Cephalosporins & other β lactam antibiotics

1. Cephalosporins & other β-
Lactam Antibiotics.

2. β- Lactam Antibiotics
β-lactam antibiotics, inhibit bacterial growth
by interfering with bacterial cell wall
synthesis.
The β-lactam antibiotics may be further sub-
divided into two categories:
Penicillin
Cephalosporin

3. Cephalosporins
Cephalosporins are similar to Penicillins,
but more stable to bacterial β lactamases
and therefore have a broader spectrum of
activity.

4. History
The 1st source of Cephalosporins,
Cephalosporium acremonium(Fungus), was
isolated in 1948 by Giuseppe from the sea
near a sewer outlet of the Sardinian Coast.
The crude filtrates from this fungus were
found to inhibit the in vitro growth of β-
lactamase producing S. aureus and to cure
the Staphylococcal infections and typhoid
fever in humans.

5. Subsequently, Abraham and his colleagues
identified three distinct antibiotics from the
culture fluid of fungus.
These antibiotics were named
Cephalosporin N and C (which were
chemically related to penicillin) and
Cephalosporin P, a steroid antibiotic that
resembles Fusidic Acid.

6. Chemistry
The nucleus of Cephalosporins, 7-
aminocephalosporanic acid bears a close
resemblance to 6-aminopencillanic acid.
The core of the basic cephalosporin molecule
consists of a two ring system which includes
a β-lactam ring condensed with
dihydrothiazine ring. The core itself can
also be referred to as 7-
aminocephalosporanic acid which can be
derived by hydrolysis from the natural
compound Cephalosporin C.

8. Chemical compounds
containing this core
are relatively stable to
acid hydrolysis and
tolerance to β-
lactamases.
Cephalosporin C ring
structure contains a
side-chain.

9. Modification of side
chains on the relevant
positions has been used
to create a whole new
class of cephalosporin
antibiotics.
Modification of side-chains at position 7 of the
lactam ring seems to affect the antibacterial
activity while position 3 of the dihydrothiazine
ring alters pharmacokinetic properties and
receptor binding affinity.

10. Mechanism of Action
Cephalosporins exert bactericidal effect in
manner similar to that of Penicillins.
Binding to specific PBPs
Inhibition of cell wall synthesis by
inhibiting transpeptidation of
Peptidoglycan
Activation of Autolytic enzymes Autolysins
or Murein Hydrolases

11. Classification
Cephalosporins can be classified into four
major groups or generations, depending
mainly on the spectrum of antimicrobial
activity.
Recently, Fifth generation cephalosporins were
developed in the lab to specifically target
against resistant strains of bacteria
particularly Methicillin Resistance
Staphlococcus Aureus (MRSA).

12. 1st Generation Cephalosporins
The agents included in this group have good
activity against gram-positive cocci, such
as pneumococci, streptococci and
staphylococci but not active against
methicillin resistant strains of
staphylococci, and relatively modest
activity against gram-negative
microorganisms (E.Coli and Klebsiella
pnumoniae).

13. 1st generation Cephalosporins include:
Cefazolin (IV/IM)
Cefadroxil (PO)
Cephalexin (PO)
Cephalothin (IV/IM)
Cephapirin (IV/IM)
Cephradine (PO)

14. 2nd Generation Cephalosporins
These compounds show modest activity
against gram-positive bacteria (less active
than 1st generation drugs) and display
greater activity against gram-negative
microorganisms including Haemophilus
influenza, some Enterobacter and Neisseria
Species.

15. In comparison to 1st generation, they have
some what increased activity against gram-
negative bacteria but this activity is much
less than the activity of 3rd generation
compounds.

16. The drugs included in this class are:
Cefaclor (PO)
Cefamandole (IV/IM)
Cefonicid (IM/IV)
Cefuroxime (IV/IM/PO)
Cefprozil (PO)
Loracarbef (PO)
Ceforanide (IM/IV)

17. 3rd Generation Cephalosporins
Though greatly inferior to 1st generation
cephalosporins in regard to their activity
against gram-positive cocci, the 3rd
generation cephalosporins exhibit much
more activity against gram-negative bacilli,
most other enteric organisms and β-
lactamase producing strains of
Haemophilus and Neisseria.

18. Drugs of this group have superiority over the
other two generation in having ability to
reach CNS (cross BBB). They include:
Cefoperazone (IV/IM)
Cefotaxime (IV/IM)
Ceftriaxone (IV/IM)
Cefixime (PO)
Ceftazidime (IV/IM)
Moxalactam (IM/IV)

19. 4th Generation Cephalosporins
They have an extended spectrum of activity
as compared to the 3rd generation and have
increased stability from hydrolysis by β-
lactamases.

