-lactam Antibiotics

Linrong

professor
Department of pharmacology
Email:linrong@mail.xjtu.edu.cn

-lactam Antibiotics
-Lactam Characteristics
Mechanism of Action
Mechanisms of Resistance
Classification of penicillins
Pharmacokinetics
Spectrum of activity
Therapeutic uses
Adverse effects

-lactam Antibiotics

Penicillins

Other Penicillins
Cephalosporins

Penicillinase-resistant penicillins
Broad-spectrum penicillins
Antipseudomonal penicilins
Beta-lactamase inhibitors
Mechanism of action
Spectrum of Activity and Clinical uses
Adverse effects

-lactam Antibiotics
All of the drugs in this group contain
a -lactam ring in their structure
S

N
O

N
O

Penicillins

Cephalosporins

N
O

Carbapenems

share similar
features of chemistry,
mechanism of action,
pharmacologic and
clinical effects.

Monobactams

-lactam Antibiotics

-Lactam Characteristics
l

l
l
l

Same Mechanism of Action : Inhibit

cell wall synthesis
Bactericidal (except against Enterococcus
sp.); time-dependent killers
Short elimination half-life
Primarily renally eliminated
Cross-allergenicity - except aztreonam
5

ALL -lactams
Mechanism of Action
Interfere with cell wall synthesis by
binding to penicillin-binding proteins
(PBPs) which are located in bacterial
cell walls
Inhibition of PBPs leads to inhibition of
peptidoglycan synthesis Cell death

-lactam Antibiotics
-lactam Antibiotics: -Lactam Characteristics
Mechanism of Action

Mechanisms of Resistance

1. Production of-lactamase enzymes

2. Trapping mechanism
3. Modification of target PBPs
4. Impaired penetration of drug to target PBPs
5. The shortage of autolytic enzyme.
6. The presence of an efflux pump.

ALL -lactams
Mechanisms of Resistance
1. production of-lactamase enzymes
most important and most common
hydrolyzes beta-lactam ring causing
inactivation

2. Trapping mechanism.
w Some -lactams tightly bind with lactamase and stay outside the bacterial cell.
Thus, these beta-lactams cant enter the
bacterial cell wall to combine with the PBPs.

ALL -lactams
Mechanisms of Resistance
3. Modification of target PBPs.
w responsible for methicillin resistance in
staphylococci and penicillin resistance in
pneumococci.

4. Impaired penetration of drug to

target PBPs.
w which occurs only in G- species, is due to
impermeability of the outer membrane that is
present in G- but not in G+ bacteria.
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ALL -lactams
Mechanisms of Resistance
5. The shortage of autolytic enzyme.
w Under this circumstance, the beta-lactams
have normal inhibiting action, but their kill
effects are very poor.

6. The presence of an efflux pump.

w Some organisms also may transport betalactam antibiotics from the periplasm back
across the cell wall via an efflux pump
10

Mechanisms of Resistance
1. Production of-lactamase enzymes
2. Trapping mechanism
3. Modification of target PBPs
4. Impaired penetration of drug to
target PBPs
5. The shortage of autolytic enzyme
6. The presence of an efflux pump.
11

-lactam Antibiotics
Penicillins

Classification of penicillins
Pharmacokinetics
Spectrum of activity
Therapeutic uses
Adverse effects

Other Penicillins
Cephalosporins

12

Penicillins
Alexander Fleming
discovered penicillin
in 1928
1928: Alexander Fleming isolated
the antibiotic substance penicillin
from the fungus Penicillium
notatum on September 15, for
which he shared a Nobel Prize in
1945.
Penicillin is a antibiotic used in
the treatment of bacterial
infections caused by susceptible.
13

Penicillins
1. The structure of the penicillins consists
of a thiazolidine ring connected to a
beta-lactam ring, which is attached to a
side chain.
2. All penicillins are derived from 6-Aminopenicillanic acid.
3. The various penicillins differ
in their side chain structure.
14

Classification of penicillins
Penicillins are divided into natural and
semisynthetic ones (antistaphylococcal,extendedspectrum penicillins et .al)
Natural penicillins: extracted from the
cultural solution of penicillia.

