Download Doctrine about Antibiotics

Chair of Medical biology, Microbiology, Virology,
and Immunology
Doctrine about antibiotics.
Antimicrobial chemotherapy.
Clinical use of antibiotics
Lecturer Prof. S.I. Klymnyuk
Lectures schedule
1. History of antibiotics discovery.
2. Classification of antibiotics.
3. Examination of bacterial susceptibility to
antibiotics.
Complication of antibioticotherapy.
- Diarrheal diseases - 4 billions cases,
- Malaria - 500 mln,
- acute infection of respiratory tract - 395 mln,
- sexual transmitted diseases - 330 mln,
- measles - 42 mln,
- whooping cough - 40 mln
- tuberculosis – 1,9 bln of infected persons,
9 mln of new cases of diseases
- AIDS – 50 mln cases, 6 mln people died
- SARS, hemorrhagic fever
The earliest evidence of successful
chemotherapy is from ancient Peru, where the
Indians used bark from the cinchona tree to
treat malaria. Other substances were used in
ancient China, and we now know that many of
the poultices used by primitive peoples
contained antibacterial and antifungal
substances. Modern chemotherapy has been
dated to the work of Paul Ehrlich in
Germany, who sought systematically to
discover
effective
agents
to
treat
trypanosomiasis and syphilis. He discovered
p-rosaniline, which has antitrypanosomal
effects, and arsphenamine, which is effective
against syphilis. Ehrlich postulated that it
would be possible to find chemicals that were
selectively toxic for parasites but not toxic to
humans.
This idea has
been called the
"magic bullet"
concept
It had little success until the
1930s, when Gerhard Domagk
discovered the protective effects
of prontosil, the forerunner of
sulfonamide. Ironically, penicillin
G was discovered fortuitously in
1929 by Fleming, who did not
initially appreciate the magnitude
of his discovery. In 1944
Waksman isolated streptomycin
and subsequently found agents
such
as
chloramphenicol,
tetracyclines, and erythromycin in
soil samples.
A. Fleming
In 1939 Florey and colleagues at Oxford University again
isolated penicillin
G. Florey
E. Chainy
S. Waksman
Antibiotics are chemical substances
produced by microorganisms (such as
bacteria, fungi, actinomyces) or other
organisms which suppress the growth of
other microorganisms and eventually
destroy them. Some antibiotics have been
produced by chemical synthesis or semisynthetically from natural substances.
Microbial antagonism is the basis of modern use
of antibiotics
L. Pasteur
The term “antibiotics” proposed in 1942 S. Waksman
It means: anti – against, bios - life
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in
International Unit
Classification of antibiotics according to
their origin
1. Antibiotics from fungi:
Penicillins (Penicillium notatum, P. chryzogenum),
Cephalosporins (Cephalosporium
salmosynnematum),
Griseofulvinum (P. griseofulvum, P. patulum,
P. nigricans),
Fusidin (Fusidium coccineum),
Antibiotics from Actinomyces: а) Aminoglicosides:
Streptomycin (Streptomyces griseus), neomycin (S. fradiae),
kanamycin (S. kanamyseticus), tobramycin (S. tenebrarius),
gentamycin (Micromonospora purpurea), sisomicin
(Micromonospora inyoensis);
б) Tetracyclines: chlortetracycline (S. aureofaciens),
oxytetracycline (S. rimosus);
в) Chloramphenicol (S. venezuelae);
г) Macrolides: oleandomycin, (S. antibioticus), erythromycin (S.
erythreus),
д) Linkomycin (S. lincolniensis); е) Rifampicin (S. mediterranei);
є) Polyenes: nystatin (S. noursei), levorin (S. levorys Krass),
amphotericin B (S. nodosus);
ж) Inhibitors of beta-lactamases: klavulanic acid (S.
clavuligerus), Carbapenem (S. olivaceus), thienamycin
(S. cattleya).
