Transcript ANTIBIOTICS Lector prof. Posokhova K.A.

ANTIBIOTICS
Lector prof. Posokhova K.A.
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
superbugs
microorganisms with multiply resistance
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MRSA - methicillin/oxacillin-resistant
Staphylococcus aureus
VISA - vancomycin intermediate resistant
Staphylococcі
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases
(microorganisms – resistant to cephalosporins and
monobactams)
PRSP - penicillin-resistant Streptococcus pneumoniae
1952 – 100 % Staphylococcus infections were cured by penicillin
1982 – only 10 % infections
At nowadays ?........
MRSA causes 19 000 deaths annually in USA (more than VIL)
Principles of rational antibiotic
therapy
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Presence of substantiated indications for
prescription of an antibiotic
Choosing of the most effective and the least toxic
drug, in time administration
Introduction of optimal doses with optimal
frequency, taking into consideration complexity of
the disease
Choosing of the optimal way of introduction
Estimation of duration of treatment
Control after treatment
Monitoring and prophylaxis of negative side effects
Decision on expediency of combined antibiotic
therapy
ANTIBIOTICS
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Beta-lactam antibiotics:
А. Penicillins
Б. Inhibitors of beta-lactamases and combined 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 locus 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 i.v. infusion or 3-6
times/24h)
Aminoglycosides
Fluoroqinolones
Metronidazol
Amphotericin B
Beta-lactames
Glycopeptides
Macrolides
Linkozamides
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:
1 antistaphylococci penicillinase resistant penicillins –
izoxazolil-penicillins (oxacillin, dicloxacillin, methicillin);
2 of a spread spectrum – aminopenicillins (ampicillin,
amoxicillin);
3 antipseudomonade – carboxypenicillins (carbenicillin,
ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin);
4 combined 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
cell-wall 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
schemes on introduction of biosynthetic penicillins
Antibiotic, way of
introduciton
One time dose
Frequency of
introduction
Benzylpenicillini
0,5-2 mln U (till 10 Every 4-6 hours
sodium salt,
i.m., mln)
(every
i.v.
6 hours)
Benzatyn
benzylpenicillin
(bicillin-1), i.m.
0,3-0,6 mln U
1,2 mln U
1 time/week
1 time/2 weeks
Bicillin-3, i.m.
0,6 mln U
1 time/week
Bicillin-5, i.m.
1,5 mln U
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
semisynthetic 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, destroyed 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
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+
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+
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
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)
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
Injection
Cefaloridin
Cefadroxil*
Cefazolin*
Cefalexin*
Cephradin*
Cefamandole* Cefotaxime*
Cefpirome*
Cefoxytyn*
Ceftriaxone*
Cefepime*
Cefuroxime* Cefoperazone*
Ceftazidime*
Oral
Cephalexin *
Cefadroxil*
Cefuroxime
axetyl*
Cefaclor *
Cefixime *
Ceftibuten *
fourth IV
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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
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-
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+/-
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+
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+
+
ІV
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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, seizures, coma)
Cephalosporines
Not recommended
to combine with other nephrotoxic drugs
(aminoglycosides)
Contraindicated
to combine with loop diuretics (furosemid,
etacrinic acid)
Monobactams
Aztreonam
Action spectrum - Gram (-) bacteria, including
Escherichia coli, Clebsiellas, Proteus, 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 tract, 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
Gram (-) bacteria, including those which
produce beta-lactamase
Classificaion of macrolides
І. Natural substances: erythromycin,
oleandomycin, spiramycin,
jozamycin, midecamycin.
ІІ. Semi-synthetic substances:
roxythromycin, clarithromycin,
flurythromycin, dyrythromycin,
miokamycin, rokitamycin.
III. Azalides (neutrogen atom is
introduced in lacton ring):
azithromycin.
Erythromycin
Macropen (midecamycin)
Sumamed (azithromycin)
spectrum of action of maclrolides
and azalides
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staphylo-, strepto-, hono-, anaerobe cocci,
enterobacteria
 H.influenzae (clarythromycin, azithromycin)
 intracellular situated microorganisms (strains
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 concentration 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, gynecological infections,
skin and soft tissues infections; ulcer
disease; dyphteria; whooping-cough;
honorrhea; syphilis; typhoid fever
(azithromycin).
