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Cephalosporins Prof.P.RavisankarVignan Pharmacy CollegeVadlamudiGuntur (Dist)Andhra Pradesh, India.banuman35@gmail.comPhon...
CephalosporinsCephalosporins What are cephalosporins?What are cephalosporins?Cephalosporins are the second major groupCep...
Why Cephalosporins?Why Cephalosporins? Broad spectrum of activityBroad spectrum of activity Stability toStability to ββ-...
Introduction:The cephalosporins are β-Lactam antibiotics that areclosely related both structurally and functionally to th...
• The cephalosporins are isolated from:- Cephalosprium species- Prepared semisynthetically.• In 1945Giuseppe Brotzu`s disc...
In 1948Abraham and his colleagues have been supplied culturesof the fungus and was isolated three principal antibioticcomp...
• Penicillin N (Cephalosporin N)*Most of the antibiotics introduced since 1965 have beensemisynthetic cephalosporins.
Cephalosporin C:It is an analogue of 7-amino cephalosporanic acid abbrevatd as 7-ACA.Cephalosporin C contains a dihydrothi...
Historical background ofHistorical background ofcephalosporinscephalosporins Cephalosporin compounds were first isolated ...
 1945 - Cephalosporins were first1945 - Cephalosporins were first detecteddetected in cephalosporium acremonium.in cephal...
Biological sourcesBiological sources Cephalospoium acremonium is the most important source for theCephalospoium acremoniu...
Mechanism of actionMode of actionCephalosporins are bactericidal and have the same mode of action as otherbeta-lactam anti...
Mechanism of actionMechanism of action•Some PBP havetranspeptidase activity.• Transpeptidase activity isessential in cell ...
The meChanism of resisTanCe of m.o- Alteration of binding site.- Decrease permeability.- Production of β–lactamase enzymes...
 Classification of cephalosporins:-Classification of cephalosporins:-1STGenarationParenteralCephalothinCephaloridineCefaz...
The CephalosporinsThe Cephalosporins (generalized)(generalized)11ststGenerationGeneration Gram (+)Gram (+)22ndndGeneration...
Structures of some important cephalosporins andStructures of some important cephalosporins andcephamycinscephamycins11STST...
The acetoxy group is important to the mechanism of inhibition and acts as a goodLeaving group where as the alcohol is much...
* CefazolinNSONHCCCH2OO OHCefazolinNNN NNSCH3CH2S*CephalexinNSONHCH3CCCHOO OHNH2CephalexinGood for absorptionand bad for a...
* CephradineNSONHCH3CCCHOO OHNH2Cephradine* CefadroxilNSONHCH3CCCHOO OHHONH2Cefadroxil(Velosef)
• Most cephalosporins are produced semisynthetically by the chemicalattachment of side chains to 7-aminocephalosporanic ac...
Second generation:* CefoxitinNSOCH3ONHCCH2OCNH2CCH2SOOO OHCefoxitinNSONHCCH3OCOO OHCefmetazoleNCCH2SCH2NNNNCH2SCH3NSONHCCH...
* CefaclorNSONHClCCCHOO OHNH2Cefachlor* CefuroximeNSONHCCH2OCNH2COO OHCefuroximeCNOCH3OO
* Cefuroxime axetilNSONHCCH2OCNH2COOCefuroxime axetilCNOCH3OOO CHOCCH3OCH3* CefonicidNSONHCCOO OHCefonicidNNNNCH2SCH2SO3HC...
* CeforanideNSONHCCOO OHCeforanideNNNNCH2SCH2CO2HCH2CH2NH2NSONHCCOO OHCefamandoleNNNNCH2SCH3CHOHCefamandole
Third generation:*CefotaximeNSCH2OCCH3CONHOHOOCCONOCH3SNH2NCefotaxime*CeftizoximeNSONHCHCOO OHCeftizoximeCNOCH3SNH2N
NSONHCCOO OHCeftriaxoneCNOCH3SNH2N NNN OHCH2S OCH3*Ceftriaxone*CefiximeNSNHCCH=CH2OCCSNH2NOO OHCefiximeNOCH2CO2H
*Cefpodoxime proxetilNSNHCH2OCH3COCOONOCH3Cefpodoxime proxetilSNH2N CO CHOCOCH(CH3)2OCH3
Third generation cephalosporins with good activity againstPseudomonas:*1-CefoperazoneNSONHCCH2SCOO OHCefoperazoneCSNH2NNHC...
