cephalosporin
TRANSCRIPT
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 .