Transcript ANTIBIOTICS

ANTIBIOTICS
The problem
drug companies have little
interest in financing the testing
of their newly discovered
antibiotics, because they are
more focused on drugs that
people require daily for the rest
of their lives
Principles of rational antibiotic
therapy

Presence of substantiated indications for prescription of an
antibiotic
 Choosing of the most effective and the least toxic drug, intime
administration
 Introduction of optimal doses with optimal frequency, taking
into consideration complexity of the disease
 Choosing of the optimal way of introduction
 Estimation of treatment duration
 Control after treatment
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Monitoring and prophilactics of negative side effects
Decision on expediency of combinated antibiotic therapy
ANTIBIOTICS
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Beta-lactam antibiotics:
А. Penicillins, Б. Inhibitors of beta-lactamases and
combinated drugs,
 В. Cephalosporins
 Г. Monobactams
 Д. Tienamycin (carbapenems).
 Macrolides, azalides, streptogramins, prystinamycines.
 Linkozamides.
 Tetracyclines.
 Aminoglycosides.
 Chloramphenicols.
 Glycopeptides.
 Cyclic polipeptides (polimixins).
 Other antibiotics
ANTIBIOTICS
Dose-dependent
Time-dependent
Antibacterial effect directly
depends
on
their
concentrations in the source of
inflammation
(high doses 1-2 times/24h)
Effectiveness depends on a
period of time, during which
concentration
in
blood
overwhelms
MIC
for
a
particular causative agent
(constant infusion or 3-6
times/24h)
Beta-lactames
Glycopeptides
Macrolides
Linkozamides
Aminoglycosides
Fluoroqinolones
Metronidazol
Amphotericin B
PENICILLINS
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Natural (biosynthetic) penicillins:
benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin
V), novocain salt of benzylpenicillin (benzylpenicillin procain),
bicillin-1 (benzatyn benzylpenicillin), bicillin-3, bicillin-5.
Semisynthetic penicillins:
1antistaphylococci penicillinase resistant penicillins – izoxazolilpenicillins (oxacillin, dicloxacillin, methicillin);
2of a spread spectrum – aminopenicillins (ampicillin,
amoxicillin);
3antipseudomonade – carboxypenicillins (carbenicillin,
ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin);
56combined with inhibitors of beta-lactamases - “protected”
penicillins
(amoxicillin/clavulanate, ampicillin/sulbactam,
ticarcillin/clavulanate, piperacillin/tazobactam).
S
H2 N
CH3
CH3
T
L
O
N
C
O
OH
Nucleus of penicillin molecule
L – beta-lactame ring, T – thiazoline ring
Mechanism of penicillins action
They form complexes with enzymes - transand carboxypeptidases (PCP), which control
synthesis of peptidoglycan – component of cellwall of microorganisms
Spectrum of action of biosynthetic penicllins
Gram-positive
microorganisms
Streptococci
Bacillus anthracis
Causative agents of
tetanus, gas gangrene
Actinomycets
Listeria
Gram-negative
microorganisms
Gonococci
Meningococci
Moraxella
Causative agent of
syphilis
Leptospiras
Directing schemes on introduction og biosynthetic
penicillins
Antibiotic, way of
introduciton
One time dose
Frequency of
introduction
Benzylpenicillini
0,5-2 mln OD (till Every 4-6 hours
sodium salt,
i.m., 10 mln)
(every
i.v.
6 hours)
Benzatyn
benzylpenicillin
(bicillin-1), i.m.
0,3-0,6 mln OD
1,2 mln OD
1 time/week
1 time/2 weeks
Bicillin-3, i.m.
0,6 mln OD
1 time/week
Bicillin-5, i.m.
