Beta-Lactam Antibiotics

Dr. Vishaal Bhat

Melaka Manipal Medical College

The Beta-Lactam Antibiotics

Cell wall active agents

Prevent the final step in the synthesis of the bacterial cell wall
Range from very narrow spectrum to very broad

spectrum

Introduction
Most widely produced and used antibacterial drugs

in the world since 1941.

-Lactams are divided into several classes based on
their structure and function.
Often named by their origin, but all classes have a
common -Lactam ring structure.

BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
The major subdivisions are:
(a) penicillins whose official names
usually include or end in cillin
(b) cephalosporins which are
recognized by the inclusion
of cef or ceph in their
official names.
(c) carbapenems (e.g. meropenem,
imipenem)
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam).

A. FLEMING
(18811955)
Penicillin G
- P. notatum

I. PENICILLINS

(1929)

Penicillium chrysogenum

History
1928- Alexander Fleming discovers a mold which

inhibits the growth of staphylococcus bacteria

1940- penicillin is isolated and tested on mice by
researchers at Oxford
1941- penicillin mass produced by fermentation for
use by US soldiers in WWII
1950s- 6-APA is discovered and semi-synthetic
penicillins are developed.
1960s to today- novel -lactams/ -lactamase
inhibitors are discovered and modified from the
natural products of bacteria

Classification
Penicillins
Natural penicillins
PenG, PenVK, Benzathine Pen, Procaine Pen
Aminopenicillins
Ampicillin, Amoxicillin
Anti-Staph penicillins
Oxacillin, Dicloxacillin, Methicillin, Nafcillin
Anti-Pseudomonal
[Carboxy] Ticarcillin
[Ureido] Piperacillin

How do they work?

1.
2.
3.

4.

The -lactam binds to Penicillin Binding Protein

(PBP)
PBP is unable to crosslink peptidoglycan chains
The bacteria is unable to synthesize a stable cell
wall
The bacteria is lysed

Peptidoglycan Synthesis

Penicillin binding
protein

Mechanism of Action

Bacterial Resistance
Bacteria have many methods with which to combat

the effects of -lactam type drugs.

Intrinsic defenses such as efflux pumps can remove
the -lactams from the cell.
-Lactamases are enzymes which hydrolyze the
amide bond of the -lactam ring, rendering the drug
useless.
Bacteria may acquire resistance through mutation at
the genes which control production of PBPs, altering
the active site and binding affinity for the -lactam .

PK/PD
The -lactams are time-dependent killers
The effect is directly proportional to the amount of TIME the
concentration of the antibiotic at the site of infection is ABOVE
the MIC of the organism.
The -lactams are BACTERICIDAL (at
therapeutically attainable levels)

Time Dependant

H Derendorf

Absorption,distribution &
metabolism
Oral absorption of most penicillins is poor
Exception: penicillin v
Amoxicillin
Food interferes with absorption
To increase GI absorption: give ester form:
Bacampicillin
Carbenicillin

Distribution
Widely distributed
Relatively insoluble in lipid
Hence, have poor penetration into cells and BBB
Inflammation ( eg. Meningitis ) permits entrance into CSF

Absorp., metabolism ( cont. )

Protein binding differs :
Ampicillin and penicillin G
20% bound
Nafcillin, oxacillin,
90% bound
cloxacillin , dicloxacillin
Metabolism and excretion
Not metabolized in human
Excreted mostly unchanged in urine( except.
Nafcillin,oxacillin, cloxacillin, dicloxacillin )
Probenecid blocks their secretion
Half-life 30-60 min ( increased in renal failure)

Penicillin G
Used i.m ,slow i.v or infusion
Highest activity against Gram-positive organisms but susceptible
to Beta-lactamase.
Effective against:
Gram-positive aerobic cocci
Staph. aureus- not producing penicillinase,
S.pneumoniae ( group A ), S.pyogenes
Gram-negative aerobic cocci- N.meningitides, N. gonorrheano longer of choice
Gram- positive bacilli: Bacillus anthracis
Spirochetes: T. pallidum drug of choice
Anaerobes
Clostridium spp but inactive against B.fragilis
Actinomycetes israelii (actinomycosis)

Repository penicillins
Developed to prolong duration of penicillin G in the
blood
1. Penicillin G procaine
Duration 12- 24 hr
It is given i.m and not i.v( risk of procaine toxicity)
Seldom used now ( increased frequency of
penicillinase producing N. gonorrhea

Repository penicillins ( cont.)