Drugs of choice for: mycoplasma, chlamidia,
legionella pneumonia
Side affects of macrolides
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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
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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
 A lot of side effects
Linkomycini
hydrochloridum
Dalacyn C (clindamycini
hydrochloridum)
Tetracyclines
1. Natural - biosynthetic:
chlortetracycline, oxytetracycline,
tetracycline,
dimethylchlortetracycline.
2. Semisynthetic:
doxycycline (vibramycin), metacycline
(rondomycin), minocycline.
Tetracycline
Doxycycline
Vibramycin (doxycycline)
Shemes of tetracyclines
administration
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Tetracycline - 0,25-0,5 g 4 times per 24
hours
 Methacycline – 0,3-0,6 g 2 times per 24
hours
 Doxycycline – 0,2 g (first day), 0,1g (next
days) 1 time per 24 hours
Pharmacokinetics of tetracyclines when combined with
other drugs
Drugs
Results of combined administration
Antacides (Ca+, Mg+
etc.)
Decrease of absorbtion
Iron preparations
Decrease of absorbtion
Rifampicin
Increase of elimination
Side effects of tetracyclines
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Dispeptic disorders, stomatitis, glositis,esophagitis,
pruritus etc).
 Disbacteriosis and superinfection with Candida fungi,
proteus, pseudomonadas or staphylococci.
 Photodermatosis.
 Liver toxicity.
 Absorbtion by bones and teeth of a featus or a child:
hipoplasia of dental enamel, disorder of teeth
formation, tendency for caries.
 Antianabolic action, damage of kidneys (when using
tetracyclines with long termed storage, using big
doses).
Tetracyclines are forbidden for children under the age of
8/12, during pregnancy, liver diseases, kidney
insufficiency, miastenia
Photosensitization - tetracyclines
tetracyclines
AMINOGLYCOSIDES
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І generation: streptomycin,
neomycin, monomycin, kanamycin
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ІІ generation: gentamycin
(garamycin), tobramycin, syzomycin
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ІІІ generation: netilmycin
(netromycin), amikacin.
Gentamycin
spectrum of action of aminoglycosides
wide
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gram-negative bacteria (escherichia coli,
salmonella, klebsiella, especially K.
рneumoniae, proteus, iersinia, brucella,
campilobacteria, helicobacters, serratsia,
shigella etc.).
 some gram-positive microorganisms,
including staphylococci which are resistant
to other antibiotics
Indications for usage of aminoglycosides
- at the beginning stage of infectious processes of unknown
ethiology and severe complexity (combined with betalactamase);
- considerable purulent-inflammatory component of heavy
infections (peritonitis, sepsis, mediastinitis, abscesses and
flegmones of soft tissues);
- acute attack of chronical purulent-inflammatory diseases,
including secondary immune defficiency;
- early stage of development of secondary bacterial
meningitis;
- bacterial endocarditis;
- infections of urinary tracts;
- for prophilaxis of postoperative pustural complications
(combined with beta-lactamase antibiotics, metronidazole
or other antianaerobe drugs);
- skin infections and subcutaneous fat tissue infections, burns.
Concentration of aminoglycosides in
blood should not overcome:
kanamycin –
35-40 mkg/ml
 Gentamicin, tobramycin –
10-12 mkg/ml
 Amikacin,
Complications in administration of
aminoglycosides
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Ototoxicity
Nephrotoxicity
Neurotoxicity
According to extent of toxicity
netilmicin < gentamicin <tobramycin <
amikacin < neomycin < streptomycin <
monomycin < kanamycin
Leuko-, thrombocytopenia, hemmorhages,
hemolisis
Allergic reactions
Chloramphenicol –
levomycetin
Indications:
meningitis, typhoid fever, paratyphoid fever,
brucellosis, tularemia
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Side effects:
Hypochrome and aplastic anemia
Granulocytopenia, thrombocytopenia
«Grey syndrome of a featus»
Disbacteriosis and superinfection
Glycopeptide antibiotics
Vankomycin, Teikoplanin
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Active towards МRS і MRCNS
 Drugs of choice for
C. difficile - associated colitis