V.THIRUMALAI

LECTURER

DEPARTMENT OF PHARMACOLOGY

RVS.DENTAL COLLEGE AND HOSPITAL

INTRODUCTION

• β – lactam antibiotics comprised of four different groups .

Penicillins

Cephalosporins

Monobactams

Carbapenems

CEPHALOSPORINS

• Isolated from fungus “Cephalosporinumacremonium”.

• Chemical structure comprises, β – lactam ring and dihydrothiazideActive nucleus : 7-aminocephalosporinic

acidChemically similar to penicillin, so it

shares the mechanism of action and adverse effects with that .

CEPHALOSPORINS Vs

PENICILLINSCephalosporins are ,

• More acid stable

• More resistant to β – lactamase(cephalosporinase) degradation

Therefore have a broad spectrum of activity against Gm –ve bacteria and anaerobes compared to penicillin .

CLASSIFICATION PARENTERAL ORAL

FIRST GENERATION1960

Cephalothin *,

cefazolin

Cephalexin,

cephradine, Cefadroxil

SECOND GENERATION1970

Cefuroxime, Cefoxitin* Cefaclor, Cefuroxime

Axetil, Cefotetan

THIRD GENERATION1980

Cefotoxime,

Ceftizoxime,

Ceftriaxone,

Ceftazidime,

Cefoperazone

Cefixime, Cefpodoxime

proxetil, Cefdinir,

Ceftibuten, Ceftamet

pivoxil

FOURTH GENERATION1997-1998

Cefepime, Cefpirome

FIFTH GENERATION Ceftobiprole -

SPECTRUM OF ACTIVITY CEPHALOSPORINS

MORE ACTIVE AGAINST

MODERATELY ACTIVE AGAINST

I generation Gm+ Ve Cocci Gm-ve cocci, Gm+ve bacilli & Anaerobic Gm+ve cocci .

II generation Anaerobs , Gm-ve cocci & Gm-ve bacilli

Gm+ Ve Cocci & Gm+ve bacilli

III generation Anaerobs , Gm-ve cocci & Gm-ve bacilli

Gm+ Ve Cocci & Gm+ve bacilli

IV generation* Gm-ve cocci & Gm-vebacilli (resistant to III gen)

Gm+ Ve Cocci

* No activity against anaerobes and Gm+ve bacilli

No action against ; Enterococcus faecalis, Methicillin resistant Staphylococcus aureus (MRSA)& Listeria monocytogenes.

CEPHALOSPORINS

Gm+ve Gm-ve CSF penetration

I generation None

II generation None . Exc. Cefuroxime

III generation ALL . Exc. Cefoperazone & cefixime.

IV generation : good Gm+ve and Gm-ve activity , and good resistant against β – lactamase.

MECHANISM OF ACTION CEPHALOSPORINS

BIND TO CBP

INHIBITS TRANSPEPTIDATION IN BACTERIAL CELL WALL SYNTHESIS

IMPERFECT CELL WALL

OSMOTIC DRIVE FROM ECF.

INSIDE HYPERTONIC BACTERIAL CYTOPLASM.

ACTIVATION OF AUTOLYSIN ENZYME LEADS TO AUTOLYSIS OF BACTERIA.

BACTERIOCIDAL ACTIVITY

Cefazolin:

• Prototype for I generation drug.• Active against most PnG sensitive

organisms , i.e Streptococci, C.diphtheriae, gonococci, meningococci, H.Influenzae, clostridia& actinomycetes .

• PK : route – i.m and i.vt ½ - longer (2 h )

• preferred in parenteral I generation drug for surgical prophylaxis .

Cefuroxime:• II generation drug • Resistant to β – lactamases.• High activity against organisms producing

enzymes including PPNG & amp- resistant H. Influenza.

• Significant activity against Gm+ve cocci and certain anaerobes.

• Route : parenteral (i.m/i.v)• Higher CSF level and well tolerated by i.m . • Sigle dose i.m therapy of gonorrhoea due to

PPNG is available.

Cefotaxime: • Prototype for III generation drug.

• Potent action on aerobic Gm-ve as well as Gm+ve.

• No activity on anaerbes, Staph.areus and Ps.aeruginosa.

• Indications : meningitis(Gm-ve bacilli), life threatening resistant / hospital acquired infections , septiceamias and immunocompromised patients.

• PK: route – im/i.v

metabolism – deacetylation

t ½ - 1 Hr

Cefixime:

• III generation , orally active .• High activity against Enterobacteriaceae,

H.influenzae .• Resistant to many β – lactamases. • No activity against Staph.aureus,

Pneumococci and Pseudomonas.• t ½ - 3 hr• Indication – respiratory, urinary & biliary

tract infection .• Side effects : stool changes & diarrhoea.

USES

• Alternative to Pn G (particularly in allergic patients not in anaphylactic reaction).

• H.influenza infection :

E.g : Cephalexin (I)< Cefazolin (I)< Cefuroxime (II)< Cefaclor (II)< Cefixime (III)

• Respiratory , urinary and soft tissue Gm –veinfections.

