CEPHALOSPORINS AND CEPHAMYCINSAND CEPHAMYCINS

Dr. Deepak K Gupta

Introduction• Cephalosporins N, C or P - steroidal antibiotic that

resembles fusidic acid.

• first isolated from Cephalosporium fungus

• Semisynthetic broad-spectrum cephalosporins -produced by addition, to the cephalosporin C produced by addition, to the cephalosporin C nucleus

• water-soluble and relatively acid-stable

• cephamycins are β-lactam antibiotics -Streptomyces organisms– closely related to the cephalosporins

Generations of CephalosporinOral Parentral

1st generation

Cephalexin Cephalothin

Cephradine Cefazolin

Cefadroxil

2nd generation

Cefaclor CefuroximeCefaclor Cefuroxime

Cefuroxime axetil Cefoxitin

3rd generation

Cefixime Cefotaxime

Cefdinir Ceftizoxime

Ceftibuten Ceftriaxone

Ceftamer pivoxil Ceftazidime

4th generation

Cefepime

Cefpirome

Mechanism of action

• Similar to that of the penicillins

• Interference with bacterial peptidoglycansynthesis

• Resistance to this group of drugs has • Resistance to this group of drugs has increased - plasmid-encoded or chromosomal β-lactamase in bacteria

1st Generation1 Generation

First Generation Cephalosporin• Active against gram-positive cocci, such as

pneumococci, streptococci, and staphylococci.• Traditional cephalosporins - not active against MRSA

strain.• E coli, K pneumoniae , and Proteus mirabilis are often

sensitivesensitive• Clinical Use– drug of choice for surgical prophylaxis– urinary tract infections– cellulitis or soft tissue abscess– cannot be used to treat meningitis– Alternative to penicillin allergic individual

Cefazolin

• 1st cephalosporin – active against most PnGsensitive organism

• Streptococci, gonococci , meningococci, C. diptheriae, H. influenzae, clostrodia and ActinomycesActinomyces

• Given I.M. or I.V., longer t1/2 – 2hrs – slow tubular secretion

• Preferred parentral – 1st generation ceph

• Dose : 0.25 g X 8 hrs - mild, 1 g X 6 hrs - severe

Cephalexin

• 1st oral ceph, similar to cefazolin but less active against penicillinase producing Staphylococci and H. influenza.

• Little bound to plasma proteins – high • Little bound to plasma proteins – high concentration in bile

• t ½ - 60 min

• Most commonly used cephalosporin

• 0.25 – 1 g – (6 - 8 hrs), child : 25-100 mg/kg/day

Cefadroxil

• Close congener of cephalexin, antibacterial similar

• Good tissue penetration – sustained action at the site of infectionthe site of infection

• t ½ - 1 hr.

• Excreted unchanged on urine.

• Dose: 0.5 – 1 g BD

Second Generation

Second generation Cephalosporin

• More active against gram negative organism, with some members active against anerobes

• But none inhibits P. aeruginosa.• Replaced by third generation – more active• Clinical Use• Clinical Use– treat sinusitis, otitis, and lower respiratory tract

infections– treat mixed anaerobic infections such as peritonitis,

diverticulitis, and pelvic inflammatory disease– community-acquired pneumonia– less effective in treatment of meningitis

Cefuroxime

• Resistance to gram negative beta-lactamase

• Highly active against PnG and ampicillinresistant H. influenza.

• Well tolerated by i.m. route and attains • Well tolerated by i.m. route and attains relatively higher level in CSF (ideal for meningitis)

• Single dose i.m. theraphy – Gonorrhoea

• Dose : 0.75 – 1.5 g i.m. or i.v. 8hrly, Child : 30-100 mg/kg/day

Cefuroxime axetil

• Esters of cefuroxime

• Effective orally – absorption is incomplete

• Activity depends on in vivo hydrolysis and release of cefuroxime.release of cefuroxime.

• Dose: 250-500 mg BD, Child: half dose

Cefaclor

• Significant activity by oral route

• More active than first generation compound again H. influenzae, E. coli, and Pr. Mirabilis

• Dose: 0.25 -1.0 g X 8 hrly• Dose: 0.25 -1.0 g X 8 hrly

3rd generation Cephalosporin3rd generation Cephalosporin

3rd generation Cephalosporin

• Expanded gram-negative coverage, and some are able to cross the blood-brain barrier

• Also effective against β-lactamase-producing strains of haemophilus and neisseria.

• Ceftazidime and cefoperazone are the• Ceftazidime and cefoperazone are theonly two drugs with useful activity against P. aeruginosa.

• Not reliably active against Enterobacter species -hydrolyzed by β lactamase.

• Serratia, Providencia and Citrobacter -cephalosporinase

Clinical Use

• Treat a wide variety of serious infections caused by organisms that are resistant to most other drugs

• avoided in treatment of enterobacter infections• Ceftriaxone and cefotaxime - meningitis, including

meningitis caused by pneumococci, meningococci, meningitis caused by pneumococci, meningococci, H influenzae and susceptible enteric gram-negative rods, but not by L-monocytogenes

• empirical therapy of sepsis of unknown cause inboth the immunocompetent and the immunocompromised patient

• Hospital Acquire infection

Cefotaxime

• Prototype of 3rd generation ceph.

• Potent action – aerobic gram-negative as well as some gram positive bacteria, but not active against anaerobes ( S. aureus, Ps. aeruginosa)against anaerobes ( S. aureus, Ps. aeruginosa)

• Single dose therapy – urethritis

• T ½ - 1 hr

• Dose : 1-2 gm i.m/i.v 8-12 hrly, child dose : 50-100 mg/kg/day

Cefixime

• Orally active 3rd generation ceph

• Highly active against Enterobacteriacae, H. influenzae, but resistant to beta-lacatmaserelasing microbes ( S. aureus, most pneumococci & Pseudomonas)pneumococci & Pseudomonas)

• Respiratory, urinary and bilary infection

• T ½ - 3 hr

• Stool changes and diarrhoea – s/e

• Dose : 200-400 mg BD, Child dose : half

4th generation Cephalosporin4 generation Cephalosporin

4th generation Cephalosporin

• more resistant to hydrolysis by chromosomalβ lactamases - Enterobacter

• Like the third-generation compounds, it is hydrolyzed by extended spectrum β hydrolyzed by extended spectrum β lactamases

CEFEPIME• Similar to 3rd generation but highly resistant to beta-

lactamase.• Active against many bacteria which used to not get

killed by earlier generation• Enterobacteriacae, H. influenzae, S. aureus, most

pneumococci & Pseudomonas.pneumococci & Pseudomonas.• high potency – serious infection acquired from hospital– Pneumonia– Febrile neutropenia– Bacteraemia– Septicaemia

• Dose: 1-2 gm (50 mg/kg) i.v. 8-12 hrly

Adverse effect of Cephalosporin

• Pain

• Diarrhoea

• Hypersensitivity

• Nephrotoxicity• Nephrotoxicity

• Bleeding

• Neutropenia and thrombocytopenia - rare