Transcript Clarithromycin (克拉霉素)

Section 3
Macrolides,
Lincomycins &Vancomycins
Yun-Bi Lu, PhD
卢韵碧
Dept. of Pharmacology,
School of Medicine, Zhejiang University
[email protected]
Part A Macrolides
• Erythromycin (红霉素)
• Clarithromycin (克拉霉素)
• Azithromycin (阿奇霉素)
• Telithromycin(泰利霉素)
14 member rings
14 member rings
15 member rings
General properties of Macrolides
1. Antimicrobial spectrum：
• G+ organisms
• G- cocci: Streptococcus pyogenes and
pneumoniae
• Mycoplasma pneumoniae(肺支原体) and
Legionnella (军团菌)etc.
2. Antimicrobial activity:
• bactericidal and bacteriostatic,
depending on the concentration.
• more active at alkaline
3. Mechanism of action:
subunit
macrolide
4. Mechanism of resistance:
• modification of the ribosomal binding site
• production of esterase that hydrolyze
macrolides.
• reduced permeability of cell membrane or
active efflux system is involved.
• Cross-resistance is complete between
erythromycin and the other macrolides.
General properties of Macrolides
4. ADME
1) Absorption:
Stearate and ester of erythromycin
are fairly acid-resistant and
somewhat batter absorbed. Food
interferes with absorption.
General properties of Macrolides
4. ADME
2) Distribution: does not cross BBB.
3) Elimination: it is concentrated in the
liver, where some is unactived, while
some is excreted in active form in
the bile.
General properties of Macrolides
5.Clinical Uses:
1) Mycoplasma (支原体) infections.
2) Legionnaire’s disease (军团菌病).
3) Chlamydia infections (衣原体感染).
4) Streptococcus (链球菌) infections.
5) Diphtheria (白喉), chincough (百日咳).
6) toxoplasmosis(弓形虫病).
General properties of Macrolides
6.Adverse response:
1) GI Effects: nausea, vomiting,
abdominal cramps(痉挛)…
2) Liver Toxicity: Cholestatic hepatitis
(胆汁淤积性肝炎).
3) Cardiotoxic effects
4) Auditory impairment (Ototoxicity)
Hypersensitivity reactions
Superinfections
General properties of Macrolides
7. Drug interactions
• Erythromycin metabolites can
inhibit cytochrome P450
enzyme.
Macrolides
• Erythromycin (红霉素)
• Clarithromycin (克拉霉素)
• Azithromycin (阿奇霉素)
• Telithromycin(泰利霉素)
Part B
Lincomycin & Clindamycin
• Lincomycin (林可霉素)
• Clindamycin (克林霉素)
Lincomycin & Clindamycin
Antimicrobial properties
• resemble erythromycin in
antibacterial spectrum,
activity, mechanism and
resistance.
 Mechanism of action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
Lincomycin & Clindamycin
Pharmacokinetics
• about 90% protein-bound
• excretion via the liver,bile, and
urine
• penetrate well into most tissue,
including bone, but not CSF.
Lincomycin & Clindamycin
Clinical Uses
•
•
•
•
severe anaerobic infection
aerobic G+ cocci infection
combination with pyrimethamine (乙胺嘧啶)
for AIDS-related toxoplasmosis（弓形体病）
combination with primaquine (伯氨喹) for
AIDS-related pneumocystis carinii
pneumonia（肺囊虫性肺炎）.
Lincomycin & Clindamycin
Adverse response:
1) GI effects: Antibiotic-associated
colitis (pseudomembranous colitis
伪膜性结肠炎).
2) allergic reaction
3) impaired liver function
Vancomycins
Vancomycin (万古霉素)
Norvancomycin (去甲万古霉素)
Teicoplanin (替考拉宁，太古霉素)
Vancomycins
Antibacterial activity
bactericidal for G+ bacteria
( especially G+ ococci,
including MRSA & MRSE)
Vancomycins
• Antibacterial Mechanism
Inhibiting cell wall synthesis by
binding to the D-Ala-D-Ala terminus
of nascent peptidoglycan pentapeptide.
• Resistance
occurred because of the alteration of
D-Ala-D-Ala to the D-Ala-D-Ser.
Fig. Antibacterial Mechanism of Vancomycins
Vancomycins
• ADME
• Oral administration (poorly absorbed).
• Intravenous administration, is excreted by
glomerular filtration (accumulates when renal
function is impaired).
• Widely distributed in the body, including CSF
when the meninges is inflamed.
Vancomycins
• Clinical Uses
1) severe infection caused by MRSA etc.
2) alternative for b-lactam
3) enterococcal or staphyococcal
endocarditis (combination with
gentamicin).
