Dr.

Aniruddha Mukherjee
Department of Pharmacology
Dr. B. C. Roy College of Pharmacy & AHS
 Content
β Lactum antibiotic:
Penicillins, cephalosporins
Introduction – classification & unitage
Mechanism of action,
Adverse Drug Reaction
therapeutic application

Other β-lactam antibiotics

&
β-Lactanase inhibitors
 β Lactum antibiotic

Chemistry:
 A thiazolidine ring (A)
 β-lactam ring (B)
 A side chain (R).
 Penicillin nucleus biological activity
 The side chain determines particular type of penicillin.
 Penicillin G (benzylpenicillin) has the greatest antimicrobial activity of
natural where side chain (R) is a phenyl-methyl substituent.
 Classification
Benzylpenicillin:
Injection, short half-life and is destroyed by β-lactamases
spectrum: Gram-positive and Gram-negative cocci and some Gram-negative
bacteria
β-Lactamase-resistant penicillins (e.g. flucloxacillin):
Given orally.
Broad-spectrum penicillins (e.g. amoxicillin):
Given orally, destroyed by β-lactamases, less potent, active against Gram-
negative bacteria.
Extended-spectrum penicillins (e.g. ticarcillin):
Given orally; destrtoyed by β-lactamases, broad-spectrum - active against
pseudomonads.
Unitage:
The international unit of penicillin is the specific penicillin activity contained in 0.6 mg of
the crystalline sodium salt of penicillin G.
One milligram of pure penicillin G sodium thus equals 1667 units;
(1.0 mg of pure penicillin G potassium represents 1595 units.)
 Mechanism of action
Peptidoglycan is a heteropolymeric component of the cell wall (rigidity &
mechanical stability)
In gram-positive microorganisms, the cell wall is 50 to 100 molecules thick, but it
is only 1 or 2 molecules thick in gram-negative bacteria
The peptidoglycan is composed of glycan chains [linear strands of two alternating
amino sugars (N-acetylglucosamine-NAG and N-acetylmuramic acid-NAM)] that
are cross-linked by peptide chains.
Three steps fo biosynthesism:
1. First stage: precursor formation: to produce uridine diphosphate (UDP)-
acetylmuramyl-pentapeptide,
Addition of D-alanyl-D-alanine - involves prior racemization of L-alanine and
condensation catalyzed by D-alanyl-D-alanine synthetase.
2 . Second stage: UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are
linked to form a long polymer.
3 .Third stage: Formation of cross-link by a transpeptidation by linked to the fourth
residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-alanine)
 Trans peptidation is inhibited by the β-lactam antibiotics
Stereomodels reveal that the conformation of penicillin is very similar to that of D-
alanyl-D-alanine. The transpeptidase probably is acylated by penicillin; that is,
penicilloyl enzyme apparently is formed, with cleavage of the – CO-N - bond of the
β-lactam ring.
Additional targets termed penicillin-binding proteins (PBPs).
S. aureus has four PBPs, Escherichia coli has at least seven.
PBPs vary in their affinities for different β-lactam antibiotics.
The higher-molecular-weight PBPs of E. coli (PBPs 1a and 1b) include the
transpeptidases responsible for synthesis of the peptidoglycan (maintenance of the
rodlike shape of the bacterium and for septum formation at division).
Lethality involve both lytic and nonlytic mechanisms:
1. Penicillin's disruption of the balance between PBP-mediated peptidoglycan
assembly and murein hydrolase activity results in autolysis.
2. Nonlytic killing by penicillin may involve holin-like proteins in the bacterial
membrane that collapse the membrane potential.
 N-acetylmuramic acid-NAM

+ Pentapeptide

NAG - N-acetylglucosamine

Uridine diphosphate (UDP)-acetylmuramyl-pentapeptide

1st step: Precursor formation: to produce UDP-acetylmuramyl-pentapeptide

2nd step: UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked to form a

long polymer
 D-alanine

Transpeptidase
Transpeptidation (Penicillin binding protein)
 Therapeutic Uses
Pneumococcal Infections: Listeria Infections. (L. Monocytogenes)
Pneumococcal Pneumonia. Lyme Disease. (Borrelia)
Pneumococcal Meningitis. Erysipeloid (Erysipelothrix rhusiopathiae)
Streptococcal Infections.
Pasteurella multocida. (wound infections after
Infections with Anaerobes.
a cat or dog bite)
Staphylococcal Infections.
Meningococcal Infections.
Gonococcal Infections.
Syphilis:
Actinomycosis. Prophylactic Uses of the Penicillins.
Diphtheria. Recurrences of Rheumatic Fever.
Anthrax. Syphilis.
Clostridial Infections. Surgical Procedures in Patients with Valvular
Fusospirochetal Infections.
Heart Disease.
Rat-Bite Fever. (Spirillum minor and Streptobacillus moniliformis)