Fourth Generation Cephalosporins:* CefpiromeNNSHNOH HCO2CCNSH2NNO-OCH3Cefpirome+3NSHNOH HCO2NCCNSH2NNO-OCH3CefepimeH3C+* C...
55ththGeneration cephalosporinGeneration cephalosporin CeftobiproleCeftobiprole ((ZefteraZeftera//ZevteraZevtera) is a 5t...
Pharmacokinetics1- Administration:All cephalosporins except cefadroxil, cephalexin, cephradine,cefaclor, cefuroxime axetil...
3- Fate:- Elimination occurs through tubular secretion and/or glomerularfiltration.Cefoperazone are excreted through the b...
Adverse reactionsThe most common adverse reactions are:1- Allergic and hypersensitivity reactions2- A disulfiram-like effe...
Therapeutic uses- When Gm +ve bacteria is involved a 1stgeneration agents ispreferable.- When the pathogen is gm –ve and t...
Clinical uses of first gen.Clinical uses of first gen.cephalosporinscephalosporins
Second-generation cephalosporins• The second generation agents have inferior activity againstpenicillin-resistant S. pneum...
3rd generation cephalosporins3rd generation cephalosporinsClinical usesClinical uses
Third generation cephalosporins• Third generation cephalosporins have been considered to bethe drugs of choice for serious...
• Ceftazidime + aminoglycoside is the drug of choice forPseudomonas meningitis.• The antimicrobial spectrum of cefotaxime ...
The fourth generation• The fourth generation are indicated for the empirical treatmentof nosocomial infections where antib...
55ththGenaration cephalosporinsGenaration cephalosporinsCeftobiprole (Zeftera/Zevtera) is a 5th generation cephalosporin a...
This compound has been modified by the addition of differentside chains to create a whole family of cephalosporin antibiot...
Structure-activity relation ship of cephalosporin CStructure-activity relation ship of cephalosporin CThere is a limited n...
Cephalosporins advantages over penicillinsCephalosporins advantages over penicillins Increased acid stability compare to ...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceut...
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Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceutical chemistry)

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Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceutical chemistry.
P.Ravisankar
Vignan Pharmacy College
Vadlamudi, Guntur, Andhra Pradesh, India.

Cephalosporins- History,Classification,Sar,Synthesis,Mechanism of action,Uses,side effects,(Medicinal chemistry,Pharmaceutical chemistry)

  1. 1. Cephalosporins Prof.P.RavisankarVignan Pharmacy CollegeVadlamudiGuntur (Dist)Andhra Pradesh, India.banuman35@gmail.comPhone: 9059994000
  2. 2. CephalosporinsCephalosporins What are cephalosporins?What are cephalosporins?Cephalosporins are the second major groupCephalosporins are the second major groupofof β-lactum,broadspectrum,Penicillinaaseβ-lactum,broadspectrum,Penicillinaaseresistance antibiotics derived from theresistance antibiotics derived from themicro organism ‘Acrimoniummicro organism ‘Acrimoniumchrysogenum. These are closely related tochrysogenum. These are closely related tothe penicillins in both structure and modethe penicillins in both structure and modeof action and are used to treat bacterialof action and are used to treat bacterialinfection.infection.
  3. 3. Why Cephalosporins?Why Cephalosporins? Broad spectrum of activityBroad spectrum of activity Stability toStability to ββ-lactamase-lactamase Oral and parenteralOral and parenteralpreparationspreparations Widely acceptedWidely accepted Treats ‘day to day’ as well asTreats ‘day to day’ as well as‘serious infections’‘serious infections’ High safety profileHigh safety profile
  4. 4. Introduction:The cephalosporins are β-Lactam antibiotics that areclosely related both structurally and functionally to thepenicillins. Mechanism of action, mechanism of resistance andsome other properties of cephalosporins are identicalto penicillins Cephalosporins are one of the most widely usedantibiotics and are equal in importance to penicillin.