Prototype is penicillin G
Is pH sensitive. Therefore not given orally.
Effective against Gram-positive cells
Susceptible to penicillinase
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Penicillins-Chemistry

16

Penicillins G

17

Classification of penicillins
Semisynthetic penicillins:
Produce by growing Penicillium in culture
so that only the nucleus is synthesized.
Attach R group in lab.
Or, grow Penicillium, extract
natural penicillin, remove R
group, and attach wanted R group.
Have broader spectrum. Are effective
against Gram-negative cells, too.
Are not resistant to penicillinases

18

Classification of penicillins
Semisynthetic penicillins:
vAcid-stable penicillins (e.g. penicillin V);
vPenicillinase-resistant penicillins
(e.g. oxacillin);
vExtended-spectrum penicillins
(e.g. ampicillin and antipseudomonal);
vAntistaphylococcal penicillins
(e.g. nafcillin).
19

Mechanisms of Resistance -

Penicillins

1. Inactivation of antibiotic bylactamase enzymes

2. Modification of target PBPs
3. Impaired penetration of drug to
target PBPs
4. The presence of an efflux pump

20

Mechanism of Action

- Penicillins

21

Penicillins G
Pharmacokinetics
It is relatively unstable in acid, thus the
bioavailability is low.
There is poor penetration into the
cerebrospinal (CSF), unless inflammation
is presetent.
Active renal tubular secretion results in a
short half-life.
22

Penicillins G
Spectrum of activity
vG+ cocci : Pneumococci , Staphylococci,
Streptococci , (many Staphylococci are now
resistant)

vG- cocci: Meningococci and gonococci

vG+ bacilli: Bacillus perfringens, bacillus
diphtheriae
vSpirochetes: Treponema pallidum,
Leptospira. and Actinomyces
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Penicillins G

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Penicillins G
Therapeutic uses
qIt is the drug of first choice for treating the
infections of the above mentioned pathogens.
qThe simultaneous administration of the relevant
antitoxin is often necessary for the treatment of
diphtheria and tetanus.
qThe combination of an aminoglycoside is also
necessary for bactericidal effects in enterococcal
endocarditis.
25

Acid-stable Penicillins- penicillin V

vThe oral form of penicillins,
vIndicated only in minor infections because
of their relatively poor bioavailability,
weaker antimicrobial activity, the need for
dosing many times
vNarrow antimicrobial spectrum.
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Penicillins: Adverse effects

Hypersensitivity 5 to 20 %
skin

rashes, fever, eosinophilia, angioedema,

serum sickness, and anaphylactic shock.
Cross-reactivity exists among all penicillins
and even other -lactams
The most serious hypersensitivity reaction is
anaphylactic shock. (very rare, the ratio is
about 0.5 to 1 of 10000 patients )
As soon as anaphylactic shock occurs,
instantly inject adrenaline to deliver trachea
edema and spasm.
27

Penicillins : Adverse effects

Other adverse effects:
Gastrointestinal upset, ( orally
administered preparations)

Nephrotoxicity, is very rare.

Superinfections.
results from alterations in intestinal
flora. A higher incidence occurs with
broad-spectrum penicillins.
28

-lactam Antibiotics
Penicillins

Other Penicillins

Classification of penicillins
Pharmacokinetics
Spectrum of activity
Therapeutic uses
Adverse effects

Acid-stable Penicillins- penicillin V

Penicillinase-resistant penicillins
Broad-spectrum penicillins
Antipseudomonal penicilins
Beta-lactamase inhibitors

Cephalosporins
29

Acid-stable Penicillins- penicillin V

vThe oral form of penicillins,
vIndicated only in minor infections because
of their relatively poor bioavailability,
weaker antimicrobial activity, the need for
dosing many times
vNarrow antimicrobial spectrum.
30

Penicillinase-resistant penicillins
Methicillin and isoxazolyl penicillins
(e.g. oxacillin, cloxacillin and dicloxacillin)
They are the drugs of first choice for treating
infections of the penicillase-productive
aurococcus. But penicillin-susceptible strains of
streptococci and pneumococci are also
susceptible
Enterococci and methicillin-resistant strains of
staphylococci are resistant to these penicillins 31

Broad-spectrum penicillins
Ampicillin and amoxicillin
They are similar to penicillin G in the
activity against gram-positive organisms
but are weaker than the latter.
They are more satisfactory for the
treatment of enterococci and
streptococcus viridians.
32

Broad-spectrum penicillins
They are similar to chloramphenicol in
the activity against gram-negative
organisms.
They are acid-resistant but are not
penicillase-resistant.
Pseudomonas aeruginosa are fail to
respond to these drugs.
33

