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Cephalosporins
Cephalosporins are β-lactam antibiotics similar to penicillins, with a spectrum of action against various bacteria and classified into five generations. They possess a similar mechanism of action and resistance patterns, though each generation has distinct uses and pharmacokinetics. Common indications include treatment of respiratory infections, surgical prophylaxis, and urinary tract infections, while they may cause adverse effects such as allergic reactions and nephrotoxicity.
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Cephalosporins
- 1. CEPHALOSPORINS Dr Naser AshrafTadvi Associate Professor Department of Pharmacology Ayaan Institute of Medical Sciences
- 2. CEPHALOSPORINS •The cephalosporins areβ-Lactam antibiotics closely structurally and functionally to the penicillins. •Mechanism of action, mechanism of resistance and some other properties of cephalosporins are identical to penicillins) •Cephalosporins are one of the most widely used antibiotics and are equal in importance to penicillin.
- 3. HISTORY OF CEPHALOSPORINS •In1945 Giuseppe Brotzu`s discovered that cultures of Cephalosporium acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria.
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- 5. MECHANISM OF ACTIONOF CEPHALOSPORINS cephalosporins Bind & inactivate CBP on cell wall of susceptible bacteria Inhibit transpeptidase Autolysis & cell death Prevent peptidoglycan synthesis Cell wall deficient forms
- 6. MECHANISMS OF RESISTANCE •Alterationof binding site. •Decrease permeability. •Production of β–lactamase enzymes (enzymatic inactivation)
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- 8. FIRST GENERATION CEPHALOSPORINS (SPECTRUMOF ACTION) +Cocc i - Bacilli > Streptococ ci Pneumoco cci MSSA Proteus Ecoli Klebsiella Peptococci
- 9. PHARMACOKINETICS • Oral cephalosporinsare well absorbed • Do not cross BBB • Primarily excreted by the kidney • Probenecid prolongs their half life • All administered 6-8 hourly except cefadroxil which is administered 12 hourly
- 10. INDICATIONS / USES •Not used for serious infections and ineffective in meningitis • Minor staphylococcal infections • Infections like cellulitis and soft tissue abscess • Cefazolin has better penetration to tissues hence is drug of choice for surgical prophylaxis before cardiac surgery and orthopedic prosthesis procedures
- 11. SECOND GENERATION CEPHALOSPORINS Oral • Cefaclor •Cefuroxime axetil • Cefprozil Parenteral • Cefuroxime • Cefotetan • Cefamandole • Cefoxitin
- 12. SECOND GENERATION CEPHALOSPORINS (SPECTRUMOF ACTION) +Cocc i- Bacilli - Cocci > Extended Gram -ve coverage H Influenzae N. Gonorrhoeae Proteus E coli Klebsiella Less active against gram positive cocci and bacilli than 1st Generation S pneumoniae S Pyogenes
- 13. PHARMACOKINETICS • cefaclor, cefprozil,cefuroxime axetil good oral bioavailability • Only cefuroxime crosses BBB & achieves therapeutic concentration in CSF • More stable to beta lactamases except cefaclor • Intramuscular injections are painful •Excreted unchanged in Kidney
- 14. INDICATIONS/ USES • Cefoxitin& Cefotetan have good anaerobic activity used in anaerobic infections like peritonitis, diverticulitis, gynecological infections • Cefaclor & cefprozil used to treat respiratory tract infections • Cefuroxime • used in community acquired pneumonia, • single dose therapy iv for PPNG Gonorrhoea, • meningitis – third generation cephalosporins preferred • cefamandole preferred for treating sexually transmitted diseases
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- 16. THIRD GENERATION CEPHALOSPORINS (SPECTRUMOF ACTION) +Cocc i- Bacilli + Bacilli - Cocci > Highly effective H Influenzae Enterobacter N. Gonorrhoeae, Meningitis Proteus E coli Klebsiella Less active against gram positive cocci than 1st GenerationAnaerobes Cefoperazone and Ceftazidime effective against Pseudomonas
- 17. PHARMACOKINETICS • All cancross BBB • Ceftriaxone has t½ : 7-8 hours and high plasma protein binding 90% • Cefotaxime metabolized to active metabolite • Cefoperazone and ceftriaxone excreted through bile • All others major route of excretion is urinary
- 18. INDICATIONS/ USES • Seriousinfections caused by: Klebsiella, Enterobacter, Proteus, Haemophilus species. • Gonorrhoea: Ceftriaxone DOC for all forms • Meningitis : Cefotaxime= 1gm 6- 12 hrly , ceftriaxone = 4 gm then 2 gm IV daily OD for 7to 10 days Ceftazidime + aminoglycoside is the drug of choice for Pseudomonas meningitis •UTI: Cefixime, Cefpodoxime 200- 400 mg BD
- 19. INDICATIONS/ USES •Respiratory tractinfections: Community acquired pneumonia, chronic bronchitis, otitis media, sinusitis, pharyngitis. • Typhoid: ceftriaxone 4 gm IV daily for 2 days then 2 gm daily till fever subsides Oral cefixime 200 mg BD
