Beta Lactam Antibiotics

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Beta Lactam Antibiotics

Having a β-lactam ring (B)

Major groups
 Penicillins
 Cephalosporins

Newer additions
 Monobactams

 Carbapenems
PENICILLINS
History
 First antibiotic be used to
clinically in 1941.
 Least toxic drug (penicillin)
was the first to be discovered.
 Originally obtained from the
fungus Penicillium notatin, but
the present source is a high Nobel Prize
Fleming in 1929 found that
yielding mutant of penicillin was produced by
Penicillium mould.
P.chrysogenin. Chain and Florey culminated in the clinical
use of penicillin in 1941.
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Chemistry and properties
 Penicillin nucleus consists of thiazolidine and -lactam rings.
  The side chain can be split
off by an amidase to
produce 6-
Na+ or K+ aminopenicillanic acid.
 Other side chains can then
be attached to it resulting
in different semisynthetic
penicillins.
 Production of penicillinase
opens the β-lactam ring
and inactivates penicillin.
 At the carboxyl group
attached to the
thiazolidine ring, salt
formation occurs with Na+
and K+, these salts are
more stable.
 Constitution of bacterial cell wall

 The cell wall surrounds the plasma membrane and protects the
cell from changes in osmotic pressure and provides rigidity and
strength.
 Gram positive cell walls consist of many layers (more than 50
layers) of peptidoglycan.
 Gram negative bacteria have a
lipidprotein-lipopolysaccharide-
phospholipid outer membrane
surrounding a thin peptidoglycan
layer (one to several layers).

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 —— Inhibition of cell wall synthesis——

Precurosor of N-acetylmuramic acid

fosfomycin
N-acetylmuramic acid β-lactam
racemase vancomycin ginebatin
oxymycin
synzyme
N-acetylmuramic straight chain peptide synzyme
acid pentapeptide tenpeptide peptidoglycan
compounds solid support disaccharide
compounds

Intramembrane plasma membrane extramembrane

Mechanism of action
 β-lactam antibiotics exert bactericidal action by interfering with
the synthesis of bacterial cell wall. β-lactam antibiotics bind with
PBPs (penicillin binding proteins), inhibits its activity and block
peptidoglycan synthesis. When bacteria divide in the presence of a
β -lactam antibiotic, cell wall deficient (CWD) are produced.
Because the interior of the bacterium is hyperosmotic, the CWD
forms cell swell and burst →bacterial lysis.

 Lytic effect of β-lactam

antibiotics may also be due to
depression of some
bacterial autolysins,
which normally function
during cell division.
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Why the gram positive bacteria is higher susceptible to
penicillins than gram negative bacteria?

In gram positive bacteria, the cell wall is almost entirely

made of peptidoglycan, so that it may be regarded as a
single giant mucopeptide molecule. However in gram
negative bacteria, it consists of alternating layers of
lipoprotein and peptidoglycan.

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Classification

Penicillin G
Semisynthetic penicillin
 Acid resistant alternative to penicillin G
 Penicillinase resistant penicillins
 Extended spectrum penicillins
β-lactamase inhibitors

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PENICILLIN-G (BENZYL PENICILLIN)
Antibacterial spectrum Natural penicillin
Narrow spectrum, cidal limited to gram positive bacteria and few others.
 Cocci:
Gram positive Streptococci (except group D or enterococci);
pneumococci; Staph. Aureus;
Gram negative Neisseria gonorrhoeae and N. meningitides
 Bacilli:
Gram positive B.anthracis, Corynebacterium diphtheriae, Clostridia
(tetani and others), Listeria. Spirochetes (Treponema pallidum and
others).
Gram negative Actinomyces israelii, spirochetal

PENICILLIN-G 11
Bacterial resistance
 Production of a narrow spectrum β-lactamase —— penicillinase
which opens the β-lactam ring and inactivates PnG and some closely
related congeners.

 The target enzymes and PBPs are

located deeper under lipoprotein
barrier where PnG is unable to
penetrate or have low affinity for
PnG.
 Some gram negative bacteria
become resistant by loss or (1) Site of action of penicillinase
alteration of porin channels, (2) Site of action of amidase

which permeate various β-lactam

antibiotics.
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Pharmacokinetics

 Acid labile —— destroyed by gastric acid.

 About 60% is plasma protein bound. Distributed mainly
extracellularly; reaches most body fluids but penetration in serous
cavities and cerebrospinal fluid is poor. However, in the presence
of inflammation adequate amounts may reach these sites.
 Little metabolized because of rapid renal excretion. Plasma t1/2 is
30 min.
 Tubular secretion of PnG can be blocked by probenecid.

