CEPHALOSPORINS ( PHARMACOLOGY)

1. CEPHALOSPORINS
PRESENTED BY : GUIDED BY:
Kshitij B. Mankar Dr. BRIJESH TAKSANDE SIR
M.PHARM 1st year HOD OF PHARMACOLOGY
Department of Pharmacology SMT.KISHORITAI BHOYAR COLLEGEOF PHARMACY,KAMPTEE
SMT.KISHORITAI BHOYAR COLLEGE OF PHARMACY, KAMPTEE

2. DEFINATION
These are a group of semisynthetic antibiotics derived from
“cephalosporin-C” obtained from a fungus Cephalosporium.
 Cephalosporins are the most important antibiotics having β-lactam
ring and are obtained from a fungus Acremonium, also known as
cephalosporium.
The wide use of cephalosporins against bacteria in various severe
infections such as respiratory tract infection (RTI), skin infection and
urinary tract infection (UTI)

3. HISTORY
The Cephalosporines are isolated from
▪ Cephalosporium species
▪ Prepared semisynthetically
The first chemical compounds of the cephalosporin group were
isolated from Cephalosporium acremonium, a cephalosporin
producing fungus,
first discovered by Giuseppe Brotzu in 1948. GIUSEPPE BROTZU
(1895-1976) Italy.

4. ▪ It is chemically related to Penicillins
▪ The nucleus consist of a beta-lactam ring fused to a
dihydrothiazine ring ( 7-aminocephalosporanic acid).
▪ By addition of different side chains at position 7 of beta
lactam ring and at position 3 of dihydrothiazine ring.
Possible modifications :
▪ •7-Acylamino side chain (altering spectrum of activity)
▪ •3-Acetoxymethyl side chain (affecting pharmacokinetics)
▪ •Substitution at C-7
CHEMISTRY

5. ▪ Broad spectrum activity
▪ They are water soluble
▪ The molecular weight of cephalosporins is 400-450
▪ Relatively stable to pH and temperature changes
▪ Nucleus of cephalosporin is 7-amino cephalosporanic acid
▪ Nucleus Consists of dihydrothiazine ring fused to a β–lactam ring
▪ Range from very narrow spectrum to very broad spectrum.
Properties of cephalosporins

6. The synthesis of peptidoglycan
 The cell wall of bacteria contains peptidoglycan, a substance that does not
occur in eukaryotes.
 It is the equivalent of a non-stretchable string bag enclosing the whole
bacterium.
 In Gram-negative bacteria, this bag consists of a single thickness, but in Gram-
positive bacteria there may be as many as 40 layers of peptidoglycan.
 Each layer consists of multiple backbones of amino sugars—alternating N-
acetylglucosamine and N-acetylmuramic acid residues.

7. Schematic diagram of a single layer of
peptidoglycan

8. Synthesis
SYNTHESIS OF UDP-NAG
Fructose-6-phosphate
glucosamine-1-phosphate
acetyl-coA
CoA
N-Acetylglucosamine-1-phosphate
UDP-NAG
▪ UDP-NAG
PEP
Pi
NADPH
NADP+
UDP-NAM
▪
▪ UDP-NAM Penta peptide

9. Biosynthesis of Peptidoglycan in
bacterial cell wall
▪ First, N-acetylmuramic acid, attached to uridine diphosphate (UDP) and a pentapeptide, is
transferred to the C55 lipid carrier in the membrane, with the release of uridine monophosphate.
▪ This is followed by a reaction with UDP–N-acetylglucosamine, resulting in the formation of a
disaccharide pentapeptide complex attached to the carrier.
▪ This complex is the basic building block of the peptidoglycan.
▪ In Staphylococcus aureus, the five glycine residues are attached to the peptide chain at this
stage.

10. Biosynthesis of Peptidoglycan in
bacterial cell wall
▪ The building block is now transported out of the cell and added to the growing end
of the peptidoglycan, the ‘acceptor’, with the release of the C55 lipid, which still has
two phosphates attached.
▪ The lipid carrier then loses one phosphate group and thus becomes available for
another cycle.
▪ Crosslinking between the peptide side-chains of the sugar residues in the
peptidoglycan layer then occurs, the hydrolytic removal of the terminal alanine
supplying the requisite energy.