  5. 5. • The cephalosporins are isolated from:- Cephalosprium species- Prepared semisynthetically.• In 1945Giuseppe Brotzu`s discovered that culturesof Cephalosporium acremonium inhibitedthe growth of a wide variety of Gram-positiveand Gram-negative bacteria.
  6. 6. In 1948Abraham and his colleagues have been supplied culturesof the fungus and was isolated three principal antibioticcomponents:- Cephalosporin P, (a steroid antibiotic that resembles fusidicacid) with minimal antibacterial activity, obtained fromfusidium coccineum.- Cephalosporin N, later discovered to be identical withsynnematin N (a penicillin derivative now called penicillin N)-It was found tobe derivative of 6-amino penicillanic acid.It isgreater activity against gram-ve bacteria, which is due toits amino acid side chain. Salmonella typhi causativeorganism of typhoid fever was successful.
  7. 7. • Penicillin N (Cephalosporin N)*Most of the antibiotics introduced since 1965 have beensemisynthetic cephalosporins.
  8. 8. Cephalosporin C:It is an analogue of 7-amino cephalosporanic acid abbrevatd as 7-ACA.Cephalosporin C contains a dihydrothiazine ring A and a diamino adipoyl sideChain.7-amino cephalosporanic acid ie. 7-ACA is still serving as a lead nucleusIn the development of various agents belonging to the cephalosporin family.1964 the first semi synthetic cephalosporin i.e. cefalothin was launched in theMarket by Eli Lilly and company.From then onwards therewas no looking back and various cephallosporins areStill being synthesized by making suitable modifications in the lead nucleus.NSNHH HOHO OOCH3OOOHNH2 OCephalosporin CNSOHO OOCH3ONH27- aminocephalosporinic acid12345675432167Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanicacid. Compounds containing 7-aminocephalosporanic acid are:- Relatively stable in dilute acid.- Highly resistant to penicillinase, regardless of the natureof their side chains and their affinity for the enzyme.Cephalosporin C
  9. 9. Historical background ofHistorical background ofcephalosporinscephalosporins Cephalosporin compounds were first isolated from cultures ofCephalosporin compounds were first isolated from cultures ofCephalosporium acremoniumCephalosporium acremonium from a sewer infrom a sewer in SardiniaSardinia in 1948in 1948by Italian scientistby Italian scientist Giuseppe BrotzuGiuseppe Brotzu.. He noticed that these cultures produced substances that wereHe noticed that these cultures produced substances that wereeffective againsteffective against Salmonella typhiSalmonella typhi, the cause of, the cause of typhoid fevertyphoid fever,,which hadwhich had beta-lactamasebeta-lactamase.. Guy NewtonGuy Newton andand Edward AbrahamEdward Abraham at theat theSir William Dunn School of PathologySir William Dunn School of Pathology at theat theUniversity of OxfordUniversity of Oxford isolatedisolated cephalosporin Ccephalosporin C.. The cephalosporin nucleus, 7-aminocephalosporanic acid (The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA7-ACA), was derived from.), was derived from. Modification of the 7-ACA side-chains resulted in theModification of the 7-ACA side-chains resulted in thedevelopment of useful antibiotic agents, and the first agentdevelopment of useful antibiotic agents, and the first agentcephalothin (cephalothin (cefalotincefalotin) was launched by) was launched by Eli LillyEli Lilly in 1964in 1964