Antipseudomonal penicilins
carbenicillin, ticarcillin
Extend the ampicillin spectrum of activity
to P.aeruginosa and enterobacter
species. But their activity to G+ cocci is
less than that of ampicillin.
They are not acid-resistant and
penicillase-resistant.
Ticarcillin is more active than
carbenicillin against P.aeruginosa and
enterobacter species.
34

Antipseudomonal penicilins
Chiefly used to treat serious infections
caused by G- microorganisms, particular
P.aeruginosa, indole-positive proteus
and enterobacter.
Generally used in combination with an
aminoglycoside for pseudomonal
infections.
35

Beta-lactamase inhibitors
clavulanic acid, sulbactam, tazobactam
Inactivate bacterial beta-lactamases and
are used to enhance the antibacterial
actions of beta-lactam antibiotics.
Only have weak antibacterial action.

36

Beta-lactamase inhibitors
Inhibitors of many but not all bacterial
beta-lactamases and can protect
hydrolyzable penicillins from inactivation
by the enzymes.
Available only in fixed combinations with
specific penicillins.
The companion penicillin, not the beta-lactamase
inhibitor, determines the antibacterial spectrum of
the combination.
37

-lactam Antibiotics
-lactam Antibiotics
Penicillins

Penicillinase-resistant penicillins
Broad-spectrum penicillins
Antipseudomonal penicilins
Beta-lactamase inhibitors

Other Penicillins
Mechanism of action
Cephalosporins Spectrum of Activity and Clinical uses
Adverse effects

38

Cephalosporins & Cephamycins

Although some bacteria can

produce a beta-lactamase
called cephalosporinase that
acts on the cephalosporin
nucleus to destroy its
antibacterial activity, however,
many of them are resistant to
the enzyme.

The cephalosporins
are derivatives of 7amino-cephalosporanic
acid and are closely
related in structure to
penicillin.
They have a betalactam ring.
They are relatively
stable in dilute acid and
are highly resistant to
penicillinase.
39

Mechanism of action

Cephalosporins inhibit the peptidoglycan synthesis of bacterial cell wall

in a manner similar to that of penicillin
and are considered bactericidal.

40

Spectrum of Activity and

Clinical uses of Cephalosporins
All cephalosporins are active against most G+
cocci, including penicillinase-producing
staphylococci and many strains of G- bacilli,
but relatively ineffective against enterococci.
Divided into 4 major groups called
Generations
Are divided into Generations based on
w parallel their chronological development
w their antimicrobial spectrum

41

Characteristics of the generations

- First-generation cephalosporins
-Second-generation cephalosporins
- Third-generation cephalosporins
- Fouth-generation cephalosporins

42

First Generation Cephalosporins

EXAMPLES: cephalothin, cefazolin, and cephalexin et al
They have a stronger antimicrobial action on G+
bacteria than that of the other generations, but
they action on G- bacteria is relatively poor.
These cephalosporins have nephrotoxicity to a
certain degree.
They are NOT effective against pseudomonas.
43

First Generation Cephalosporins

Comparatively, they are stable for betalactamase (penicillinase ).
They are chiefly used in treating infection of
the penicillinase-productive aurococcus
(S.aureus ) and surgical prophylaxisction.

Cefazolin do not penetrate the central

nervous system and can not be used to
treat meningitis.
44

Second Generation Cephalosporins

cefamandole, cefoxitin, cefaclor, cefonicid,
cefuroxime, cefotetan, cefprozil.
Action of this generation on G+ bacteria is
the same or a little bit less than that of the
first generation.
Their antimicrobial action on G- bacteria
is obviously increased
Some of them are effective against
anaerobes such as B.fragilis.
45

Second Generation Cephalosporins

Ineffective against p.aeruginosa.
They are stable to many kinds of betalactamases and have less nephrotoxicity
than the first generation.
Cefuroxime is the only second-generation
drug that crosses the blood-brain barrier
well enough to be used for the treatment
of meningitis, especially H.influenzae
meningitis, and sepsis.
46

Third Generation Cephalosporins

cefotaxime, ceftizoxime, ceftriaxone,
cefoperazone, ceftazidime, cefixime,
cefpodoxime
The broadest spectrums of all cephalo The highest activities against G- bacteria.
The lowest activities against G+ bacteria.
The highest resistance to-lactamase.
47

Third Generation Cephalosporins

The best penetration into the CSF;
almost no nephrotoxicity.
Ceftizoxime have good activity against
B.fragilis.
Some of them are effective against
P.aeruginosa and enteric bacilli.
48

Third Generation Cephalosporins

They are chiefly used in the infections
of the urethral or biliary tract with the
drug-resistant strains and
Pseudomonas.
They are also used in some serious
pneumonia, sepsis and meningitis.