1,5 mln OD
1 time/week
Complications of biosynthetic
penicillins
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Allergic reactions (10 %)
Endotoxic shock
Disorders of electrolyte balance
Neurotoxic reactions (in using of big doses) –
encephalopathy (hyperreflexia, seizures,
hallucinations, coma)
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Daily dose of BP during intratecal
introduction should not overcome 10 000 U (5
000 U – for children)
 Interstitial nephritis
Oxacillin
Antistaphylococci penicillinase-resistant
halfsynthetic penicillin, acid stable
Administration: intramuscular, intravenously, oraly
3-6-8 g/24 hours (4-6 times of injections)
Spectrum of action of aminopecillins
(ampicillin, amoxicillin)
wide spectrum, destructed by beta-lactamases
.
Influence on: streptococci, Haemophilus influenzae, causative
agent of wooping cough, gonococci, meningococci, proteus,
Escherichia coli, salmonella, shigella
Ampicillin
Amoxicillin
Differences between ampicillin and amoxicillin
Parameters
Activity towdards
pneumococci
H. pylori
salmonella
shigella
Bioavailability after oral
administration
Influence of food on
bioavailability
Level in sputum
Level in urine
Appearance of diarrhea
Ampicillin
Amoxycillin
++
+
++/+++
+++
+++
+++
+++
+
40 %
90 %
dicreases in 2 times
low
high
no influence
high
very high
frequently
rarely
Indications for administration of amoxicillin
Localisation of ifection
Drug of choice
Respiratory tracts
Acute midlle otitis
Acute pharingitis
Bacterial sinusitit
Chronical bronchitis
Acute bronchitits
Extrahospital
pneumonia of light or
medium-severe
complexity
Kidneys and urinary
tracts
Acute pielonephritis
Chronical pielonephritis
Acute cystitis
Acute prostatitis
Bacteriouria in children Gonorrhea
and pregnant women
Digestive tract
Other pathology
Alternative drug
Cholangitis, cholecystitis
Typhoid fever
Borreliosis
Leptospirosis
Ampiox (ampicillin+oxacillin)
Side effects of semisynthetic
penicillins
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Irritation of mucous membrane of digestive tract
(diarrhea)
Disbacteriosis
Superinfection (colonizing of gut with Candida fungi,
enterococci, Pseudomonas aeruginosa, clostridia)
Pain in injection area, aseptical inflammation,
phlebitis
Allergic reactions
Granulocytopenia (oxacillin)
Reduction of platelets agregation (ampicillin)
Disorders of liver function
Encephalopathy (in introduction of high doses)
Inhibitors of beta-lactamases
Clavulanic acid
Sulbactam
Tazobactam
Unasyn (ampicillin/sulbactam)
Inhibitor-protected (“screened”, “protected”)
penicillins
Amoxicillin/clavulanate
(amoxyclav, augmentin, enhatsin)
Ampicillin/sulbactam
(sultamycillin, unasin)
Ticarcillin/clavulanate
(timentin)
Piperacillin/tazobactam
S
H2N
L
O
D
N
CH2
C
O
CO
O
OH
Structure of cephalosporins
L – beta-lactame ring, D – dihydrothiazine ring
CH3
Classification of cephalosporins
Way of
introduction
Generation of cephalosporin antibiotics
first I
second II
third III
fourth IV
Injection
Cefaloridin
Cefadroxil*
Cefazolin*
Cefalexin*
Cephradin*
Cefamandole*
Cefoxytyn*
Cefuroxime*
Cefotaxime*
Ceftriaxone*
Cefoperazone*
Ceftazidime*
Cefpirome*
Cefepime*
Oral
Cephalexin *
Cefadroxil*
Cefuroxime
axetyl*
Cefaclor *
Cefixime *
Ceftibuten *
-
Cefazolin-sodium (C I)
Cezolin (Cefazolin, C I)
Cefalexin ( C I)
Zinnat (Cefuroxime, C II)
Cefotaxime (C III)
Claphoran (cefotaxime, C III)
Cefobid (Cefoperazone, C III)
Antimicrobial spectrum of cephalosporins
Generation of
cephalosporins
Active towards
Grampositive
bacteria
Gramnegative
bacteria
Stability towards betalactamase