11. Schematic Diagram of the biosynthesis of
peptidoglycan in a bacterial cell

12. Composition of Peptidoglycan
▪ Bacteria have a cell wall containing a semirigid, tight knit molecular complex called peptidoglycan.
 Peptidoglycan, also called murein, is a vast polymer consisting of interlocking chains of identical
peptidoglycan monomers.
 A peptidoglycan monomer consists of two joined amino sugars, N-acetylglucosamine (NAG) and N-
acetylmuramic acid (NAM), with a pentapeptide coming off of the NAM .
▪ The types and the order of amino acids in the pentapeptide, while almost identical in gram-positive
and gram-negative bacteria, show some slight variation among the domain Bacteria.
▪ Peptidoglycan is composed of cross-linked chains of peptidoglycan monomers (NAG-NAM-
pentapeptide).

13. ▪ Transglycosylase enzymes join these monomers join together to form chains.
▪ Transpeptidase enzymes then cross-link the chains to provide strength to the cell wall and enable
the bacterium to resist osmotic lysis.
▪ (left) In a peptidoglycan monomer of S. aureus, the pentapeptide coming off the NAM is composed
of the amino acids L-alanine, D-glutamine, L-lysine, and two D-alanines.
▪ The peptide cross-link forms by formation of a short peptide interbridge consisting of 5 glycines.
▪ . In the process the terminal D-alanine is cleaved from the pentapeptide to form a tetrapeptide in
the peptidogycan.
▪ (right) In a peptidoglycan monomer of E. coli, the pentapeptide coming off the NAM is composed of
the amino acids L-alanine, D-glutamic acid, meso-diaminopimelic acid, and two D-alanines.

14. ▪ The peptide cross-link forms between the diaminopimelic acid of one peptide chain with the D-alanine of
another and in the process the terminal D-alanine is cleaved from the pentapeptide to form a tetrapeptide
in the peptidogycan.
▪ (left ) A peptidoglycan monomer consists of two joined amino sugars, N-acetylglucosamine (NAG)
and N-acetylmuramic acid (NAM), with a pentapeptide coming off of the NAM. In E. coli, the pentapeptide
consists of the amino acids L-alanine, D-glutamic acid, meso diaminopimelic acid,
and two D-alanines.
▪ (right)A peptidoglycan monomer consists of two joined amino sugars,
N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), with a
pentapeptide coming off of the NAM. In S. aureus,
the pentapeptide consists of the amino acids L-alanine,
D-glutamine, L-lysine, and two D-alanines.

15. CLASSSIFICATION:
1) FIRST GENERATION:
PARENTRAL : Cefazolin
ORAL : Cephalexin, Cefadroxil
2) SECOND GENERATION:
PARENTRAL : Cefuroxime , Cefoxitin
Oral : Cefaclor, Cefuroxime axetil, Cefprozil

16. 3)THIRD GENERATION
PARENTRAL : Cefotaxime , Ceftizoxime, ceftriaxone, ceftazidime, cefoperazone
ORAL : Cefixime, Cefpodoxime proxetil,Cefdinir, Ceftibuten, Ceftamet pivoxil
4) FOURTH GENERATION
PARENTERAL : Cefepime, cefpirome
5) FIFTH GENERATION
PARENTRAL : Ceftaroline fosamil,Ceftobiprole medocaril

17. Mechanism of action of Cephalosporin
▪ Peptidoglycan layer is important for cell wall structure integrity of bacteria .
▪ All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall peptidoglycan
▪ After attachment of Cephalosporin to penicillin-binding proteins(PBPS) on bacteria (there may be
seven or more types in different organisms), they inhibit the transpeptidation enzyme that
crosslinks the peptide chains attached to the backbone of the peptidoglycan.
▪ The final bactericidal event is the inactivation of an inhibitor of autolytic enzymes in the cell wall,
leading to lysis of the bacterium.