Competitive inhibition of excretion

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Adverse Effects
One of the most nontoxic antibiotics
1. Hypersensitivity a major problem, 1%~10%.
 Common manifestations are rash, itching, urticaria
and fever.
 Anaphylaxis (e.g. shock) is rare but maybe fatal.
 Unpredictable.
 Partial cross sensitivity between different types of
penicillin.

Prevention measures
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 Prevention & treatment

History of allergy must be inquired

The drug solution must be Prepared freshly

A scratch test or intradermal test must be performed

Rescue drugs: adrenaline, glucocorticoids, histamine

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Treatment of drug allergy
 Skin tests (intradermal, patch) may forewarn in case of Type I
hypersensitivity. However, these tests are not entirely reliable.
False positive and false negative results are not rare.
 The offending drug must be immediately stopped.
 Anaphylactic shock or angioedema of larynx
 Put the patient in reclining position, administer oxygen at high
flow rate and perform cardiopulmonary resuscitation if
needed.
 Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000 solution) i.m.;
repeat every 5-10 min in case patient dose not improve or
improvement is transient. This is the only life saving measure.
Adrenaline should not be injected i.v. (can itself be fatal) unless
shock is immediately life threatening. If adrenaline is to be
injected i.v., it should be diluted to 1:10,000 or 1:100,000 and
infused slowly with constant monitoring.
 Administer a H1 antihistaminic (chlorpheniramine 10-20 mg)
i.m. /slow i.v. It may have adjuvant value.
 Intravenous glucocorticoid (hydrocortisone sod. succinate
100-200 mg) should be added in severe/ recurrent cases. It acts
slowly, but is specially valuable for prolonged reactions.
2. Local irritancy and direct toxicity pain at i.m.
injection site thrombophlebitis of injected vein.
3. Jarisch-Herxheimer reaction
sudden release of spirochetal lytic products
in treatment of syphilitic

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Uses
1. Streptococcal infections
Like pharyngitis, otitis media, scarlet fever, rheumatic fever,
subacute bacterial endocarditis.
2. Pneumococcal infections
Not recommended because of highly resistant.
3. Meningococcal infections
Meningitis and other infections.
4. Gonorrhoea
Become unreliable due to spread of resistant strains.
5. Syphilis T. pallidum
Early and latent syphilis, late syphilis, cardiovascular and
neurosyphilis.
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 Penicillin is ineffective
to exotoxin.
Gram positive cocci：
PnG + Phytomycin

Gram negative bacilli:

6. Diphtheria PnG + antitoxin
Antitoxin therapy is of prime importance
7. Tetanus and gas gangrene
Antitoxin and other measures are more important.
8. Rare infections
Anthrax, actinomycosis, trench mouth, rat bite fever and those
caused by Listeria monocytogenes, Pasteurella multocida.
9. Prophylactic uses
Rheumatic fever, gonorrhoea or syphilis, bacterial endocarditis,
agranulocytosis patients, surgical infections

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 The advantages and disadvantage of PnG

Advantages
 Higher curative effect
 Lower toxicity
Disadvantages
 Low price
 Poor oral efficacy
 Susceptibility to penicillinase
 Narrow spectrum of activity
 Hypersensitivity

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 SEMISYNTHETIC PENICILLINS
1. Acid resistant alternative to penicillin G
Phenoxy methyl penicillin (Penicillin V).
2. Penicillinase resistant penicillins
Classification
Methicillin, oxacillin, cloxacillin.
3.Extended spectrum penicillins a)
a) Aminopenicillins: Ampicillin, bacampicillin, amoxicillin.
b) Carboxy penicillins: Carbenicillin, carbenicillin indanyl,
carbenicillin phenyl (carfecillin), ticarcillin.
c) Ureidopenicillins: Piperacillin, mezlocillin.
d) Mecillinam (Amdinocillin)
β-lactamase inhibitors Clavulanic acid, sulbactam.
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ACID RESISTANT ALTERNATIVE TO PENICILLIN-G

Phenoxymethyl penicillin
(Penicillin V)
 Acid stable
 Antibacterial spectrum: identical to PnG
 Used only for streptococcal infections, prophylaxis of
rheumatic fever, less serious pneumococcal infections
and trench mouth

Acid resistant , not penicillinase resistant

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PENICILLINASE RESISTANT PENICILLINS

Cloxacillin
 Penicillinase resistant
 More active against penicillinase producing
Staph

Acid resistant and penicillinase resistant

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EXTENDED SPECTRUM PENICILLINS

 Aminopenicillins
Extended spectrum, acid resistant , not
Ampicillin, amoxicillin. penicillinase resistant

 Carboxy penicillins
Carbenicillin
Extended spectrum (gram negative
 Ureidopenicillins bacilli, pseudomonas aeruginosa )
Piperacillin

 Mecillinam (Amdinocillin)

Narrow spectrum
(gram negative)

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Ampicillin

Antibacterial spectrum
Active against all organisms sensitive to PnG
Many gram negative bacilli are inhibited.

