CEPHALOSPORINSTeaching Basics

1. CEPHALOSPORINS
Teaching Basics
Dr.T.V.Rao MD
Dr.T.V.Rao MD 1

2. 2
Cephalosporins
• Cephalosporin discovery credited to
Brotzu in 1945 in sewer water off coast of
Sardinina
• Several compounds isolated from mold
Acremonium chrysogenum with
cephalosporin C as basic nucleus for
future drugs
• First introduced into clinical use in 1964
(cephalothin)
Dr.T.V.Rao MD

3. • The cephalosporins
structurally related
to the penicillin's
consist of a –beta
lactam ring
attached to a
dihydrothiazoline
ring. Substitutions of
chemical groups result
in varying
pharmacologic
properties and
antimicrobial activities.
What are Cephalosporins
Dr.T.V.Rao MD 3

4. 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. He noticed that these
cultures produced substances that were
effective against Salmonella typhi, Researchers
at the Sir William Dunn School of Pathology at
the University of Oxford isolated cephalosporin
C, which had resistance to β-lactamases but
was not sufficiently potent for clinical use.
Dr.T.V.Rao MD 4

5. Resembles Penicillin
• The cephalosporin nucleus,
7-aminocephalosporanic acid (7-ACA),
was derived from cephalosporin C and
proved to be analogous to the penicillin
nucleus 6-aminopenicillanic acid.
Modification of the 7-ACA side-chains
resulted in the development of useful
antibiotic agents, and the first agent
cephalothin (cefalotin) was launched by
Eli Lilly in 1964.
Dr.T.V.Rao MD 5

6. How Cephalosporins work
• Cephalosporins are bactericidal and have the same
mode of action as other beta-lactam antibiotics (such as
penicillins). Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls. The
peptidoglycan layer is important for cell wall structural
integrity. The final transpeptidation step in the synthesis
of the peptidoglycan is facilitated by transpeptidases
known as penicillin binding proteins (PBPs). PBPs bind
to the D-Ala-D-Ala at the end of muropeptides
(peptidoglycan precursors) to crosslink the
peptidoglycan. beta-lactam antibiotics mimic this site and
competitively inhibit PBP crosslinking of peptidoglycan.
Dr.T.V.Rao MD 6

7. 7
Cephalosporins
• Mechanism of action: binds to penicillin binding
proteins and inhibition of formation of cell wall
• Mechanisms of resistance:
– Changes in drug target of penicillin binding proteins -
methicillin-resistant Staphylococcus aureus
– Lack of access of the drug to the penicillin binding protein
target
• Efflux pumps – MexAB-OprM efflux pump in Pseudomonas
aeruginosa
• Decreased permeability of cell wall – less common for
cephalosporins
– Alteration of drug itself by hydrolysis by beta-lactamases
• Numbers and types of beta-lactamases increasing
• Can be chromosomally or extra-chromosomally (more easily
transmitted to other organisms) mediated
Dr.T.V.Rao MD

8. Cephalosporins
• Resistance to one
cephalosporin can
result in resistance
others depending on
mechanism
• Resistance to
cephalosporins can
confer resistance to
other beta-lactam
drugs like penicillins
as well Dr.T.V.Rao MD 8

9. • Cephalosporin
drugs fall into
five classes or
generations.
Each subsequent
generation of
these drugs
demonstrates
greater efficacy
against gram-
negative bacteria.
Generation of Cephalosporins
Dr.T.V.Rao MD 9

10. 10
Cephalosporins
• Divided into “generations” for convenience but
many drugs in same “generation” not
chemically related and different spectrum of
activity
• Currently five generations of cephalosporins
but which generation a particular drug
belongs often a matter of debate
• Generalization that with increasing “generation” activity in
vitro against Gram positive organisms decreases while
activity against Gram negatives increases (but an
oversimplification)
Dr.T.V.Rao MD

