Transcript 2. Mechanisms

Aminoglycosides & Spectinomycin
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
General properties
1. Antimicrobial activity:
i) rapidly bactericidal to resting bacterium
ii) broad-spectrum： G- bacilli and cocci，G+ organisms，TB
iii) more active at alkaline
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. Mechanism of action:
• inhibit protein synthesis
• act as Ionic-absorbent, act directly on
permeability of the cell membrane of
bacterium.
Inhibiting protein synthesis:
P
A
Aminoglycosides
2.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.
iii) causing breakup of polysomes into nonfunctional
monosomes.
iv) disrupt the normal cycle of ribosomal, make the
ribosomal exhausted.
3. Mechanism of resistance
produces enzymes
Changes of Porins
Altered ribosomal subunit
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.
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.
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.
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 and fluoroqunolones
• 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!!
Auditory and vestibular damage).
ii) Nephrotoxicity
• consists of damage to the kidney tubules and
be reversed if stop using.
General properties
Adverse reactions
iii) Neuromuscular blockade (paralysis)
• generally occurred after intra-pleural or intraperitoneal instillation of large doses of an
aminoglycosides
• Calcium salt or inhibitor of cholinesterase
(neostigmine) is the preferred treatment for this
toxicity.
iv) Allergic reaction
• skin rashes fever, eosinophiliay , anaphylactic
shock, etc.
Aminoglycosides
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Streptomycin
Gentamicin
Tobramycin
Amikacin
Netilmicin
Neomycin
Kanamycin
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Arbekacin
Dibekacin
Micronomicin
Sisomicin
Etilmicin
Isepamicin
Astromicin
Streptomycin
1. ADME
i) Absorption: IM
ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves
therapeutic concentrations with inflamed meninges.
iii) Excretion: 90%, kidney
2.Clinical uses
i) plague and tularemia: combination with an oral tetracycline.
ii) tuberculosis: as first-line agent
iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.),
streptomycin and penicillin produce a synergistic bactericidal.
3. Adverse reactions
i) Allergic reaction
skin rashes, fever, anaphylactic shock
ii) Ototoxicity: disturbance of vestibular function, deafness of newborn
iii) Nephrotoxicity
iv) Neuromuscular blockade (paralysis)：Myasthenia Gravis, anesthetics,
scoline
Gentamicin
1. ADME
Gentamicin can accumulate in cortex of the kidney .
2.Clinical use :
i) serious G- bacillary infections (sepsis, pneumonia, etc.).
ii) infection induced by enterococcal, viridans streptococcal,
staphylococcal etc. (in combination with other antibiotics, e.g.
b-lactams)
iii) prevent the infection induced by operation (e.g.,
gastrointestinal operation )
iv) local application or intrathecal administration (rarely use)
3. Adverse reactions
i) Nephrotoxicity (reversible and mild)
ii) Ototoxicity (irreversible!)
iii) Nausea and vomiting etc.
Tobramycin
1. antimicrobial activity &
pharmacokinetics: very similar to
those of gentamicin; has crossresistance to gentamicin.
2. Adverse reactions: Ototoxicity and
Nephrotoxicity (may be less than dose
gentamicin).
Netilmicin
1. similar to gentamicin & tobramycin in its
pharmacokinetic properties.
2. broad spectrum, against aerobic G- bacilli.
3. tolerance to many aminoglycosides (gentamicin,
tobramycin) - inactivating enzymes.
4. less toxic
Amikacin
1.Antibacterial activity: the broadest in the group.
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.
3. Adverse reactions
i) Ototoxicity
ii) Nephrotoxicity
iii) Neuromuscular blockade (paralysis)
iv) skin rashes, fever, nausea and vomiting etc.
Macrolides and lincomycin
Structure
Representative drugs
First
generation
Erythromycin
Dirithromycin
Meleumycin
Josamycin
Acetylspiramycin
Midecamycin
Rokitamycin
Roxithromycin
Second
Clarithromycin
generation Azithromycin
Acetylmidecamycin
flurithromycin
Penicillin-resistant Staphylococcus
Penicillin-allergic patients
Penicillin-resistant Staphylococcus
Penicillin-allergic patients
1. Antibacterial spectrum
board bactericidal or bacteriostatic drugs
G+ and G- bacteria, cocci, Neisseria
gonorrhea, gram-positive bacilli, and
spirochetes, mycoplasma, rickettsiosis
2. Mechanisms
Inhibition of protein synthesis
(1) reversible binding to 50S subunit of
ribosome (23S rRNA)
(2) L22 protein binding in 50S subunit,
lead to disruption of ribosome
3. Clinical Usage
(1) Streptococci infection
(2) Legionella pneumophila
(3) infection from spirochetes, mycoplasma, rickettsiosis
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) superinfection: infection that occurs while treating another infection.
