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Transcript
Cephalosporins 1 • Cephalosporin antibiotics –derived from “cephalosporin C” –obtained from fungus Cephalosporium acremonium • Cephalosporin nucleus Consists of dihydrothiazine ring fused to a β–lactam ring –7-aminocephalosporanic acid 2 • 7-aminocephalosporanic acid has been modified by addition of different side chains to create a whole family of cephalosporin antibiotics. • these have been conventionally divided into 5 generations 3 Mechanism of action • All cephalosporins are bactericidal. • MOA same as penicillin- Inhibit cell wall synthesis in a manner similar to penicillins • Bind to different proteins than those which bind penicillin. PBP-1 &PBP-3 – This explains diffenece in spectrum, potency & lack of resistance. 4 • • • • • Inhibition of transpeptidation Imperfect cell wall Osmotic drive Activation of autolysin enzymes Lysis of bacteria • BACTERICIDAL 5 CLASSIFICATION • Based on –antimicrobial spectrum –Chronological sequence of development –Divided into generations. 6 First-generation agents • • • • Cephalexin (O) Cefadroxil (O) Cefazolin (i.m, i.v) Cefalothin (withdrawn) 7 • Exhibit good activity against gram-positive bacteria but modest activity against gram negative organisms. – Most gram-positive cocci – Strepto, – Pneumo, – Methicillin sens. Staph. are susceptible to first-generation cephalosporins • Modest activity against E. coli, K. pneumoniae & Proteus mirabilis Most oral cavity anaerobes are sensitive. However, the Bacteroides fragilis group is resistant. 8 Second-generation agents –Cefaclor (O) –Ceforanide –Cefuroxime acetil (O) –Cefuroxime (i.m , i.v) –Cefoprozil –Cefamandole (Banned) –Cefoxitin (Banned) –Cefotetan (Banned) 9 • Exhibit somewhat increased activity against gram negative organisms, – but much less active than third generation agents. • Less active against gram positive cocci & bacilli compared to first gen. drugs. • Use declined • Clinically replaced by 3rd & 4th generation drugs . 10 Third-generation agents • • • • Cefotaxime Ceftriaxone Cefdinir Cefibuten • Cefpodoxime • Ceftizoxime • Ceftazidime • Cefoperazone (withdrawn) 11 • Highly augmented activity against gram-negative organisms • Less active than first generation agents against gram positive cocci & anaerobes. • All are highly resistant to β-lactamases from gram negative bacteria. • Some inhibit psuedomonas as well; ceftazidime, cefoperazone(withdrawn) 12 • Some members of this group have enhanced ability to cross the blood-brain barrier eg. Ceftriaxone and are effective in treating meningitis caused by pneumococci, meningococci, H. influenzae and susceptible gram negative rods. 13 Fourth-generation agents • Cefpirome P/E (im/iv) • Cefepime P/E (iv) • Cefozopran P/E 14 • Highly active against G –ve organisms • Similar to third gen drugs for g +ve bacteria • The fourth generation drugs comparable to third generation but more resistant to hydrolysis by β-lactamases. – Effective against bacterial infections resistant to earlier drugs 15 Fifth-generation agents • Ceftobiprole • Ceftaroline • Active against, g +ve cocci especially MRSA • penicillin resistant S. pneumoniae • and enterococci 16 Resistance • Impermeability to the antibiotic. – to reach its site of action • Alteration in PBPs -antibiotics bind with low affinity • Elaboration of β-lactamases; that can hydrolyze the β-lactam ring and inactivate the cephalosporin (most prevalent mech) 17 Adverse reactions • Pain after im injection • Thrombophlebitis of injected vein. • Diarrhoea more common with – oral Ceferadine – P/E Cefoperazone (Banned) 18 • Hypersensitivity reactions – Identical to penicillins, incidence is lower. – shared β-lactam structure – Allergic to penicillins- allergic to cephalosporins. CROSSREACTIVITY. • Rashes, frequent, anaphylaxis, angioedema, asthma, urticaria have also occurred. 19 • Cephalosporins potentially nephrotoxic drugs – Cephaloridine (withdrawn) RTN – Cephalothin (withdrawn) Acute tubular necrosis • Serious bleeding – Cefoperazone(Banned), – Moxalactam(Banned). – Due to hypoprothrombinemia. 