  10. 10.  1945 - Cephalosporins were first1945 - Cephalosporins were first detecteddetected in cephalosporium acremonium.in cephalosporium acremonium. 1948 - Cephalosporins are semisynthetic antibiotic derivatives of1948 - Cephalosporins are semisynthetic antibiotic derivatives ofcephalosporin C . Brotzucephalosporin C . Brotzu publishedpublished his results in 1948.his results in 1948. 1964 - Alarmed by the need to keep ahead of rapidly mutating bacterial1964 - Alarmed by the need to keep ahead of rapidly mutating bacterialstrains, researchers since then have developedstrains, researchers since then have developed 44 generation cephalosporins.generation cephalosporins. 1971 -In january 19711971 -In january 1971 Eli Lilly introduced KeflexEli Lilly introduced Keflex, generic name Cephalexin, generic name Cephalexin 1996 - In jan 1996 a progressive reintroduction of cephalosporins was1996 - In jan 1996 a progressive reintroduction of cephalosporins wasincluding the novelincluding the novel 44ththgeneration cephlalosporin cefepinegeneration cephlalosporin cefepine.. 2003 - Feb 11, 2003-2003 - Feb 11, 2003- RanbaxyRanbaxy laboratories has rolled out its high-endlaboratories has rolled out its high-endcephalosporin orcephalosporin or cefprozilcefprozil under the brand name Refzil.under the brand name Refzil.Cephalosporins have an estimated RsCephalosporins have an estimated Rs 1000-crore in india1000-crore in india.. 2005 - Infact the risk that a patient with a history of penicillin allergy2005 - Infact the risk that a patient with a history of penicillin allergywill experience a reaction to a first generation cephalosporin notwill experience a reaction to a first generation cephalosporin notmore than 0.5%, second generation cephalosporin not more than 0.2% and a thirdmore than 0.5%, second generation cephalosporin not more than 0.2% and a thirdgeneration cephalosporin practicallygeneration cephalosporin practically nil in at least 25 studiesnil in at least 25 studies.... 2010 - Feb 28,2010 Most patients who have a history of penicillin allergy can safely take2010 - Feb 28,2010 Most patients who have a history of penicillin allergy can safely takeantibiotics called cehalosporinsantibiotics called cehalosporins,US,US researchers say.researchers say.
  11. 11. Biological sourcesBiological sources Cephalospoium acremonium is the most important source for theCephalospoium acremonium is the most important source for theproduction of cephalosporins.production of cephalosporins.Presently major source for the production of cephalosporins include..Presently major source for the production of cephalosporins include..CephalosporinCCephalosporinCPenicillinVPenicillinVCephamycinCCephamycinCCephalosporins are semisynthetically prepared from 7-aminoCephalosporins are semisynthetically prepared from 7-aminocephalosporanic acid(7-ACA) which is obtained fromcephalosporanic acid(7-ACA) which is obtained fromcephalosporinC and also prepared from (7-ADCA) i.e. 7-amino 3-cephalosporinC and also prepared from (7-ADCA) i.e. 7-amino 3-deacetoxy cephalosporanic acid.deacetoxy cephalosporanic acid.
  12. 12. Mechanism of actionMode of actionCephalosporins are bactericidal and have the same mode of action as otherbeta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases.Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls.The peptidoglycan layer is important for cell wall structural integrity. The finaltranspeptidation step in the synthesis of the peptidoglycan is facilitated bytranspeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink thepeptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBPcrosslinking of peptidoglycan
  13. 13. Mechanism of actionMechanism of action•Some PBP havetranspeptidase activity.• Transpeptidase activity isessential in cell wallsynthesis.•cephalosporins and β-lactumsbind PBP (Penicillin BindingProteins).
  14. 14. The meChanism of resisTanCe of m.o- Alteration of binding site.- Decrease permeability.- Production of β–lactamase enzymes (enzymatic inactivation).
  15. 15.  Classification of cephalosporins:-Classification of cephalosporins:-1STGenarationParenteralCephalothinCephaloridineCefazolinOralCephalexin(Keflex)Cephadroxil(Durecef)Oral and parenteralCephradine2ndGen.ParenteralCefamycinCCefoxitinCefotitanCefmetazoleCefuroximeOral:CefachlorCefprozil3rdGenParenteralCefotaximeCeftazidimeCeftriaxoneOralCefiximeCefdinirCeftibuten4thGen.ParenteralCefepimeCefpyrome5thGen.ceftobiproleGenerations of cephalosporins ,parenteral and oral..
