vancomycin Transglycosylase Chain elongation/polymerization Beta-lactam antibiotics Transpeptidase Polymeric cross-linking lattice work
- 9. Resistance Many bacteria are inherently insensitive to PnG because the PBPs and target enzymes are located deep under lipoprotein barrier or have low affinity for PnG Mechanism of acquired resistance: • Production of beta-lactamase • Altered penicillin-binding site • Decrease in permeability of the outer membrane
- 10. Antibacterial spectrum Gram +ve cocci: Streptococcus pyogenes, Pneumococci, Staphylococcus aureus (resistant), Enterococcus faecalis and anaerobic Streptococci (less sensitive) Gram –ve cocci: N. meningitides, N. gonorrhoeae (resistant) Gram +ve bacilli: Bacillus anthracis, corynebacterium diphtheria, Clostridium tetani, Cl. perfringens, Listeria monocytogenes
- 11. Antibacterial spectrum Gram –ve bacilli: No activity Other organisms: Actinomycetes, Spirochaetes such as treponema pallidum, Leptospira, Borrelia bugrdorferi
- 12. Pharmacokinetics of PnG • PnG is destroyed by gastric acid….. So used by i.m or i.v route but not orally • Widely distributed… but does not cross BBB in normal conditions. BUT, if the meninges are inflamed (meningitis), it reaches the brain in therapeutic conditions • Plasma t ½ is 30 mins • Eliminated by tubular secretion….tubular secretion can be inhibited by probenecid • Repository forms are longer acting
- 13. Adverse effects • Hypersensitivity reaction • Jarisch Herxheimer reaction • Local irritation • Skin rashes • GI upset • Hepatitis • Interstitial nephritis • Neurotoxicity
- 14. Clinical uses • Streptococcal infections • Pneumococcal infections • Meningococcal infections • Syphilis • Tetanus and Gas gangrene • Diphtheria
- 15. Clinical uses • Actinomycosis • Leptospirosis/Weils disease • Lyme disease • Listeriosis • Anthrax • Gingivostomatitis, rat-bite fever, Erysipeloid, paturella multocida infection • Prohylactivally in rheumatic fever, bacterial endocarditis, agranulocytosis patients
- 16. Repository form of Penicillin G • Procaine Penicillin suspension • Benzathine penicillin suspension
- 17. Semisynthetic penicillins • These have been produced to overcome the shortcomings of PnG: • Poor oral efficacy • Susceptibility to penicillinase • Narrow spectrum of activity • Hypersensitivity reactions • Beta-lactamse inhibitors have been developed which are themselves not antibacterial, but augment the activity of penicillins
- 18. Acid resistant alternative to PnG • Phenoxymethyl penicillin (PnV) Differs from PnG in being acid-stable Oral absorption is better
- 19. Penicillinase-resistant penicillins • Indicated in infections produced by penicillinase producing Staphylococci • Not active against MRSA • Not resistant to beta-lactamases produced by gram –ve bacteria
- 20. Extended spectrum penicillins • Ampicillin Active against all organisms sensitive to PnG in addition to many gram- negetive bacilli Orally absorbed but food interferes with absorption Partly excreted in bile but undergoes enterohepatic circulation Excreted mainly through kidneys
- 21. Ampicillin Uses: UTI, RTI, Meningitis, Gonorrhoea, Enteric fever, Bacillary dysentery, Cholecystitis, SABE, ANUG Adverse effects: Diarrhoea is frequent The unabsorbed drug irritates the lower intestine and also causes alteration of bacterial flora Rashes in patients of AIDS, EB virus infection, lymphatic leukemia Hydrocortisone inactivates ampicillin if mixed in the same syringe
- 22. Amoxicillin • Congener of ampicillin, BUT • Oral absorption is better – food does not interfere with absorption • Incidence of diarrhoea is lower • More active against penicillin resistant Strep pyogenes • Preferred drug for bronchitis, UTI, SABE and gonorrhoea • It is a component of anti-H.pylori therapy
- 23. Carboxypenicillins • Active against Pseudomonas aeruginosa and Proteus • Less active against E.coli and Enterobacter • Klebsiella is resistant • Inactive orally and excreted rapidly in urine • High doses have caused bleeding by interfering with platelet function • Use: Burns, UTI, Septicemia