Deer ticks
 Jarisch-Herxheimer reaction
Secondary syphilis develop Jarisch-Herxheimer reaction
first injection of penicillin, chills, fever, headache, myalgias, and arthralgias.
Syphilitic cutaneous lesions more prominent, edematous, and brilliant (due to
release of spirochetal antigens ).
Rash begins to fade within 48 hours.
Does not recur with the second or subsequent injections of penicillin

Untoward Reactions to Penicillins

Hypersensitivity Reactions: maculopapular rash, urticarial rash, fever,

bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson
syndrome, and anaphylaxis.
Penicillins and breakdown products act as haptens (penicilloyl moiety [major
determinant moiety (MDM)]).
IgE-mediated reactions are to the MDM
Antipenicillin antibodies are detectable.
Scarlatiniform, morbilliform, urticarial, vesicular, and bullous eruptions may
develop.
Henoch-Schonlein purpura. Contact dermatitisn, exfoliative dermatitis and
exudative erythema multiforme - Stevens-Johnson syndrome.
 Other Adverse Reactions.
Bone marrow depression, granulocytopenia, and hepatitis.
Impairment of platelet aggregation (interference with to platelet receptors).
Pain and sterile inflammatory reactions - Serum transaminases and lactic
dehydrogenase
Nausea, with or without vomiting, and severe diarrhea.
Sciatic nerve - severe pain
Intrathecal injection of penicillin G arachnoiditis or severe and fatal
encephalopathy.
Intraventricular administration of penicillins should be avoided.
(lethargy, confusion, twitching, multifocal myoclonus, or localized or generalized
epileptiform seizures).
Injection of penicillin G procaine - dizziness, tinnitus, headache, hallucinations,
and sometimes seizures.
Contraindication:
Renal insufficiency, localized lesions of the central nervous system (CNS), or
hyponatremia.
 Cephalosporins

Cephalosporium acremonium:- first source of the cephalosporins (1948-Brotzu)

from the sea near a sewer outlet off the Sardinian coast.
Contain three distinct antibiotics - cephalosporin P, N and C.
Cephalosporin C, (7-aminocephalosporanic acid) + side chains.
Chemistry:
Cephalosporin C:
A side chain derived from D-α-aminoadipic acid
Condensed with a dihydrothiazine β-lactam ring system (7-aminocephalosporanic
acid).
7-aminocephalosporanic acid are relatively stable in dilute acid.
7th β-lactam ring are associated with alteration in antibacterial activity
3rd dihydrothiazine ring are metabolism and pharmacokinetic properties.
The cephamycins a methoxy group at position 7 of the β-lactam ring of the 7-
aminocephalosporanic acid nucleus.
 Classification
Cephalosporins Oral Parentral

1st genaration Cephradine (monocef) Cefazolin (Kefzol)

Cephalexin(Keflex) Cephalothin
Cephadroxil(Cefabect)

2nd genaration Cefaclor(ceclor) Cefotetan

Cefprozil(cefzil,Zilpro) Cefuroxile

3rd genaration Cefixime Cefotaxime

Ceftazidime
Ceftriaxone(Norbac)
Cefoperazone(Cefobid)

4th genaration Cefepime(Maxipime)

 First generation: (G+)
e.g. Cephalexin, Cefazolin, Cephalothin, Cephradine

Active against G+ cocci ( except.enterococci & MRSA ):

e.g. s.pneumoniae, s.pyogenes,s. aureus, s. epidermidis
Indicated for streptococcal pharyngitis ( e.g. cephalexin)
Commonly used ( eg. Cefazolin) as prophylacic for surgical procedures.

Second generation: Decreasing Gram (+) and Increasing Gram (-)

Cefoxitin active against bowel anaerobes (B. fragilis )

Cefuroxim active against H. influenzae, M. catarrhalis, S. pneumoniae
Cef. Axetil- oral form of cefuroxim
Cefaclor active against H. influenzae, M. catarrhalis &E.coli
Cefprozil- similar to cefaclor, c. axetil and augmentin- Liked by children