Compared to PnG
• More active for Strep. Viridans and enterococci;
• Equally active for pneumococci, gonococci
and meningococci;
• Less active against other gram positive cocci.

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Uses
1. Urinary tract infections
Choice for most acute infections.
2. Respiratory tract infections
Bronchitis, sinusitis, otitis media.
3. Meningitis
First line drug. Usually combined with a third
generation cephalosporin/chloramphenicol for initial
therapy.
4. Gonorrhoea
First line drug
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5. Typhoid fever
Infrequently used due to emergence of resistance
6. Bacillary dysentery (diarrhea)
Shigella infections
7. Cholecystitis
A good drug, high concentrations in bile.
8. Subacute bacterial endocarditis
May be used in place of PnG.
Concurrent gentamicin is advocated.
9. Septicaemias and mixed infections
Combined with gentamicin
or one of the newer cephalosporins.
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Interactions

 Hydrocortisone inactivates ampicillin if mixed in

the i.v. solution.
 Interfere with deconjugation and enterohepatic
cycling of oral contraceptives --- failure of
contraception.
 Probenecid retards renal excretion of ampicillin.

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BETA-LACTAMASE INHIBITORS

β-lactamases inactivate β-lactam antibiotics

by opening the β-lactam ring.
 clavulanic acid and sulbactam

clavulanic acid sulbactam

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 Weak effect，Auxiliary administration

What’s the result of using this β-lactamase inhibitors ?

Decrease
drug
resistant

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Clavulanic acid

Mechanism
 Inhibits a wide variety β-lactamases produced by
both gram positive and negative bacteria.
 Permeates the outer layers of the cell wall of gram
negative bacteria and inhibits the periplasmically
located β-lactamase.
 “Progressive”inhibitor.
 “Suicide”inhibitor.

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Pharmacokinetics
 Rapid oral absorption.
 Bioavailability of 60%.
 tissue distribution matches amoxicillin.
 Eliminated mainly by glomerular filtration and
elimination t1/2 is 1 hour.

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Uses

Addition of clavulanic acid reestablishes the activity of

amoxicillin against β-lactamase producing organisms.
Amoxicillin sensitive strains are not affect by the addition
of clavulanic acid.
Coamoxicillin(clavulanic acid+amoxicillin) is indicated for:
 Skin and soft tissue infections, intraabdominal and
gynaecological sepsis, urinary, biliary and respiratory tract
infections
 Gonorrhoea (including penicillinase-producing Neisseria
gonorrhoeae）

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Adverse effects
Coamoxicillin
 The same as amoxicillin alone.

 Candida stomatitis/vaginitis
(superinfection) and rashes.
 Hepatic injury.

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Sulbactam

 Chemically and activity as well as clavulanic

acid.
 Oral absorption is inconsistent, it is
preferably given parenterally.
 Combined with ampicillin for use against β-
lactamase producing resistant strains.

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CEPHALOSPORINS
History
 Derived from "cephalosporin-C' obtained from a
fungus Cephalosporium.
 Chemically related to penicillins
 Includes 4 generations.

Cephalosporins
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CEPHALOSPORINS

FIRST GENERATION THIRD GENERATION

 Cephalothin  Cephradine Cefepime
 Cefazolin  Cefotaxime
 Cephalexin  Ceftizoxime
 Cefadroxil  Ceftriaxone
 Cephradine  Ceftazidime
 Cefoperazone
SECOND GENERATION  Cefixime
 Cefoxitin
FOURTH GENERATION
 Cefuroxime
 Cefepime
 Cefuroxime axetil
 Cefpirome
 Cefaclor

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 Four generations of Cephalosporins

Drugs Antibacterial spectrum Stability to Nephro- Clinical uses

(Generation) β-lactamase toxicity

penicillinase resistant
G+
1st Partly stable High staphylococcus aureus
infections