E.g: cefuroxime (II),cefotaxime (III), ceftriaxone(III)

• Septicaemias (Gm-ve).

E.g: cefotoxime(III) , ceftriaxone(III), cefoperazone(III), cefepime(IV), cefprione(IV).

Cont...

• Surgical prophylaxis (surgical prosthesis like art.herat valve, art.joints etc) .

E.g : Cefazolin(I)

• Meningitis : (gm-ve)

E.g: cefotaxime (III), ceftriaxone (III) & ceftazidime (III).

• Gonorrhoea: (pen.p.org)

E.g: ceftriaxone(III) , cefuroxime(II), cefotaxime (III).

Cont...• Typhoid .

E.g cefoperazone (III), ceftriaxone (III).

Organism which are resistant to chloramphenicol, ampicillin and cotrimaxazole. Alternative drug for fluroquinolone (children).

• Mixed infection (aerobic + anaerobic) , cancer, colorectal surgery and obstetric complications (peritonitis,diverticulitis ) .

E.g: cefuroxime (II).

Cont...

• Hospital acquired infection like pneumonia. E.g: cefotaxime(III), ceftizoxime (III), cefiprime (IV), cefipirone(IV).

• Prophylaxis and treatment for neutropenic patients .

E.g : ceftazidime (III).

ADVERSE DRUG EFFECTS

• Pain after I.m injection

• Diarrhoea

• Hypersensitive reaction

• Nephrotoxicity-E.g: cephalothin (alternative aminoglycoside with loopdiuretics).

• Bleeding disorders due to hypoprothrobinemia –E.g: cefoperazone(III), ceftriaxone (III).

• Thrombocytopenia and neutropenia . E.g : ceftazidime (III).

• Disulfiram like reaction – cefoperazone (III), cefotetan (II)

Which bacteria are resistant to

Cephalosporins?

• MRSA

• Listeria

• Enterococci

Name the Cephalosporins which

can penetrate into CSF?

• Cefuroxime

• Ceftazidime

• Cefotaxime

• Ceftriaxone

• Cefipime

• cefpirome

Why is Cefazolin preferred as a

prophylactic antibiotic prior to

surgery ?• It is the most active cephalosporin against

Methicillin suceptible S.aureus (MSSA) and other gm+ve organisms.

• It has a long t ½ (1.8 h) as compared to others .

• It penetrates well into the tissues.

• It is the most active against the most likely pathogens encountered during clean surgeries.

Why ceftriaxone is not

recomended in premature infants

and neonates?• It can displace bilirubin from protein

binding sites and can cause hyperbilirubinemia.

Which cephalosporins are used in

Pseudomonas infection ?

• Cefoperazone

• Cefrazidime

• Cefuslodine

• Cefpiramide

• Cefepime

• cefpirome

Which cephalosporins are used in

biliary infections and biliary sepsis ?

• Cefoperazone

• Ceftriaxone

• Cefixime

• cefpiramide

WHO –RECOMMENDED ESSENTIAL MEDICINE

• Cefalexin

• Cefazolin

• Cefixime

• Ceftriaxone

• Cefotaxime

• Ceftazidime

WHO –RECOMMENDED ESSENTIAL MEDICINE

• Cephalexin (I)

• Cefazolin (I)- surgical prophylaxis.

• Cefixime (III- O)- Only for single‐dose treatment of

uncomplicated ano‐genital gonorrhoea.

• Ceftriaxone (III)- Do not administer with calcium and

avoid in infants with hyperbilirubinemia

• Cefotaxime (III) choice for use in

• Ceftazidime (III) hospitalized neonates.

MONOBACTAM

• Aztreonam: only monobactam currently available in clinical .

• MOA- binds PBP 1a & 3 . Inhibits cell wall synthesis.

• Spectrum of activity : aerobic gm –ve only

• Only i.m /i.v ; (poorly absorbed orally)

Cont...

• Resistant to β – lactamase .

• No cross sensitivity to penicillin & cephalosporins.

• Synergistic with aminoglycosides.

• Side effects : diarrhoea , pain at injection site and skin rashes.

What is the role of Aztreonam in

clinical practice ?

• An Alternative to aminoglycosides and III generation cephalosporins in Gm-veinfections and is preferred in patients with renal impairments where aminoglycosides are to be avoided.

CARBAPENEMS

• Structurally related to β – lactamantibiotics.

• Imipenem, Meropenem and Faropenemare in clinical use now.

• MOA: species specific binding to PBP

• Spectrum of activity : gm +ve (inc . Pen. Resistant sp ) , gm-ve (inc. P.aeruginosa) and anaerobes.

Cont...

• Renal effects : imipenem – rapidly hydrolyesed by dehydroxypeptidase I (renal brush border) resulting in lower urinary concentration.

• Combination with cilastatin (a reversible dehydroxypeptidaseinhibitor) is advisable .