11. 11
Usage of Cephalosporins in
Human Medicine
• 3rd and 4th generation cephalosporins used
in hospital setting in seriously ill patients for
serious and life-threatening diseases
• Many of these diseases due to organisms
that reside in the gastrointestinal tract
• Drugs of last resort for serious infections
due to food-borne pathogens Salmonella
and Shigella
– These organisms may be resistant to other drugs
– Quinolones may be effective but avoid in children due to
potential for toxicitiesDr.T.V.Rao MD

12. Important I st Generation
Cephalosporins
• Cefacetrile (cephacetrile)
• Cefadroxil (cefadroxyl; Duricef)
• Cefalexin (cephalexin; Keflex)
• Cefaloglycin (cephaloglycin)
• Cefalonium (cephalonium)
• Cefaloridine (cephaloradine)
• Cefalotin (cephalothin; Keflin)
• Cefapirin (cephapirin; Cefadryl)
• Cefatrizine
• Cefazaflur
• Cefazedone
• Cefazolin (cephazolin; Ancef, Kefzol)
• Cefradine (cephradine; Velosef)
• Cefroxadine
• Ceftezole
Dr.T.V.Rao MD 12

13. Classification of Cephalosporin
1. First generation Cephalosporins
Cefazolin
Loracarbef
Cephalexin
Cefoperazone
Cefotetan
Disodium
Cefoxitin Na
Cefaclor
Cefprosil
Cefadroxil
Cephradine
Cefuroxime Na
Cefixime
Dr.T.V.Rao MD 13

14. Advantages of I st generation
Cephalosporins
• Very active against Gram + ve cocci
Including penicillin senstive Pneumococci,
Viridians streptococci
Group A hemolytic streptococci
Staphylococcus aureus
Not useful against Enterococci, Methicillin
resistant Staphylococcus
Activity against H.influenzae, and Pencillin
resistant Streptococci is poor
Effective against gram – ve as E.coli,Klebsiella
pneumonia, Proteus mirabilis
But not effective
Dr.T.V.Rao MD 14

15. Clinical uses
• Orally useful in Urinary tract infection.
• Intravenous preparations are useful in
surgical prophylaxis in clean cases
• But 2nd and 3rd generation drugs are
more useful in colorectal surgeries and
Hysterectomy cases
• Ist Generation drugs are not useful in
Meningitis.
Dr.T.V.Rao MD 15

16. Second Generation
Cephalosporins
• The are heterogeneous group with
Individual differences
• Against Gram Negative organisms as like
Ist generation Cephalosporins with
extended spectrum of activity against
Indole positive Proteus,
Klebsiella, Moraxella catarrhalis
Neisseria species
Dr.T.V.Rao MD 16

17. Effective against Anaerobes
• Second generation
cephalosporins
with antianaerobial
activity
• Cefmetazole
• Cefotetan
• Cefoxitin
Dr.T.V.Rao MD 17

18. Second generation Cephalosporins
• Cefuroxime useful in H influenza including Beta
lactam producing strains
• Lesser in activity against Serratia and B.fraglilis
• Cefoxitin and Cefotetan active against B.fraglilis
• Majority of 2nd generations are less active
against Gram + ve organism than Ist generation
compounds except cefuroxime
• Not active against P aeruginosa
Dr.T.V.Rao MD 18

19. Classification of Cephalosporin
Second generation Cephalosporins
> have a greater Gram-negative
spectrum while retaining some activity
against Gram-positive cocci. They are
also more resistant to beta-lactamase.
Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
Cefonicid (Monocid)
Cefprozil (cefproxil; Cefzil)
Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroks
Cefuzonam
Dr.T.V.Rao MD 19

20. Clinical Uses
• 2nd generation cephalosporins are more useful
in Beta lactamases producing H influenza,
Moraxella catarrhalis
• Apart from Aerobic infections Cefoxitin,
Cefmetazole, and Cefotetan can be used to treat
mixed anaerobic infections, including peritonitis,
and diverticulitis
• However it is proved that in life threating
infections better to choose alternative antibiotics
• Cefoxitin and Cefotenan are useful as
prophylaxis in colorectal surgeries,vaginal or
abdominal hysterectomies and appendicitis ,
because of activity against B.fraglilis.
Dr.T.V.Rao MD 20