- 24. Ureidopenicillins • Piperacillin is an anti-pseudomonal penicillin (8 times more active than carbenicillin) • Also active against Klebsiella, Enterobacter and Bacteroides • Use: Serious gram –ve infections in neutropenic/immunocompromised patients • Burn patients
- 25. Beta-lactamase inhibitors • Beta-lactamases are enzymes produced by gram-positive and gram- negative bacteria • Open up the beta lactam ring and thus inactivate beta-lactam antibiotics • Clavulanic acid • Sulbatam • Tazobactam
- 26. Clavulanic acid • Obtained from Streptomyces clavuligerus. • Inhibits beta-lactamases produced by both gram-positive and gram- negative bacteria • Progressive inhibitor • Suicide inhibitor • Added to amoxicillin (Co-amoxiclav) Use: Skin and soft tissue infection, intra-abdominal and gynaecological sepsis UTI, RTI, biliary tree infection, Gonorrhoea
- 27. Cephalosporins
- 28. Cephalosporins • Semisynthetic antibiotics obtained from Cephalosporium • Beta lactam ring is fused with a dihydrothiazine ring • Properties: Bactericidal Inhibit bacterial cell wall synthesis Mechanism of resistance is similar to penicillins There are 5 generations based on chronological order
- 29. Classification: 1st generation • Parenteral: • Cefazolin • Oral: • Cephalexin, cefadroxil
- 30. Classification: 2nd generation • Parenteral: • Cefuroxime • Cefoxitin • Oral: • Cefaclor • Cefuroxime axetil • Cefprozil
- 31. Classification: 3rd generation • Parenteral: • Cefotaxime • Ceftizoxime • Ceftriaxone • Ceftazidime • Cefoperazome • Oral: • Cefixime • Cefpodoxime proxetil • Cefdinir • Ceftibuten • Ceftamet pivoxil
- 32. Classification: • 4th generation: Cefepime Cefpirome • 5th generation: • Ceftaroline • Ceftobiprole
- 33. Therapeutic uses • Upper respiratory infections • Cutaneous infections • Lower respiratory tract infection • Urinary tract infection • Soft tissue infections • Septicemia • Surgical prophylaxis • Meningitis • Gonorrhoea • Typhoid • Mixed infections • Nosocomial infections • Prophylaxis and treatment of infections in immunocompromised
- 34. Adverse effects • Pain after i.m injection • Thrombophlebitis • Diarrhoea • Hypersensitivity • Nephrotoxicity • Bleeding
- 35. Monobactams • Aztreonam: • Inhibits gram –ve enteric bacilli, H.influenza and Pseudomonas • Does not inhibit gm +ve cocci • Can be used in patients sensitive to penicillins/cephalosporins • Use: Nosocomial infections • A/E: rashes, rise in liver enzymes
- 36. Carbapenems • Imipenem • Meropenem • Faropenem • Doripenem
- 37. Imipenem • Broad spectrum antibiotic • Used as a “reserve drug”- in serious hospital-acquired infections • Rapidly destroyed by renal dehydropeptidase • Dehydropeptidase is inhibited by “cilastatin” • Imipenem-cilastatin combination is used • Can cause seizures Meropenem is not hydrolysed by renal peptidase
- 38. Misc. Cell wall inhibitors
- 39. Vancomycin • Tricyclic glycopeptide active against aerobic and anaerobic gram positive bacteria including MRSA, MRSE, Enterococcus and C.difficile • Frequency of administration depends on renal function: 90% of drug is eliminated by glomerular filtration • Monitoring of creatinine clearance is required for optimal dosing • Optimal cure rates are seen at trough concentration = 10-20 mcg/ml MOA: Bactericidal Binds to peptidoglycan precursors, disrupting polymerization and cross-linking in the cell wall
- 40. Vancomycin Adverse effects: • Nephrotoxicity • Infusion related reaction (red-man syndrome and phlebitis) • Ototoxicity • Given parenterally (poorly absorbed from GIT) • Oral vancomycin: used for antibiotic-associated colitis caused by C.difficile 90% of the drug is removed by glomerular filtration
- 41. Thank you
Notas del editor
- Penicillins are destroyed by beta-lactamases. 3rd and 4th gen cephalosporins are resistant. Monobactams are resistant to beta-lactamse and active against grm –ve bacteria except pseudomonas. Carbapenems are highly resistant to beta-lactamase.
