Transcript Chapter 42 Synthesized Antimicrobial Agents

Chapter 42 Synthesized
Antimicrobial Agents
Department of pharmacology
Liu xiaokang(刘小康）
2010,3
Quinolones
• Common properties
• Structure:
• Antimicrobial activity:
• Quinolones are bactericidal agents. (1) First
generation: narrow spectrum (some G-),
rapid resistance emergence. e.g. nalidixic
acid; (2) second generation: better activety
against G– than 1st Generation, still many
advers effects. e.g. pipemidic acid.
• (3) third generation: Fluoroquinolones,
include norfloxacin, ofloxacin,
ciprofloxacin, levofloxacin, lomefloxacin,
fleroxacin, sparfloxacin etc. Broad spectrum,
Acting on most enterobacter spp. G– bacilli,
G+ coccus, chlamydia, mycoplasma,
legionella and Mycobacterium tuberculosis.
(4) Fourth generation: similar antibacterial
spectrum with third generation, but greater
activity on some anaerobe, G+ bacteria and
Pseud. aeruginosa.
• Mechanism of action:
• (1) Inhibit the A subunits of DNA gyrase, a
type II topoisomerase.
• (2) Inhibit topoisomerase IV.
• Hence inhibits relaxation of supercoiled
(packed) DNA needed for DNA replication,
increases double-strand DNA breakage.
• Inhibits two major topisomerases -- specific
one favored depends on organism, G–
topoisomerase II and G+ topoisomerase IV.
• (3) The properties of DNA gyrase : (a)Nicks &
seals DNA during replication; (b) Needed for
DNA to uncoil and recoil; (c) mammalian cells
do not have DNA gyrase, but do have stimilar
type II DNA topoisomerase. Requires 100 to
1000 μg/mL drug to inhibit these enzymes; (d)
Has two A subunits and two B subunits; (e) "Asubunits" are responsible for cutting the DNA.
Fluoroquinolones inhhibit this step; (f) Requires
0.1 to 10 μg/ml to inhibit A subunit; (g) Gyrase
required for plasmid replication,
Fluoroquinolones may reduce plasmid mediated
resistance in other drugs.
• Pharmacokinetics:
• Well absorbed, Food not impair absorption;
wide distribution, in some tissues
concentration is higher than plasma.
Pefloxacin, ofloxacin and ciprofloxacin can
reach effective concentration in CSF. Renal
excretion is primary route for most
fluoroquinolones.
• Clinical uses: (1) Urinary tract infections,
caused by enterococcus, Pseud. aeruginosa
and enterobacteriaceae. (2) Intestinal tract
infections: G– bacteria, include
campylobacter, shigella and salmonella. (3)
Respiratory tract infections: e.g. Strep.
pneumoniae, hemophilus influenzae and
Moraxella infections; (4) Bone and joint
infections; (5) Skin and soft tissue infection.
(6) Pefloxacin can be used for meningitis or
sepsis caused by klebsiella, enterobacter
and serratia.
• Adverse reactions: (1) Gastrointestinal
tract: nausea or vomiting abdominal or
stomach pain or discomfort. (2) CNS:
Dizziness or lightheadedness, headache,
nervousness, drowsiness, insomnia. Rarely
incidence: Seizures, CNS Stimulation -acute psychosis, agitation, confusion,
hallucinations, tremors (incidence rare). (3)
Allergies: Hypersensitivity can occur rarely,
such as angioneuroedema, skin rash and
itching, or shortness of breath and
photosensitive dermatitis. (5) others: hepatic
function impairment, interstitial nephritis.
• Contraindication:
• All quinolones contraindicated in patients
with history of convulsions.
• Resistance:
• (1) alterations in DNA gyrase and
topoisomerase IV; Mutation of gyrA gene
that encode the A subunit confer the
resistance, causing reduction of gyrase
affinity for drug. (2) Decreased intracellular
accumulation of the drug due to
modifications of membrane proteins.
• Drug interaction:
• Fluroquinolones interfere with hepatic
biotransformation -- may cause toxicity due
to excess of the following: theophylline and
warfarin.
Properties and clinical uses of
commonly used quinolones
• Norfloxacin: Act on G– bacteria, F=35%45%, original form excreted in urine about
45%-60%. Used for treatment of
gastrointestinal and urinary tract infections.
• Ciprofloxacin: Broad antibacterial
spectrum. Higher activity on G+ bacteria
than norfloxacin. F=38%-60%. Mainly used
for urinary tract, gastrointestinal tract,
respiratory tract, bone, joint, abdominal
cavity, skin and soft tissue infections.
• Ofloxacin: Well absorbed, F=80%-90%.
Wide distribution, in prostate gland, lung,
bone and sputum can reach effective
concentration. Used for urinary tract,
gastrointestinal tract, respiratory tract, bone,
joint, abdominal cavity, skin, soft tissue,
biliary tract, eye and ear, nose, throat
infections. Also used for the treatment of
tuberculosis and mycoplasma infection.
Relatively less adverse reactions.