18. ▪ Cephalosporin comptitively inhibit PBP.
▪ As it disrupting the cross-linking process the cell wall will lose its strength which results in cell lysis.
▪
▪ Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics; such as
penicillins.
▪ The peptidoglycan is an important substance for cell wall structural integrity.
▪ Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls by binding to
enzymes called penicillin binding proteins (PBPs).These enzymes are essential for the synthesis of the
bacterial cell wall

19. Bacterial resistance mechanisms
β-lactam antibiotics interact with penicillin binding proteins in susceptible pathogens. Each strain of bacteria
has different types of penicillin binding proteins
▪ Gram negative bacteria have different varieties of penicillin binding proteins (PBP) than gram positive
bacteria.
▪ Mutations in PBPs can reduce the penetration of antibiotics having β-lactam ring for certain bacteria.
▪ An excessive concentration of drug is essential to inhibit growth of such type of bacteria. Higher
concentrations of drug must be available in proximity of mutated PBPs to inhibit bacterial growth.
▪ In acute infections of ear caused by penicillin-non-susceptible Streptococcus pneumonia (PNSP), higher
doses of drug (amoxicillin) are needed.

20. ▪ Another common way for the development of resistance is the formation of beta-lactamase that causes the
breakdown of beta-lactam ring.
▪ It inhibits antibiotic to react with PBPs.
▪ TEM-1 β-lactamase is one of the most well-known antibiotic resistance determinants around. It confers
resistance to penicillins and early cephalosporins and has shown an astonishing functional plasticity in
response to the introduction of novel drugs derived from these antibiotics.
▪ TEM-1 β-lactamase is an example of Non-typeable Haemophilus influenza which is responsible for
ineffectiveness of cefaclor and cefprozil.

21. Antimicrobial Spectrum & Therapeutic
Uses
1) FIRST GENERATION:
▪ •High activity against gram-positive bacteria
Most gram-positive cocci –Strepto, –Pneumo
▪ Modest activity against E. coli, K. pneumoniae & Proteus mirabilis
▪ They are less active against gram negative bacteria
▪ Although several strains of Klebsiella, Proteus mirabilis and E.coli species are sensitive.
▪ They have no activity against methicillin-resistant Staphylococus epidermidis and
methicillin-resistant Staphylococus aureus, Bacteroids fragalis, Enterococci, Listeria
mnocytogenes, Proteus other than mirabilis, enterobacter, pseudomonas, Serratia and
propvidencia organisms.

22. ▪ Useful for: MSSA(methicillin-susceptible Staphylococcus aureus),
ß-hemolytic Streptococcus
▪ Not useful for: Enterococci, gut anaerobes
▪ USES : Skin & Soft tissue infections • Prophylaxis before surgery
(Cefazolin)

23. 2) SECOND GENERATION:
▪ They are more effective against Haemophilus influenza and certain gram negative
aerobic bacteria.
▪ Less active against gram positive cocci & bacilli compared to first gen. drugs.
▪ Gram negative aerobes: H. influenza, Moraxella catarrhalis, Proteus . mirabilis, E. coli,
Klebsiella, Neisseria gonorrhea
▪ • Anaerobes- B. fragilis
▪ • No efficacy against Pseudomonas, Enterococci

24. ▪ Second generation agents of cephalosporins are not active against L. monocytogenes, enterococci,
Methicillinresistant Stapylococcus epidermidis, Methicillin resistant S.aureus.
▪ Cefotetan has more activity against gram negative aerobic bacilli than the second generation
compounds.
▪ USES: Respiratory tract infections ,Acute sinusitis , Otitis media , Uncomplicated UTI .

