HISTORY
n 1928 Fleming discovered penicillin
n 1940
isolated and determined structure
n
1941
First cure in human
n
1943
Industrialized produced, and soon been important on the field in WWII
n
1965
Park & Strominger deduced mechanism
OUTLINE
n
OVERVIEW: Basic struture, Classification,
mechanism and resistance
n
The penicillins
Penicillin
G:PK,AM activity, therapeutic uses,
Semi- and synthetic penicillins
n
The cephalosporins
the generation development
n
Other Beta-lactam
antibiotics
•Structures & classification
beta lactam ring
Mode of Beta-lactams action
l
Same Mechanism : Inhibit cell wall synthesis
l
Rapidly bactericidal
l
Time-dependent bactericidal (except
against Enterococcus sp.)
l
Short elimination half-life
l
Primarily renally eliminated
l
Cross-allergenicity except aztreonam
•Mechanism of Action
1.
Interfere with cell wall synthesis by
binding to penicillin-binding proteins (PBPs) which are located
in bacterial cell walls
2.
Murein hydrolase activated → cell autolysis (both lytic and nonlytic mechanisms
are changed)
Factors that
influenc Beta-lactams action
n Bacterium
type and strain
n ABA type
and properties
n Penetration
ability
n Stability
to -lactamase
n Affinity to
PBPs
•Resistance
Mechanisms of
Resistance
1. Production of Beta-lactamase
2. Modification of target PBPs
3. Trapping mechanism
4. Impaired penetration of drug
to target PBPs
¨
porin alteration: OmpF/OmpC are channels for
b-lactams.
¨
In E.coli: OmpF/OmpC↓↓→Cefazolin/Cefalotin penetration↓↓→MIC↑↑
¨
In Pseudomonas Aoruginosa: Loss of OprF→b-lactams resistance
Loss of OprD→Imipenem
resistance
5. The shortage of antolytic
enzyme
6. The presence of an efflux
pump.
Parmacokinetics of
PG
n Absorption:
¨ Oral: acid
sensitive → poor
bioavailability
¨ i.m: rapid
and complete absorption, arrives Cs.peak in 30min, t1/2 ~0.5 h
n Distribution: Vd: 0.35L/kg
¨ widespread
in tissues, organs, and body fluid
¨ Not readily
enter the cerebrospinal fluid(CSF)
n Excretion:
¨ mainly
(60%~90%) via kidney as prime drug
¨ Remainder
is metabolized to penicilloic acid.
n prolonged action preparation:
slow
absorption, long-lasting effect
Penicillin G Procaine:
400000U/24h
Benzathine
Penicillin G: 1.2MU/15d
Spectrum
G+ coccus: Hemolytic
Streptococcus, Streptococcus viridans, Diplococcus pneumoniae
G+ bacillus: Corynebacterium
diphtheriae, Clostridium tetani，Bacillus
aerogenes capsulatus (Gas-gangrene),
Bacillus anthracis
G- coccus: meningococcus,
gonococcus
G-
bacillus: Pertussis
Spirochetes: Treponema
pallidum, Leptospira. and Actinomyces
Resistance
Staphylococcus A.: above 90％
Gonococcus: common
Indication
n 1st
option for susceptible infections :
• Pheumococcal: Pneumonia,
Meningitis
• Streptococcus: Pharyngitis,
endocarditis,
• Staphylococcus: Meningitis,
• G+ bailli: Diphtheria, anthrax,
Clostridial
• Spirochetes: Syphilis, Leptospirosis, Relapsing
Fever, Rat-bite Fever
Rare and mild adverse effect
1. Hypersensitivity – 5 to 20 %
n Allergen:
PCN-protein complex, degradent, PCN polymers
n Cross-reactivity
exists among all penicillins and even other b-lactams
n Manifestations
moderate: skin
rashes, fever, eosinophilia, angioedema, serum sickness
n The most
serious hypersensitivity reaction is anaphylactic shock. (10%
dead in 1/60000 cases)
n
As soon as anaphylactic shock occurs, instantly
inject adrenaline to deliver trachea edema and spasm
Prevention and treatment for anaphylactic shock :
1. enquire history of drug allergy
2. skin test
3. stay observing for ≥30min
4. prepare emergency drugs and equipment，and 0.1% Adrenaline
0.5～1 ml i.m
Classes of Penicillins
1. Natural Penicillins: Pen G, Pen VK, Benzathine
¨
Used on Streptococcal infection, syphillis,
spirochetes
¨
Highly susceptible to Beta-lactamases
2. Antistaphylococcal Penicillins: Methicillin,