2. Penicillin G benzathine (i.m)
Duration 3- 4 weeks
Painful at the injection site ( limits its use )
Uses
1. Syphilis
2. Rheumatic fever prophylaxis( inhibits
group A beta- hemolytic streptococci)
3. Streptococcal pharyngitis

Disadvantages of penicillin G

A. Destroyed by gastric HCL

B. Inactivated by penicillinase
C. Narrow spectrum of activity

Acid resistant penicillins

Phenoxy- methyl penicillin ( penicillin v), p.o.
( spectrum of activity is similar to penicillin G )
Uses
Group A Streptococcal pharyngitis
Prophylaxis against group A streptococci in pts with
history of rheumatic heart disease.
Disadvantages
Readily hydrolyzed by beta-lactamase

Penicillinase-resistant penicillins
Methicillin
Oxacillin
Cloxacillin
Dicloxacillin
Floxacillin
Nafcillin
Lower activity against G+ compared to Penicllin G
but
Are the choice for infections caused by penicillinase
producing S. aureus.
However, MRSA & ORSA has emerged.
Not effective against G- aerobes( E.coli, klebsiella,
N.gonorrhea or pseudomonas spp.)
Less active than penicillin on anaerobes.
High protein and food binders

Extended- spectrum penicillins

a) Ampicillin, Ampicillin- sulbactam, Bacampicillin,
Amoxicillin, Amoxicillin- clavulanic acid.
Less active than penicillin G against G+ cocci. Active
against G- organisms.

Extended-spectrum penicillins
Uses
H. Influenza infections ( otitis media, sinusitis, chronic
bronchitis, pneumonia, bacterial meningitis ).
M.catarrhalis
E. Coli infections ( Urinary & biliary infections ).
Samonella infections ( typhoid fever )
Shigella infections ( ampicillin )
Gonococcal infections ( alternative for penicillin in the
treatment of gonorrhea )
Prophlaxis of infective endocarditis

Disadvantages
Amoxicillin & ampicillin alone are readily destroyed by Staph.
Penicillinase.

Antipseudomonal penicillins ( cont )

Ticarcillin-clavulanic acid, piperacillin,piperacillintazobactam ( Tazocin )
Uses
Pseud. aeruginosa. For pseud. septicemia, they
should be given together with an aminoglycoside
( eg. Gentamicin ).
Disadvantages
Ticarcillin and piperacillin alone are readily
destroyed by S. penicillinase. High dose may lead
to hypernatraemia due to sodium content.

Adverse effects of penicillins

1.Hypersensitivity reactions ( occur in 1-10% of pts;
fatality occur in 0.002%)
( immediate, accelerated & late allergic rxns) ** Cross-reactions

Urticarial rash
Fever
Bronchspasm
Serum sickness
Exfoliative dermatitis
Stevens- Johnson syndrome
Anaphylaxis
2. Super infections
3. Diarrhoea
4. May cause convulsions after high doses by i.v or in
renal failure

-Lactamases
-Lactamases were first discovered in 1940 and
originally named penicillinases.
These enzymes hydrolyze the -lactam ring,
deactivating the drug, but are not covalently bound
to the drug as PBPs are.
Especially prevalent in Gram (-) bacteria.
Three classes (A,C,D) catalyze the reaction using a
serine residue, the B class of metallo- -lactamases
catalyze the reaction using zinc.

-Lactamase Inhibitors

How do you evade a -lactamase?

1.

2.

Use a non--lactam agent

Steric Inhibition

3.

Penicillins with large side chains

Cephalosporins

-lactam + -lactamase inhibitors

Not all -lactamases are inhibitable (!)

-Lactamase Inhibitors
There are currently three clinically available lactamase inhibitors which are combined with lactams; all are produced through fermentation.
These molecules bind irreversibly to -lactamases but
do not have good activity against PBPs. The rings are
modified to break open after acylating the enzyme.

-Lactam/Inhibitor combinations
Aminopenicillins:
ampicillin-sulbactam
amoxicillin-clavulante
Extended-Spectrum Penicillins
piperacillin-tazobactam
ticarcillin-clavulanate