3. Antibiotics from bacteria: а) Bacillus:
polymyxin (B. polymyxa), licheniformin (B.
licheniformis), gramicidin С (B. brevis), subtilin
(B. subtilis);
б) Pseudomonas: piocianin (P. aeruginosa),
sorbistin (P. sorbistini),
в) other bacteria: monobactams
(Chromobacterium violaceum), nisin
(Streptococcus lactis), prodigiosin (Serratia
marcescens), coliformin (E. coli), streptosin,
diplococcin (штами Streptococcus), azomycin,
nocardamin (nocardia)
Antibiotics from plants
а) Chorellin (Chlorella vulgaris);
в) Arenarin (Helichrysum arenarium);
c) Gordecin (barley);
d) Chinin (cinchona tree);
e) Alicin (garlic, Allium sativum);
f) Raphanin (radish, Raphanus sativum);
g) Phaseolin (haricot bean, Phaseolus vulgaris).
5. Antibiotics from animal tissues:
а) interferons (spleen, macrophages, tissue
cells),
б) lysozyme (most body fluid, salive, eggs);
в) erythrin (red cells, liver);
г) ecmolin (fish)
Classification of antibiotics according to the
spectrum of biological action
1. Antibacterial:
А. Narrow spectrum of action which are active against grampositive bacteria: а) natural Penicillins; b) semi-synthetic
Penicillins (methicillin, oxacillin); c) Cephalosporins
d) Lincomycin; е) Macrolodes.
Б. Broad spectrum of action а) semi-synthetic Penicillins
(Ampicillin, Amoxicillin); b) Cephalocporins of ІІ-IV
generation;
c) Tetracyclines; d) Chloramphenocol;
e) Aminoglycosides;
f) Polymixins; g) Fluoride quinolones
2. Antifungal (amphotericin).
3. Antiviral (amantadin, vidarabin).
4. Antiprotozoal (emethin, хінін, фумагілін).
5. Antineoplastic (bleomycin, mitomycin C,
actinomycines).
Antimicrobial agents may be either bactericidal, killing
the target bacterium or fungus, or bacteriostatic,
inhibiting its growth.
Bactericidal agents are more effective, but bacteriostatic
agents can be extremely beneficial since they permit the
normal defenses of the host to destroy the
microorganisms.
Antibacterial drugs
Beta-lactam antibiotics
A. Penicillins
B. Beta-lactamase inhibitors
C. Cephalosporins
D. Thienamycins (carbapenems)
E. Monobactams (monocyclic beta-lactams)
F. Some pharmacokinetic aspects of beta-lactam
antibiotics
G. Adverse reactions of beta-lactam antibiotics
H. Interactions of beta-lactam antibiotics
I. Aminoglycosides and polymyxins
A. Aminoglycosides
B. Polymyxins
J. Macrolides, lincomycin and clindamycin
A. Macrolides
B. Lincomycin and clindamycin
K. Tetracyclines and chloramphenicol
A. Tetracyclines
B. Chloramphenicol
L. Glycopeptides and fusidanes
A. Vancomycin
B. Fusidic acid
L. Rifamycins
M. Fosfomycin
O. Sulfonamides and trimethoprim
P. The new quinolones
Q. Nitroimidazoles
R. Antifungal agents
S. Antiviral agents
Basic structures of ß-lactam antibiotics
Vancomycin interrupts cell wall synthesis by
forming a complex with the C-terminal D-alanine
residues of peptidoglycan precursors
Diagrammatic representation of inhibition sites of
protein biosynthesis by various antibiotics that bind to
the 30S and 50S ribosomes
Examination of susceptibility of bacteria to
antibiotics
serial dilutions:
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
- to be standard and provide
conditions for microbial growth;
optimal
 do not have inhibitors of bacterial growth
and a lot of stimulators;
 do not have substances, which inhibit
antibiotic activity
Disc diffusion method
Serial dilution in liquid medium
Serial dilution in solid medium
Rapid methods
 examination of changes of microbial enzymes activity
under the influence of antibiotics;
 examination of color of redox-indicators;
 cytological evaluation of morphological changes;
 automatic
Automatic metod of examination of bacterial
susceptibility
General principles
1. The first question to ask before prescribing an
antibiotic is whether its use is really necessary. There is
no point in prescribing it if, for instance, the disease is not
due to an infection (fever does not always indicate the
presence of an infection), or if the infection is due to
agents such as viruses, which do not respond to
antibiotics.