G+ and G－
2nd Stable Low G－ infections
anaerobes

G+ and G－
urinary tract infections
3rd anaerobion Very stable No
serious infections
pseudomonas eruginosa

Substitute for 3rd generation

4th G－ bacilus Very stable No
on G－ infections
The features of the 3rd generation cephalosporins

1. Extensive antibacterial
spectrum
2. Strong bactericidal
activity
3. Stable to β-lactamase
4. Longer t½, wide distribution, better
penetration
4. No nephrotoxicity, less hypersensitive
5. Extensive clinical uses

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Compared with penicillins

 S a m e m e c h a n i s m a nd
bactericidal action as that of penicillin
 High stability to β-lactamase
 Extensive antibacterial spectrum,
strong bactericidal activity
 Less hypersensitive, Partial cross
sensitivity with penicillins.

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Compared with penicillins —— Resistance

the same basis as for penicillins

 Alteration in target proteins (PBPs)
reducing affinity for the antibiotic.
 Impermeability to the antibiotic so that it
does not reach its site of action.
 Elaboration of β-lactamases which destroy
specific cephalosporins.

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Adverse effects

Cephalosporins are generally well tolerated but are

more toxic than penicillin.
1. Pain after i.m. injection.
2. Diarrhoea
3. Hypersensitivity reactions
4. Nephrotoxicity
5. Bleeding
6. Neutropenia and thrombocytopenia
7. A disulfiram-like interaction with alcohol

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Indications

1. Alternatives to PnG in patients developing rashes or

other allergic reactions.
2. Respiratory, urinary and soft tissue infections caused
by gram negative organisms.
3. Penicillinase producing staphylococcal infections.
4. Septicaemias caused by gram negative organisms.
5. Surgical prophylaxis.
6. Meningitis caused by H. influenae,
enterobacteriaceae.

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7. Gonorrhoea
caused by
penicillinase
producing
organisms.
8. Typhoid.
9. Mixed aerobic-anaerobic infections seen in cancer
patients, those undergoing colorectal surgery,
obstetric complications.
10. Prophylaxis and treatment of infections in neutropenic
patients.
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 THIRD GENERATION CEPHALOSPORINS

Cefotaxime
 potent action on aerobic gram
and negative and positive bacteria.
 Not so active on anaerobes, Staph.
aureus and Ps. auruginso

 Prominent indications are meningitis caused by gram negative

bacilli, life threatening resistant/hospital acquired infections,
septicaemias and infections in immunocompromised patients.

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Ceftriaxone

 Long duration of action (t1/2= 8 hour)

 Good CSF penetration, eliminated equally in urine
and bile.
 High efficacy in a wide range of serious infections
including bacterial meningitis, multiresistant
typhoid fever, complicated urinary tract infections,
abdominal sepsis and septicaemias.
 Hypoprothrombinemia and bleeding are specific
adverse effects.

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Ceftazidime

 High activity against Pseudomonas, specifically used in

febrile neutropenic patients with haematological
malignancies, burn etc.
 Activity against enterobacteriaceae is similar to that
of cefotaxime.
 Plasma t1/2 = 1.5-1.8 h.
 Neutropenia, thrombocytopenia, rise in plasma
transaminases and blood urea have been reported.

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FOURTH GENERATION CEPHALOSPORINS

Cefepime
 Antibacterial spectrum similar to that of 3rd
generation compounds.
 Highly resistant to β-lactamases, hence active
against many bacteria resistant to the earlier
drugs.
 Effective in many serious infections like hospital
acquired pneumonia, febrile neutropenia,
bacteremia, septicaemia etc.

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Cefpirome
 Available for the treatment of serious and resistant
hospital acquired infections including septicaemias,
lower respiratory tract infections etc.
 Better penetration through porin channels of gram
negative bacteria.
 Resistant to many β-lactamases; inhibits β-lactamase
producing enterobacteriaceae.
 More potent against gram positive and some gram
negative bacteria than the 3rd generation compounds.

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 MONOBACTAMS

Aztreonam
 Novel β-lactam antibiotic, inhibits gram negative enteric bacilli
and H. influenzae at very low concentrations and Pseudomonas
at moderate concentrations.
 Resistant to gram negative β-lactamases.
 Indications are hospital acquired infections originating from
urinary, biliary, gastrointestinal and female genital tracts.

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 CARBAPENEMS

Imipenem
 Extremely potent and very broad spectrum.
 Rapid hydrolysis by dehydropeptidase, need
to be combined with cilastatin.

Imipenem+cilastatin=Tienam(Primaxin)

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