Review:

Mechanism
• Quinolones
inhibit topoisomerase II (DNA gyrase) and
fluoroquinolones topoisomerase IV

• Sulfonamides
+TMP

• Metronidazole DNA bacteriostatic agent

Review:
Antimicrobial spectrum and clinic application
• Quinolones G- • legionella
G+ • pseudomonas aeruginosa
fluoroquinolones chlamydia
mycoplasma anaerobic bacteria
mycobacteria
G-
• Sulfonamides G+
+TMP chlamydia
sensitive protozoas

• Metronidazole anaerobic bacteria

sensitive protozoas
Review:
Adverse reaction caution in
children and
Photosensitivity adolescent
• Quinolones
Arthropathy
fluoroquinolones

• Sulfonamides Urinary tract disturbances

+TMP

• Metronidazole unpleasant metallic taste in the mouth

 Chapter 43
ß-lactam Antibiotics
Objectives:
• Pharmacological effects, Clinical uses, adverse effect of Penicillin G;
• Pharmacological effects of broad spectrum
Penicillins and penicillinase-resistant Penicillins;
• Spectrum of activity, clinical use and adverse effects
of cephalosporins;
β-lactam antibiotics (β内酰胺类抗生素)
β-lactam antibiotics contain a β-lactam ring in structure which include
penicillins and cephalosporins.
The penicillins and cephalosporins differ in that

B A B A

6-aminopenicillanic acid 7-aminocephalosporanic acid

6-APA 7-ACA
 Classification of β-lactam antibiotics
• Penicillins
Ø natural penicillins, e.g., penicillin G and penicillin V;
Ø semisynthetic penicillins， e.g., oxacillin
• Cephalosporins
Ø the First generation cephalosporins
Ø the Second generation cephalosporins
Ø the third generation cephalosporins;
Ø the fourth generation cephalosporins.
• Other β-lactams
The discovery of Penicillin G
• In the late 1920s, Alexander Fleming
discovered an antibacterial substance when
studying Staphylococcus variants in his
laboratory. Fleming named the antibacterial
substance penicillin because it came from
Penicillium.
• in 1940 other scientists succeeded in
developing penicillin as a systemic
therapeutic agent.
Penicillin G (青霉素G)
Structure of penicillins and products of their enzymatic hydrolysis
Spectrum of activity of penicillin G
The penicillin-susceptible organisms include
• Gram-positive cocci, e.g., Streptococcus pyogenes
（A,B,C,G,F), non-β-lactamase producing staphylococcus aureus, sensitive
streptococcus pneumoniae
• Gram-positive bacilli, e.g., corynebacterium diphtheriae
• gram-negative cocci. e.g., nesseria meningitides
• spirochetes
• some actinomyces
 Mechanism of action of penicillin G
inhibit the formation of cell wall and are bactericidal in action
1) inhibit the activity of penicillin-binding protein （ transpeptidase）
2) enhance the activity of cell-wall autolytic enzyme

The bacterial cell wall consists of glycopeptide polymers

(a NAM-NAG amino-hexose backbone) linked via
bridges between amino acid side chains
The cross-linking is catalyzed by a transpeptidase, the
enzyme that penicillins and cephalosporins inhibit.
NAM, N-acetyl-muramic acid; NAG, N-acetyl-glucosamine.
 Mechanism of action of penicillin G
Notes
• The action does not occurred in human or animals who do not posses the cell wall
surrounding the cell membrane.
• Since penicillins prevent new cross-links during the formation of cell walls and do
not disrupt established cross-links, they interfere only with growing not resting
cells.
• Penicillin insensitive bacteria have structurally different cell walls (contain less
peptidoglycan) such as gram-negative bacilli.
Bacterial resistance of Penicillin G
1) Penicillinase is a beta-lactamase which hydrolyzes the beta-lactam ring of penicillin to
form penicilloic acid( 青霉噻唑酸 ), a substance that has no antibacterial activity.
Microorganisms that are capable of producing penicillinase includes S. aureus, Bacillus
species and so on.

2) Many bacterial can alter PBPs with

decreased affinity for β- lactam antibiotics.
3)The concentration of antibiotics in target site
is very low （increased active antibiotics
efflux)
 Pharmacokinetics of Penicillin G
• Absorption When orally administrated, penicillin G is rapidly destroyed by gastric
acid and has poor absorption.
It is usually used by i.m or i.v
• Distribution
1) Penicillin is readily absorbed from intramuscular sites and widely distributed
the body but does not pass across the blood-brain barrier. throughout
2) In the inflammation of pneumococcal and meningococcal meningitis, penicillin
level in the cerebrospinal fluid will be increased, partly due to increased
permeability of meninges.
• Metabolism：Penicillin is metabolized slightly by the liver and mainly is excreted by
the kidney in the parent form.
• Elimination：90% of Penicillin is eliminated by tubular secretion
10% by glomerular filtration.
 seriously infect
Therapeutic uses of Penicillin G Penicillin G +Exotoxin antibody
a wide variety of infectious diseases induced by most cocci, gram-positive bacilli, and
spirochetes, and certain gram-negative bacilli.
• the first choice when the following infections are indicated.
ü Streptococcal infections, infective endocarditis caused by streptococci.
ü Pneumococcal infections.
ü Staphylococcal infections.
ü Meningococcal infections, meningitis caused by meningococi.
ü gonococcal infections.
ü syphilis infections(梅毒）.
ü Diphtheria（白喉), anthrax（炭疽）.
 nontoxic

Adverse reactions of Penicillin G

• Allergic reactions
• All penicillins are cross-sensitizing and cross-reacting
• The responsible antigenic determinants of penicillins appear to be degradation products
of penicillins, particularly penicilloic acid products bound to host protein.
• Three types of allergic reactions
Ø Immediate reaction: very rare, within 20 minutes, apprehension, itching(pruritus),
paresthesia (numbness and tingling), wheezing, chocking, fever, edema, and
generalized urticaria-hives. It can lead to hypotension, shock, loss of consciousness,
and death.
Ø Accelerated reaction:1~72 hours, urticaria-hives
Ø Late reaction: more common, 72hours~several weeks, skin rash
Adverse reactions of Penicillin G
Most patients allergic to penicillins can be treated with alternative drugs.