Second Generations are used primarily for URTIs ( acute otitis media, sinusitis ) and
Lower RTIs ( acute exacerbation of chronic bronchitis)
 Third generation: Gram (-), but also some GPC

e.g. Ceftriaxone, Cefotaxime, Cetazidime, Cefoperazone, Cefixime

They have enhanced G- activity,
H. influenzae, N. meningitidis, N.gonorrhea, P. aeruginosae, M. catarrhalis,
E.coli, most Klebsiella
Ceftriaxone has long half-life.
Not advised in neonates (interferes with bilirubin metabolism )
Cefotaxime preferred in neonate (does not interfere with bilirubin metabolism),
as may ceftriaxone.
Ceftazidime & cefoperazone have excellent activity against p. aeruginosae.
Cefixime has similar activity to amoxicillin & cefaclor for actute otitis media

Fourth Generation: Gram (+) and Gram (-)

Cefipime
Active against G+ bacteria than cefazolin against s. pyogenes, s.pneumoniae but
lower against s. aureus.
Similar to cefotaxime against E.coli & K. pneumoniae but for p. aeruginosa.
 Adverse effects
Hypersensitivity reactions:
Most common Anaphylaxis, bronchspasm, urticaria, Maculopapular rash
(common)

Nephrotoxicity: (esp. Cephradine)

Thrombophlebitis ( i.v admin. )

Superinfections

Diarrhea-
Oral cephalosporins, cefoperazone, ceftriaxone & moxalactam.

a) bleeding disorders
b) Flushing, tachycardia, vomiting with alcohol intake
cefamandole, moxalactam & cefoperazone
 Therapeutic uses
1. Alternative to penicillin in allergic patients :

2. Upper respiratory tract infections and otitis media:

cefaclor cefuroxime axetil
cefixime cefprozil

3. Septicaemia caused by G- bacteria ( P.aeruginosae):

A penicillin(eg.Piperacillin/ Ticarcillin) +aminoglycoside
OR
A cephalosporin(eg. ceftazidime ) + aminoglycoside
4. Urinary tract infections:
Cefuroxime, Cefixime
5. Prophlaxis in surgery:
A. Appendectomy (bowel anaerobes ) eg. Cefoxitin
B. Obstetrical &gynecological, urological, orthopedic procedures, etc (S.
aureus & S. epidermidis ) eg. Cefazoline
6. Meningitis:
N. Meningitidis (Ceftriaxone, Cefotaxime ( pref. in neonate)
7. Gonococcal infections:
Ceftriaxone
 Other β-lactam antibiotics
Neither penicillins nor cephalosporins have been developed.

Carbapenems

Fused β-lactam ring and a five-membered ring unsaturated and containing a carbon atom.
Broader spectrum.
Imipenem. Imipenem is marketed in combination with cilastatin, a drug that inhibits the
degradation of imipenem by a renal tubular dipeptidase.

Source and Chemistry. Imipenem is derived from a compound produced by Streptomyces

cattleya. The compound thienamycin is unstable, but imipenem, the N-formimidoyl
derivative, is stable. The structural formula of imipenem is as follows:

Antimicrobial Activity.
Resistant to hydrolysis by most β-lactamases.
wide variety of aerobic and anaerobic microorganisms.

Pharmacokinetics and Adverse Reactions. Not absorbed orally.

The drug is hydrolyzed rapidly by a dipeptidase found in the brush border of the proximal
renal tubule. cilastatin, an inhibitor of the dehydropeptidase.
A preparation has been developed that contains equal amounts of imipenem and cilastatin.
ADR: Nausea and vomiting (1% to 20%). 1.5% of patients.

Therapeutic Uses.
UTI and LRTI; intra-abdominal and gynecological infections; and skin, soft tissue, bone,
and joint infections. cephalosporin-resistant nosocomial bacteria. Imipenem should not be
used as monotherapy for infections owing to P. aeruginosa because of the risk of resistance
developing during therapy.
Meropenem:
Meropenem is a dimethylcarbamoyl pyrolidinyl derivative of thienamycin.
It does not require coadministration with cilastatin because it is not sensitive to renal
dipeptidase.

Ertapenem. larger serum half-life that allows once-daily dosing and. Its spectrum of activity
against gram-positive organisms, Enterobacteriaceae, and anaerobes makes it attractive for
use in intra-abdominal and pelvic infections.
Aztreonam. Aztreonam is a monocyclic β-lactam compound (a monobactam) isolated from
Chromobacterium violaceum. Its structural formula is as follows:

Aztreonam interacts with penicillin-binding proteins of susceptible microorganisms and

induces the formation of long filamentous bacterial structures.

The antimicrobial activity resembles that of an aminoglycoside.

only against gram-negative bacteria; it has no activity against gram-positive bacteria and
anaerobic organisms. However, activity against Enterobacteriaceae is excellent, as is that
against P. aeruginosa.

Aztreonam is administered either intramuscularly or intravenously. most of the drug is

recovered unaltered in the urine. The half-life is prolonged to about 6 hours in anephric
patients.