  16. 16. The CephalosporinsThe Cephalosporins (generalized)(generalized)11ststGenerationGeneration Gram (+)Gram (+)22ndndGenerationGenerationDecreasing Gram (+)Decreasing Gram (+)and Increasing Gram (-)and Increasing Gram (-)33rdrdGenerationGenerationGram (-), but also someGram (-), but also someGPCGPC44ththGenerationGeneration Gram (+) and Gram (-)Gram (+) and Gram (-)*Not effective vs. Enterococcus or Listeria
  17. 17. Structures of some important cephalosporins andStructures of some important cephalosporins andcephamycinscephamycins11STSTGENARATION CEPHALOSPORINSGENARATION CEPHALOSPORINS::11ststgeneration cephalosporins offer advantageous over penicillinsgeneration cephalosporins offer advantageous over penicillinsThey have greaterstability to acid,They have greaterstability to acid,ββ-lactamases,good ratio of activity-lactamases,good ratio of activityAgainst Gram+ve and Gram-ve bacterial. How ever they are genarally poor inAgainst Gram+ve and Gram-ve bacterial. How ever they are genarally poor inOral availability and are generally lower in activity.Oral availability and are generally lower in activity.Prototypical Early cephalosporin: Cephalothin1. Less antibiotic activity than Penicillin G against Gram positive bacteria2. More activity than Pen G against Gram negative bacteria3. Can be used on patients who are allergic to penicillin4. Side chain acetoxy group is hot point for metabolic inactivationDisadvantage of cephalosporin is the factThat the acetyloxy group at position 3 isReadily hydrolysed by esterase enzyme toGive less active alcohol
  18. 18. The acetoxy group is important to the mechanism of inhibition and acts as a goodLeaving group where as the alcohol is much poorer leaving group.Replacing the ester with a metabolically stable pyridinium group gives cephaloridine.Pyridine can still act as a good leaving group for the inhibition mechanism but notCleaved by esters.Exists as a zwitterion and issoluble in water.
  19. 19. * CefazolinNSONHCCCH2OO OHCefazolinNNN NNSCH3CH2S*CephalexinNSONHCH3CCCHOO OHNH2CephalexinGood for absorptionand bad for activity.Since it is not a goodleaving group, itPrevents theDeactivation ofCephalexin upto someExtent.It is not much clear that why 3- methyl group is so advantageous.Although the methyl group at position is bad for activity the presenceOf hydrophilic amino group at the α-carbon of the acylamino sideChain helps to compensate.
  20. 20. * CephradineNSONHCH3CCCHOO OHNH2Cephradine* CefadroxilNSONHCH3CCCHOO OHHONH2Cefadroxil(Velosef)
  21. 21. • Most cephalosporins are produced semisynthetically by the chemicalattachment of side chains to 7-aminocephalosporanic acid.• Cephalosporins (7α-H) and cephamycins (7α-OCH3):Cephalosporins123456NSOHO OXNHHRO7Cephamycin123456NSOHO OXNHOCH3RO7Most natural cephalosporin and cephamycin are not usedclinically for side effects, but semi-synthetic products are used.Second Genaration cephalosporins:Cephamycins:`A methoxy substituent at position 7 of thecephalosporin skeleton has provedAdvantageous. Compounds such as these areknown as cephamycins.The parent compound cephamycin C was isolatedfrom a culture ofStreptomyces clavuligerus.stabilizes
  22. 22. Second generation:* CefoxitinNSOCH3ONHCCH2OCNH2CCH2SOOO OHCefoxitinNSONHCCH3OCOO OHCefmetazoleNCCH2SCH2NNNNCH2SCH3NSONHCCH3OCOO OHCefotetanNNNNCH2SCH3SSCCCOOH2NHOCefotetanCefmetazole(Structures of some important cephamycins)
  23. 23. * CefaclorNSONHClCCCHOO OHNH2Cefachlor* CefuroximeNSONHCCH2OCNH2COO OHCefuroximeCNOCH3OO
