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CEPHALOSPORINS
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  • 1. BYV. SUSHIL
  • 2. THEY ARE ANTIBIOTICS, CHEMICALLYRELATED TO PENICILLINS, DERIVEDFROM ‘CEPHALOSPORIN-C’ .CEPHALOSPORIN-C WAS ISOLATED BYGUY NEWTON & EDWARD ABRAHAM.CEPHALOSPORINS WERE FIRSTISOLATED FROM CULTURES OFCephalosporium acremonium, afungus, by an Italian scientist ‘GIUSEPPEBROTZU’.HE NOTICED THAT THEY WEREEFFECTIVE AGAINST Salmonella typhi(typhoid fever) WHICH HAD BETA-LACTAMASES.
  • 3. CEPHALOSPORIUMCULTURE (COLONIES) MICROSCOPIC VIEWCephalosporium acremonium
  • 4. BY ADDITION OF DIFFERENT SIDE CHAINS: AT POSITION 7 (beta-lactam ring) antibacterialspectrum against specific organisms can be altered.At position 3 of dihydrothiazine ring , pharmacokineticscan be altered as required.
  • 5. Mechanism of action Inhibition of bacterialcell wall synthesis, similarmechanism as that ofpenicillin.Transpeptidases enzymeis inhibited leading tofailure of cross linking ofpeptide chains of strands,no stability to cell wall.Bactericidal action isexhibited by lysis of cellwall deficientforms(CWD’s).
  • 6. RESISTANCE Acquired resistance to cephalosporin couldbe due to:1.Alteration in the target proteins.2.Impermeability to the antibiotic preventingit from reaching its site of action.3.Cephalosporinases(beta lactamases)against specific cephalosporins They are not susceptible to hydrolysis bystaphylococcal penicillinase. Cephalosporins may be susceptible toextended- spectrum Beta-lactamases.E.g. Cefazolin is susceptible tostaphylococcal Beta-lactamase.
  • 7. PHARMACOKINETICSAdministration:Many of thecephalosporinsmust beadministered IV orIM ,but oralcephalosporinshave also beendevelopedAll cephalosporinsdistribute very well intobody fluids. However,adequate therapeuticlevels in the CSF,regardless ofinflammation, areachieved only with thethird-generationcephalosporins. Forexample, ceftriaxone orcefotaxime are effectivein the treatment ofneonatal and childhoodmeningitis caused byHaemophilus influenzae.Elimination:It occurs throughtubular secretion andglomerularfiltration.Thereforedoses must beadjusted in cases ofsevere renal failure toguard againstaccumulation andtoxicity. Ceftriaxone isexcreted through thebile into the feces andtherefore, isfrequently employedin patients with renalinsufficiency.Distribution:All cephalosporinscross the placenta.
  • 8. FIRST GENERATION SECOND GENERATIONTHIRD GENERATION FOURTH GENERATIONCEPHALOSPORINSORALCEPHALEXINCEPHRADINECEFADROXILPARENTERALCEPHALOTHINCEFAZOLINORALCEFACLORCEFUROXIME-AXETILCEFPROZILPARENTERALCEFUROXIMECEFOXITINORALCEFIXIMECEFDINIRCEFTIBUTENCEFPODOXIME-PROXETILCEFTAMETPIVOXILPARENTERALCEFOTAXIMECEFTIZOXIMECEFTRIAXONECEFTAZIDIMECEFOPERAZO-NEPARENTERALCEFEPIMECEFPIROME
  • 9. CHARACTERISTICS AND ACTIONS: Prototype first generationcephalosporin. Mainly used as penicillin Gsubstitute. Long plasma half –life (2hours) , longer duration ofaction, hence used forsurgical prophylaxis. Dose :0.25g 8hourly(mildcases) i.m. / i.v.1g 6hourly(severecases) i.m. / i.v.CEFAZOLINStreptococcus pyogenesStreptococcus viridansStreptococcus pneumoniaeGonococci, meningococciKlebsiellaE.ColiProteusmirabilisActinomycesClostridia
  • 10. CEPHALEXINPrototype of first generation , oralcephalosporin.Similar in anti-bacterial spectrum to cefazolin.High concentrations attained in bile, excretedunchanged in urine.Plasma half-life 1 hour.Dose: 0.25-1g 6 to 8 hourly.children 25-100 mg/kg/day used in treatment of minor infections likeabscess, cellulitis,pharyngitis.