oxacillin, dicloxacillin…
¨
More stable to beta lactamases, due to
modifications near Beta-lactam
ring
¨
Poor entry into gram-
3. Amino Penicillins: Ampicillin, amoxicillin…
¨
Enhanced Gram- coverage (due to amination)
¨
Highly susceptible to Beta-lactamases
4. Antipseudomonal Penicillins: Carbenicillin,
Ticarcilline, Piperacillin…
¨
Enhanced Gram- coverage (due to extensive side
chain addition)
¨
Highly susceptible to beta lactamases
5. PCNs against G- bacillus Mecillinam, Pivmecillinam, Temocillin
¨
narrow spectrum vs. G- bacillus
¨
against E.coli and urinary infection by susceptible
germs
¨
combination with other ABAs vs. severe G- germ
infection
Generations of
Cephalosporins
1st Gen: Cephalexin, Cefadroxil, Cefazolin
¨
Good gram positive, limited gram negative activity
2nd Gen: Cefaclor, cefuroxime,
Cefoxitin, ceforanide
¨
Good gram positive, moderate gram negative activity
¨
Cefoxitin and cefotetan have reasonable anaerobic
activity
3d Gen : Ceftriaxone,
cefotaxime, ceftazidime, cefoperazone…
¨
Only Ceftriaxone has usable activity against S.
aureus
¨
All have very good activity against gram negatives,
BUT activity against pseudomonas is limited to ceftazidime and cefoperazone.
4th Gen: cefepime
¨
Very good activity against gram postives, including
S. aureus
¨
Very good activity against gram negatives,
including P.aeruginosa
Advantages vs. Penicillins
l More stable
to Beta-lactamase
l Wider
spectrum
l Stronger
activity
l Rarer
allergy
l Lower
toxicity
Pharmacokinetics
l Most CSRs
need im or iv.
Exception:
Cephalexin, Cephradine, Cefaclor
l Wide
distribution after im:
G3 CSRs
reach effective concentration in prostate, CSF, aqueous fluid
l Short t1/2:
0.5~2h.
Exception: Ceftriaxone t1/2
~8h
Adverse effect (rare and mild)
l
Allergy: rare, 5~10％ cross
reaction with Penicillins
l
Kidney toxicity: Cephalothin, Cephalexin cause impairment of
proximal convoluted tubule in large dose
l
Phlebitis: accidental after iv
Imipenem (Carbapenems)
Preparation:
Tienam
Ingredients:
Imipenem+Cilastatin sodium
Latter inhibit degradation of Imipenem in
kidney
Properties
n Broad
spectrum.
n Excellent
activity
n Resistance:
rare/no cross resistance
n Efficient: agranulocytosis concurred
with infection
n Adverse
effect: mild
Aztreonam (Monobactams)
n
Very narrow coverage: G- bacilli
n
Restricted: Utility limited, usually used for gram-
Urinary tract infection (UTI) in PGs
allergic patients.
n
Dose: 1mg Q8h Cost:
$55.77/day
Beta-lactamase inhibitor
Clavulanic Acid<Sulbactam<Tazobactam
Action: (useless alone)
inhibit -lactamase→enhance
-lactams action
Property
¨ Wide
spectrum: runner up after Tienam
¨ Fine
therapeutic effect: loose indication
¨ Rare
resistance: effective vs. MRSA/P.A.
¨ Rare
adverse effect: cautious of allergy
Combinations
All have
activity against staphylococci comparable to methicillin
n
Amoxicillin + clavulanate (Augmentin)
Active against most respiratory
tract, and some GI tract gram negative organisms
n
Ampicillin + sulbactam (Unasyn)
Very good activity against GI and
respiratory tract gram negatives
n
Piperacillin + tazobactam (Zosyn)
Excellent activity against GI and
respiratory tract gram negatives, including Pseudomonas aeruginosa
n Ticarcillin + Clavulanic Acid (
Timentin )
Tazocillin
Ingredient: Piperacillin＋Tazobactam
4g 0.5g
8g 1.0g
n
Please describe the general mechanism of
antimicrobial agents.
n
How many mechanisms do bacteria resist
antimicrobial effect?
n
What is the chief structural of penicillin, and how
do it effect?
n
What is the most dangerous AR of penicillin, and
how to prevent or rescue?
n
Please describe the development of different
generation of synthesis penicillins and cephalosporins(2 tables).
n
What benefit for therapy when Beta-lactam
combinated with Beta-lactam inhibitor?
