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Chapter 39
Tetracyclines (四环素)&
Chloramphenicol(氯霉素)
Tetracyclines
Tetracyclines -Chemical structure
•Tetracycline (四环素)
Tetracyclines
• Clinical used tetracyclines:
•
Tetracycline(四环素);
•
Demeclocycline(地美环素, 去甲金霉
素);
•
Metacycline(美他环素, 甲烯土霉素);
•
Doxycycline(多西环素, 强力霉素);
•
Minocycline(米诺环素, 美满霉素).
(Antimicrobial activity enhanced from up
to down)
Tetracyclines -Overview
Tetracyclines
Crude product
Tetracycline(四环素),Chlortetracycline
(金霉素),Oxytetracycline (土霉素)
Semisynthetic derivative
Doxycycline(多西环素), Minocycline(米诺环素)
Tetracyclines
Antimicrobial activity
(1) Bacteriostatic
(2) Bactericidal (at high concentration )
(3) Minocycline > Doxycycline >
Tetracycline
Tetracyclines
Antimicrobial spectrum
Broad-spectrum antibiotic
(1) Active against a wide range of aerobic and anaerobic
gram-positive and gram-negative bacteria.
(2) Effective against Rickettsia(立克次体）,Coxiella
burnetii（螺旋体）,Mycoplasma pneumoniae（支原
体）,Chlamydia (衣原体), and Plasmodium （疟原虫）.
(3) They are not active against fungi,virus.
Tetracyclines
Mechanism of action
(1) Enter bacteria by passive diffusion through
the protein channel formed by porin proteins of
outer cell membrane(G- organisms) and active
transport by an energy-dependent system that
pumps all tetracyclins across cytoplasmic
membrane (G+ organisms) .
(2) Inhibit protein synthesis in susceptible
microorganisms.
(3) Increase the permeability of the cell
membrane
Mechanism of resistance
Tetracyclines
Mechanism of action
Tetracyclines
Mechanism of action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
•Inhibits binding of 30S
subunit with A site
•Interfering with the
binding of aminoacyl-tRNA
with aminoacyl site(A site)
Mechanism of resistance
Tetracyclines
(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.
Tetracyclines
ADME
(1) Absorption are impaired by food (except
doxycycline and minocycline ）
• Tetracyclines manly differ in their
absorption after oral administration.
(2) Distributed widely to tissue and body
fluid except for CSF.
(3) Excreted mainly in bile and urine.
ADME
Tetracyclines
(4) Tetracyclines across the placenta and
are also excreted in the milk.
(5) Bound to- and damage- growing bones
and teeth
• As a result of chelation with calcium
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.
Tetracyclines
Adverse reaction
(1)Gastrointestinal effects.
(2)Superinfections.
(3) Bony Structures and Teeth:
Deposition of the drugs in growing
teeth and bones.
(4)Hepatic toxicity and renal toxicity.
(5)Photosensitivity.
(6)Pseudotumer cerebri(脑假瘤)
(7)Vestibular reaction(前庭反应 )
Tetracyclines
Recent research
•Tetracycline and its derivatives doxycycline
and minocycline were found to have antiinflammatory and anti-apoptotic properties.
•Protect mice from brain ischemia, traumatic
brain injury, Huntington’s disease, etc.
•The mechanism partially though caspase-1, 3,
iNOS, COX-2 etc.
Tetracyclines
• A newly approved tetracycline analog, tigecycline,
is a glycylcycline and a semisynthetic derivative
of minocycline.
Tetracyclines
• Tigecycline, the first glycylcycline to reach the clinic, has
several unique features that warrant its consideration apart
from the older tetracyclines. Many tetracycline-resistant
strains are susceptible to tigecycline because the common
resistance determinants have no activity against it. Its spectrum
is very broad. Coagulase-negative staphylococci and
Staphylococcus aureus, including methicillin-resistant,
vancomycin-intermediate, and vancomycin-resistant strains;
streptococci, penicillin susceptible and resistant; enterococci,
including vancomycin-resistant strains; gram-positive rods;
Enterobacteriaceae; multidrug-resistant strains of
Acinetobacter sp; anaerobes, both gram-positive and gramnegative; atypical agents, rickettsiae, chlamydia, and legionella;
and rapidly growing mycobacteria all are susceptible. Proteus and
P aeruginosa, however, are intrinsically resistant.
Tetracyclines
•
•
Tigecycline, formulated for intravenous administration only, is given as
a 100-mg loading dose; then 50 mg every 12 hours. As with all
tetracyclines, tissue and intracellular penetration is excellent;
consequently, the volume of distribution is quite large and peak serum
concentrations are somewhat blunted. Elimination is primarily biliary,
and no dosage adjustment is needed for patients with renal
insufficiency. In addition to the tetracycline class effects, the chief
adverse effect of tigecycline is nausea, which occurs in up to one third
of patients, and occasionally vomiting. Neither nausea nor vomiting
usually requires discontinuation of the drug.
Tigecycline is FDA-approved for treatment of skin and skin-structure
infection and intra-abdominal infections. Because active drug
concentrations in the urine are relatively low, tigecycline may not be
effective for urinary tract infections and has no indication for this use.
Because it is active against a wide variety of multidrug-resistant
nosocomial pathogens (eg, methicillinresistant S aureus, extendedspectrum -lactamase-producing gram-negatives, and Acinetobacter
species), tigecycline is a welcome addition to the antimicrobial drug
group.
Chloramphenicol
Chloramphenicol (氯霉素)
Chemical structure
p 1246
p776pharm
Chloramphenicol
Antimicrobial activity
(1)Chloramphenicol possesses a wide
antimicrobial spectrum.
(2) Primarily bacteriostatic , although it
may be bactericidal to certain species.
Chloramphenicol
Mechanism of action
1. Inhibit protein synthesis in susceptible
bacteria, and to a lesser extent, in
mammalian cell
2. 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
Chloramphenicol
Mechanism of
action:
①Chloramphenicol
②Macrolides,
Clindamycin
③Tetracyclines
Mechanism of Resistance
Chloramphenicol
(1) Resistance usually caused by a
plasmid-encoded acetyltransferaes(乙
酰转移酶) that inactive the drugs.
(2) The permeability of bacterial cell
membrane is changed.
Clinical uses
Chloramphenicol
(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 （立克次体病）
and brucellosis （布鲁杆菌病）, etc.
Adverse reactions
Chloramphenicol
(1) Gastrointestinal Disturbances
(2) Bone Marrow Disturbances:
• By dose-related toxic effect that presents
anemia, leukopenia and or
thrombocytopenia （血小板减少）
• By special response manifested by aplastic
anemia, leading in many cases to fatal
pancytopenia （全血细胞减少）.
Adverse reactions
Chloramphenicol
(2) Toxicity for newborn infants:
• Gray baby syndrome(灰婴综合征).
(3)other reactions:
• hypersensitivity reaction, etc.
Drugs interactions
Chloramphenicol
• Inhibits hepatic microsomal
cytochrome P450 enzyme, and thus
may prolong the t 1/2 of drugs that
metabolized by this system, e.g.
warfarin, phenytoin, etc.