BETA-LACTAM

ANTIBIOTICS
Beta lactam antibiotics are widely
prescribed drugs that share a
common structure and mechanism
of action.
 BETA LACTAMS ;General classification

• PENICILLINS
• CEPHALOSPORINS
• MONOBACTAMS
• CARBAPENEMS
2
 All of the drugs in this group
contain a β-lactam ring in
their structure
S S

N N
O O
Penicillins Cephalosporins
.

N N
O O

Carbapenems Monobactams
6
 Mechanism of action of Beta
lactam antibiotics
The rigid cell wall of the bacteria maintains the
integrity, shape and protects it from lysis due
to osmotic pressure
Peptidoglycan – a complex polymer, is an
important component of the cell wall.
It consists of glycan chains which are crossed
linked by peptide chains ; glycan chains made
up of alternating NAG & NAM.
This cross linking ( via peptide chains )in between the
peptidoglycan strands provide necessary strength to
the bacterial cell wall.
This process of crosslinking/cross bridging
is called as transpeptidation reaction.
The last step in synthesis of peptidoglycan chain is
transpeptidation with the help of enzymes
transpeptidases( Penicillin binding proteins)
Eventually several layers of peptidoglycan are
formed,all of which are crossed-linked to
create the cell wall
Role of beta lactams
antibiotics?????????????????
Beta lactam antibiotics covalently bind to PBPs
and inhibit the synthesis of peptidoglycans
resulting in cell wall deficient bacteria.
The formation of an imperfect cell wall leads to
an osmotic drive of the fluid from outside to
the inside of the bacteria which then swells
up and burst to die.
The antibiotic-Penicillin binding protein
complex stimulates release of autolysins
that are capable of digesting the existing
cell wall.
Since rapid cell wall synthesis takes place when
bacteria are multiplying, penicillins are lethal
in multiplying phase rather than dormant
phase of the bacteria
19
History
Who discovered Penicillin?

Alexander Fleming

(1881-1955)
Classification of penicillins
 Classification of Penicillins
Narrow spectrum penicillins
Extended spectrum penicillins
Narrow spectrum penicillins
Extended spectrums Penicillins
 Natural penicillins

Penicillin G ( Benzyl
penicillin)
source
Originally obtained from fungus Penicillium
notatum,
but at present high yielding source:
Penicillium chrysogenum.
Antibacterial spectrum
Antibacterial spectrum
Antimicrobial spectrum
Highly effective vs G+ve
cocci, G+ve bacilli,
spirochetes

Moderately active vs G-
ve cocci and
actinomycetes

Negligible activity vs G-ve

bacilli and bacteriodes
The bactericidal activity of penicillins is greater against
G+ve bacteria compared to G-ve bacteria.
Difference is due to the organisation of both of their
cell wall.
G+ve
• Thick layer of
peptidoglycan and
teichoic acid
• Easily accessible
• Easier inhibition of
transpeptidation
 Gram
negative
• G-ve : 2 cell
membranes;
cytoplasmic
membrane & outer
membrane with thin
layer of peptidoglycan
sandwiched between
the two….Outer
membrane consists of
lps with narrow porin
channels which
function as barriers to
permeability of beta
lactam antibiotics 
weaker activity
Antimicrobial spectrum
Highly effective vs
G+ve cocci, G+ve
bacilli, spirochetes

Moderately active vs
G-ve cocci and
actinomycetes

Negligible activity vs
G-ve bacilli and
bacteriodes
 pharmacokinetics
• Benzyl penicillin is destroyed by gastric juice,
has very low bioavailability  hence given
parenterally.
• Food interferes with absorption: given 2hrs
before /after food
• Widely distributed into most tissues and body
fluids, but remains mostly extracellularly as
they are polar compounds.
• Generally does not cross BBB, but in the
presence of inflammation,therapeutic conc
are attained in the CSF.
• Attains peak levels in 15-30 mins t ½ 30-
60 mins 60% bound to plasma albumin

• Rapidly excreted by kidneys

10% glomerular filtration
90% tubular secretion

• Role of Probenecid ??
• competes with beta lactams for active
tubular secretion and retards their
excretion,thereby increases the plasma
concentration as well as duration of
action of beta lactams
Limitations of Penicillin G
• Acid labile  orally not effective

• Short duration of action half life 30 mins

Repository penicillins

• Narrow spectrum of antibacterial activity ; mainly

G+ve organisms

• Destroyed by penicillinase enzyme

• Possibility of anaphylaxis
• ⇨hence , semisynthetic penicillins were obtained
in an effort to overcome this disadvantage.
 Repository penicillin
• Oral penicillin can be used only in minor
infections and benzyl penicillin is short-acting.
• Hence,repository forms like procaine penicillin
and benzathine penicillin are formulated so that
they have delayed but a sustained absorption and
consequently have a prolonged half life.

• By combining it with poorly water soluble

compounds,such as procaine/ benzathine

Long acting (every 12 h ) . Acid

unstable Penicillinase sensitive

 Used to prevent subacute bacterial endocarditis
due to dental extraction or tonsillectomy in
patients with congenital or acquired valve
disease .

45
 Long acting (every 3-4

weeks ) Acid unstable

 Penicillinase
Treatment sensitive
of β-hemolytic streptococcal
pharyngitis.
 Used as prophylaxis against reinfection with β-
hemolytic streptococci so prevent rheumatic fever .
Once a week for 1-3 weeks for treatment of syphilis
 (2.4 million units I.M.)