  24. 24. * Cefuroxime axetilNSONHCCH2OCNH2COOCefuroxime axetilCNOCH3OOO CHOCCH3OCH3* CefonicidNSONHCCOO OHCefonicidNNNNCH2SCH2SO3HCHOH
  25. 25. * CeforanideNSONHCCOO OHCeforanideNNNNCH2SCH2CO2HCH2CH2NH2NSONHCCOO OHCefamandoleNNNNCH2SCH3CHOHCefamandole
  26. 26. Third generation:*CefotaximeNSCH2OCCH3CONHOHOOCCONOCH3SNH2NCefotaxime*CeftizoximeNSONHCHCOO OHCeftizoximeCNOCH3SNH2N
  27. 27. NSONHCCOO OHCeftriaxoneCNOCH3SNH2N NNN OHCH2S OCH3*Ceftriaxone*CefiximeNSNHCCH=CH2OCCSNH2NOO OHCefiximeNOCH2CO2H
  28. 28. *Cefpodoxime proxetilNSNHCH2OCH3COCOONOCH3Cefpodoxime proxetilSNH2N CO CHOCOCH(CH3)2OCH3
  29. 29. Third generation cephalosporins with good activity againstPseudomonas:*1-CefoperazoneNSONHCCH2SCOO OHCefoperazoneCSNH2NNHCNNOOOC2H5NNNNCH3*2-CeftazidimeNSONHCCOO OHCeftazidimeCSNH2NNOC CO2HCH3CH3NCH2+
  30. 30. Fourth Generation Cephalosporins:* CefpiromeNNSHNOH HCO2CCNSH2NNO-OCH3Cefpirome+3NSHNOH HCO2NCCNSH2NNO-OCH3CefepimeH3C+* Cefepime
  31. 31. 55ththGeneration cephalosporinGeneration cephalosporin CeftobiproleCeftobiprole ((ZefteraZeftera//ZevteraZevtera) is a 5th generation) is a 5th generation cephalosporincephalosporin antibioticantibioticwith activity againstwith activity against methicillin-resistantmethicillin-resistant Staphylococcus aureusStaphylococcus aureus, penicillin-, penicillin-resistantresistant Streptococcus pneumoniaeStreptococcus pneumoniae,, Pseudomonas aeruginosaPseudomonas aeruginosa, and, andEnterococciEnterococci. It was discovered by. It was discovered by Basilea PharmaceuticaBasilea Pharmaceutica[6][6] and wasand wasdeveloped bydeveloped byJohnson & Johnson Pharmaceutical Research and DevelopmentJohnson & Johnson Pharmaceutical Research and Development.. Ceftobiprole cannot be given by mouth and so is given intravenouslyCeftobiprole cannot be given by mouth and so is given intravenously Ceftobiprole inhibits the 2aCeftobiprole inhibits the 2a penicillin-binding proteinpenicillin-binding protein (pbp) of(pbp) ofMethicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureus and the 2x pbp ofand the 2x pbp ofStreptococcus pneumoniaeStreptococcus pneumoniae as well as the classic PBP-2 of MSSA.as well as the classic PBP-2 of MSSA.Ceftobiprole is resistant to staphylococcalCeftobiprole is resistant to staphylococcal β-lactamaseβ-lactamase..
  32. 32. Pharmacokinetics1- Administration:All cephalosporins except cefadroxil, cephalexin, cephradine,cefaclor, cefuroxime axetil, cefdinir, cefixime and ceftibutenmust be administered intravenously because of their poor oralabsorption.2- Distribution:- All of cephalosporins distribute very well into body fluids.However, several cephalosporins penetrate into CSF in sufficientconcentration to be useful for the treatment of meningitis.These include:Cefuroxime (2ndgen.), ceftriaxone, cefotaxime andceftizoxime (3rdgen.).
  33. 33. 3- Fate:- Elimination occurs through tubular secretion and/or glomerularfiltration.Cefoperazone are excreted through the bile and are frequentlyused in patients with renal insufficiency.
  34. 34. Adverse reactionsThe most common adverse reactions are:1- Allergic and hypersensitivity reactions2- A disulfiram-like effect3-Bleeding:- Bleeding can occur with cefamandole, cefotetan, cefmetazolemoxalactam and cefoperazone (containing an N-methyl-5-thiotetrazole moiety at the 3 position) b/c of antivitamin Keffects, administration of the vitamin corrects the problem.4- Nephrotoxicity.