20. Aerobic gram-negative bacilli resistant to 3rd
generation cephalosporins can be
successfully treated with 4th generation
drugs.
Drugs included in this class are:
Cefepime (IV)
Cefpirome (IV)
Cefozopran (IV)

21. 5th Generation Cephalosporins
These 5th generation cephalosporins are
active against Methicillin resistant
staphylococci.
Agents under this class include:
Ceftaroline Fosamil (IV)
Ceftobiprole (IV)
 Ceftolozane

22. FDA has approved Ceftaroline under the
trade name Teflaro which was developed
by modifying the structure of 4th generation
cephalosporin Cefozopran.
Ceftobiprole has powerful antipseudomonal
characteristics and appears to be less
susceptible to development of resistance
and are now on the FDA fast-track.

23. Currently, ceftaroline and ceftobiprole are on
an unnamed subclass of cephalosporins by
the Clinical and Laboratory Standards
Institute (CLSI) but generally classified
under the category of 5th generation
cephalosporins.

24. Others
 Cefaloram
 Cefaparole
 Cefcanel
 Cefedrolor
 Cefmatilen
 Cefmepidium
 Cefrotil
 Cefsumide
 Nitrocefin

25. Nitrocefin isa chromogenic cephalosporin
substrate routinely used to detect the
presence of beta-lactamase enzymes
produced by various microbes. As
a cephalosporin, nitrocefin contains a beta-
lactam ring which is susceptible to beta
lactamase mediated hydrolysis. Once
hydrolyzed, the degraded nitrocefin
compound rapidly changes color from
yellow to red. Although nitrocefin is
considered a cephalosporin, it does not
appear to have antimicrobial properties.

26. Resistance to Cephalosporins
Resistance to cephalosporins can be due to
following mechanisms:
Poor penetration of drug into bacteria
Lack of specific PBPS for a particular
agent
Degradation of the drug by β-lactamases
Failure of activation of Autolytic enzymes
in the bacterial cell wall.

27. Therapeutic Uses
Cephalosporins are widely used antibiotics.
Unfortunately, overuse of these agents in
situations where drugs with less broad
spectrum activity would be more
appropriate has led to the emergence of wide
array of cephalosporin resistant bacteria.
Cephalosporins are effective as both
Prophylactically & Therapeutically.

28. Chemoprophylaxis
Single dose of Cefazoline (1-2 g IV/IM ≤60
minutes before procedure) just before
surgery is preferred prophylaxis for
procedures in which skin flora are likely to
be pathogenic.

29. Alternative to Penicillins
Cephalosporins are still useful alternatives to
Penicillins for a variety of infections in
patients who cannot tolerate penicillins.

30. Infections
Cefotaxime and ceftriaxone are approved for
use in essentially all pediatric bacterial
infections, including sepsis, meningitis,
pneumonia, those of the skin and soft
tissues, septic arthritis, osteomyelitis, intra-
abdominal, and infections of the
genitourinary tract.

31. Ceftazidime is the most active third-
generation cephalosporin against P
aeruginosa. It exhibits excellent
penetration to the CSF and is effective in
the treatment of meningitis caused by P
aeruginosa. Ceftazidime commonly is
combined with an aminoglycoside for the
treatment of acute exacerbations of
bronchopulmonary infections in patients
who have cystic fibrosis.

32. Ceftolozane is combined with the β-
lactamase inhibitor tazobactam, as multi-
drug resistant bacterial infections will
generally show resistance to all β-lactam
antibiotics unless this enzyme is inhibited.

33. Treatment of Gonorrhoea
Ceftriaxone (as a single dose 125mg by
injection) and Cefixime (400mg oral dose)
are drugs of 1st choice for the treatment of
all forms of gonorrhoea.

34. Treatment of Typhoid
Cefoperazone and Ceftriaxone (1-2g BD,
IV/IM for 7-10 days) have been used
effectively for the treatment of typhoid fever.

35. Meningitis
Ceftriaxone and Cefotaxime, currently are
the drug of choice for empirical treatment
of meningitis in non immunocompromised
adults and children older than 3 months.
They are proven effective for the treatment
of meningitis caused by Haemophilus
influenzae, Neisseria meningitidis.

