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

MRSA -

methicillin/oxacillin-resistant
Staphylococcus aureus
VISA - vancomycin intermediate resistant
Staphylococc
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
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

Beta-lactam antibiotics:
. Penicillins
. Inhibitors of beta-lactamases and combined drugs,
. Cephalosporins
. Monobactams
. 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

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

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

Bicillin-5, i.m.

1,5 mln U

1 time/week
1 time/week

Complications of biosynthetic
penicillins
Allergic reactions (10 %)
Endotoxic shock
Disorders of electrolyte balance
Neurotoxic reactions (in using of big doses)

encephalopathy (hyperreflexia, seizures,

hallucinations, coma)

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

++
+
++/+++
+++

+++
+++
+++
+

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

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

CH2
C

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*
Cefpirome*
Ceftriaxone*
Cefepime*
Cefoperazone*
Ceftazidime*

Oral

Cephalexin *
Cefadroxil*

Cefuroxime
axetyl*
Cefaclor *

Cefixime *
Ceftibuten *

Cefazolin-sodium(CI)

Cezolin(Cefazolin,CI)

Cefalexin(CI)

Zinnat(Cefuroxime,CII)

Cefotaxime(CIII)

Claphoran(cefotaxime,CIII)

Cefobid(Cefoperazone,CIII)

Antimicrobial spectrum of cephalosporins

Generation of
cephalosporins

Active towards
Grampositive
bacteria

Gramnegative
bacteria

Stability towards betalactamase

Staphylo
cocci

Gramnegative
bacteria

+++

+/-

++

++

++

+/-

+++

++

+++

++

++

Complications, caused by
cephalosporins

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
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
. Natural substances: erythromycin,
oleandomycin, spiramycin,
jozamycin, midecamycin.
. 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
staphylo-,

strepto-, hono-, anaerobe cocci,

enterobacteria
H.influenzae (clarythromycin, azithromycin)
intracellular situated microorganisms (strains
of Helicobacter, Chlamydia, Legionell,
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
12-20 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

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 (dont 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
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

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
generation:

streptomycin,
neomycin, monomycin, kanamycin

generation:

gentamycin
(garamycin), tobramycin, syzomycin

generation:

netilmycin
(netromycin), amikacin.

Gentamycin

spectrum of action of aminoglycosides

wide
gram-negative

bacteria (escherichia coli,

salmonella, klebsiella, especially K.
neumoniae, 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:
Amikacin, kanamycin

35-40 mkg/ml
Gentamicin, tobramycin
10-12 mkg/ml

Complications in administration of
aminoglycosides

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
Side effects:
Hypochrome and aplastic anemia
Granulocytopenia, thrombocytopenia
Grey syndrome of a featus
Disbacteriosis and superinfection

Glycopeptide antibiotics
Vankomycin, Teikoplanin
Active towards RS

MRCNS
Drugs of choice for
C. difficile - associated colitis