. اليوزبكي. . وحدة د م أHead of Department of Pharmacology- College of

Medicine- University of Mosul-2014

Cephalosporins

3

ObjectivesObjectivesAt end of this lecture, the students will be able to:At end of this lecture, the students will be able to:

1-1- Identify the chemical structure and the classes of Identify the chemical structure and the classes of cephalosporin.cephalosporin.

2-2- Discuss the clinically important features of each Discuss the clinically important features of each individual class of cephalosporin (Its pharmacokinetic individual class of cephalosporin (Its pharmacokinetic properties, antibacterial activities, clinical uses and side properties, antibacterial activities, clinical uses and side effects). effects).

3-3- Clarify the differences between different classes of Clarify the differences between different classes of cephalosporin.cephalosporin.

4-4- State other agents affecting the cell wall. State other agents affecting the cell wall.

- At a level accepted to the quality assurance standards for - At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.the College of Medicine/ University of Mosul.

CephalosporinCephalosporin - -They are They are B-lactam antibioticsB-lactam antibiotics that are closely that are closely

related both structurally and functionally to the related both structurally and functionally to the penicillinpenicillin . .

- The chemical nucleus of the cephalosporin is 7-- The chemical nucleus of the cephalosporin is 7-amino cephalosporanic acid bears a close amino cephalosporanic acid bears a close resemblance to 6-amino penicillanic acid of resemblance to 6-amino penicillanic acid of penicillin.penicillin.

- Both penicillin and cephalosporin are safe during - Both penicillin and cephalosporin are safe during pregnancy.pregnancy.

Cephalosporin Chemical Cephalosporin Chemical structurestructure

-The chemical nucleus -The chemical nucleus of the cephalosporin of the cephalosporin

is is 7-amino 7-amino cephalosporaniccephalosporanic

acid.acid.

- Most cephalosporin - Most cephalosporin are produced semi-are produced semi-synthetically by the synthetically by the

chemical attachment chemical attachment of side chains to 7-of side chains to 7-

aminocephalospora-aminocephalospora-nic acid.nic acid.

Mechanism of action of Mechanism of action of cephalosporincephalosporin

- -CephalosporinCephalosporin inhibit cell wall synthesis in a way inhibit cell wall synthesis in a way similar to that of penicillinsimilar to that of penicillin..

- -The cephalosporin are The cephalosporin are bactericidal bactericidal drugs with drugs with both gram positive and gram negative activityboth gram positive and gram negative activity. .

- -They are more stable than penicillin to many They are more stable than penicillin to many bacterial Beta Lactamases and therefore usually bacterial Beta Lactamases and therefore usually have a broader spectrum of activityhave a broader spectrum of activity..

Classification of Classification of CephalosporinCephalosporin

- -Cephalosporins have been classified as 1st, 2nd, Cephalosporins have been classified as 1st, 2nd, 3rd , 4th or 5th generation on the basis of 3rd , 4th or 5th generation on the basis of bacterial susceptibility pattern & resistance tobacterial susceptibility pattern & resistance to B-lactimaseB-lactimase::

11 - -First GenerationFirst Generation::OrallyOrally:: Cefadroxil, Cephalaxin, CephalothinCefadroxil, Cephalaxin, Cephalothin..PrenterallyPrenterally:: CefazolinCefazolin..

22 - -Second GenerationSecond Generation::PrenterallyPrenterally:: Cefoxitin, Cefotetan, Cefonicid, Cefoxitin, Cefotetan, Cefonicid,

CefamandoleCefamandole . .OralOral:: Cefuroxime axetil, CefprozilCefuroxime axetil, Cefprozil..

Classification of Classification of CephalosporinCephalosporin

33 - -Third GenerationThird Generation :: OralOral:: Cefixime, CeftibutenCefixime, Ceftibuten..

PrenterallyPrenterally:: Cefotaxime, Ceftriaxone, Ceftizoxime, Cefotaxime, Ceftriaxone, Ceftizoxime, CeftazidimeCeftazidime..

44 - -Forth GenerationForth Generation: : Cefepime Cefepime is the most clinically useful. Must be is the most clinically useful. Must be administered parenterallyadministered parenterally..

55 - -Fifth GenerationFifth Generation::Ceftobiprole : Ceftobiprole : New drugNew drug..

First Generation First Generation CephalosporinCephalosporin

Antibacterial Activity:Antibacterial Activity:- - -These are highly effective against These are highly effective against gramgram

-positive (G+) bacteriapositive (G+) bacteria including strep., including strep., pneumococcus & staph.---(as penicillin G)pneumococcus & staph.---(as penicillin G) . .

- - -Also They have low activity against Also They have low activity against gram gram negative organismsnegative organisms including: including: PProteus roteus mirabilis,mirabilis, E E coli & coli & KKlebsiella pneumonia lebsiella pneumonia (PEcK)(PEcK)

Clinical Uses ofClinical Uses of First Generation First Generation

CephalosporinCephalosporin - -They are not used for serious systemic infection. They are not used for serious systemic infection.