36. Treatment of Lyme Disease
Lyme is an inflammatory disease spread
by infected Tics bite by Borrelia specie.
Ceftriaxone (2 g once daily
iv for 14–28 days) or
Cefotaxime (2 g iv
every 8 h) is the treatment
of choice for severe forms of Late Lyme
Disease.

37. Adverse Effects
Allergic Reactions (Rare)
Nephrotoxicity
Diarrhoea (cefixime, cefoperazone)
Disulfiram like Reaction (cefoperazone and
cefamandole)
Hypoprothrobinemia (common with
cefoperazone and cefamandole)
Phlebitis, pain on IM Injection (cefotaxime,
cefalothin)

38. Other β-Lactam Antibiotics
& Cell Wall Destructor

39. Other β-Lactam Antibiotics
β-Lactamase Inhibitors
Clavulanic Acid
Salbactum
Tazobactum
Monobactams
Aztreonam

40. Carbapenems
Doripenem
Imipenem
Ertapenem
Meropenem

41. β-Lactamase Inhibitors
β-lactamase inhibitors are used in
conjunction with a β-Lactam antibiotic to
extend its spectrum of activity.
Although β-lactamase inhibitors have little
antibiotic activity of their own, they instead
inhibit the activity of β-lactamases, (a
family of enzymes that break the beta-
lactam ring) that allows penicillin-like
antibiotics to work, thereby conferring
bacterial resistance.

42. Hence β-lactamase inhibitors are often given
in combination with penicillins to tackle the
problem of the resistance caused by the
presence of β-lactamases from bacterial
cells.
An example is Co-Amoxiclav [Augmentin],
which is a combination of amoxicillin and
clavulanic acid. Salbactum usually combined
with Ampicillin (Unasyn) and Tazobactum
with Piperacillin (Zosyn).

43. Monobactams
Monobactams are drugs with a monocyclic
β- lactam ring.
They are resistant to β-lactamases and
active against gram-negative rods.
They have no activity against gram-positive
bacteria or anaerobes.
Penicillin-allergic patients tolerate
aztreonam without reaction.

44. Carbapenems
Imipenem has good activity against gram-
negative, gram-positive and anaerobic
organisms.
Imipenem is inactivated by
dehydropeptidases in renal tubules.
It is administered with an inhibitor of renal
dehydropeptidase, cilastatin, for clinical use.
Meropenem and ertapenem are not degraded
by renal dehydropeptidase.

45. Cell Wall Destructor
Vancomycin
Fosfomycin
Polymyxin
Cycloserine

46. Vancomycin
Vancomycin is active against gram-positive
bacteria, particularly staphylococci.
Machanism: Inhibits cell wall synthesis by
binding to the D-Ala-D-Ala terminus of
peptidoglycan pentapeptide, preventing
peptidoglycan elongation and cross-linking.

47. β-lactamase producing staphylococci and
those resistant to nafcillin and methicillin
are killed by vancomycin.
Vancomycin is poorly absorbed from the GI
tract.

48. It is used orally only for antibiotic-
associated enterocolitis caused by C.
difficile.
Metronidazole is preferred as initial therapy
and vancomycin is reserved for refractory
cases.
Parenteral vancomycin is used in sepsis
caused by methicillin-resistant
staphylococci.

49. Vancomycin is irritating to tissue, resulting
in phlebitis at the site of injection.
 A common reaction is "red man" or "red
neck" syndrome (infusion related flushing).
It can be largely prevented by prolonging
the infusion period to 1-2 hours or
increasing the dosing interval.

50. Fosfomycin
It inhibits bacterial cell wall biogenesis by
inactivating the cytoplasmic enzyme,
enolpyruvate transferase.
Fosfomycin is active against both gram-
positive and gram-negative organisms.
Fosfomycin is used for treatment of
uncomplicated urinary tract infections.

51. Polymyxins
Polymyxins antibiotic primarily used for
resistant Gram-negative infections.
Alters bacterial outer membrane permeability
by binding to a lipopolysaccharide layer
resulting in disruption of membrane
integrity.

52. Polymyxin is applied topically to treat
infections such as those of the eye, ear,
and skin.
Because polymyxins also react with the
membranes of human cells, they can
cause kidney damage and neurotoxicity. The
availability of better antibiotics limits the use
of polymixins.

53. Cycloserine
Cycloserine is used only to treat
tuberculosis resistant to first-line agents.
Cycloserine causes serious CNS toxicity
with headaches, tremors, acute psychosis,
and convulsions.

54. Thanks