- 20. FOURTH GENERATION CEPHALOSPORINS • cefipime,cefpirome, cefozopran • Methicillin-sensitive Staphylococcus aureus • Streptococcus Gram + • HENPEcK. • Serratia • Acinetobacter • Pseudomonas aeruginosa Gram -
- 21. FIFTH GENERATION CEPHALOSPORINS • Ceftaroline,ceftobiprole • Bind to and inhibit altered PBP 2a Produced by MRSA and penicillin resistant Streptococcus Pneumoniae • Retain spectrum of 4th generation cephalosporins and notable increase in activity against gram positive cocci ( MRSA, streptococcus pneumoniae and pyogenes, enterococcus) •Limited activity against anaerobes
- 22. S p e c t r u m c e p h a l o s p o r i n s I Generatio n Gm - ve PEcK Gm + ve HENPEcK HENPEcK Enterobacteraciae,ba ct.Fragilis, pseudomonas I I Generation I I I Generation IV Generation Also against serratia, acinebacter V Generation MRSA, S. Pneumoniae
- 23. ADVERSE EFFECTS • Allergicand hypersensitivity reactions • Disulfiram-like effect: cefamandole, cefaperazone • Bleeding: cefamandole, & cefoperazone • Nephrotoxicity: Cephalothine • Ceftriaxone: pseudolithiasis • Neutropenia & thrombocytopenia: ceftazidime • Superinfection, pseudomembranous enterocolitis and diarrhoea : • Pain at the injection site
- 24. OTHER B-LACTUM ANTIBIOTICS Monobactums: Aztreonam Monocyclic Low affinity for PBP OF Staph, strepto & anaerobes Spectrum: Aerobic Gm –ve , enteric bacilli & H-influenzae at low conc. Pseudomonas at moderate conc Klebsiella, proteus, citrobacter, yersinia, salmonella, shigella, serratia, & neisseria Resistant to Gm – ve B-lactamases
- 25. AZTREONAM: CONTINUED Uses: Gm–ve infections where aminoglycosides are to be avoided Hospital acquired infections: urinary, biliary , GIT, female genital tract Promising feature: Lack of cross sensitivity to other B-Lactum antibiotics Pharmacokinetics: Not bioavailable, IM/IV Mainly excreted by kidneys 60 – 70 % Side effects: Diarrhoea, skin rash, pain
- 26. CARBAPENEMS Imipenem Broad spectrum betalactum effective against Gm + cocci, enterobacteraciae, pseudomonas, listeria, Bacteroides , cl difficle Rapid hydrolysis by dehydropeptidase I Can be combined with cilastatin, a reversible inhibitor of dehydropeptidase- I Dose: 0.5 gm iv 6 hrly max 4 gm/day Can cause seizures in high doses
- 27. CARBAPENEMS Meropenem Not hydrolysedby dehydropeptidase Effective against both Gm + & Gm – bacteria, Aerobes as well as anaerobes Reserve drug for treatment of serious nosocomial infections like septicaemia, febrile neutropenia Cephalosporin resistant Intra-abdominal and pelvic infections With aminoglycosides for pseudomonas infection Dose: 0.5 – 2 gm slow IV 8 hrly
- 28. FAROPENEM Orally active againstmany Gm + & Gm – bacteria including some anaerobes Used mainly in respiratory tract infections Strep pneumoniae, H influenzae, moraxella ENT, genitourinary infections Dose: 200 -300 mg oral TDS
- 29. Other antibiotics inhibitingcell wall synthesis Vancomycin, teicoplanin (Glycopeptides) Daptomycin (lipopeptide) Bacitracin ( polypeptide) Fosfomycin & cycloserine (D-alanine analog)
Editor's Notes
- #3 Except for first generation the rest are more resistant to beta lacatamase and have spectrum of action broader against gram negative organisms and anaerobes Less effective against Enterococcus fecalis, MRSA and Gram positive bacilli
- #4 Cephalosporins are obtained from fungus cephalosporium acremonium , cephamycins are obtained from streptomyces lactamdurans
- #5 Dihydrothiazine ring fused with a beta lactam ring containing appropriate side chains at position 7 and 3 many drugs in use today are synthetic or semisynthetic and are obtained by chemical modification at position 3 and 7 Cefamycins have 7 alpha methoxy structure (och3) examples of cephamycin os cefoxitin and cefotetan
- #9 No activity against anaerobic gram negative bacteroides fragilis
- #11 For impetigo : cefalothin is used Cellulitis ( cephalexin) 250 mg 6-8 hourly Prophylaxis of surgical wound infections (cefazolin) 0.25 gm 8 hrly IM/IV
- #13 No activity against anaerobic gram negative bacteroides fragilis
- #14 Cefuroxime axetil is ester prodrug form in which the ester is hydrolysed during passage through intestinal passage
- #17 No activity against anaerobic gram negative bacteroides fragilis
- #18 All are highly resistant to degradation by beta lactamases produced by gram negative bacteria
- #21 Used against hospital acquired infections, pneumonia, bacteremia, septicaemia, slso useful in utis respiratory infections, empiric therapy for febrile neutropenia patients
- #24 Disulfiram-like effect: cefamandole, cefotetan, cefaperazone Bleeding: cefamandole, & cefoperazone (containing an N-methyl-5-thiotetrazole moiety at the 3 position) b/c of antivitamin K effects, administration of the vitamin corrects the problem.
- #25 Lacks cross sensitivity with other penicillins Dose: 0.5 – 2 gm IM/IV 6-12 Hrly
- #28 More potent on gram negative aerobes but less potent on gm positive cocci