Download 14 Antibiotics-1. Antibiotics

ANTIBIOTICS-1
Bacteria Shapes
(a) Round cocci
(b) Rod-like bacilli
(c) Spiral-shaped spirochetes
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
Some clinically important antibiotics
Antibiotic
Producer organism
Activity
Site or mode of action
Penicillin
Penicillium chrysogenum
Gram-positive bacteria
Wall synthesis
Cephalosporin
Cephalosporium acremonium
Broad spectrum
Wall synthesis
Griseofulvin
Penicillium griseofulvum
Dermatophytic fungi
Microtubules
Bacitracin
Bacillus subtilis
Gram-positive bacteria
Wall synthesis
Polymyxin B
Bacillus polymyxa
Gram-negative bacteria
Cell membrane
Amphotericin B
Streptomyces nodosus
Fungi
Cell membrane
Erythromycin
Streptomyces erythreus
Gram-positive bacteria
Protein synthesis
Neomycin
Streptomyces fradiae
Broad spectrum
Protein synthesis
Streptomycin
Streptomyces griseus
Gram-negative bacteria
Protein synthesis
Tetracycline
Streptomyces rimosus
Broad spectrum
Protein synthesis
Vancomycin
Streptomyces orientalis
Gram-positive bacteria
Protein synthesis
Gentamicin
Micromonospora purpurea
Broad spectrum
Protein synthesis
Rifamycin
Streptomyces mediterranei
Tuberculosis
Protein synthesis
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
-
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
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+/-
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-
ІІ
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+
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+/-
ІІІ
+
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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)
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
ANTIBIOTICS -2
Classification 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
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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
12-20 times, they get accumulated in source
of inflammation - macrolides paradoxis
Side affects of macrolides
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
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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
 A lot of side effects
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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
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
Concentration of aminoglycosides in
blood should not overcome:
Amikacin, kanamycin –
35-40 mkg/ml
 Gentamicin, tobramycin –
10-12 mkg/ml
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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
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Leuko-, thrombocytopenia, hemmorhages,
hemolisis
Allergic reactions
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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
Sulfonamides
One of the first groups of antibасterial agents
 sulfadiazine
 sulfamethizole
 sulfamethoxazole
 sulfisoxazole
Sulfonamides: Mechanism of
Action
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Bacteriostatic action
 Prevent synthesis of folic acid required for
synthesis of purines and nucleic acid
 Does not affect human cells or certain
bacteria—they can use preformed folic acid
Structure of sulfonamides
para-Aminobenzoic acid
sulfonamide
Classification of sulfonamides
(accordingly to duration of action)
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Short action: streptocid, sulfadimezine, aethazole,
norsulfazole, urosulfan, sulfizoxazole, sulfacyl-sodium
 Medium duration of action: sulfamethoxazole (is a part
of co-trimoxazole)
 Longlasting action: sulfadimethoxyn, sulfapirydazin,
sulfamonomethoxyn
 Super longlasting action: sulfalen, sulfadoxyn (is a part
of fansidar)
Sulfonamides: sulfamethoxazole
Therapeutic Uses
Azo-Gantanol
 Combined
with phenazopyridine
(an analgesic-anesthetic that affects the mucosa
of the urinary tract).
 Used to treat urinary tract infections (UTIs) and
to reduce the pain associated with UTIs.
Bactrim
 Combined
with trimethoprim.
 Used to treat UTIs, Pneumocystis carinii
pneumonia, ear infections, bronchitis, gonorrhea,
etc.
Co-trimoxazole (Bactrim)
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480 - for adults
 960 - for adults
 120 – for children
 240 – for children
Orally 2 times daily
Co-trimoxazole = Bactrim (trimethoprim +
sulfamethoxazole)
Sulfonamides: sulfisoxazole
Therapeutic Uses
Azo-Gantrisin
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Combined with phenazopyridine
 Used for UTIs
Pediazole
 Combined with erythromycin
 Used to treat otitis media
Sulfonamides: Side Effects
Body System
Effect
Blood
Hemolytic and aplastic
anemia, thrombocytopenia
Photosensitivity, exfoliative
dermatitis, Stevenssyndrome, epidermal
necrolysis
Integumentary
Johnson
Sulfonamides: Side Effects
Body System
Effect
GI
diarrhea,
Other
Nausea, vomiting,
pancreatitis
Convulsions, crystalluria,
toxic nephrosis, headache,
peripheral neuritis,
urticaria
Sulfonamides’ Dispensing
Issues
 Avoid
the sun
 Maintain adequate fluid intake