e.g. oral fungal infection
(4) Ototoxicity
(5) allergic reaction
Lincomycin & Clindamycin
• Antibacterial spectrum
(1) board bactericidal or bacteriostatic drugs, similar to the macrolides
(2) Anaerobic G+ and G- bacteria
2. Mechanisms
Inhibition of protein synthesis
L16 protein binding in 50S subunit,
lead to disruption of ribosome. Avoid to using with erythromycin
(same binding sites), antagonistic effects.
3. Clinical Usage
(1) Aerobic bacteria
(2) anaerobic bactreria
(3) infection from staphylcoccus in bone tissues (osteomyelitis )
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) allergic reaction
Tetracyclins and chloramphenicol
Natural products
Semisynthesis
Chlortetracycline
Oxytetracycline
tetracycline
Doxycycline
Methacycline
minocycline
1. Antibacterial spectrum
board bacteriostatic drugs
G+ and G- bacteria, cocci, spirochetes, mycoplasma, rickettsiosis,
chlamydia.
2. Mechanisms
(1) Cell membrane transportation
(2) Inhibition of protein synthesis
30S subunit of ribosome
(3) permeability
3. Clinical Usage
(1) spirochetes
(2) mycoplasma
(3) rickettsiosis,
(4) chlamydia
(5) bacteria
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) superinfection: infection that occurs while treating another infection.
e.g. oral fungal infection
(4) teeth and bone
(5) renal toxicity
(6) photosensitized reaction
(7) ototoxicity
chloramphenicol
1. Antibacterial spectrum
board bacteriostatic bactericidal drugs
G+ and G- bacteria, spirochetes, mycoplasma, rickettsiosis,
2. Mechanisms
Inhibition of protein synthesis
70S ribosome complex, 50S
hematopoietic stromal cell in bone marrow,
mammary 70S is similar to baterial 70S, lead to bone marrow suppression
3. Clinical Usage
(1) bacterial meningitis, purulent Meningitis in Children
(2) Corynebacterium diphtheriae infection
(3) eye infection (bacteria)
(4) anaerobic infection
4. Adverse reaction
(1) GI
(2) Gray baby syndrome: disturb the ribosome function in mitochondria
ability of detoxication via glucuronic acid conjugation
ability of renal excretion
(3) bone marrow suppresion:
AA, anemia, granulocytopenia, thrombopenia
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
***Overuse should be avoided, in view of limited options for
treatment of resistant gram positive infections.
Vancomycins
• Adverse Reactions
1) Hypersensitive reaction
(e.g. red man syndrome)
2) Ototoxicity
3) Nephrotoxicity
4) Gl effects, Phlebitis etc.
Part B
Synthetic antimicrobial agents
Synthetic antimicrobial agents
• Quinolones
Generation Example
1
Nalidixic acid
2
Pipemidic acid
3
Norfloxacin
4
Clinfloxacin
time
1962
1973
1980’s
1990’s
• Sulfonamides
• Other Synthetic antimicrobial
Trimethoprim, Nitrofurans
From chloroquine to nalidixic acid
First generation fluoroquinolones
R 6
5
８
R
4
1
7
R
3
2
From ofloxacin to levofloxacin
Fluoroquinolones
General properties of Quinolones
Antimicrobial activity & spectrum:
(1) bactericidal and have significant PAE.
(2) aerobic G- bacteria, Pesudomonas,
aerobic G+ bacteria, Chlamydia spp.,
Legionella pneumophila , anaerobic
bacteria,
mycobacteria,
multipleresistance strains.
Mechanism of action
DNA gyrase
Topoisomerase
Key enzymes in DNA replication: bacterial DNA is supercoiled.
Mechanism of action
porin
DNA gyrase
Gram (-)
Topo
isomerase
Gram (+)
Mechanism of action
DNA gyrase
Catalytic subunite
Fluoroquinolones:
4 stacked molecules
DNA gyrase
ATP binding subunite
Mechanism of resistance
decreased
permeability
active efflux
system
porin
DNA gyrase
Gram (-)
Topo
isomerase
mutation of
the enzymes
Gram (+)
ADME of fluoroquinolones
• Absorption: well absorbed; bound by divalent cations
– Do not administer with iron, magnesium, calcium
• Distribution: all distribute widely (even in CSF), and most
concentrate in urine
• Metabolism:
– hepatic metabolism diminishes the activity of norfloxacin
and ciprofloxacin
– Several have predominately hepatic clearance
(Grepafloxacin, Sparfloxacin, Trovafloxacin)
• Excretion: urinary excretion predominates for the first
generation fluoroquinolones
Clinical Uses
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Urinary tract infections.
