Download Я-lactam antibiotics

ß-lactam antibiotics
Liming Zhou
Department of pharmacology
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Classification of drug
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The mechanism of antibacterial action
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Bacteria Resistance
ß-lactam antibiotics in this chapter are
classified into three sub-class.
 I. The penicillins
 II. Cephalosporins
 III. Other β-lactams
I. The penicillins
 A. natural penicillins: Penicillin G and
penicillin V
 B. Semisynthetic penicillins.
II. Cephalosporins
 A. First generation cephalosporins
 B. Second generation cephalosporins
 C. Third generation cephalosporins
 D.The fourth generation
cephalosporins
III. Other β-lactams
 A. Cephamycins
 B. Carbapenems
 C. Monobactams
 D. Oxacephems
 E.β-lactamase inhibitor
The mechanism of antibacterial
action
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The peptidoglycan is composed of glycan chains
of N-acetyglucosamine and N-acetylmuramic acid.
The biosynthesis of peptidoglycan can be
considered in three stages which the last one
involves the completion of the cross-link.
This is accomplished by a tranpeptidation reaction,
which involves transpetidase.
The ß-lactam antibiotics combine with and
inactivate the tranpeptidase.
The mechanism of antibacterial
action
The mechanism of antibacterial
action
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The tranpeptidase is inactivated by ß-lactam
antibiotics, they are the targets of β-lactam
antibiotics and are named penicillin-binding
protein (PBPs).
The PBPs vary in their affinities for different
ß-lactam antibiotics and several kinds of
PBPs have confirmed.
Table -1 Characteristics of PBPs in Staphylococcus aureus.
PBPs
Molecular size (KD)
Functions
PBP-1
PBP-2
PBP-3
PBP-3’
PBP-4
87
50
75
70
41
Primary glycopeptide transferase
Transpeptidase; react in non growth bacteria
Transpeptidase; concerned with forming of septum
Transpeptidase; concerned with forming of septum
Carboxypeptidase and transpeptidase in second stage cross
link of glycopeptide.
Bacteria Resistance
In generally, there are three main mechanism
of ß-lactam antibiotics resistance.
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(1) Nearly all bacteria can produce βlactamase after contact with β-lactam
antibiotics. β-lactamase can inactivate ßlactam antibiotics through rupture the ßlactam ring. Different microorganisms
produce a number of distinct β-lactamase.
Bacteria Resistance
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(2) Many bacterial can alter PBPs with decreased
affinity for ß-lactam antibiotics. This can result in
failure of antibiotics binding to active sites.
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(3) The concentration of antibiotics in target site is
too low because of lacking of porin protein, such
us OmpF and OmpC. This permeability block is
particularly seen in resistance gram-negative
bacteria that possess a complex outer layer.
Increased active antibiotics efflux which reduce
the drug in bacteria is the other reason for low
concentration in target site
Penicillins
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I. Natural penicillins
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Benzylpenicillin (Penicillin G)
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It is the one of the natural penicillins used
clinically and instable in water solution,
gastric juice at pH 2.
Structure
Antibacterial action
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Penicillin has great antibacterial activity to a
variety of sensitive bacteria.
The antibacterial spectrum includes:
Gram-positive cocci: Streptococcus pyogenes
(group A, B, C, G, F), non-β-lactamase producing
staphylococcus aureus, sensitive streptococcus
pneumoniae, aerobic Gram positive cocci.
Gram-positive bacilli: corynebacterium
diphtheriae; bacillus anthracis; anaerobic
clostridium tetani; clostridium perfringens;
clostridium botulinum; actinomyces.
Antibacterial action
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Gram-negative cocci: nesseria meningitides;
neisseria gonorrhoeae.
Spirochetes: Treponema pallidum;
leptospira spp.; borrelia burgdorferi.
Pharmacokinetics
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When oral administrated, penicillin G is rapidly destroyed
by gastric acid and has poor absorption. Often it is used by
i.m or i.v.
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The peak concentration time in blood is about 0.5 h, and it
is nearly completely eliminated mainly by the kidney in 6 h
when penicillin G is administrated by i.m.
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The half-life is about 0.5 h. It has broad distribution, but
cannot pass the blood-brain barrier, cannot reach the
aqueous humor and succus prostaticus.