25. 3)THIRD GENERATION
▪ The third generation agents of cephalosporins (parentaral agents) have less activity against staphylococcus
bacteria but extended activity against gram negative bacteria.
▪ Highly augmented activity against gram-negative organisms
▪ All are highly resistant to β-lactamases from gram negative bacteria. Some members of this group have
enhanced ability to cross the blood-brain barrier eg. Ceftriaxone.
(ceftriaxone, cefotaxime):
Broad-spectrum :
▪ Gram positive coverage: MSSA (reasonable coverage), Streptococcus (excellent coverage)
▪ Gram negatives: N.menigitidis, N.gonnorhea (ceftriaxone)
▪ oral anaerobes

26. ▪ With/without aminoglycoside infections by Klebsiella, Enterobacter,
Proteus, Hemophilus sp, Providencia
▪ Ceftriaxone all forms of gonorrhea; severe Lyme disease
▪ Cefotaxime & Ceftriaxone initial Rx of meningitis
▪ Ceftazidime+ aminoglycoside Pseudomonas meningitis
▪ •CommunityAcquired Pneumonia

27. ceftazidime
Less broad-spectrum vs. ceftriaxone/cefotaxime
 Gram positive coverage: poor
▪ Gram negatives: including Pseudomonas
 NOT useful for: enterococcus, gut anaerobes
Useful for: treatment of documented Pseudomonal infections,
empiric Gram negative coverage where Pseudomonal coverage is
desired.

28. Cefixime
Less broad-spectrum vs. ceftriaxone/cefotaxime
▪ Gram positive coverage: poor
▪ Gram negatives: N. gonorrhea
NOT useful for: enterococcus, gut anaerobes, Pseudomonas
Useful for: treatment of N. gonnorhea (niche) (increasing resistance
rate & treatment failures)

29. Cefdinir
Less broad-spectrum vs. ceftriaxone/cefotaxime
▪ Gram positive coverage: Good, >20% of Pneumococcus resistant
▪ Gram negatives: Moraxella, H.influenza
NOT useful for: enterococcus, gut anaerobes, Pseudomonas

30. 4) FOURTH GENERATION
▪ Active against Gram negative, Enterobacteriaceae, Pseudomonas.
▪ • Uses: Nosocomial infections
▪ • No activity: penicillin-resistant S. pneumonia, MRSA, MRSE, Staphylococci,
Enterococcus, L. monocytogenes, Legionella pneumophila, L. micdadei, C. difficile,
Campylobacter jejuni, gut anaerobes.
▪ Useful for: treatment of documented Pseudomonal infections, empiric Gram
negative coverage where Pseudomonal coverage is desired.

31. 5) FIFTH GENERATION
▪ • Gram positive cocci: MRSA, MRSE, Penicillin Resistant Streptococcus, Enterococcus faecalis
▪ Gram negative: E. coli, Pseudomonas
▪ Uses- Acute Bacterial Skin and Skin Structure Infections
▪ Ceftaroline:
▪ Similar activity to ceftriaxone but with improved GM+ve activity
▪ -Active against MRSA/MRSE
▪ -No anaerobic activity
▪ -Considered to be ineffective against P.aeruginosa, Enterococcus species (including
vancomycinsusceptible and -resistant isolates), ESBL producing or AmpC overexpressing
Enterobacteriaceae.

32. Ceftolozone/tazobactam
▪ - Active against most ESBL/AmpC producers pseudomonase
▪ -No MRSA/MRSE activity
▪ -Still weak anaerobic activity
▪ -ceftobiprole: cover pseudomonas, No MRSA.
▪ Ceftolozane is a novel cephalosporin currently being developed with the β-
lactamase inhibitor tazobactam for the treatment of complicated urinary tract
infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-
associated bacterial pneumonia (VABP).

33. ADVERSE EFFECTS
▪ Hypersensitivity reactions:
a) Immediate : anaphylaxis, bronchospasm, urticaria
b) Late : Maculopapular rash with/without fever, eosinophilia
▪ Cross reactivity
▪ Nephrotoxicity
▪ Antibiotic induced colitis
▪ Intolerance to alcohol (disulfiram like reaction)
▪ Thrombocytopenia/ platelet dysfunction
▪ Rarely, bone marrow depression: granulocytopenia.