46
 Uses of Penicillin G ( PnG)
• PnG is the DOC for infections caused by
organisms susceptible to it, unless the patient
is allergic to this antibiotic

• However, use has declined very much due to

fear of causing anaphylaxis
 Streptococcal infections Like pharyngitis, otitis media,
scarlet fever, rheumatic fever respond to ordinary
doses of PnG because Strep. pyogenes has not
developed significant resistance. However, the risk of
injecting PnG for this infection is seldom taken now.
For subacute bacterial endocarditis (SABE) caused by
Strep. viridans or faecalis high doses (10–20 MU i.v.
daily) along with gentamicin given for 2–6
weeks is needed.
 Pneumococcal infections : PnG is not used now
for empirical therapy of pneumococcal (lobar)
pneumonia and meningitis because many
strains have become highly penicillin resistant.
However, PnG 3–6 MU i.v. every 6 hours is the
drug of choice if organism is sensitive.
 Meningococcal infections are still mostly
responsive; meningitis and other infections
may be treated with intravenous injection of
high doses.
 Meningococcal infections are still mostly
responsive; meningitis and other infections
may be treated with intravenous injection of
high doses.
Syphilis
T. pallidum has not shown any
resistance and PnG is the drug of choice
Syphilis

◦ Early/Latent Syphilis
 Procaine Pn 1.2 MU i.m. daily for 10 days OR
 Benzathine Pn 2.4 MU i.m. weekly for 4 weeks
◦ Late Syphilis
 Benzathine Pn 2.4 MU weekly for 4 weeks
◦ Cardiovascular/Neurosyphilis
 Sodium PnG 5 MU i.m. 6 hourly for 2 weeks
Leptospirosis: PnG 1.5 MU injected i.v. 6 hourly
for 7 days is curative.
Diphtheria :Antitoxin therapy is of prime
importance.
Procaine penicillin 1–2 MU daily for 10 days is
used to prevent carrier state.
Tetanus and gas gangrene Antitoxin and other
measures are more important; PnG 6–12
MU/day is used to kill the causative organism
and has adjuvant value.
 Prophylactic uses

(a) Rheumatic fever: Low concentrations of

penicillin prevent colonization by streptococci
that are indirectly responsible
for rheumatic fever. Benzathine penicillin 1.2
MU every 4 weeks till 18 years of age or 5
years after an attack, whichever is more.

(b) Bacterial endocarditis: Dental extractions,

endoscopies,
(b) Bacterial endocarditis: Dental extractions,
endoscopies, catheterization, etc. cause
bacteremia which in patients with valvular
defects can cause endocarditis. PnG can afford
protection, but amoxicillin is preferred now.
 Adverse Effects
Hypersensitivity-
◦ rash, itching, urticaria, fever
◦ wheezing, angioneurotic edema, serum sickness,
exfoliative dermatitis (less common)
◦ Anaphylaxis
(rare, but fatal)
 Adverse Effects
Hypersensitivity-

*Commonly seen after PARENTERAL

administration
*Incidence highest with PROCAINE pn
*History of penicillin allergy should be
elicited
*Scratch test or Intradermal Test dose
- negative test does not rule out
delayed hypersensitivity reactions!
 Adverse Effects
Superinfections
◦ Rare with PnG
◦ Bowel, respiratory and cutaneous microflora can
undergo changes

Jarisch- Herxheimer Reaction

◦ Shivering, fever, myalgia, exacerbation of lesions,
vascular collapse
◦ Seen in syphilitic patients injected with Penicillin
◦ Due to sudden release of spirochetal lytic
products
◦ Symptomatic treatment with aspirin and sedation
 Adverse Effects
Local irritation
◦ Pain at injection site
◦ Thrombophlebitis
Neurotoxicity
◦ Mental confusion, muscular twitching,
convulsions, coma
Bleeding
◦ Due to interference of platelet
function
Intrathecal
PnG injections (not
recommended)
◦ Arachnoiditis, degenerative changes
in spinal cord
 PENICILLIN V
• Acid resistant penicillin
• Given orally ( absorption is better)
• Used only in mild infections as it has low
bioavailability
• Short duration of action : 6hours
• Spectrum similar to that of PnG, but its is
poorly absorbed, thus not used for rx of
bacteremia.
 Uses

• Streptococcal pharyngitis
• Sinusitis
• Trench mouth
• Otitis media
Semisynthetic Penicillins
 Narrow spectrum- continued
Beta lactamase resistant group; semi synthetic
Aka antistaphylococcal penicillins
Spectrum: same as PnG +sensitive strains of
beta lactamase producing S.aureus,
S.epidermidis

Primary use: in the treatment of

known/suspected staphylococcal infections
• Methicillin no longer used because of
nephrotoxicity, yet S.aureus resistant to
cloxacillin/nafcillin labelled as MRSA

• MRSA fairly common and such staphylococci

are resistant to other penicillins
• Oxacillin, Cloxacillin, dicloxacillin are relatively
acid stable but food interferes with their
absorption, therefore, to be given 1hr before
or after food

• Nafcillin: acid labile and erratic absorpion from

the gut thus given parenteral.
• Nafcillin is highly resistant to penicilinase and
also has useful activity vs non penicilinase
producing organisms

• Excreted in bile, so dose adjustment not

needed in renal failure