GI and abdominal infections.
Respiratory tract infections.
Bone, joint and soft tissues infections, Osteomyelitis.
Meningitis
STD: Neisseria gonorrhea and Chlamydia (Quinolone
resistance in gonorrhea increasing)
Adverse reactions
• Gastrointestinal effects.
• CNS side effects.
• Allergic reaction.
• Hepatotoxicity, nephrotoxicity.
• Joint/cartilage toxicity, Tendinopathy
– Achilles tendon rupture
– Limited FDA approval for children (under 18)
Fluoroquinolones agents
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Norfloxacin
Ciprofloxacin
Ofloxacin
Levofloxacin
Lomefloxacin
Fleroxacin
Sparfloxacin
Clinafloxacin
Gatifloxacin
Sulfonamides : Inhibitors of
Folate Synthesis
2,4-Diaminoazobenzen-4’-sulfonamide
Prontosil
Gerhard Domagk
Nobel Laureate 1939
Antimicrobial activity:
•A wide antimicrobial spectrum.
•Exerting only bacteriostatic effect.
Mechanism of action
Pteridine+PABA
Dihydropteroate
synthase
Blocked by
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
Dihydrofolate
reductase
NADPH
Blocked by trimethoprim
NADPH
Tetrahydrofolic acid
Mechanism of Resistance
• A lower affinity for sulfonamides by the
dihydropteroate synthase
• Decreased cell permeability or active efflux
of the drug
• An alternative pathway to synthesis the
essential metabolites
• An increased production of essential
metabolites
Classification & Clinical uses :
• Oral absorbable agents (Systemic infections)
─ Short-acting agents: Sulfafurazole (SIZ)
─ Medium-acting agents:
Sulfadiazine (SD) [Co: pyrimethamine → toxoplasmosis]
best in the CSF and brain → → meningitis
Sulfamethoxazole (SMZ) [Co: trimethoprim, named
trimoxazole / TMP-SMZ
─ Long-acting agents: Sulfadoxine (SDM) [Co:
pyrimethamine → malaria]
• Oral nonabsorbable agents (Intestinal infections)
Sulfasalazine
• Topical agents (Infections of burn and wound)
Mafenide (SML)
Sulfadiazine sliver
Sulfacetamide (SA)
ADME of sulfonamides
• Approximately 70%-100% of an oral dose is
absorbed.
• Distributing throughout all tissues of the body, even
in CSF ( sulfadiazine and sulfisoxazole, may be
effective in meningeal infections) ;readily passing
through the placenta.
• Metabolized in the liver by acetylation.
• Eliminated mainly in the urine as the unchanged
drug and metabolic product. In acid urine, the
eliminated may precipitate, thus induced renal
disturbance.
Adverse reactions
• Hypersensitivity reaction
• Urinary tract disturbances: Sulfonamide
crystalluria
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Hematopoietic system disturbances
Kernicterus
Hepatitis
GI effects
Drugs interactions
• All sulfonamides are bound in varying
degree to plasma protein.
Combination agents: Co-trimoxazole
1) Features
• Trimethoprim in combination with
Sulfamethoxazole (1:5,eg,160mg:800mg for
p.o.) exerts a synergistic effects
(bacteriocidal effect ).
• Co-block essential enzymes of folate
metabolism.
• The ADME of the two agents is similar.
Pteridine+PABA
Dihydropteroate
synthase
Blocked by
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
Dihydrofolate
reductase
NADPH
Blocked by trimethoprim
NADPH
Tetrahydrofolic acid
2)Clinical Uses
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Chronic and recurrent infections in the urinary tract
Bacterial respiratory infections
GI infections (e.g. induced by Salmonella)
pneumocystis carinii pneumonia
3)Adverse reactions
• There is no evidence that co-trimoxazole, when given in
recommended dose, induced folate deficiency in normal
persons.
• Trimethoprim(TMP): megaloblastic anemia
• Sulfamethoxazole (SMZ): all adverse reactions mentioned
• HIV patients (fever, rashes, leukopenia, diarrhea, hyperkalemia)
• Drug interactions: warfarin, phenytoin, etc.