Cephalosporins

Pharmacology of cephalosporins, monobactums and carbapenums including their mechanism of action, indications, adverse effects.
The various generations of cephalosporins and their spectrum of action

1. Cephalosporins Dr Naser Ashraf Tadvi Associate Professor Department of Pharmacology Ayaan Institute of Medical Sciences

2. Cephalosporins The cephalosporins are β -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 In 1945 Giuseppe Brotzu`s discovered that cultures of Cephalosporium acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria.

4. Structure of Cephalosporins

5. Mechanism of action of 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 Alteration of binding site. Decrease permeability. Production of β–lactamase enzymes (enzymatic inactivation)

7. Classification of CEPHALOSPORINS First generation Second generation Third generation Fourth generation Fifth Generation Parenteral Cephalothin Cefazolin Cefuroxime Cefoxitin Cefotaxime Ceftriaxone Cefoperazone Ceftazidime Ceftizoxime Cefepime Cefpirome Ceftaroline Ceftobirole Oral Cephalexin Cephradine Cefadroxil Cefaclor Cefuroxime axetil Cefprozil Cefixime Cefpodoxime Cefdinir Ceftibuten - -

8. First Generation cephalosporins (Spectrum of action) +Cocci - Bacilli > Streptococci Pneumococci MSSA P roteus Ec oli K lebsiella Peptococci

9. Pharmacokinetics Oral cephalosporins are 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 (Spectrum of action) +Cocci - Bacilli - Cocci > Extended Gram - ve coverage H Influenzae N. Gonorrhoeae P roteus E c oli K lebsiella Less active against gram positive cocci and bacilli than 1 st 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

15. Third Generation cephalosporins Oral Cefixime Cefpodoxime Cefdinir Ceftibuten Ceftolazone Parenteral Cefotaxime Ceftriaxone Cefoperazone Ceftazidime Ceftizoxime

16. Third Generation cephalosporins (Spectrum of action) +Cocci - Bacilli + Bacilli - Cocci > Highly effective H Influenzae Enterobacter N. Gonorrhoeae, Meningitis P roteus E c oli K lebsiella S erratia Less active against gram positive cocci than 1 st Generation Anaerobes Cefoperazone and Ceftazidime effective against Pseudomonas

17. Pharmacokinetics All can cross 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 Serious infections 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 tract infections: 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

21. Fifth generation cephalosporins Ceftaroline , ceftobiprole Bind to and inhibit altered PBP 2a Produced by MRSA and penicillin resistant Streptococcus Pneumoniae Retain spectrum of 4 th 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 um c e p h a l o s p o r i n s I Generation Gm - ve PEcK Gm + ve HENPEcK HENPEcK Enterobacteraciae,bact . Fragilis , pseudomonas I I Generation I I I Generation IV Generation Also against serratia , acinebacter V Generation MRSA, S. Pneumoniae

23. Adverse Effects Allergic and 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 beta lactum 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 hydrolysed by 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 against many 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 inhibiting cell wall synthesis Vancomycin , teicoplanin (Glycopeptides) Daptomycin ( lipopeptide ) Bacitracin ( polypeptide) Fosfomycin & cycloserine (D- alanine analog)