34. ▪ Allergic reaction :
Anaphaylaxis ,Serum sickness , Urticaria ,Skin rash , Haemolytic anaemia etc
▪ GIT upset :
▪ Nausia ,Vomiting , Diarrhoea
▪ Nephrotoxicity:
▪ Interstitial Nephritis , RenalTubular necrosis
▪ Others:
Disulfiram-like reaction ,Local irritation after I/M injection ,Thromboflavitis after
repeated I/V ,Bleeding tendency ,Eosinophilia and thrombocytosis ,Defect of newborn
babies ,Pharyngitis (Throat infection) ,Stillbirth or Miscarriage

35. CONTRAINDICATIONS
▪ Cephalosporins are contraindicated in patients who are allergic to them or to penicillins or other
beta lactams.
▪ Cefaclor: may cause serum sickness like reaction mainly in children < 5 years with symptoms of
fever, rash, erythema multiforme and arthralgia often during second or third exposure.
▪ Cefditoren: Hypersensitivity milk protein,C/I in carnitine deficiency or inborn errors of metabolism
that may result in clinically significant carnitine deficiency.
▪ Ceftriaxone: C/I in hyperbilirubinemic neonates (<28 days) because it displaces bilirubin from
albumin binding sites, concomitant use with IV calcium-containing solutions/products in neonates
(≤28days), IV use of ceftriaxone solutions containing lidocaine and in neonates <41 weeks
postmenstrual age.

36. ▪ Pregnancy category: Category B (all cephalosporins cross the
placenta)
▪ Renal dose adjustment: All of the cephalosporins except ceftriaxone
need renal dose adjustment.
▪ No hepatic dose adjustment is needed

37. RENAL DOSE ADJUSTMENT ( CrCl:creatinine clearance)

38. References
1) Rang & Dale's Pharmacology
2) Kd-Tripathi-Essentials-of-Medical-Pharmacology 8th Edition -2019
3) Biosynthesis of the Peptidoglycan of Bacterial CellWalls
XVII. BIOSYNTHESISOF PEPTIDOGLYCANAND OF INTERPEPTIDE BRIDGES IN LACTOBACILLUS
VIRIDESCENSRoland Plapp Jack L. Strominger
OpenAccess DOI:https://doi.org/10.1016/S0021-9258(18)62978-3
4) From the regulation of peptidoglycan synthesis to bacterial growth and morphologyAthanasios
Typas, Manuel Banzhaf, Carol A. Gross &WaldemarVollmer ,Nature Reviews Microbiology.
5) Cephalosporins: pharmacology and chemistryDecember 2017
Pharmaceutical and Biological Evaluations 4(6):234 , DOI:10.26510/2394-0859.pbe.2017.36
Project: Perfect Health Pakistan Australia USA Project

39. 6)The Peptidoglycan CellWall
https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Kaiser)/Unit_1%3A_Introduction_t
o_Microbiology_and_Prokaryotic_Cell_Anatomy/2%3A_The_Prokaryotic_Cell_-
_Bacteria/2.3%3A_The_Peptidoglycan_Cell_Wall#:~:text=1%3A%20Peptidoglycan%20is%20composed%20of
,bacterium%20to%20resist%20osmotic%20lysis.
7)Natural evolution ofTEM-1 β-lactamase: experimental reconstruction and clinical relevance .
Merijn L.M. Salverda, J. Arjan G.M. DeVisser, Miriam Barlow
FEMS Microbiology Reviews,Volume 34, Issue 6, November 2010, Pages 1015–1036, https://doi.org/10.1111/j.1574-
6976.2010.00222.x

40. 8)Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor
combination with activity against multidrug-resistant gram-negative bacilli
▪ George G Zhanel1, PhillipChung, Heather Adam, Sheryl Zelenitsky,Andrew Denisuik, Frank
Schweizer, Philippe R S Lagacé-Wiens, Ethan Rubinstein,Alfred S Gin,Andrew Walkty, Daryl
J Hoban, Joseph P Lynch 3rd, James A Karlowsky
PMID: 24352909 DOI: 10.1007/s40265-013-0168-2