Anaphylactic shock
• Ask the medical history
• Skin tests with penicilloyl-polylysine, with alkaline hydrolysis products will identify
many hypersensitive individuals.
• Observe patient reactions during and half an hour after administration
• Adrenaline, corticosteroids should be prepared for prevention of anaphylactic
shock.
 Adverse Rections of Penicillin G
• Herxheimer reaction: after penicillin treatment of spirochete infection, some patients
show symptoms of ague, fever, laryngeal pain, headache and tachycardia. It is
sometimes life threatening. This reaction is due to the large number of killed
spirochete.
• The intramuscular administration may cause local pain, induration, thrombophlebitis.
• All penicillins are irritating to the central nervous system and greatly increase the
excitability of neurons.
Semisynthetic penicillins
• Acid stable penicillins
• Penicillinase-resistant penicillins
• Broad spectrum penicillins
 for oral
Acid stable (β-lactamase unstable) penicillins
penicillin V; pheneticillin(非奈西林）
• Antibacterial action
Similar with penicillin G with the same antibacterial spectrum but lower activity.
• Clinical applications
slight infection caused by gram-positive cocci.
• Adverse effects
allergic reaction and gastrointestinal reaction
 Penicillinase-resistant penicillins
oxacillin（苯唑西林), methicillin（甲氧西林）.
Antibacterial activity and therapeutic application
• acid-stable and can be given orally as well as intravenously and intramuscularly.
• It is penicillinase-resistant.
• It has a spectrum similar to that of penicillin G.
• treatment of infection caused by beta-lactamase-producing staphylococci.
 Broad-spectrum penicillins
Amipicillin 氨苄青霉素 Carbenicillin 羧苄青霉素
• Amipicillin 氨苄青霉素
– In addition to being effective against gram-positive organisms, amipicillin is effective
against many gram-negative organisms such as E. coli, H. influenzae, Salmonella(沙门
菌), and some Proteus species.
– It is acid-stable
– It is not penicillinase-resistant.
• Carbenicillin 羧苄青霉素
– It has a spectrum of activity similar to that of amipicillin, is used in severe gram-
negative infections caused by proteus and pseudomonas aeruginosa strains.
– It is acid labile (not active orally)
– It is not penicillinase-resistant.
Cephalosporins 头孢霉素
• Chemistry
Cephalosporins are structurally related to penicillins. The nucleus of the
cephalosporin, 7-amino-cephalosporanic acid(7-ACA), resemble 6-aminopenicillanic
Acid (6-APA), the nucleus of penicillin.

Ø Cefalotin 头孢噻吩(first)
Ø Cefalexin 头孢氨苄(first)
Ø Cefradin 头孢拉定(first)
Ø Cefuroxime 头孢呋辛，西力欣 (second) B A
Ø Cefoperazone 头孢哌酮 (third)
Ø Cefotaxime 头孢噻肟 (Third)

7-aminocephalosporanic acid
7-ACA
Spectrum of activity of Cephalosporins
• Cephalosporins have a broad spectrum of antimicrobial activity and are effective against a
variety of gram-positive and some strains of gram-negative bacteria such as E. coli,
klebsiella, and proteus species.
• The third-generations of cephalosporins are effective against pseudomonas aeruginosa
strains.

Mechanisms of action of Cephalosporins

• Cephalosporins inhibit bacterial cell-wall synthesis in a manner similar to that of penicillin
and are considered bactericidal.
Pharmacological effects and clinical uses
• 1st generation compounds of cephalosporin is similar to that of penicillin G. It is mainly
used for infections caused by staphylococcal aureus resistant to penicillin G. It is also used
for infections caused by some gram-negative bacilli.
• 2nd generation compounds of cephalosporin is more effective against gram-negative
bacilli. Some of them are effective against anaerobic infections.
• 3rd generation compounds of Cephalosporin is most effective against gram-negative
bacilli especially pseudomonas aeruginosa infections compared to the first and second
generation.
• 4th-generation cephalosporins have similar antibacterial activity with third generation on
most gram-negative bacilli, but more stable to β-lactamase.
Adverse reaction of Cephalosporins
• Hypersensitivity reactions
Cephalosporins, like Penicillins, elicit a spectrum of reactions that range from mild
skin rash to anaphylaxis.
• Across-sensitivity reaction to the Cephalosporins occurs in about 10 percent of individuals
who have experienced an allergic manifestation following the administration of penicillin.
• Renal damage 1st, 2nd generation
• severe disulfiram-like reactions
Alcohol and alcohol-containing medication must be advoided
• Nausea, vomiting
• Intravenous administration can cause thrombophlebitis
• Superinfection 3rd, 4th generation