All therapy is a calculated risk in which the probable
benefits must outweigh the drawbacks, and antibiotics are
no exception to this rule. To use them when they are not
indicated and when the "probable benefits" are nonexistent means exposing the patient to the risk of adverse
reactions, or worse.
2. Patients with similar infections react differently.
This may be due to previous contact with the same
pathogen or to the individual immune response. The
presence of hepatic or renal disease may necessitate
changes in the dosage or the choice of antibiotic.
Knowledge of any past adverse reactions to
antibiotics is also essential.
3. The doctor must be familiar with the typical
response of infections to proper antibiotic treatment.
Acute infection with group A streptococci or
pneumococci responds rapidly (usually within 48
hours) to penicillin G, while the temperature curve in
typhoid fever treated with chloramphenicol may not
show any change for four or five days.
4.
The doctor must know which bacteria are
commonly found in which situations, for instance
Pseudomonas in extensive burns (sepsis is frequent
and often fatal) and in the expectoration of children
with cystic fibrosis, or Streptococcus pneumoniae and
Haemophilus influenzae in chronic bronchitis of the
adult.
5. Ideally, treatment with antibiotics should not be
instituted before samples for sensitivity testing have
been collected. Such tests can be dispensed with,
however, when the causative organism is known and
its response to the antibiotic is predictable. But the
sensitivity of, for instance, many gram-negative
strains can change, even during treatment, making an
alternative treatment necessary. In addition, the
clinical results may be at odds with the findings of the
sensitivity tests. Even a severe infection may show a
satisfactory clinical response despite apparent lack of
sensitivity.
Failure of antibiotic therapy
Antibiotic treatment is considered a failure if no response is seen
within three days. Failure may be due to various causes:
1. Wrong diagnosis (a viral infection does not respond to antibiotics).
2. Wrong choice of antibiotic.
3. Wrong dosage (wrongly dosed by doctor or poor patient
compliance).
4. Development of resistance during therapy (as sometimes occurs
in tuberculosis and infections due to gram-negative pathogens).
5. Superinfection by resistant bacteria.
6. Accumulation of pus necessitating surgical drainage (buttock
abscess).
7. Underlying disease (lymphoma, neoplasia) of which the infection
is only an intercurrent complication.
8. Drug fever.
Secondary action of antibiotics
І. Allergic reactions
- dangerous for life (anaphylactic shock, angioneurotic
oedema of larynx)
- non-dangerous for life (skin itching, urticaria, rash, rhinitis,
glossitis, conjunctivitis, photodermatoses (tetracyclines)
ІІ. Toxic reactions
- dangerous for life (agranulocytosis, aplastic anemia,
endotoxic shock)
- non-dangerous (neuritis of N. vestibularis and N. auricularis
- aminoglycosides; periferal neuritis, vomiting, nausea, diarrhea,
hepatotoxic and nephrotoxic effects, embriotoxic effect
(pigmentation of the teeth)
ІІІ. Dysbacteriosis
- dangerous for life
(generalized candidiases sepsis,
staphylococcal enterocolitis, secondary pneumonia, which
cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Mechanisms of Resistance
Types of resistance
Natural resistance
Acquired resistanse
- primary
- secondary
R-Plasmids
Resistance transfer factors, or RTFs
Transposons
Staphylococci, Enterobacteria – transposon Tn551
(erythromycin),
Tn552
(penicillin),
Tn554
(erythromycin, spectinomycin). They can integrate
with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance.
Proper selection of new antibiotics will be a major force
in slowing the development of antimicrobial resistance.
Proper hygiene practices will reduce plasmid transfer
and the establishment of multiple drug-resistant
bacteria in the hospital and will delay the appearance
of such species in the community. There are a number
of mechanisms to prevent bacterial resistance. The
health care provider must be continually alert to the
appearance of antibiotic resistance within the hospital
and community.