  • 11. FIRST GENERATION CEPHALOSPORINS Orally active drug , alsoavailable for parenteraluse. Dose: 0.25-1g 6-12hourly oral/i.m/i.v. Good tissue penetrationand sustained action atsite of infection. Plasma half –life 1 hour,can be given 12 hourly. Dose: 0.5-1g BD.CEPHRADINE CEFADROXIL
  • 12. SECOND GENERATION CEPHALOSPORINS They are more active against gram negativebacteria, and some anaerobes.Clinically, largely replaced by third generationcephalosporins.CEFUROXIME Resistant to gram-negative beta-lactamases.Well tolerated by i.m route and crosses the blood –brain barrier, attains higher CSF levels. Dose: 0.75-1.5g i.m/i.v. 8 hourly.children: 30-100 mg/kg/day
  • 13. CEFACLOR Orally effective second generation drug.Serum sickness-adverse effect seen insome cases.Dose: 0.25-1 g 8 hourly.CEFOXITIN Good activity against anaerobes,particularly Bacteroidesfragilis.Useful in patients with intra-abdominal sepsis andagainst gynecologic sepsis,pelvic inflammatory disease.
  • 14. CEFUROXIME AXETIL This is an ester of cefuroxime.Orally effective, cefuroxime is released by hydrolysis in thebody.Dose: 0.25-1.0g 8 hourly.THIRD GENERATION CEPHALOSPORINSGRAMNEGATIVEBACILLIENTEROBACTERPSEUDOMONASGRAM ‘-’COCCINEISSERIAGONORRHOEAGRAM +COCCI
  • 15. THIRD GENERATION CEPHALOSPORINSPrototype of third generationcephalosporin. potent action on aerobic gramnegative bacteria.Used against meningitis causedby gram negativebacilli,septicaemias,hospitalacquired infections.Attains high CSF levels. plasma T1/2-1hr. DOSE:1-2gm i.m or i.v. 8-12 hrly.CEFOTAXIME
  • 16. Potent action against Bacteroidesfragilis.Plasma T1/2 1.5-2hr.DOSE:0.5-2gm i.m/i.v. 8-12hrly.Longest duration of action(plasmaT1/2 -8hrs).Good CSF penetration.USES:Bacterial meningitis.Multiresistant typhoid fever.Urinary tract infections.Abdominal sepsis.ADVERSE EFFECTS:Hypoprothrombinemia & bleeding.Haemolysis in some cases.CEFTIZOXIMECEFTRIAXONE
  • 17. High activity against pseudomonas.Plasma T1/2 1.5-1.8hr.USES:Febrile neutropenic patients with haematologicalmalignancies,burns.DOSE:0.5-2gm i.m/i.v. 8hrly.Children:30mg/kg/day.Stronger activity on pseudomonas.Susceptible to beta-lactamases.Plasma T1/2-2hrs.Disulfiram –like reaction with alcohol reported in some cases.Indications :severe urinary billiary respiratoryinfections,skin&soft tissue infections.DOSE:1-3gm i.m/i.v. 8-12hrly.CEFTAZIDIMECEFOPERAZONE
  • 18. Oral third generation drug highly activeagainst enterobactericiae,Haemophilusinfluenzae.Resistant to many beta-lactamases.Longer action;T1/2 -3hrs.DOSE:400mg BDOrally active ester prodrug of cefpodoxime.Inhibits staphylococcus aureus.Also active againstenterobacterioceae&streptococci.USES:respiratory,urinary,skin infections.Dose:200mg BDCEFPODOXIMEPROXETILCEFIXIME