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When having cerebra inflammation, it can pass the
damaged blood-brain barrier into cerebrospinal fluid.
Clinical uses
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1. Infection of streptococcus: S. pyogenes
group A can caused pharyngitis（咽炎）,
scarlatina（猩红热）, cellulitis（蜂窝织
炎）, suppurative arthritis, pneumonia,
puerperal（分娩的）fever and blood
poisoning. S. pyogenes group B, S.
pneumoniae, S. viridans and S. faecalis can
caused respiratory infection, meningitis,
endocarditis, and blood poisoning.
Clinical uses
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2.Pneumococcal infections: pneumococcal
pneumonia, pneumococcal meningitis
3.Treatment of meningococcal meningitis.
4.Treatment of gonococcal infections such
as gonococcal urethritis, gonococcal
arthritis and gonococcemia.
Clinical uses
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5.Spirochete infection: Leptospirosis, lues and
recurrent fever.
6.Gram-positive bacilli infection: lockjaw（破
伤风）, diphtheria（白喉）and anthrax（炭
疽）.
7.Infections with sensitive anaerobes
Adverse reactions
The toxicity of penicillins is very low.
 Allergic reactions: drug rash, dermatitis,
serum sickness, anaphylactic shock and
hemolytic anemia.
 Before using this kind of drugs, the medical
institution must prepare drugs for treatment
of anaphylactic shock.
Adverse reactions
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Jarisch-Herxheimer reaction: after penicillin
treatment of spirochete infection, some
patients show symptoms of ague, fever,
laryngeal pain, headache and tachycardia. It
is sometimes life threaten. This reaction is
due to the large number of kill spirochete,
so the dose at the beginning should not be
high.
Semisynthetic penicillins
Semisynthetic penicillins
Oral administration (acid stable) β-lactamase
non-stable penicillins
 Penicillin V (phenoxymethylpenicillin).
 Antibacterial action: This kind of penicillins
is similar with penicillin G with the same
antibacterial spectrum but lower activity.
Semisynthetic penicillins
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Clinical uses: It is used in slight infection
caused by gram-posotive cocci such as
pharyngitis, amygdalitis(扁桃体炎) and
prophylactic use for rheumatic fever.
Adverse reaction: it can cause allergic
reaction (most slight reaction) and
gastrointestinal reaction (burning sensation,
nausea, vomiting and diarrhea)
B Penicillinase-resistant penicillins
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Methicillin; Dicloxacillin; Cloxacillin and
Oxacillin belong to this kind of penicillins.
Only methicillin is not stable in acid and the
other can administer orally.
Antibacterial activity: it has powerful
activity on penicillinase producing S. aureus,
less activity on streptococcus, and resistance
to gram-negative bacteria.
B Penicillinase-resistant penicillins
Clinic uses:
 These antibiotics also have many resistant
bacteria now.
 The dicloxacillin has the lowest resistant
bacteria at present.
 MRSA: Methicillin of resistance to S.
aureus
C Broad spectrum penicillins
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This kind of penicillins include ampicillin,
amoxicillin.
Antibacterial activity: ampicillin and have
amoxicillin similar action to penicillin G
sensitive bacteria. Antibacterial activity to
gram-negative bacteria for these penicillins
is greater than that for Penicillin G.
C Broad spectrum penicillins
Pharmacokinetics:
 The absorption of ampicillin and
amoxicillin is about 30% and 90%
respectively.
 When inflammation occurring, effective
concentration of these drugs can obtained
in tympanitis effusion, bronchia secretion,
ascitic fluid, articular cavity effusion and
cerebrospinal fluid.
D Penicillins of treatment for Pseud.
aeruginosa infection
These drugs include Carbenicillin and
piperacillin
 Antibacterial activity: The antibacterial
spectrum of these drugs is effective for
pseud. aeruginosa and bacillus proteus.
 Therapeutic uses: It is usually used to
infection of Pseud. aeruginosa and ßlactamase producing bacteria that resistant
to ampicillin.
E Penicillins of treatment for Gramnegative bacilli infection
These drugs include mecillinam and
temocillin
 Antibacterial activity: The antibacterial
spectrum of these drugs is effective for
Gram-negative bacilli infection,
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Therapeutic uses: These penicillins can be
used in urinary tract infection.