4) pseudomembranous colitis
Pseudomembranous
enterocolitis
Pseudomembranous colitis.
Endoscopic en face view of colon wall
demonstrating several
pseudomembranes (arrows).
Hurley and Ngueyn Arch Intern Med. 2002;162:2177-2184.
Pseudomembranous enterocolitis
Normal
Focal ulceration can be seen at
the tips of the mucosa. The
exudate of fibrin and
inflammatory tissue.
Vancomycins
• Adverse Reactions
1) Hypersensitive reaction
(e.g. red man syndrome)
2) Ototoxicity
3) Nephrotoxicity
4) Gl effects, etc.
Section 4
Aminoglycosides & polymyxins
Part A
Aminoglycosides
Overview
• History and Source : the research made
by Waksman and coworks within 19391943
• Clinical Applications: for the
treatment of aerobic G- bacterial
infections and tuberculosis
• Two classes: crude product and
semisynthetic derivative
Aminoglycosides
General properties
1. Antimicrobial activity:
i) rapidly bactericidal to resting
bacterium
ii) broad-spectrum
iii) more active at alkaline
General properties
1. Antimicrobial activity:
iv) concentration-dependent activity
v) the duration of post antibiotic effect (PAE) is
concentration- dependent (10 hours).
vi) first exposure effect (FEE)
Peak Concentration
Blood
Concentration
Bacterial growth is inhibited long
after concentration below the MIC
MIC
Time (h)
General properties
2. Antimicrobial spectrum：
• aerobic G- bacilli and cocci
• aerobic G+ organisms
• Streptomycin and kanamycin are
also active against Mycobacterium
tuberculosis
General properties
3. Mechanism of action:
• inhibit protein synthesis
• act as Ionic- sorbent, act directly on
permeability of the cell membrane of
bacterium.
Mechanism of action - inhibit protein synthesis
•Blocks the initiation of protein synthesis
Mechanism of action - inhibit protein synthesis
•Blocks the initiation of protein synthesis
Mechanism of action - inhibit protein synthesis
Mechanism of action - inhibit protein synthesis
Mechanism of action - inhibit protein synthesis
•Incorporation of incorrect amino acid
Mechanism of action - inhibit protein synthesis
•Blocks further translocation and
elicits premature terminations
Mechanism of action - inhibit protein synthesis
•disrupt the normal cycle of ribosomal,
make the ribosomal exhausted
Mechanism of action - inhibit protein synthesis
i) Interfering with the initiation complex of
peptide formation.
ii) Inducing misreading of mRNA, which causes
the incorporation of incorrect amino acid into
peptide, resulting nonfunctional or toxic
protein.
Mechanism of action - inhibit protein synthesis
iii) causing breakup of polysomes into
nonfunctional monosomes.
iv) disrupt the normal cycle of
ribosomal, make the ribosomal
exhausted.
Mechanism of resistance
produces enzymes
Altered ribosomal subunit
Changes of Porins
Active efflux system
Mechanism of Resistance
i) The microorganism produces a transferase
enzyme or enzymes that inactivate the
aminoglycoside by adenylyation, acetylation,
or phosphorylation.
ii) Impaired entry of aminoglycoside into the cell.
iii) The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a result
of mutation.
General properties
ADME
i) Absorption: not absorbed after po, but
rapidly absorbed after IM, peak time 0.5-2h.
ii) Distribution: Binding to plasma protein is
minimal, do not enter cell, nor do they cross
BBB,but they cross the placenta, reach high
concentrations in secretions and body fluids.
Tissue level is low expect in the cortex of
kidney.
General properties
ADME
iii) Elimination: excreted mainly by
glomerular filtration. If renal function
is impaired, accumulation occurs
with a increase in those toxic effects
which are dose related.
T1/2=2-3h
General properties
Clinical Uses
• be mostly used against aerobic G- bacteria
(bacilli, enteric) and in sepsis, be almost always
used in combination with b-lactam antibiotic or
fluoroqunolones (氟喹诺酮类)
• against aerobic G+ bacteria and in sepsis, be
almost always used in combination with
penicillins or vancomycin
• against Mycobacterium tuberculosis
General properties
Adverse reactions
i) Ototoxicity
• involves progressive damage to and destruction of the
sensory cells in the cochlea and vestibular organ in the
ear (irreversible!! ).
Ototoxicity (cochlea)
• Kanamycin(1.6%)> Amikacin> Sisomicin> Gentamicin>
Tobramycin(0.4%)
Ototoxicity (vestibular organ)
• Kanamycin(4.7%)> Streptomycin> Sisomicin>
Gentamicin> Tobramycin(0.4%)
General properties
Adverse reactions
ii) Nephrotoxicity
• consists of damage to the kidney tubules and
be reversed if stop using.
