1. CEPHALOSPORINS
O
R
C
H
N
H
H
S
N
OAc
O
CO2H

2. INTRODUCTION
•
Antibacterial agents which inhibit bacterial cell wall synthesis
•
Discovered from a fungal colony Cephalosporium
acremonium in Sardinian sewer water (1948)
•
Cephalosporin C identified in 1961
•
These are β-lactam antibiotics that are closely related both
structurally and functionally to the pencillins
•
Most cephalosporins are produced semisynthetically by the
chemical attachment of side chains to
7-aminocephalosporanic acid

3. Why Cephalosporins?
• Broad spectrum of activity
• Stability to -lactamase
• Oral and parenteral preparations
• Widely accepted
• Treats ‘day to day’ as well as
‘serious infections’
• High safety profile

4. Cephalosporins
-Limitations
• Emerging resistance patterns
• Some III & IV generation cephalosporins were
available only as parenteral formulations
• Pharmacoeconomics

5. Dihidrothiazine ring
PK
O
R
Side chain
Spect
C
H
N
H
H
S
N
OAc
O
CO2H
Β-lactam
ring

6. Mechanism of action
• Identical to pencillins, i.e.,
– Binding to cephalosporin binding proteins
(PBP)
– Inhibition of transpeptidation process
– Activation of autolysin enzyme

7. Mechanism of action

8. Resistance
1. Bacteria produce -lactamase: -lactamases are
either constitutive, or more commonly, are acquired by
the transfer of plasmids.
2. Altered PBPs: Modified PBPs have a low affinity for lactam antibiotics.
3. Decreased concentration of antibiotics in target
site: altered porin (either in the number or function);
increased active efflux system.

9. Classification
• Have been classified as first, second, third and fourth
generation, based on their bacterial spectrum and
resistance to β-lactamases
Note: Cephalosporins are ineffective against MRSA, L.
monocytogenes, Clostredium dificile and the
enterococci

10. Classification
Generation
Parenteral
Agents
First-generation(1960s) Cefazolin, Cephalothin
Oral Agents
Cefadroxil,
cephalexin,cephradine
Second-generation
(1970s)
Cefotetan, cefoxitin,
cefuroxime
Cefaclor, cefprozil,
cefuroxime axetil
Third-generation
(1980s)
Cefotaxime, ceftazidime,
ceftizoxime, ceftriaxone
Cefdinir, cefditoren,
cefpodoxime proxetil,
ceftibuten, cefixime
Fourth-generation
(1997-98)
Cefepime, cefpirome

11. First Generation Cephalosporins
Pharmacokinetics:
• Oral cephalosporins are generally well absorbed
• IM injection of cephalothin is very painful and hence
given by IV route
• Except for cefazolin, which is 80-90% protein bound,
others exhibit a poor protein binding
• Good distribution to most tissues except in CSF
• Metabolism is not a major elimination path
• Primarily excreted through kidney
• Probenecid increases plasma half life
• All are sensitive to β-lactamase enzyme degradation

12. Antimicrobial spectrum

13. Antimicrobial spectrum
Gram-positive bacteria
Gram-negative bacteria
+
Streptococcus pyogenes,
Some viridans streptococci,
Some Staphylococcus aureus,
Some Streptococcus pneumoniae
Some Escherichia coli,
Some Klebsiella pneumonia, Some Proteus
mirabilis
Cocci >
-
Bacilli >
+
Bacilli >
-
Cocci

14. Uses
• UTI’s
• Minor staphylococcal infections
• Cellulitis or soft tissue abscess
• Ineffective in meningitis (do not cross BBB)
• Cefazolin is drug of choice for surgical
prophylaxis before cardiac surgery and before
orthopedic prosthesis procedures (has better
penetration to tissues)

15. Second Generation Cephalosporins
Pharmacokinetics:
• Cefaclor and cefuroxime can be given orally and have
good bioavailability
• Cefuroxime axetil is an ester prodrug formulation in which
the ester is hydrolyzed during drug passage through the
intestinal mucosa
• The free cefuroxime then enters the systemic circulation
• Only cefuroxime crosses BBB among 2nd gen
• Only cefoxitin is 80-90% protein bound; others have poor
protein binding

16. Second Generation Cephalosporins
• More stable to β-lactamase degradation than 1st gen
• Their IM injections are painful and hence preferably
given administered by IV route
• These are excreted unchanged through kidney
• Probenecid increases plasma half life

17. Antimicrobial spectrum
• The second-generation cephalosporins have a greater
Gram-negative spectrum while retaining some activity
against Gram-positive cocci.