21. Antipseudomonal activity
• Cephalosporins
with
Antipseudomonal
activity
• Cefoperazone
(Cefobid)
• Ceftazidime
(Fortum, Fortaz)
Dr.T.V.Rao MD 21

22. Classification of Cephalosporin
Third generation Cephalosporins
Third-generation cephalosporins have a broad spectrum of
activity and further increased activity against Gram-negative
organisms.
 They may be particularly useful in treating hospital-acquired
infections, although increasing levels of extended-spectrum
beta-lactamases are reducing the clinical utility of this class of
antibiotics.
 They are also able to penetrate the CNS, making them useful
against meningitis caused by pneumococci, meningococci, H.
influenzae, and susceptible E. coli, Klebsiella, and penicillin-
resistant N. gonorrhoeae.
Dr.T.V.Rao MD 22

23. Classification of Cephalosporin
Third generation Cephalosporins
Cefcapene
Cefdaloxime
Cefdinir (Omnicef, Cefdiel)
Cefditoren
Cefetamet
Cefixime (Suprax)
Cefmenoxime
Cefodizime
Cefotaxime (Claforan)
Cefpimizole
Cefpodoxime (Vantin,)
Cefteram
Ceftibuten (Cedax)
Ceftiofur
Ceftiolene
Ceftizoxime (Cefizox)
Ceftriaxone (Rocephin)
Dr.T.V.Rao MD 23

24. 24
Third Generation - Ceftriaxone
• Lower Respiratory Tract Infections caused by
Streptococcus pneumoniae, Staphylococcus
aureus, Haemophilus influenza, Haemophilus
Parainluenza, Klebsiella pneumoniae,
Escherichia coli, Enterobacter aerogenes,
Proteus mirabilis or Serratia marcescens.
• Acute Bacterial Otitis Media caused by
Streptococcus pneumoniae,
Haemophilus influenza (including beta-
lactamase producing strains) or
Moraxella catarrhalis (including beta-
lactamase producing strains).
Dr.T.V.Rao MD

25. Third Generation - Ceftriaxone
• Skin and Skin Structure Infections caused
by Staphylococcus aureus,
Staphylococcus epidermidis,
Streptococcus pyogenes, Viridans group
streptococci, Escherichia coli,
Enterobacter cloacae, Klebsiella oxytoca,
Klebsiella pneumoniae, Proteus mirabilis,
Morganella morganii*, Pseudomonas
aeruginosa, Serratia marcescens,
Acinetobacter calcoaceticus, Bacteroides
fragilis * or Peptostreptococcus species.
Dr.T.V.Rao MD 25

26. Preferred in cases of UTI
• Urinary Tract
Infections
(complicated and
uncomplicated)
caused by
Escherichia coli,
Proteus mirabilis,
Proteus vulgaris,
Morganella morganii
or Klebsiella
pneumoniae.
Dr.T.V.Rao MD 26

27. Third Generation – Ceftriaxone
in Gonorrhoea's
• Uncomplicated
Gonorrhoea
(cervical/urethral and
rectal) caused by
Neisseria gonorrhoea,
including both
penicillinase- and
nonpenicillinase-
producing strains, and
pharyngeal
gonorrhoea caused
by nonpenicillinase-Dr.T.V.Rao MD 27

28. 28
Third Generation - Ceftriaxone
• Pelvic Inflammatory Disease caused
by Neisseria gonorrhea. Rocephin,
like other cephalosporins, has no
activity against Chlamydia
trachomatis. Therefore, when
cephalosporins are used in the
treatment of patients with pelvic
inflammatory disease and
C. trachomatis is one of the
suspected pathogens,
appropriate anti chlamydial
coverage should be added.
Dr.T.V.Rao MD

29. In Bacterial Septicaemia
• Bacterial Septicaemia
caused by
Staphylococcus
aureus,
Streptococcus
pneumoniae,
Escherichia coli,
Haemophilus
influenza or Klebsiella
pneumoniae.
• Dr.T.V.Rao MD 29