Staphylo Gramcocci
negative
bacteria
І
+++
+/-
++
-
ІІ
++
+
++
+/-
ІІІ
+
+++
+
+
ІV
++
+++
++
++
Complications, caused by
cephalosporins
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Irritation of mucous membrane of digestive tract,
infiltrates after intromuscular introduction , phlebitis
after inrtavenous introduction
Disbacteriosis, superinfection
Allergic reactions, including cross allergy with
penicillins
Granulocytopenia (in case of treatment during more
than 2 weeks)
Hemorrhages (inhibition of synthesis of factors of
blood coagulation in liver) – cephalosporins ІІІ
Nephrotoxicity (accumulation in epithilial cells of
kidney canalicules)
Encephalopathy (hyperreflexia, судоми, coma)
Cephalosporines
Not recommended
to combine with other nephrotoxic drugs
(aminoglycosides)
Contraindicated
to combine with loop diuretics (furocemid,
etacrinic acid)
Monobactams
Aetreonam
Action spectrum - Gram (-) bacteria, including
Escherichia colli, Clebsiellas, Proteum, Haemophilus
influenzae (activity is equal to the activity of cephaloporins
of third generation)
Ways of introduction: oral (20% are being absorbed),
intramuscular, intravenous
Clinical uses: sepsis, infection of urinary tracts, soft
tissues, meningitis and others (often combined with
aminoglycosides , clindamycin, metronidazole,
vankomycin).
Carbapenems (tienamytsin)
Tienam (imipenem + cylastatin)
Meropenem
The widest spectrum of antibacterial action - most
of aerobe and anaerobe Gram(+) and Gran (-)
bacteria, including those which produse betalactamase
Classificaion of
macrolides
І. Natural substances: erythromycin,
oleandomycin,spiramycin, jozamycin,
midecamycin.
ІІ. Half-synthetic substances:
rozythromycin, clarithromycin,
flurythromycin, dyrythromycin,
miokamycin, rokitamycin.
III. Azalides (neutrogen atom is
introduced in lacton ring):
azithromycin.
Erythromycin
Macropen (midecamycin)
Sumamed (azithromycin)
Action spectrum of maclrolides
and azalides

staphylo-, strepto-, hono-, anaerobe cocci,
enterobacteria
 H.influenzae (clarythromycin, azithromycin)
 intracellular situated microorganisms (stamps
of Helicobacter, Chlamydia, Legionellа, M.
pneumoniae, U. urealyticum etc.)
Pharmacokinetics of
macrolides
Quiclkly and fully distributed through the
tissues (do not pass through HEB)
Correlation tissues/blood:
 Erythromycin – (5-10) : 1
 Azithromycin – (100-500) : 1
 Their concentration in phagocyting cells
prevails concentration in blood pasma in 1220 times, they get accumulated in source of
inflammation - macrolides paradoxis
Indications for usage of macrolides and
azalides
LOR- infections, infections of upper
respiratory tracts, hynecological infection,
skin and soft tissues infections; ulcer
disease; dyphteria; whooping-cough;
honorrhea; syphilis; typhoid fever
(azithromycin).
Drugs of choice for: mycoplasma, chlamidial,
legionela pneumonia
Side affects of microlides
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Dispeptic disorders, disbacteriosis, superinfection
 Cholestasis, cholestatic jaundice (erythromycin)
 Depression of liver microsome enzyme activity
(erythromycin, oleandomycin can not be
combined with theophylline, ergot alkaloids,
carbamazepine)
 Development of resistance in process of treatment
Linkosamides
Linkomycin
Clindamycin
Action spectrum: Gram positive aerobe cocci,
grampositive and gramnegatvie anaerobes
 Penetrate all the tissues (don’t pass through
HEB) including intracellurally
 Usage: usually in heavy infections, caused by
anaerobe microorganisms
 Complicated side affects
Linkomycini
hydrochloridum