• Amikacin < Streptomycin or Tobramycin<
Gentamicin < Kanamycin <Neomycin
Nephrotoxicity
& Ototoxicity
Blue, high frequency
Red, low frequency
General properties
Adverse reactions
iii) Neuromuscular blockade (paralysis)
• generally occurred after intra-pleural or intraperitoneal instillation of large doses of an
aminoglycosides
• Tobramycin < Gentamicin < Kanamycin or Amikacin
<Streptomycin <Neomycin
• Calcium salt or inhibitor of cholinesterase
(neostigmine) is the preferred treatment for this
toxicity.
General properties
Adverse reactions
iv) Allergic reaction
• skin rashes fever, eosinophiliay (嗜酸粒
细胞增多症）, anaphylactic shock, etc.
Aminoglycosides agents
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•
•
•
•
•
Streptomycin （链霉素）
Gentamicin （庆大霉素）
Tobramycin（妥布霉素）
Amikacin（阿米卡星）
Netilmicin（奈替米星）
Neomycin（新霉素）
Aminoglycosides agents
•
•
•
•
•
•
•
•
•
Kanamycin(卡那霉素）
Arbekacin （阿贝卡星）
Dibekacin （地贝卡星）
Micronomicin（小诺米星）
Sisomicin（西索米星）
Etilmicin（依替米星）
Isepamicin（异帕米星）
Astromicin （阿司米星，福提霉素）
Spectinomycin （大观霉素），etc.
Streptomycin
1. ADME
i) Absorption: IM
ii) Distribution: mainly at extracellular
fluid, crosses the BBB and achieves
therapeutic concentrations with
inflamed menings.
iii) Excretion: 90%, kidney
age↑→ T1/2↑
Streptomycin
2.Clinical uses
i) plague(鼠疫) and tularemia(兔热病):
combination with an oral tetracycline.
ii) tuberculosis: as first-line agent
iii) bacterial endocarditis: (enterococcal
肠球菌, viridans streptococcal 草绿色链
球菌, etc.), streptomycin and penicillin
produce a synergistic bactericidal.
Streptomycin
3. Adverse reactions
i) Allergic reaction
skin rashes, fever, anaphylactic shock
ii) Ototoxicity (cochlea > vestibular organ)
iii) Neuromuscular blockade (paralysis)
iv) Nephrotoxicity
Gentamicin
1. ADME
Gentamicin can accumulate in cortex
of the kidney .
2.Clinical use :
ii) important agent (first choice) for
serious G bacillary infections (sepsis,
pneumonia, etc.), because of its low
cost and reliable activity.
Gentamicin
2.Clinical Uses :
ii) infection induced by enterococcal,
viridans streptococcal, staphylococcal
etc. Gentamicin is used concurrently
with other antibiotics (e.g. b-lactams)
iii) prevent the infection induced by
operation
Gentamicin
2.Clinical Uses :
iv) local application: for treatment of
infected burn, wounds,or skin
lesions and the prevention of
intravenous catheter infections, etc.
Gentamicin
3. Adverse reactions
i) Ototoxicity (vestibular organ
> cochlea)
ii) Nephrotoxicity
iii) Nausea and vomiting etc.
Tobramycin
1. antimicrobial activity &
pharmacokinetics: very similar to
those of getamicin.
2. Adverse reactions: Ototoxicity and
Nephrotoxicity (may be less than dose
gentamicin).
Amikacin
1.Antibacterial activity:
The spectrum of antimicrobial
activity of amikacin is the broadest
in the group.
Amikacin
2.Clinical uses :
• Treatment of G-bacillary infections
which resistance to gentamicin and
tobramycin.
• Most strains resistance to amikacin
found is also resistance to other
aminoglycosides.
• combination with b-lactams, produce a
synergistic bactericidal.
Amikacin
3. Adverse reactions
i) Ototoxicity (cochlea > vestibular organ)
ii) Nephrotoxicity (may be less than
gentamicin or Tobramycin).
iii) Neuromuscular blockade (paralysis)，
rarely
iv) skin rashes, fever, nausea and vomiting
etc.
Netilmicin
i) similar to gentamicin & tobramycin
in its pharmacokinetic properties.
ii) broad spectrum, against aerobic Gbacilli.
iii) tolerance to many aminoglycosides
- inactivating enzymes.
iv) less toxic
Part B
Polymyxins
1. Polymyxin A,B,C,D,E
2.Notice: because of the extreme toxicity,
they are now rarely used.