30. In Bone and Joint Infections
• Bone and Joint
Infections caused by
Staphylococcus
aureus,
Streptococcus
pneumoniae,
Escherichia coli,
Proteus mirabilis,
Klebsiella
pneumoniae or
Enterobacter species.
Dr.T.V.Rao MD 30

31. Intra-Abdominal Infections
• Intra-Abdominal
Infections caused by
Escherichia coli,
Klebsiella
pneumoniae,
Bacteroides fragilis,
Clostridium species
(Note: most strains of
C. difficle are
resistant) or
Peptostreptococcus
species.
Dr.T.V.Rao MD 31

32. In Meningitis
• Meningitis caused by Haemophilus
influenza, Neisseria meningitidis or
Streptococcus pneumoniae. Rocephin has
also been used successfully in a limited
number of cases of meningitis and shunt
infection caused by Staphylococcus
epidermidis* and Escherichia coli.*
* Efficacy for this organism in this organ system
was studied in fewer than ten infections.
• Surgical Prophylaxis
Dr.T.V.Rao MD 32

33. Classification of Cephalosporin
4. Fourth generation Cephalosporins
Fourth-generation cephalosporins
are extended-spectrum agents with
similar activity against Gram-
positive organisms as first-
generation cephalosporins.
They also have a greater
resistance to beta-lactamases than
the third-generation
cephalosporins.
 Many can cross the blood-brain
barrier and are effective in meningitis.
They are also used against
Pseudomonas aeruginosa.
Cefclidine
Cefepime (Maxipime)
Cefluprenam
Cefoselis
Cefozopran
Cefpirome (Cefrom)
Cefquinome
Dr.T.V.Rao MD 33

34. 34
Fourth Generation -
Cefepime
FDA approved indications
• Pneumonia (moderate to severe) caused by
Streptococcus pneumoniae , including cases
associated with concurrent bacteremia, Pseudomonas
aeruginosa , Klebsiella pneumoniae , or Enterobacter
species.
• Empiric Therapy for Febrile Neutropenia Patients.
• Uncomplicated and Complicated Urinary Tract
Infections (including pyelonephritis) caused by
Escherichia coli or Klebsiella pneumoniae , when the
infection is severe, or caused by Escherichia coli ,
Klebsiella pneumoniae , or Proteus mirabilis , when the
infection is mild to moderate, including cases
associated with concurrent bacteremia with these
microorganisms. Dr.T.V.Rao MD

35. Fourth Generation -
Cefepime
FDA approved indications
• Uncomplicated Skin and Skin Structure
Infections caused by Staphylococcus
aureus (methicillin-susceptible strains
only) or Streptococcus pyogenes .
• Complicated Intra-abdominal Infections
(used in combination with metronidazole)
caused by Escherichia coli , viridans group
streptococci, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Enterobacter
species, or Bacteroides fragilis
Dr.T.V.Rao MD 35

36. Classification of Cephalosporin
5. Fifth generation Cephalosporins
Ceftobiprole has been described as "fifth
generation" though acceptance for this
terminology is not universal.
Ceftobiprole (and the soluble prodrug
medocaril) are on the FDA fast-track.
Ceftobiprole has powerful Antipseudomonal
characteristics and appears to be less
susceptible to development of resistance.
Dr.T.V.Rao MD 36

37. • Fifth generation
cephalosporins were
developed in the lab to
specifically target
against resistant
strains of bacteria.
In particular,
ceftobiprole is
effective against
methicillin-resistant
Staphylococcus
aureus (MRSA).
What are 5th generation
Cephalosporins
Dr.T.V.Rao MD 37

38. Fifth Generation Cephalosporin
5. Fifth generation Cephalosporins
Ceftobiprole has been described as "fifth
generation" though acceptance for this
terminology is not universal.
Ceftobiprole (and the soluble prodrug
medocaril) are on the FDA fast-track.
Ceftobiprole has powerful antipseudomonal
characteristics and appears to be less
susceptible to development of resistance.
Dr.T.V.Rao MD 38

