Cephalosporins & other ² lactam antibiotics & cell wall destructors

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this ppt cover all 5 generations of cephalosporins and about beta lactam atibiotics and cell wall destructors data available till now. hope u ll find it useful.

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  • 1. Cephalosporins & other -Lactam Antibiotics.Cell Wall Destructors.Faraza JavedMphil Pharmacology

2. - Lactam Antibiotics-lactam antibiotics, inhibit bacterial growthby interfering with bacterial cell wallsynthesis.The -lactam antibiotics may be further sub-dividedinto two categories, namely:PenicillinCephalosporin 3. CephalosporinsCephalosporins are similar to Penicillins,but more stable to many bacterial lactamases and therefore have a broaderspectrum of activity. 4. HistoryThe 1st source of Cephalosporins,Cephalosporium acremonium(Fungus), wasisolated in 1948 by Giuseppe from the seanear a sewer outlet of the Sardinian Coast.The crude filtrates from this fungus werefound to inhibit the in vitro growth of -lactamase producing S. aureus and to curethe Staphylococcal infections and typhoidfever in humans. 5. Subsequently, Abraham and his colleaguesidentified three distinct antibiotics from theculture fluid of fungus.These antibiotics were namedCephalosporin N and C (which werechemically related to penicillin) andCephalosporin P, a steroid antibiotic thatresembles Fusidic Acid. 6. ChemistryThe nucleus of Cephalosporins, 7-aminocephalosporanic acid bears a closeresemblance to 6-aminopencillanic acid.The core of the basic cephalosporin moleculeconsists of a two ring system which includesa -lactam ring condensed withdihydrothiazine ring. The core itself canalso be referred to as 7-aminocephalosporanic acid which can bederived by hydrolysis from the naturalcompound Cephalosporin C. 7. Chemical compoundscontaining this coreare relatively stable toacid hydrolysis andtolerance to -lactamases.Cephalosporin Ccontains a side-chainwhich is derived fromD-aminoadipic acid. 8. Modification of sidechains on the relevantpositions has been usedto create a whole newclass of cephalosporinantibiotics.Modification of side-chains at position 7 of thelactam ring seems to affect the antibacterialactivity while position 3 of the dihydrothiazinering alters pharmacokinetic properties andreceptor binding affinity. 9. Mechanism of ActionCephalosporins exert bactericidal effect inmanner similar to that of Penicillins.Binding to specific PBPSInhibition of cell wall synthesis byinhibiting transpeptidation ofPeptidoglycanActivation of Autolytic enzymes Autolysinsor Murein Hydrolases 10. ClassificationCephalosporins can be classified into fourmajor groups or generations, dependingmainly on the spectrum of antimicrobialactivity.Recently, Fifth generation cephalosporins weredeveloped in the lab to specifically targetagainst resistant strains of bacteriaparticularly Methicillin ResistanceStaphlococcus Aureus (MRSA). 11. 1st Generation CephalosporinsThe agents included in this group have goodactivity against gram-positive cocci, suchas pneumococci, streptococci andstaphylococci but not active againstmethicillin resistant strains ofstaphylococci, and relatively modestactivity against gram-negativemicroorganisms (E.Coli and Klebsiellapnumoniae). 12. 1st generation Cephalosporins include:Cefazolin (IV/IM)Cefadroxil (PO)Cephalexin (PO)Cephalothin (IV/IM)Cephapirin (IV/IM)Cephradine (PO) 13. 2nd Generation CephalosporinsThese compounds show modest activityagainst gram-positive bacteria (less activethan 1st generation drugs) and displaygreater activity against gram-negativemicroorganisms including Haemophilusinfluenza, some Enterobacter aerogenesand Neisseria Species. 14. In comparison to 1st generation, they havesome what increased activity against gram-negativebacteria but this activity is muchless than the activity of 3rd generationcompounds. 15. The drugs included in this class are:Cefaclor (PO)Cefamandole (IV/IM)Cefonicid (IM/IV)Cefuroxime (IV/IM/PO)Cefprozil (PO)Loracarbef (PO)Ceforanide (IM/IV) 16. 3rd Generation CephalosporinsThough greatly inferior to 1st generationcephalosporins in regard to their activityagainst gram-positive cocci, the 3rdgeneration cephalosporins exhibit muchmore activity against gram-negative bacilli,most other enteric organisms and -lactamase producing strains ofHaemophilus and Neisseria. 17. Drugs of this group have superiority over theother two generation in having ability toreach CNS (cross BBB). They include:Cefoperazone (IV/IM)Cefotaxime (IV/IM)Ceftriaxone (IV/IM)Cefixime (PO)Ceftazidime (IV/IM)Moxalactam (IM/IV) 18. 4th Generation CephalosporinsThey have an extended spectrum of activityas compared to the 3rd generation and haveincreased stability from hydrolysis byplasmid and chromosomally mediated -lactamases. 19. Aerobic gram-negative bacilli resistant to 3rdgeneration cephalosporins can besuccesfully treated with 4th generationdrugs.Drugs included in this class are:Cefepime (IV)Cefpirome (IV)Cefozopran (IV) 20. 