  35. 35. Therapeutic uses- When Gm +ve bacteria is involved a 1stgeneration agents ispreferable.- When the pathogen is gm –ve and the infection is seriousparentral use of a 3rdgeneration agent is recommended.First generation cephalosporins are:• Excellent agents for skin and soft tissue infections due toS. aureus and S. Pyogenes.• A single dose of cefazolin just before surgery is the preferredas prophylaxis
  36. 36. Clinical uses of first gen.Clinical uses of first gen.cephalosporinscephalosporins
  37. 37. Second-generation cephalosporins• The second generation agents have inferior activity againstpenicillin-resistant S. pneumoniae compared to either the 3rdgeneration agents or ampicillin and therefore should not beused for treatment of meningitis or pneumonia.• In case where Gm -ve bacteria and anaerobes are involvedsuch as intraabdominal infections, pelvic inflammatorydisease and diabetic foot infection, cefoxitin and cefotetan havebeen shown to be effective.• For colorectal surgery where prophylaxis for intestinalanaerobes is desired, cefoxitin or cefotetan (2ndgeneration)are preferred.
  38. 38. 3rd generation cephalosporins3rd generation cephalosporinsClinical usesClinical uses
  39. 39. Third generation cephalosporins• Third generation cephalosporins have been considered to bethe drugs of choice for serious infections caused by:Klebsiella, Enterobacter, Proteus, Haemophilus species.• Ceftriaxone is now the drug of choice for all form of gonorrhea.• Cefotaxime or ceftriaxone (as part of a 3-drug combination withvancomycin and ampicillin) are used for the initial treatment ofmeningitis in nonimmunocompromised adults and childrenolder than 3 months.
  40. 40. • Ceftazidime + aminoglycoside is the drug of choice forPseudomonas meningitis.• The antimicrobial spectrum of cefotaxime and ceftriaxone isexcellent for the treatment of community acquired pneumonia,i.e. that caused by pneumococci, H. influenzae, S. aureus.Third generation cephalosporins (Cont.)
  41. 41. The fourth generation• The fourth generation are indicated for the empirical treatmentof nosocomial infections where antibiotic resistance due toextended spectrum β-lactamases are anticipated.e.g. cefepime has superior activity against nosocomialisolates of Enterobacter, Citrobacter compared toceftazidime and piperacillin
  42. 42. 55ththGenaration cephalosporinsGenaration cephalosporinsCeftobiprole (Zeftera/Zevtera) is a 5th generation cephalosporin antibiotic with activityagainst methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcuspneumoniae, Pseudomonas aeruginosa, and Enterococci. It was discovered by BasileaPharmaceutica[6] and was developed by Johnson & Johnson Pharmaceutical Researchand Development.Ceftobiprole cannot be given by mouth and so is given intravenouslyCeftobiprole inhibits the 2a penicillin-binding protein (pbp) of Methicillin-resistantStaphylococcus aureus and the 2x pbp of Streptococcus pneumoniae as well as theclassic PBP-2 of MSSA. Ceftobiprole is resistant to staphylococcal β-lactamase
  43. 43. This compound has been modified by the addition of differentside chains to create a whole family of cephalosporin antibiotics.Structural features of cephalosporins:
  44. 44. Structure-activity relation ship of cephalosporin CStructure-activity relation ship of cephalosporin CThere is a limited number of placesThere is a limited number of placeswhere modifications can be made butwhere modifications can be made butthere are more Possibilities than withthere are more Possibilities than withpenicillins…penicillins… Variations at the 3-Variations at the 3-acylamino side chain.acylamino side chain. Variations at the 3-Variations at the 3-acetoxymethyl side chain.acetoxymethyl side chain. Extra substitution at carbon.Extra substitution at carbon.12224455688 8
  45. 45. Cephalosporins advantages over penicillinsCephalosporins advantages over penicillins Increased acid stability compare to penicillinsIncreased acid stability compare to penicillins Most of the drugs better absorption thanMost of the drugs better absorption thanpenicillin.penicillin. Broad antimicrobial spectrum.Broad antimicrobial spectrum. Increased activity against resistantIncreased activity against resistantmicroorganisms.microorganisms. Decreased alleregenicity.Decreased alleregenicity. Increased tolerence than penicillins.Increased tolerence than penicillins.

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