Cephalosporins

cell wall inhibitors

1. Cephalosporins Jagir R. Patel Asst Professor Dept. Pharmacology

2. I ntroduction The  cephalosporins   are a class of  β- lactam antibiotics originally derived from the  fungus Acremonium , which was previously known as " Cephalosporium”

3. C lassification 1 st Gen : Cephalothin , Cephalexin, Cefazolin Cephradine, Cefadroxil 2 nd Gen: Cefuroxime Cefaclor, Cefoxitin * Cefuroxime axetil 3 rd Gen: Cefotaxime, Cefixime, Ceftizoxime Cefpodoxime proxetil, Ceftriaxone Cefdinir, Ceftazidime Ceftibuten, Cefoperazone Ceftametpivoxil 4 th Gen : Cefepime, Cefpirome 5 th Gen : Ceftaroline fosamil, Ceftolozane, Ceftobiprole

4. Mechanism of action

5. Mechanism of action

6. Mechanism of resistance Acquired resistance to cephalosporins could have the same basis as for penicillins, i.e.: (a) alteration in target proteins (PBPs) reducing affinity for the antibiotic . (b) impermeability to the antibiotic or its efflux so that it does not reach its site of action. elaboration of p-lactamases which destroy specific cephalosporins (cephalosporinase).

7. 1 st Gen Spectrum Gram Positive Cocci, including MSSA (Does NOT cover Enterococcus) Gram Negative Rods No CNS penetration Coverage MSSA Streptococci Grp A,B,C,G Strep viridan s S. pneumoniae H. influenzae E. coli Klebsiella pneumoniae Proteus mirabilis

8. Cephalexin General information : administered orally may not cross the blood brain Barrier Side effects hypersensitivity reactions, leading to fever, skin rashes, angioedema and/or anaphylactic shock consecutive hypersensitivity to penicillins (due to cross reactivity) diarrhea (due to gastrointestinal overgrowth by cephalosporin-resistant bacteria) Medical uses treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection treatment of pharyngitis due to streptococcus infection

9. 2 nd Gen intermediate spectrum Same as 1st Generation Plus: β- lactamase positive  H. influenzae Moraxella catarrhalis Neisseria meningitidis E. coli Klebsiella pneumoniae Proteus Oral anaerobes Cefoxitin & Cefotetan cover  B. fragilis

10. Cefaclor & Cefuroxime General information : administered orally may not cross the blood brain Barrier Indications: treatment of pharyngitis due to streptococcus infection -Treatment of pneumonia due to streptococcus, enterobacter , klebsiella, proteus and/or haemophilus infection. Side effects same as cephalexin

11. 3 rd broad spectrum 3rd Generation Coverage Same as 1st Generation Plus: Expanded gram-negative coverage Oral anaerobes S. aureus  (OSSA) Strep pneumoniae Strep Grp A,B,C,G Strep viridans Gram negative rods N. gonorrhea All cover  B. fragilis  EXCEPT cefotaxime & ceftazidime P. aeruginosa  - ceftazidine only

12. C efotaxime Administered intramuscularly and/or IV may cross the blood-brain barrier Interactions: Cefotaxime + aminoglycosides = nephrotoxicity ADV : Clostridium difficile -associated diarrhoea and colitis, arrhythmias, anaphylaxis . Medical uses Pharyngitis: due to streptococcus infection M eningitis due to streptococcus, haemophilus and/or neisseria infection Gonorrhea due to neisseria infection Septicaemia Surgical prophylaxis Dose: 1-2gm per day

13. Ceftriaxone Administered intramuscularly and/or IV may cross the blood-brain barrier exctred via urine and faeces ADV : Anaphylaxis ,  Clostridium difficile -associated diarrhoea and colitis, hemolytic anemia . Indications: Uncomplicated Gonorrhoea, Prophylaxis of surgical infections Contraindications : to hypersensitive to cephalosporins

14. 4 th gen Spectrum Good gram-positive & gram-negative coverage Anti- Pseudomonal (including ceftazidime resistant isolates) Penetrates CSF Limited anaerobic coverage

15. Cefepime Absorption :  Rapidly and almost completely absorbed on IM inj. Time to peak plasma concentration: Approx 1.5 hr (IM); w/in 30 min (IV ). Distribution:  Widely distributed in body tissues and fluids; high concentrations in bile. Crosses the blood-brain barrier and enters breast milk (low concentrations). Plasma protein binding: Approx 20 %. Metabolism :  Minimally hepatic . Excretion :  Via urine (approx. 85% as unchanged drug). Plasma half-life: Approx 2 hr . ADV : Neurotoxicity (e.g. encephalopathy, myoclonus, seizures, non-convulsive status epilepticus );  Clostridium difficile -associated diarrhoea; anaphylaxis.

16. Indications: Respiratory tract infections Skin and skin structure infections Urinary tract infections Abdominal infections Empiric therapy for febrile neutropenic patients Dose: 1-2gm daily

17. Cefpirome Administration : i.v. Distribution :  Widely distributed into body tissues and fluids; enters breast milk. Protein-binding: 10 % Excretion:   Mainly by the kidneys via the urine (80-90% as unchanged); significantly removed by hemodialysis; 2 hrs (elimination half-life); prolonged in renal impairment . Adv.: Pseudomembranous colitis . Indications : Susceptible infections

18.  diarrhea, nausea, rash, electrolyte disturbances, and pain and inflammation at injection site. vomiting, headache, dizziness,  pseudomembranous colitis, superinfection, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and fever .  hypoprothrombinemia and a disulfiram-like reaction with ethanol Hypersensitive reaactions

19. General characteristics Bactericidal Bind to Penicillin Binding Proteins Resistant to Penicillinase, but not other classes of β- lactamases (e.g. Extended Spectrum Beta- Lacatamases or ESBLs) Renal excretion Side Effects Hypersensitivity reactions  (Cross-hypersensitivity with penicillins 1-3%) Superinfections:  Enterococci, Enterobacter and Candida

20. New drugs Ceftaroline fosamil is a fifth-generation ] cephalosporin  antibiotic . It is active against methicillin-resistant  Staphylococcus aureus  (MRSA) and Gram-positive bacteria. It retains the activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria. It is currently being investigated for  community-acquired pneumonia  and complicated skin and skin structure infection.

21. Ceftolozane   Ceftolozane  is a 5th generation cephalosporin antibiotic , developed for the treatment of infections with gram-negative bacteria that have become resistant to conventional antibiotics .  It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia. Ceftolozane is combined with the  β- lactamase inhibitor   tazobactam , which protects ceftolozane from degradation .   Ceftolozane- tazobactam is indicated for the treatment of complicated urinary tract infections and complicated intra abdominal infections .

22. Ceftobiprole Ceftobiprole is a new 5th-generation   cephalosporin  for the treatment of  hospital-acquired pneumonia ( HAP, excluding ventilator-associated pneumonia, VAP) and  community-acquired pneumonia  (CAP ). Ceftobiprole has high affinity for PBP2a  of  methicillin resistant   Staphylococcus aureus  (MRSA) strains