Cephalosporins
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Cephalosporins are the
semisynthetic antibiotics
derived from 7-Amino
cephalosporanic acid (7ACA)—the cephem
nucleus of cephalosporins.
They are similar to
penicillins in terms of
mechanism of action,
chemical structure, and
toxicities
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First generation cephalosporins
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Cefazolin; Cefadroxil; Cefalexin; Cefalothin;
Cefapirin; cefradine.
First generation cephalosporins
Pharmocological properties
It exhibits good activity against gram-positive bacteria, but
less activity against gram negative organisms:
 (a) greater activity to gram-positive bacteria than the
second and third generation,
 (b) Less stable than second and third generation to βlactamase,
 (c) Less activity than second and much less activity than
third generation to gram-negative bacilli;
 (d) some drugs have kidney toxicity.
First generation cephalosporins
Clinical uses
 These antibiotics are often used to treat grampositive bacteria infection.
 Injecting route drugs are used for moderate
infection caused by aerobic bacteria and some
severe infection by sensitive bacteria.
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Second generation cephalosporins:
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Cefuroxime, cefamandole, cefaclor
ceforanide
Second generation cephalosporins
Pharmocological properties
Second-generation drugs exhibit enhanced activity
against gram-negative bacteria, but much less
enhancement compared to third generation
agents:
(a) better anti-bacteria activity to gram-negative than
first generation cephalosporins, but less than do
third generation drugs,
(b) (b) more stability to β-lactamase than first
generation cephalosporins,
(c) (c) less kidney toxicity than first generation.
Second generation cephalosporins
Clinical uses
 It is the first choice drugs for gram-negative
bacteria infectious diseases, and the other
indications are similar with first generation
cephalosporins.
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Third generation cephalosporins
Cefotaxime, ceftazidime, ceftriaxone,
cefoperazone, ceftizoxime, cefixime,cefodizime
Third generation cephalosporins
Pharmocological properties
Third-generation drugs exhibit the lest activity against grampositive bacteria, but most potent activity against gramnegative bacteria :
(a) extended antibacterial spectrum, include Pseud.
aeruginosa;
(b) less activity on gram-positive bacteria than first and
second generation;
(c) most active on gram-negative bacteria;
(d) high stability with β-lactamase;
(e) easy penetrate to different tissues, and then have broad
distribution;
(f) little kidney toxicity.
Third generation cephalosporins
Clinical uses
 These drugs are used for severe gram-negative
resistant bacilli infection.
 And also used for complex infection.
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The fourth generation cephalosporins
Cefepime and cefpirome have similar
antibacterial activity with third generation
on most gram-negative bacilli, but more
stable to β-lactamase.
Other β-lactams
Cephamycins
 Natural product is cephamycin and the
semisynthetic cefoxitin is in clinical use.
 It has similar antibacterial activity with secondgeneration cephalosporins, and good activity to
anaerobe. It is used for mixed infection of
aerobe and anaerobe.
Other β-lactams
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Carbapenems
Carbapenems includes Imipenem,
meropenem and panipenem.
It has most powerful bactericidal effect on
most bacteria, and has super broad
antibacterial spectrum.
Nearly all gram-negative and gram-positive
bacteria infection can be treated with this
kind of drug.
Other β-lactams
Monobactams
 Aztreonam and carumonam belong to
Monobactams.
 It is highly resistant to ß-lactamases.
 It is effective in treating Gram-negative urinary
tract infections, lower respiratory tract, skin, intra
abdominal, gynecologic infections and septicemia.
 Aztreonam may be given together with other
antibiotics which are active against Gram-positive
bacteria and anaerobes in mixed infections.
Other β-lactams
Oxacephems
 Latamoxef and flomoxef belong to
Oxacephems.
 It has similar spectrum, antibacterial activity
with ceftazidime.
 It has better activity on anaerobe than first,
second and third generation cephalosporins.
Other β-lactams
β-lactamase inhibitor
 This kind of drug include clavulanic acid,
sulbuctam and tazobactam.
 These agents are potent inhibitors of many
kind of ß-lactamases and are used together
with penicillins to protect them from
inactivation.
Home work
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1. How are agents in this chapter classified?
2. What are the major differences among the
cephalosporin antibiotics by generations?
3. Describe the pharmacological effects of
penicillin G.