So used inSo used in:: - -OralOral : : widely used for the treatment of widely used for the treatment of RTI, RTI,

uncomplicated UTI uncomplicated UTI & & soft tissue infection soft tissue infection (cellulites) (cellulites) && soft tissue abscess soft tissue abscess (minor staph. (minor staph. Infection)Infection)..

- -PrenterallyPrenterally:: CephazolinCephazolin penetrate well into most penetrate well into most tissues mainly bone (not CNS). It is the drug of tissues mainly bone (not CNS). It is the drug of choice for choice for surgical prophylaxissurgical prophylaxis & also for the & also for the

biliary tract & endocarditisbiliary tract & endocarditis..

Second Generation CephalosporinSecond Generation Cephalosporin

Antibacterial ActivityAntibacterial Activity:: - -In general they are active against organisms In general they are active against organisms

affected by first generation drugs (affected by first generation drugs (slightly less slightly less activity against gram positive organismsactivity against gram positive organisms))..

- It has also activity against three additional - It has also activity against three additional G- G- negative microorganism:negative microorganism:

HHaemophilus influenzae, some aemophilus influenzae, some EEnterobacter nterobacter aerogenes & some aerogenes & some NNeisseria species (in eisseria species (in

addition to Proteus mirabilis, E coli & Klebsiella addition to Proteus mirabilis, E coli & Klebsiella pneumonia) pneumonia) (HEN PEcK).(HEN PEcK).

Clinical Uses ofClinical Uses of Second Generation Second Generation

CephalosporinCephalosporin Oral agentsOral agents are used for : are used for :

1-1- The lower RTI such as The lower RTI such as sinusitis, otitis media & sinusitis, otitis media & acute bronchitisacute bronchitis (against B-lactimase (against B-lactimase

producing H.Influenzae).producing H.Influenzae).2-2- Because Because Cefoxitin & CefotetanCefoxitin & Cefotetan, pocess activity , pocess activity

against anaerobic bacteroid, including bacteroid against anaerobic bacteroid, including bacteroid fragilis, can be useful in the treatment of fragilis, can be useful in the treatment of mixed mixed

anaerobic infection (anaerobic infection (peritonitisperitonitis & & DiverticulitisDiverticulitis).).

3- 3- Used for Used for community acquired pneumonia.community acquired pneumonia.

Clinical Uses ofClinical Uses of Second Generation Second Generation CephalosporinCephalosporin

PrenteralPrenteral Agents Agents : :

- -Used for the treatment of mixed anaerobic Used for the treatment of mixed anaerobic infection such as infection such as abdominal & pelvic abdominal & pelvic infection as peritonitisinfection as peritonitis..

33 - -Third Generation CephalosporinThird Generation Cephalosporin

Antibacterial Activity:Antibacterial Activity:- Their activity against gram positive organisms is Their activity against gram positive organisms is

less than that of the first generation. less than that of the first generation. - They have greater activity against gram negative They have greater activity against gram negative

bacteria than first or second generations bacteria than first or second generations plus plus other enteric organisms & Serratia marcescensother enteric organisms & Serratia marcescens. .

- - CeftazidimeCeftazidime has activity against has activity against pseudomonas pseudomonas aeroginosa.aeroginosa.

Clinical Uses ofClinical Uses of Third Generation Third Generation CephalosporinCephalosporin

- -They are used to treat They are used to treat serious infectionsserious infections caused caused by organisms that are resistant to most other by organisms that are resistant to most other drugsdrugs::

- -ParenteralParenteral:: Used for the treatment ofUsed for the treatment of: : Brain Brain abscess, Meningitis, Gonorrhoea, Peritonitis, abscess, Meningitis, Gonorrhoea, Peritonitis, Pneumonia, Surgical prophylaxis, Septicemia, Pneumonia, Surgical prophylaxis, Septicemia, syphilis, Biliary tract infections, Skin infectionssyphilis, Biliary tract infections, Skin infections..

- -Oral PreparationsOral Preparations: : used for used for : : Gonorrhoea, Otitis Gonorrhoea, Otitis media, pharyngitis, bronchitis and UTIsmedia, pharyngitis, bronchitis and UTIs..

Forth Generation Forth Generation CephalosporinCephalosporin

--CefepimeCefepime is the most clinically useful is the most clinically useful. . Must Must be administered be administered parenterallyparenterally..

- -It has a wide antibacterial activity being It has a wide antibacterial activity being active against streptococci & staphylococci active against streptococci & staphylococci ((only those Methicillin susceptibleonly those Methicillin susceptible))..

- -It is also effective against aerobic GIt is also effective against aerobic G--veve organisms such as Enterobacter, E coli, K organisms such as Enterobacter, E coli, K pneumoniae, Proteus mirabilis & pneumoniae, Proteus mirabilis & pseudomonas aeroginosapseudomonas aeroginosa..

Fifth Generation Fifth Generation CephalosporinCephalosporin

CeftobiproleCeftobiprole:: - -New drugNew drug with activity against methicillin- with activity against methicillin-

resistant Staphylococcus aureus, penicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae and resistant Streptococcus pneumoniae and EnterococciEnterococci..