  • 19. CEFDINIR Potent againstrespiratorypathogens(grampositive cocci). Indications:pneumoniaacute exacerbation ofchronic bronchitis,ENTinfections. Dose:300mg BD Orally acting,stable tobeta-lactamases. Active against grampositive &gramnegativebacteria(exceptpneumococci,staphylococcus aureus) plasmaT1/2 2-3hrs. Dose:200mg BD 400mg OD.CEFTIBUTEN
  • 20. FOURTH GENERATION CEPHALOSPORINSCEFEPIMECEFPIROMEBetter penetration through porin channels ofgram ‘-’ bacteria due to zwitterion nature.Indications: resistant hospital acquiredinfections,septecaemias.Dose: 1-2 g i.m/i.v. 12hourlyHighly resistant to beta-lactamases.High potency against Pseudomonasaeruginosa &Staph. aureus.Dose: 1-2g i.v. 8-12hourly
  • 21. ADVERSE EFFECTS PAIN: i.m. or i.v. infusion is usually painful.severe pain with cephalothin is experienced.thrombophlebitis of injected vein can occur. Diarrhoea : mostly seen with cephradine and cefoperazone(dueto excretion in bile). Nephrotoxicity: cephalothin,cephaloridine exhibit renal toxicitywhen administered. Ceftriaxone is excreted mostly in bilehence, used in patients with renal insufficiency. It also hasgood bone penetration.(cefazolin) Bleeding: due to hypoprothrombinaemia seen commonly inpatients with cancer, renal failure. Ceftazidime has been associated with neutropenia ,thrombocytopenia.
  • 22. Hypersensitivity: incidence is lower thanpencillins.10% penicillin allergic patientsexhibit cross-sensitivity to cephalosporins.Frequent manifestations:rashes,anaphylaxis,angioedema,asthma andurticaria
  • 23. THROMBOPHLEBITIS OF INJECTED VEIN
  • 24. FIFTH GENERATION CEPHALOSPORINSCEFTAROLINE:Advanced generation cephalosporin antibiotic.Active against MRSA & gram positive bacteria.Being investigated for community acquired bacterial pneumonia &complicated skin & skin structure infection.Has received approval from U.S. FDA.BINDS TO & INHIBITS ‘PBP-2a’( typeproduced by MRSA)Clinical trials- common adverseeffects:diarrhoea, nausea, rash.Known serious hypersensitivity &anaphylactoid reactions have been reported.TEFLARO
  • 25. CEFTOBIPROLEActivity against MRSA ,penicillin resistant Streptococcuspneumoniae, Pseudomonas aeruginosa, Enterococci.Inhibits the 2a PBP of MRSA, 2X PBP of Strep. pneumoniae.Given i.v. , but not FDA approved for use in children. is under review , approved in some countries.
  • 26. TYPHOID (ALTERNATIVES TOFLUOROQUINOLONES)CEFTRIAXONE4 g x 2 days, followed by2 g x 2 daysGONORRHOEA -PENICILLIN PRODUCINGCEFTRIAXONECEFUROXIME250 mg i.m250 mg i.mMENINGITIS BACTERICIDAL ACT. INCSF.CEFTRIAXONE/CEFOTAXIMEINFECTIONS-GRAM ‘–’BACTERIACEFUROXIMECEFOTAXIME 1-2 g i.m / i.v. 12 hrlySURGICALPROPHYLAXISCEFAZOLINALTERNATIVES TOPnG(ALLERGIC)CEFAZOLINCEPHALEXIN0.25 g 8 hrly0.25-1 g 6-8 hrlyHOSPITAL ACQUIREDINFECTIONSCEFOTAXIMECEFEPIME 1-2 g i.v. 12 hrlyINFECTIONS IN CEFTAZIDIME 0.5-2 g i.m /i.v. 8 hourlyINDICATIONS OF CEPHALOSPORINS
  • 27. USE ANTIBIOTICS JUDICIOUSLY!THANK Q