3. Antibacterial activity: they are
restricted to G- bacilli (Narrow
spectrum)
4.Mechanism of action: they interact with
phospholipids and penetrate into and
disrupt the structure of cell membranes.
Lipopoly
-saccharide
Outer
membrane
Peptidoglycan
Cytoplasmic
membrane
polymyxins
Part B
Polymyxins
4. Clinical uses: infection of
Pseudomonas aeruginosa (铜绿假单胞
菌属) and other G- bacilli, local
application.
Resisitance rarely happened.
Part B
Polymyxins
5. Adverse reaction(25%):
i) Nephrotoxicity (22.2%)
ii) Neurotoxicity:
Neuromuscular blockade
(paralysis)
iii) Allergic reaction
iv) others: hepatotoxicity
Section 5
Tetracyclines & Chloramphenicol
Part A
Tetracyclines
Part A Tetracyclines
 Two classes:
• crude product
Tetracycline(四环素)
Cholortetracycline (金霉素)
Oxytetracycline (土霉素)
• semisynthetic derivative
Doxycycline(多西环素)
Minocycline(米诺环素)
General properties of Tetracyclines
 Antimicrobial activity:
• bacteriostatic
• bactericidal (high concentration)
• Minocycline > Doxycycline > Tetracycline
General properties of Tetracyclines
“broad-spectrum” antibiotic
• Rickattsiae (立克次体)
• a number of aerobic and anaerobic G+
& G- bacteria
• Chlamydia (衣原体)
• Coxiella burnetii (螺旋体)
• Mycoplasma pneumoniae (支原体)
• Plasmodium (疟原虫)
• not active against fungi, virus.
General properties of Tetracyclines
 Mechanism of action:
Bind to 30S subunit of ribosome,
preventing access of aminoacyl tRNA to
acceptor (A) site on the mRNA-ribosome
complex
General properties of Tetracyclines
 Mechanism of action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
General properties of Tetracyclines
 Resistance Mechanism:
(1) Decreased intracellular
accumulation due to either impaired
influx or increased efflux by a active
transport protein pump.
(2) Ribosome protection that interfere
with the tetracycline binding to the
ribosome.
(3) Enzyme inactivation of tetracycline.
General properties of Tetracyclines
 ADME :
(1) Absorption are impaired by food (except
doxycycline and minocycline).
(2) Distributed widely to tissue and body fluid except for
CSF.
• across the placenta and are also excreted in the milk.
• tetracyclines are bound to- and damage- growing
bones and teeth (chelation with calcium).
(3) Excreted mainly in bile and urine.
General properties of Tetracyclines
 Clinical Uses
(1) Rickettsial(立克次体) infections.
(2) Mycoplasma(支原体) infections.
(3) Chlamydia(衣原体) infection.
(4) Leptospira(螺旋体) infection.
(5) Bacterial infection.
General properties of Tetracyclines
 Adverse reactions
(1) Gastrointestinal effects.
(2) Superinfections.
(3) Deposition of the drugs in growing teeth and
bones.
(4) Hepatic toxicity and renal toxicity.
(5) Photosensitivity.
(6) Vestibular toxicity (minocycline).
Brown discoloration of teeth due to tetracycline exposure.
Tetracyclines
agents
• Tetracycline (四环素)
• Doxycycline (多西环素)
• Minocycline (米诺环素)
Part B
Chloramphenicol
Chemical structure
p 1246
p776pharm
Chloramphenicol
1. Antimicrobial activity:
(1) a wide antimicrobial spectrum.
(2) primarily bacteriostatic , may be
bactericidal to certain species.
Chloramphenicol
2. Mechanism of action
Acts primarily by binding reversibly to
the 50 S ribosomal subunit (near the
site of action of macrolides and
clindamycin, which it inhibits
competitively).
 Mechanism of action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
Chloramphenicol
2. Mechanism of Resistance
(1) a plasmid-encoded
acetyltransferase that inactives the
drugs
(2) low permeability of bacterial cell
membrane
Chloramphenicol
3. Adverse reactions
(1)Hematological Toxicity:
• dose-related toxic effect
anemia, leukopenia, thrombocytopenia
• idiosyncratic response
aplastic anemia(再障), fatal pancytopenia.
(2) Gray baby syndrome.
(3) hypersensitivty reaction, etc.
4. Drugs interactions
inhibits Cy P450 enzyme mediated
metabolism of warfarin, phenytoin, etc.
Chloramphenicol
5.Clinical uses
(1) Bacterial meningitis.
(2) Typhoid fever(伤寒) and other types of
systemic Salmonella infections.
(3) Eye bacterial infection.
(4) Anaerobic infection.
(5) Rickettsial disease and brucellosis, etc.
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