- -Ceftobiprole cannot be given by mouth. Given Ceftobiprole cannot be given by mouth. Given parentrallyparentrally..

- -Ceftobiprole is Ceftobiprole is notnot licensed to be used in licensed to be used in childrenchildren

- - -Ceftobiprole has been approved for use in Ceftobiprole has been approved for use in Canada and Switzerland (after Feb 2008), and is Canada and Switzerland (after Feb 2008), and is under review by regulatory authorities in the under review by regulatory authorities in the United States, the European Union, Australia, United States, the European Union, Australia, Russia and South AfricaRussia and South Africa..

Side effects of Side effects of CephalosporinCephalosporin

1- Allergic Reactions1- Allergic Reactions of the penicillin type of the penicillin type such as rash, urticaria and anaphylaxis. such as rash, urticaria and anaphylaxis.

-There is -There is cross allergy between penicillincross allergy between penicillin and cephalosporins involving and cephalosporins involving about 10%about 10%

of patients.of patients.

2- Pain at the site of IM injection2- Pain at the site of IM injection and and thrombophlebitis after IVthrombophlebitis after IV use can occur. use can occur.

3-3- All cephalosporins can produce All cephalosporins can produce pseudomembranous colitispseudomembranous colitis caused by caused by

Clostridium difficile.Clostridium difficile.

4- 4- If cephalosporins are continued for more If cephalosporins are continued for more than 2 weeks , than 2 weeks , thrombocytopenia, thrombocytopenia, leucopenia, interstitial nephritis or leucopenia, interstitial nephritis or

abnormal liver function testsabnormal liver function tests may occur may occur especially at high dosage. These reversed especially at high dosage. These reversed

on stopping the drug.on stopping the drug.

Other agents affecting the Other agents affecting the cell wallcell wall

11 - -VancomycinVancomycin::Vancomycin is a tricyclic glycopeptide Vancomycin is a tricyclic glycopeptide that has become increasingly important that has become increasingly important because of its because of its effectiveness againsteffectiveness against multiple drug resistant organismsmultiple drug resistant organisms such such

as as methicillin-resistant staphylococcimethicillin-resistant staphylococci..

Mechanism of actionMechanism of action VancomycinVancomycin Vancomycin inhibits synthesis of bacterial cell wall Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan layer at a phospholipids as well as peptidoglycan layer at a site earlier than that inhibited by the B-lactam site earlier than that inhibited by the B-lactam antibioticsantibiotics..

Antibacterial spectrumAntibacterial spectrum:: - -In order to limit the increase in vancomycin-In order to limit the increase in vancomycin-

resistant bacteria, it is important to restrict its use resistant bacteria, it is important to restrict its use to the treatment of to the treatment of serious infections caused by serious infections caused by B-lactam-resistant gram-positive microorganisms, B-lactam-resistant gram-positive microorganisms, or for patients with gram-positive infections who or for patients with gram-positive infections who have a serious allergy to the B-lactamshave a serious allergy to the B-lactams..

Clinical uses of VancomycinClinical uses of Vancomycin

11--It is also used for potentially It is also used for potentially life-threatening life-threatening antibiotic-associated colitisantibiotic-associated colitis due to Clostridium due to Clostridium difficile (difficile (pseudomembranous colitis)pseudomembranous colitis) or or staphylococcistaphylococci..

22 - -Vancomycin is used in individuals with Vancomycin is used in individuals with prosthetic heart valvesprosthetic heart valves or in patients being or in patients being

implanted with prosthetic devicesimplanted with prosthetic devices.. 33 - -Vancomycin Vancomycin actsacts synergistically with the synergistically with the

aminoglycosidesaminoglycosides and this combination can be and this combination can be used in the treatment of used in the treatment of enterococcal enterococcal

endocarditisendocarditis..

Side effects Side effects of Vancomycinof Vancomycin

- -Side effects are a Side effects are a serious problemserious problem with with vancomycin and includevancomycin and include::

11-- Fever, chills, and/or phlebitis at the infusion site. Fever, chills, and/or phlebitis at the infusion site. 2- 2- Shock has occurred as a result of rapid Shock has occurred as a result of rapid administrationadministration..

-33-- Flushing ("red man syndrome") and shock Flushing ("red man syndrome") and shock result due to histamine release caused by rapid result due to histamine release caused by rapid

infusioninfusion . .-44 - -Dose-related hearing loss has occurred in Dose-related hearing loss has occurred in

patients with renal failure who accumulate the patients with renal failure who accumulate the drugdrug..

Other agents affecting the Other agents affecting the cell wallcell wall

22 - -BacitracinBacitracin:: - -Bacitracin is a mixture of polypeptides that Bacitracin is a mixture of polypeptides that

inhibits bacterial cell wall synthesisinhibits bacterial cell wall synthesis.. - - -It is active against a wide variety of It is active against a wide variety of

gram-positive organismsgram-positive organisms . .- - -Its use is restricted to topical Its use is restricted to topical

application because of its potential for application because of its potential for nephrotoxicitynephrotoxicity..