18. Antimicrobial spectrum
Gram-positive
bacteria
Gram-negative
bacteria
Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis,
Haemophilus influenzae, Neisseria
spp.
Anaerobic bacteria
-
True cephalosporins have activity
equivalent to first-generation agents.
Cefoxitin and cefotetan have little
activity
Cefoxitin and cefotetan have
moderate anaerobic activity.
Cocci - Bacilli >
Anaerobes
+
Bacilli, Cocci

19. Uses
• Cefaclor: URTI’s
• Cefuroxime: commonly acquired pneumonia,
gonorrhoea and meningitis
• Cefoxitin & cefotetan: peritonitis and diverticulitis
and some gynecological infections (anaerobic
infection)

20. Third Generation Cephalosporins
Pharmacokinetics:
• All these drugs distribute very well into body
compartments
• Adequate levels in the CSF regardless of inflammation,
are achieved only with these 3rd gen
• Thus these are used to treat meningitis
• Ceftriaxone differs from others by its long plasma half
life(7-8hrs) and high protein bound (90%)- OD
• Metabolism is not major path for elimination
• Cefotaxime is metabolized to active metabolite –
desacetyl cefotaxime

21. Third Generation Cephalosporins
• Cefoperazone and ceftriaxone are excreted through bile, so
no dose adjustment requied for renal insufficiency
• Urinary excretion is the major elimination route
• Probenecid may increase the plasma half life
• All are highly resistant to degradation by β-lactamases
from gram-negative bacteria

22. Antimicrobial spectrum

23. Antimicrobial spectrum
Gram-positive bacteria
Streptococcus pyogenes, Viridans streptococci,
Many Streptococcus pneumoniae, Modest
activity against Staphylococcus aureus
Gram-negative bacteria
Escherichia coli, Klebsiella pneumoniae, Proteus
spp. Haemophilus influenzae, Neisseria spp.
Some Enterobacteriaceae.
Anaerobic bacteria
Atypical bacteria
Spirochetes
-
Cocci, Bacilli >
anaerobic org.
Borrelia burgorferi
+
Bacilli, Cocci

24. Ceftriaxone:
• Very effective in treating meningitis caused by N.
meningitidis, Pneumococci, H. influenza and susceptible
enteric gram-negative rods but not by Listeria
monocytogenes
• A single IM dose of 250mg is effective in gonorrhoae and
chancroid
• Excellent for treatment of community acquired
pneumonia caused by pneumococci, H. influenzae and
staph aureus
• Lyme disease caused by Borrelia burgdorferi
• Also efficacious in treating complicated UTI’s, abdominal
sepsis and septicaemias
• Also used to treat multi drug resistant typhoid fever
(doses are high)

25. Cefotaxime:
• Like ceftriaxone, has been utilized effectively for treating
meningitis and community acquired pneumonia
• A single 0.5-1g IM dose is effective in treating
gonorrhoea
• Has been used in respiratory, genitourinary, abdominal
infections, septicaemia, anaerobic and hospital acquired
infections

26. Cefoperazone:
• More active than cefotaxime against pseudomonas (but
less active than ceftadizime)
• Good for Salmonella typhi and B. fragilis also
• Used for pseudomonal UTI’s, bactreamia, and infections
in immunocompromised patients
• Other uses like meningitis, gonorrhoae and septicaemia
are common to other drugs of this series

27. Ceftazidime:
• Has excellent activity against pseudomonas (better than
cefoperazone) and other gram-negative bacilli
• Ceftadizime+aminoglycosides is the treatment of choice
for pseudomonal meningitis
• Also useful for nosocomial infections also

28. Ceftizoxime:
• More active agaist B. fragilis than cefotaxime, otherwise
similar

29. Cefixime:
• Orally administered (200-400mg BD)
• Cefixime is used to treat respiratory, urinary, biliary
infections
• In a single 400mg oral dose it provides effective
treatment of uncomplicated gonorrhoea
• Not effective against Staph. aureus and Pseudomonas
Cefpodoxime:
• Is similar to cefixime but it is active against Staph. aureus
also

30. Fourth Generation Cephalosporins
Oximinocephalosporins
•
Zwitterionic compounds
•
Enhanced ability to cross the outer membrane of Gram
negative bacteria
•
Given by IM /IV
•
Plasma half life is 2hrs
•
Protein binding is only 20%
•
Widely distributed in tissues and body fluids
•
Accumulates well in CSF

31. Fourth Generation Cephalosporins
•
It is eliminated 85-90% through kidney
•
Pharmacokinetics of cefpirone is identical to cefepime
expect that its protein binding is only 10%
•
Good affinity for the transpeptidase enzyme
•
Low affinity for some β-lactamases
•
Active vs. Gram +ve cocci and a broad array of Gram ve bacteria
•
Active vs. P. Aeruginosa

32. Antimicrobial spectrum
Gram-positive bacteria
Streptococcus pyogenes, Viridans streptococci,
Many Streptococcus pneumoniae. Modest
activity against Staphylococcus aureus
Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus
spp. Haemophilus influenzae, Neisseria spp.
Many other Enterobacteriaceae, Pseudomonas
aeroginosa.
Anaerobic bacteria
Atypical bacteria
-
Cocci, Bacilli >
+
Cocci. Noanaerobic , No
+
Bacilli

33. IV Gen. Uses
• Hospital acquired pneumonia
• Bactreamia and septicaemia
• Also useful in UTI’s, RTI’s and as empiric therapy for
febrile neutropinic patients

34. Adverse effects
• Pain after IM inj. (cephalothin)
• Diarrhoea (cephradine and cefoperazone)
• Hypersensitivity reactions
• Nephrotoxicity (cephaloridine, cephalothin and few other)
• Bleeding (cefoperazone, ceftriaxone)(N-methyl
thiotetrazole side chain at R2 position
• Disulfiram like reaction (cefoperazone)