20 • Intolerance to alcohol Disulfiram like reaction – Cefamandole (Banned) – Cefotetan (Banned) – Moxalactam (Banned) – Cefoperazone (Banned) 21 Therapeutic Uses • Extensively used & therapeutically important antibiotics • Effective therapeutic & prophylactic agents 22 First Gen agents • Excellent for skin & soft tissue infections • Surgical prophylaxis first generation drugs are the preferred for prophylaxis in procedures in which skin flora are likely pathogens. 23 Second Gen agents • Displaced by third generation agents for Gram negative infections • Oral-RTI (replaced by augmentin) 24 Third Gen agents • With/without aminoglycosides DOCsevere G -ve infections caused by • Kleibsiella • Enterobacter • Proteus • Providencia • Serratia & haemophillus species. 25 • Ceftriaxone is the therapy of choice for all forms of Gonorrhea – 250 mg i.m as single dose • i.v ceftriaxone for enteric fever • Cefotaxime & ceftriaxone –Community aquired pneumonia 26 • Cefotaxime/ceftriaxone are used for initial treatment of meningitis because of their – antimicrobial activity, – good penetration into CSF – & record of clinical success • They are DOC - Meningitis due to • H. influenzae • Sensitive S. pneumonae • N. meningitidis • G-ve enteric bacteria • Ceftazidime + aminoglycosides – Psuedomonas meningitis DOC 27 Fourth Generation Agents • Same as third generation drugs • Indicated for hospital acquired infections resistant to commonly used antibiotics 28 • Other β -lactam antibiotics 29 Other β -lactam antibiotics • Newer classes of β-lactam antibiotics are the • Monobactams • Carbapenems • Carbacephems • Important therapeutic agents with a β-lactam structure & are neither penicillins nor cephalosporins 30 Monobactams Aztreonam • Isolated from chromobacterium violaceum – Only monobactam currently in clinical use • β - lactam ring, lacking the thiazolidine ring. - a monobactam 31 • Antimicrobial activity differs from those of other β lactam antibiotics & more closely resembles that of an aminoglycoside • Primarily affects : – Aerobic gram negative microorganisms – gram positive bacteria & anaerobic organisms are resistant • Preferred-all sorts of gram negative infections in patients with renal impairment where aminoglycosides are to be avoided. 32 • Stable to most β-lactamases elaborated by gram negative bacteria. • i.m / i.v • Therapeutic conc. in CSF in the presence of inflammed meninges, Alternative to cephalosporins for therapy of meningitis caused by G-ve bacilli 33 Carbapenems • β-lactam antibiotic • Broader spectrum of activity : than most other βlactams . – gram-negative rods – gram-positive bacteria – and anaerobes. 34 Carbapenems • Imipenem • Meropenem • Ertapenem 35 Imipenem • Derived from compound produced by Streptomyces cattleya • Mechanism same as penicillins • Bactericidal • Resistant to hydrolysis by β-lactamase • Marketed in combination with cilastin – Inhibits degradation – by renal dipeptidase – Without cilastin renal dehydropeptidases inactivate the drug which results in low urinary tract concentrations. 36 Adverse effects • Nausea ,vomiting • Seizures • Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem 37 Meropenem • Therapeutic equivalence with imipenem • Coadministration with cilastin not required • Meropenem is less seizure producing compared to imipenem. 38 Ertapenem • Differs from imipenam & meropenem larger serum half life, OD. – Co-administration with cilastin not required – less seizure producing compared to imipenem. 39 • All are parenteral – i.v, im painful • • • • • • Imipenem 6 hrly Meropenam 8 hrly All are resistant to β – lactamases All bactericidal MOA same Patients allergic to other β-lactam antibiotics may have hypersenstivity reactions when given imipenem/carbapenems. 40 Therapeutic uses • Urinary tract infections • Lower respiratory tract infections • Intra-abdominal & gynaecological infections • Skin, bone, joint, & soft tissue infections • Especially cephalosporin/ penicillin resistant nosocomial bacteria. 41 Carbacephems Loracarbef • Synthetic β-lactam antibiotic • Similar to cefaclor • Antibacterial activity resembles II generation cephalosporins. 42 THANK U 43