39. FDA approves ceftaroline
fosamil
• On October 29th, FDA has approved Ceftaroline Fosamil under
the trade name Teflaro. Ceftaroline Fosamil (previously known by
the research code TAK-599, the parent drug, Ceftaroline is also
known as T-91,825) is an antibiotic indicated for the treatment of
adults with acute bacterial skin and skin structure infections
(ABSSSI) caused by susceptible Gram-positive and Gram-
negative microorganisms, such as Staphylococcus aureus
(including methicillin-susceptible and -resistant isolates),
Streptococcus pyogenes Streptococcus agalactiae,
Escherichia coli, Klebsiella pneumoniae, and Klebsiella
oxytoca, and also for the treatment of community-acquied
bacterial pneumonia (CABP) caused by susceptible Gram-
positive and Gram-negative bacteria, such as Streptococcus
pneumoniae (including cases with concurrent bacteremia),
Staphylococcus aureus (methicillin-susceptible isolates
only), Haemophilus influenzae, Klebsiella pneumoniae,
Klebsiella oxytoca, and Escherichia coli.
Dr.T.V.Rao MD 39

40. • Ceftaroline was developed by
modifying the structure of the
fourth-generation cephalosporin
cefozopran The prodrug,
ceftaroline fosamil, which
contains a phosphono group to
increase water solubility, is
rapidly converted in plasma into
the bioactive agent, ceftaroline
The 1,3-thiazole ring attached
to the 3-position of the
cephalosporin nucleus and the
oxime group in the C7 acyl
moiety are responsible for the
enhanced anti-MRSA activity
observed with ceftaroline.
Ceftaroline is modified from cefozopran
Dr.T.V.Rao MD 40

41. • Ceftaroline is an
injectable
cephalosporin active
against MRSA & MSSA
[ & RTI pathogens]
• It is approved for use
in cSSSI & CABP
• Its use may be
extended when
combined with NXL
104 to include ESBL
+ve GNB strains
• It is inactive against Non
fermenters GNB &
Carbapenemases
producers.
Advantage of Ceftaroline
Dr.T.V.Rao MD 41

42. • Ceftobiprole has been
described as "fifth
generation",] though
acceptance for this
terminology is not universal.
• Ceftobiprole (and the
soluble prodrug
medocaril) are on the FDA
fast-track. Ceftobiprole
has powerful
Antipseudomonal
characteristics and
appears to be less
susceptible to
development of
resistance.
Fifth generation Ceftobiprole
Dr.T.V.Rao MD 42

43. • Currently,
ceftaroline and
ceftobiprole are
on an unnamed
subclass of
cephalosporins
by the Clinical
and Laboratory
Standards
Institute (CLSI).
CLSI puts on the list of unnamed
class
Dr.T.V.Rao MD 43

44. 5th generation cephalosporins are not ultimate
solutions for antibiotic resistance
• Antimicrobial stewardship programmes can be
implemented to reduce inappropriate use of
antimicrobials, thereby controlling the
development of resistance. These
programmes are also useful in limiting toxicity
and overgrowth of pathogenic organisms such
as C. difficile. Typical stewardship
programmes target antimicrobials that pose a
risk of development of resistance, are
associated with significant toxicity, require
therapeutic drug monitoring, have the potential
to select for pathogenic organisms or have a
high cost.
Dr.T.V.Rao MD 44

45. 45
Conclusions
• Cephalosporins one of most widely
used drug classes in the US and
worldwide
• Mechanisms of resistance to
cephalosporins may confer resistance
to other beta-lactam agents
• Ranking of 4th generation
cephalosporins as highly important
and 3rd generation agents as critically
important in Guidance 152; both
critically important in WHO criteria
Dr.T.V.Rao MD

46. Programme Created by
Dr.T.V.Rao MD for Medical and
Paramedical Students in the
Developing World
• Email
• doctortvrao@gmail.com
Dr.T.V.Rao MD 46