- The penicillin nucleus consists of fused thiazolidine ring and beta lactam ring to which side chains are attached through an amide linkage. In this picture there is a benzyl side chain. Other side chains can be attached to produce semi-synthetic penicillins with unique antibacterial activities and different pharmacokinetic profiles. At the carboxyl end, salt formation occurs with Na and K. these salts are more stable in the dry state, but solution deteriorates rapidly at room temperature. Therefore PnG soln should always be freshly prepared. It remains stable for 3 days at 4 degrees Moreoever, PnG is thermolabile and acid -labile
- By producing penicillin destroying enzymes, beta-lactamase or penicillinase. The enzyme opens the beta-lactam ring and destroys the antibiotic. Most of the staphylococci produce beta-lactamse. Also produced by N.gonorrhoea, Hemophyllus, but not by streptococci There is a Pn binding site on the cell surface to which the Pn binds for its action. Due to alteration in the Pn binding site, Pn does not effectively bind with the bacterial cell wall, so, no antibacterial effect or reduced effect is produced, MRSA develop altered PBPs encoded by gene mecA. By decrease in the permeability of the outer membrane, so, drug cannot reach its site of action . Gm –ve bacteria have outer membrane that reduces the entry of antibiotics. It is important to note that all penicills are destroyed by beta-lactamases except for methicillin like drugs. But MRSA is resistant to any combination of Pn and beta-lactamase inhibitors.
- Antibacterial spectrum is the same as PnG
- Methicillin – must be injected as it is not acid stable Cloxacillin/Dicloxacillin
- Extended spectrum Pns are active against gm –ve bacilli as well
- Concurrent use of gentamicin or tobramycin is advised
- Inhibits class II-V beta-lactamases but not class I (cephalosporinase) Clavulanic acid does not potentiate the activity of amoxicillin against strains that are already sensitive to it Gonorrhoea: single dose of amoxicillin (3g) + clavulanic acid (0.5g) + Probenecid (1g) 125 mg of clavulanic acid is combined with amoxicillin GI tolerance is poorer esp in children. Candidiasis, stomatitis/vaginitis, rashes
- Cephalosporium is a fungus Beta lactam ring + dihydrothiazine ring = 7-aminocephalosporanic acid Moresistance= 1. alteration in PBPs 2. impermeability to the antibiotic or efflux 3. production of cephalosporinases Individual cephalosporins differ in antibacterial spectrum and potency, susceptibility to beta-lactamses and pharmacokinetic properties (many have to be injected, some are given orally…probenecid inhibits tubular secretion)
- Active against gm +ve cocci. Moderately against gm –ve. Destroyed by beta-lactamase. Most oral cavity anaerobes are susceptible except B.frag
- Gm+ve. More active against gm –ve…but not P.aeruginosa. More activity against anaerobes including B.frag
- Active against mostly gm-ve, some gm +ve and anaerobes. They are resistant to to beta-lactamases but destroyed by inducible, chromosomally encoded (class I) beta-lactamases Active against klebsiella, proteus, providencia, enterobacter, hemophilus and niesseria. Pseudomonas- ceftazidime, cefoperazone Salmonella- ceftriaxone, cefoperazone, cefotaxime, cefixime Community acquired pneumonia-cefotaxime, ceftriaxone Common meningeal pathogen-cefotaxime, ceftriaxone
- 4th gen- more active against gm –ve bacteria, active against some gm+ve and active against anaerobes. They are active against gm –ve bacilli resistant to 3rd gen cephalosporin. Resistant o beta-lactamses and also chromosomally encoded class I beta-lactamase Not resistant to ESBL (extended spectrum beta-lactamase), K.pneumonia carbapenemase (KPC) and metallo-beta-lactamases. 5th gen- active against multi-drug resistant S.aureus, including MRSA, vancoycin-intermediate staph.aureus, VRSA. However, ineffective against ESBL producing strains
- Most widely used antibiotic because they cover gm+ve and gm-ve bacteria and anaerobes (except B.fragilis or MRSA, enterococci, mycobacteria, chlamydia)
- Imipenem is active against gm +ve cocci, enterobacteriaceae, Pseudomonas, listeria as well as anaerobes such as B.fragilis and Cl.difficile Pharmacokinetics of imipenem and cilastatin is same ie. 1 hr
- Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL Red-man 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 pretreatment with an antihistamine such as diphenhydramine