• Levofloxacin:
• The potency is 2 fold of ofloxacin.
Antibacterial spectrum and activity are the
same with ofloxacin, but less adverse
effects.
• Lomefloxacin: Well absorbed, F=90%-98%,
t1/2=7 h. It can also kill quiescent cell. It
also effects on mycoplasma, chlamydia and
mycobacterium tuberculosis infection.
Special adverse reaction is the
photosensitivity.
• Sparfloxacin:
• t1/2=17.6 h. wide distributed, similar clinical
use with ofloxacin.
Sulfonamides
Common properties of
sulfonamides
• Structure:
• PABA
Sulfonamide
• Antibacterial activity:
• Broad spectrum, bacteriostatic agent.
Include G+ and G– bacteria, chlamydia,
actinomyces etc.
• Mechanism of action:
• Sulfonamides:
• (1) Compete with PABA to inhibit synthesis
of dihydrofolic acid (DHF).
• Enzyme: Dihydropteroate synthase
• (2) False synthesis: Some sulfonamides can
be incorporated into DHF-like compound;
DHF-like compound can inhibit
dihydrofolic acid reductase (DHFR)
• Mechanism of Trimethoprim (TMP)
• (1) Trimethoprim (TMP) strong inhibitor of
DHFR
• (2) Thus, blocks conversion & recycling of
DHF --> THF --> DHF --> THF --> ...
• Trimethoprim affinity for DHFR of bacteria
is 50,000 to 60,000 times greater than for
that of vertebrates. Therefore, bacterial
DHFR is inhibited at concentrations that
have essentially no effect on vertebrate DHF.
• Mechanisms of Combination:
• (1) Sequential blockade strong and
synergistic; (2) Bactericidal for some
bacteria; (3) Blocks synthesis of DHF
(sulfa); (4) Thus, blocks conversion &
recycling of DHF --> THF --> DHF -->
THF --> ...
• Selectivity:
• (1) Sulfonamide: (a)Bacteria must make
own DHF; (b) Vertebrates require as
vitamin
• (2) Trimethoprim: (a) Different binding
affinity for DHFR of vertebrates vs
microorganisms; (b) Table compares affinity
for mammalian, protozoan, and bacterial
enzyme
Concentration Required to Inhibit DHFR by 50%
DRUG
RAT LIVER
E. coli
P. berghei
IC50 (nM)
IC50 (nM)
IC50 (nM)
Pyrimethamine
700
2,500
~0.5
Trimethoprim
260,000
5
70
GG 8th, p985. Original data from Ferone, Burchall & Hitchings, 1969
• Pharmacokinetics:
• Most sulfonamides absorbed and excreted
rapidly, widely distributed. Metabolized in
liver by acetylase and eliminated primarily
by glomerular filtration.
• Clinical uses:
• (1) Systemic infection. e.g. meningitis
caused by neisseria meningitides. (2)
Intestinal tract infection. (3) Burn and hurt
infection.
• Adverse reactions:
• (1) Renal crystalluria:
• (2) Allergies: Immunogenic as haptens. fever,
itching, skin rash. Stevens-Johnson syndrome
is less frequent (arthralgia and myalgia,
redness to blistering of skin, weakness).
• (3) Blood dyscrasias: Acute hemolytic anemia,
Sometimes
hypersensitivity
or G-6-P
dehydrogenase
deficiency
in
RBCs;
Agranulocytosis; thrombocytopenia.
• (4) kernicterus.
• (5) Hepatic injury.
• Resistance:
• (1) Plasmid-borne and mutations, Change in
organism's DHPt synthase to decrease
affinity for sulfa
• (2) Increased PABA -- Some resistant
staphylococci produce 70 times as much as
susceptible parent strains.
• (3) Decreased permeability.
Properties and Usages of
commonly used sulfa
• (1) Systemic using sulfa:
• Sulfafurazole (SIZ) and sulfadimidine
(SM2): Short acting sulfonamides.
• Sulfadiazine (SD) and sulfamethoxazole
(SMZ): Median acting sulfonamides. SD
has the best distribution in CSF, 50%~80%
of plasma concentration. SMZ has less
concentration in CSF, but more solubility.
• Sulfamonomethoxine (SMM): Long acting
sulfonamides.
• (2) Topical using sulfa:
• Sulfasalazine, mafenide (SML),
sulfadiazine silver, sulfacetamide.
• (3) Combination of TMPSulfamethoxazole: co-trimoxazole.
Clinical use: (a) Urinary tract infections; (b)
Salmonella typhi and salmonella paratyphi
infection, and gastrointestinal infections. (c)
Bacterial respiratory tract infections, e.g.,
acute exacerbations of chronic bronchitis; (d)
Acute otitis media in children.
Other synthetic antimicrobial
agents
• Trimethoprim (TMP)
• Antimicrobial activity: It has similar
antimicrobial spectrum with sulfonamides,
but efficacy is 20~100 fold of sulfa.
• Mechanisms: see sulfonamides
• Clinical uses: often combination with
sulfamethoxazole (SMZ), similar
indications with sulfonamides. (The end)