49

Third Generation Cephalosporins

There are also some unique properties of
individual 3th generation.
Ceftriaxone has the longest half-life(8h) of any
cephalosporin.
Cefixime is an oral preparation.
Ceftazidime is the best anti-pseudomonal
cephalosporin.
Cefoperazone is eliminated(70%) in the bile, and
is thus very useful in patients with renal failure.
50

Adverse effects
qRelatively few and low
qThe most common ones are Allergyhypersensitivity reactions (5%-10%)
anaphylaxis, fever, skin rashes, nephritis,
granulocytopenia, and hemolytic anemia.
qDuring treatment with third-generation drugs,
these resistant bacteria, as well as fungi, often
proliferate and may induce superinfections.
51

Adverse effects
Nephrotoxicity:
The first-generation cephalosporins have
certain nephrotoxicity. (Renal damage,
including interstitial nephritis and even
tubular necrosis )
The second-generation have slight
nephrotoxicity.
The third-generation have almost no
nephrotoxicity.
52

The Other Beta-lactam antibiotics

Monobactams - Aztreonam
Aztreonam is highly resistant to beta-lactamases
It is highly active against aerobic G- bacteria,

including P.aeruginosa and penicillinaseproducing strains of H. influenzae and gonococci.

But it shows poor activity against G+ cocci and
anaerobic bacteria.
The antimicrobial spectrum of aztreonam is

similar to that of aminoglycosides

53

The Other Beta-lactam antibiotics

Carbapenems Imipenem et. al
Imipenem is easily hydrolized by dehydropeptidase in the body, so the clinical preparation
is the mixture made by imipenem and peptidase
inhibitor named cilastatin. The mixture is called
tienam.
The antimicrobial spectrum of imipenem is the
broadest one of all the beta-lactam antibiotics.
It is active against G+, G- cocci (except
methicillin-resistant staphylococci),
enterobacteriaceae, P.aeruginosa, and
anaerobic bacteria, including B.fragilis.
54

The Other Beta-lactam antibiotics

Carbapenems Imipenem et. al
Gonococci and H. influenzae strains that are
resistant to both natural penicillin and ampicillin
are still susceptible to imipenem.
Imipenem is mainly used in urinary tract,
respiratory tract, skin, and soft tissue infections.
Imipenem could also be used in staphylococcal
endocarditis, but not in CNS infections.
55

Other inhibitions of cell wall synthesis

Vancomycin
Vancomycin

Mechanism of action
Pharmacologic effects
Clinical Uses
Adverse Effects

Vancomycin is
an antibiotic
produced by
Streptococcus
orientalis.
56

Vancomycin
Vancomycin
Mechanism of action
Binds to precursor units of bacterial cell walls,
inhibiting cell wall synthesis, also inhibits RNA
synthesis

bactericidal antibiotic for gram-positive bacteria

in concentration of 0.5-10 g/mL.
57

Pharmacologic effects
Vancomycin is very effective against
most staphylococci including those
producing beta-lactamasesand other
G+ cocci such as streptococcus viridans,
enterococci, and pneumococcus.
It is also active against clostridium
species, Corynebacterium diphtheriae,
and Bacillus anthracis.
58

Vancomycin: Clinical Uses

Orally only for the treatment of antibioticassociated Pseudomembranous colitis
caused by C.difficile.
Intravenous administration is mainly used for
serious G+ coccal infections, such as
enterocolitis, septicemia

Especially for those caused by penicilin-resistant

pneumococcus and staphylococci

59

Vancomycin: Adverse Effects

Phlebitis

at the site of injection.

Nephrotoxicity and Ototoxicity

rare with monotherapy, more common

when administered with other nephro- or
ototoxins
risk factors include renal impairment,
prolonged therapy, high doses, high serum
concentrations, other toxic meds
60

Vancomycin: Adverse Effects

Red-Manor red neck Syndrome
flushing, pruritus, erythematous rash on face
and upper torso
related to RATE of intravenous infusion;
should be infused over at least 60 minutes
resolves spontaneously after discontinuation
Prevent: may lengthen infusion (over 2 to 3
hours) or pretreat with antihistamines in
some cases
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