5th Generation CephalosporinsThese 5th generation cephalosporins areactive against Methicillin resistantstaphylococci.Agents under this class include:Ceftaroline Fosamil (IV)Ceftobiprole (IV) 21. FDA has approved Ceftaroline under thetrade name Teflaro which was developedby modifying the structure of 4th generationcephalosporin Cefozopran.Ceftobiprole has powerful antipseudomonalcharacteristics and appears to be lesssusceptible to development of resistanceand are now on the FDA fast-track. 22. Currently, ceftaroline and ceftobiprole are onan unnamed subclass of cephalosporins bythe Clinical and Laboratory StandardsInstitute (CLSI) but generally classifiedunder the category of 5th generationcephalosporins. 23. Resistance to CephalosporinsResistance to cephalosporins can be due tofollowing mechanisms:Poor penetration of drug into bacteriaLack of specific PBPS for a particularagentDegradation of the drug by -lactamasesFailure of activation of Autolytic enzymesin the bacterial cell wall. 24. Therapeutic UsesCephalosporins are widely used antibiotics.Unfortunately, overuse of these agents insituations where drugs with less broadspectrum activity would be moreappropriate has led to the emergence of widearray of cephalosporin resistant bacteria.Cephalosporins are effective as bothProphylactically & Therapeutically. 25. ChemoprophylaxisSingle dose of Cefazoline (1-2 g IV/IM 60minutes before procedure) just beforesurgery is preferred prophylaxis forprocedures in which skin flora are likely tobe pathogenic. 26. Alternative to PenicillinsCephalosporins are still useful alternatives toPenicillins for a variety of infections inpatients who cannot tolerate penicillins. 27. Serious InfectionsCephalosporins (Ceftriaxone or Cefixime),alone or in combination withAminoglycosides are drugs of choice forserious infections (commonly respiratorytract infections) caused by Klebsiella,Enterobacter, Proteus, Providencia, andHaemophilus species. 28. Treatment of GonorrhoeaCeftriaxone (as a single dose 125mg byinjection) and Cefixime (400mg oral dose)are drugs of 1st choice for the treatment ofall forms of gonorrhoea. 29. Treatment of TyphoidCefoperazone and Ceftriaxone (1-2g BD,IV/IM for 7-10 days) have been usedeffectively for the treatment of typhoid fever. 30. MeningitisCeftriaxone and Cefotaxime, currently arethe drug of choice for empirical treatmentof meningitis in non immunocompromisedadults and children older than 3 months.They are proven effective for the treatmentof meningitis caused by Haemophilusinfluenzae, Neisseria meningitidis andgram-negative enteric bacteria. 31. Treatment of Lyme DiseaseLyme is an inflammatory disease spreadby infected Tics bite by Borrelia specie.Ceftriaxone (2 g once dailyiv for 1428 days) orCefotaxime (2 g ivevery 8 h) is the treatmentof choice for severe forms of Late LymeDisease. 32. Adverse EffectsAllergic ReactionsNephrotoxicityDiarrhoeaDisulfiram like ReactionBleeding DisorderSuperinfections 33. Other -Lactam Antibiotics& Cell Wall Destructor 34. Other -Lactam Antibiotics-Lactamase InhibitorsClavulanic AcidSalbactumTazobactumMonobactamsAztreonam 35. CarbapenemsDoripenemImipenemErtapenemMeropenem 36. -Lactamase Inhibitors-lactamase inhibitors are used inconjunction with a -Lactam antibiotic toextend its spectrum of activity.Although -lactamase inhibitors have littleantibiotic activity of their own, they insteadinhibit the activity of -lactamases, (afamily of enzymes that break the beta-lactamring) that allows penicillin-likeantibiotics to work, thereby conferringbacterial resistance. 37. Hence -lactamase inhibitors are often givenin combination with penicillins to tackle theproblem of the resistance caused by thepresence of -lactamases from bacterialcells.An example is Co-Amoxiclav [Augmentin],which is a combination of amoxicillin andclavulanic acid. Salbactum usually combinedwith Ampicillin (Unasyn) and Tazobactumwith Piperacillin (Zosyn). 38. MonobactamsMonobactams are drugs with a monocyclic- lactam ring.They are resistant to -lactamases andactive against gram-negative rods.They have no activity against gram-positivebacteria or anaerobes.Penicillin-allergic patients tolerateaztreonam without reaction. 39. CarbapenemsImipenem has good activity against gram-negative,gram-positive and anaerobicorganisms.Imipenem is inactivated bydehydropeptidases in renal tubules.It is administered with an inhibitor of renaldehydropeptidase, cilastatin, for clinical use.Meropenem and ertapenem are not degradedby renal dehydropeptidase. 40. IM ertapenem is irritating, so it isformulated with 1% lidocaine. A carbapenem is used for P. aureginosaresistant to other drugs and mixed aerobicand anaerobic infections. 41. Cell Wall DestructorVancomycinDaptomycinFosfomycinPolymyxinCycloserine 42. VancomycinVancomycin is active against gram-positivebacteria, particularly staphylococci.Machanism: Inhibits cell wall synthesis bybinding to the D-Ala-D-Ala terminus ofpeptidoglycan pentapeptide, which as aresult inhibits transglycosylase, preventingpeptidoglycan elongation and cross-linking. 43. -lactamase producing staphylococci andthose resistant to nafcillin and