Cephalosporins

1
Cephalosporins
2
History of Cephalosporins

• Cephalosporin compounds were first isolated from
  cultures of Cephalosporium acremonium from a
  sewer in Sardinia in 1948 by Italian scientist
  Giuseppe Brotzu
• First commercial Cephalosporin was Cephalothin
  launched by Eli Lily in 1964
• Cephalosporins disrupt the synthesis of the
  peptidoglycan layer of bacterial cell walls

3
Molecular Structure
PENICILLIN
CEPHALOSPORIN
4
Classification of Cephalosporins

• First Generation
• Cephazolin
• Second Generation
• Cefuroxime
• Cefaclor
• Cefoxitin (cephamycin)
• Third Generation
• Ceftriaxone, Cefotaxime
• Ceftazidime
• Fourth Generation
• Cefipime

Good activity v Staphs and Streps
Increased activity v Gram Negatives Slightly less
activity against Gram Positives
Very good Gram negative coverage Reasonable
against Gram Positives Ceftazidime has
anti-pseudomonal activity
Very broad spectrum activity including
Pseudomonas
5
5th Generation.

• Ceftobiprole Medocaril
• Activity v MRSA PRP.
• Has completed Phase III trials for treatment of
  soft tissue infections and HAP. Licensing
  probably imminent.

6
First Generation Cephalosporins

• Cephazolin
• Good activity v Streps Penicillin Resistant
  Staphs.
• b.d. but can be o.d. when used with Probenicid.
• Surgical prophylaxis for cardiac and vascular
  surgery, insertion of orthopaedic prostheses, HN
  surgery and most gynaecological surgery.
• Treatment of Soft tissue infections, particularly
  in the outpatient setting. (not for bite wounds
  as poor activity against anaerobes and
  Pasteurella)

7
Second Generation Cephalosporins

• Cefuroxime
• -Increased activity v H. influenzae, M.
  catarrhalis.
• Used for Community Acquired Respiratory Tract
  Infections, Surgical prophylaxis for Colorectal
  Surgery. Treatment of post-operative wound
  infections.

• Cefaclor
• Oral, good against URTIs UTIs. Moderate
  activity in Soft Tissue Infections.

8
Third Generation Cephalosporins

• Ceftriaxone
• Good, broad spectrum Gram negative cover with
  reasonable Gram Positive cover
• Long half life.
• Good CSF penetration. Drug of choice suspected
  bacterial meningitis. However due to PRP add
  Vancomycin until ID and sensitivity known.
• Relatively good v Penicillin Resistant
  Pneumococci
• Special indications- Treatment of N.
  gonorrhoeae, Chancroid, Lyme disease, Typhoid
  fever, Severe Shigella Salmonella infections,
  Gram negative Brain abscess, endocarditis by
  HACEK organisms.
• ?Outpatient treatment of Soft Tissue Infections
• Ceftazidime
• Activity v Pseudomonas also, but should not be
  used as Monotherapy for Pseudomonas infections.

9
Fourth Generation Cephalosporins

• Cefipime
• Broad spectrum including Pseudomonas
• Enhanced activity against certain Gram negative
  bacilli, including Enterobacter, Citrobacter and
  Serratia.
• Uses. Severe Community Acquired Pneumonia
  requiring Intensive Care.
• Not effective v ESBL producing organisms.

10
Cephamycins

• Eg Cefoxitin, Cefotetan
• Often grouped with 2nd generation cephalosporins.
  
• Have anaerobic activity (in particular
  Bacteroides)
• Also in-vitro activity v ESBL bacteria, but
  upregulation of efflux mechanisms limits clinical
  use for these organisms.
• Clinically useful in Surgical Prophylaxis for
  Colorectal Surgery.

11
CephalosporinsMechanisms of Resistance

• i) Antibiotic Destruction by Beta-lactamases
  (Enterobacteraciae)
• ii) Alteration in the PBP target resulting in
  reduced binding affinity (MRSA, PRP)
• iii) Reduced penetration of the antibiotic
  through the LPS membrane
• iv) Increased Efflux of the Drug

12
CephalosporinsPharmacokinetics

• Acid stable, therefore can be used as oral
  preparations.
• Poor intra-cellular concentrations, therefore not
  effective for I/C organisms like Legionella.
• Most eliminated by the kidney.
• Ceftriaxone and Cefoperazone also have
  significant elimination by the biliary system.

13
Cephalosporin prescribing in Renal Impairment

• Most, apart from Ceftriaxone, need dose
  adjustment.
• Dont guess, consult with Pharmacist regarding
  correct dosing.

14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
Cephalosporin Uses in general

• Should not be used against ESBL producing
  bacteria.
• With exception of Cefipime, should not be used
  for treatment of Enterobacter, Serratia,
  Citrobacter infections due to induction of
  chromosomal Amp C beta-lactamases in these
  bacteria.
• Not effective against Enterococci.

18
Cephalosporins and the Selection of MDROs

• 1st Generation Cephalosporins
• 2nd Generation Cephalosporins
• 3rd Generation Cephalosporins
• 4th Generation Cephalosporins

Increasing selection of MDROs
19
Summary

• Cephalosporins are good drugs with a multitude of
  different uses.
• Well tolerated.
• Make sure you have a good reason if using a
  higher generation cephalosporin.