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Chair of Medical biology, Microbiology, Virology,
and Immunology
Doctrine about antibiotics.
Antimicrobial Chemotherapy.
Clinical use of antibiotics
Lecturer As. Prof. O.V. Pokryshko
Lecture 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
Tremendous quantities of antibiotics are
produced and released into the
environment.
90 – 180 million kg/year of antibiotics are
used (enough for 25 BILLION full
treatment courses ~ 4 per human/yr!)
About 10 X more antibiotics are used in
agriculture than to treat people. (Levy
1997 estimated 30 X more in animals than
in people).
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
Paul
Ehrlich
“Magic bullet" concept
Sulfonamides
• Analogues of para-aminobenzoic
acid
• Broad spectrum
• Competitive inhibitors of
dihydropteroate synthase –
needed for folic acid synthesis
• Cidal in urine
• Mechanisms of resistance
Gerhard Domagk gets a
Nobel for Medicine, 1939.
– Altered affinity of enzyme for drug
– Decreased permeability or active
efflux
– New pathway of folic acid synthesis
It had little success until the 1930s,
when Gerhard Domagk discovered the
protective effects of prontosil, the
forerunner of sulfonamide.
Sir A. Fleming and Penicillin
Ironically, penicillin G was discovered fortuitously in 1929 by Fleming,
who did not initially appreciate the magnitude of his discovery.
Sir A. Fleming
In 1939 Florey and colleagues at Oxford University again
isolated penicillin
G. Florey
E. Chainy
S. Waksman
In 1944 S. Waksman
isolated streptomycin
and subsequently
found agents such as
chloramphenicol,
tetracyclines, and
erythromycin in soil
samples.
What are Antibiotics?
• Antibiotics means: anti – against, bios – life =
• “against life”
The term “antibiotics” was proposed in 1942 by S.
Waksman
• Antibiotics are molecules that stop microbes, both
bacteria, viruses, protpzoa, and fungi, from growing
or kill them outright.
• Antibiotics can be either natural products or manmade synthetic chemicals.
Microbial antagonism is the basis of modern use
of antibiotics
L. Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit or
Вµg/ml
Spectrum – range of
activity of a drug
Narrow-spectrum –
effective on a small
range of microbes
target a
specific cell
component
that is found
only in certain
microbes
Broad-spectrum –
greatest range of
activity
target cell
components
common to
most
pathogens
Antimicrobial agents may be either:
Bacteriostatic
Bactericidal
Bacteriostatic antibiotics inhibit
growth and reproduction of
bacteria without killing them.
Bacteriostatic agents must work
with the immune system to remove
the microorganisms from the body.
Bacteriostatic antibiotics hamper
the growth of bacteria by
interfering with bacterial:
Protein production
DNA replication
Cellular metabolism
A bacteriocide is a substance that
kills the bacteria of choice and,
preferably, nothing else.
Microbe death is usually achieved
by disruption of the bacterial cell
membrane leading to lysis.
E.g.:
Penicillins, Cephalosporins
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
Targets of antimicrobial drugs
1. Inhibition of cell
wall synthesis
2. Disruption of cell
membrane structure
or function
3. Inhibition of nucleic
acid synthesis,
structure or function
4. Inhibition of protein
synthesis
5. Inhibition of folic
acid synthesis
Drugs that affect the bacterial cell wall
• Most bacterial cell walls contain a
rigid girdle of peptidoglycan.
• Penicillin and cephalosporin block
synthesis of peptidoglycan, causing
the cell wall to lyse.
• Penicillins do not penetrate the
outer membrane and are less
effective against gram-negative
bacteria.
• Broad spectrum penicillins and
cephalosporins can cross the cell
walls of gram-negative bacteria.
Other Inhibitors of Cell Wall
Synthesis
• Antibiotics effective
against Mycobacteria:
interfere with mycolic
acid synthesis or
incorporation
– Isoniazid (INH)
– Ethambutol
Drugs that disrupt cell membrane function
• A cell with a damaged
membrane dies from
disruption in metabolism or
lysis.
• These drugs have specificity
for a particular microbial
group, based on differences
in types of lipids in their cell
membranes.
• Polymyxins interact with
phospholipids and cause
leakage, particularly in
gram-negative bacteria
• Amphotericin B and
nystatin form complexes
with sterols on fungal
membranes which causes
Inhibitors of Nucleic Acid
Synthesis
• Rifamycin
– Inhibits RNA synthesis
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections
Drugs that inhibit nucleic acid
synthesis
• may block synthesis of nucleotides, inhibit
replication, or stop transcription
• Sulfonamides and trimethoprim block enzymes
required for tetrahydrofolate synthesis needed
for DNA & RNA synthesis.
• competitive inhibition – drug competes with
normal substrate for enzyme’s active site
• synergistic effect – an additive effect, achieved
by multiple drugs working together, requiring a
lower dose of each
Drugs that block protein synthesis
Ribosomes of eucaryotes differ in size and
structure from procaryotes, so antimicrobics
usually have a selective action against
procaryotes. But they can also damage the
eucaryotic mitochondria.
пѓ�Aminoglycosides (streptomycin, gentamicin) insert
on sites on the 30S subunit and cause misreading of
mRNA.
пѓ�Tetracyclines block attachment of tRNA on the A
acceptor site and stop further synthesis.
пѓ�Macrolides: Erythromycin (gram +, used in
children)
пѓ�Chloramphenicol
Drugs that block protein synthesis
Penicillins
• Large diverse group of compounds
• The R group is responsible for the
activity of the drug, and cleavage
of the beta-lactam ring will render
the drug inactive.
• Penicillins G and V most
important natural forms
• Penicillin is the drug of choice for
gram-positive cocci (streptococci)
and some gram-negative bacteria
(meningococci and syphilis
spirochete)
• Semisynthetic penicillins –
ampicillin, carbenicillin &
amoxicillin have broader spectra –
gram negative enterics rods
• Penicillinase-resistant –
methicillin, nafcillin, cloxacillin
• Primary problems – allergies and
resistant strains of bacteria
Cephalosporins
Isolated from Cephalosporium acremonium mold
Beta-lactam ring that can be altered
Relatively broad-spectrum, resistant to most
penicillinases, & cause fewer allergic reactions
Cephalosporins
5 generations exist
� 1st generation – cefazolin, cephalothin – most effective
against gram-positive cocci
� 2nd generation – cefuroxime, cefaclor, cefonacid –
more effective against gram-negative bacteria
� 3rd generation – ceftriaxone, cephalexin, cefotaxime –
broad-spectrum activity against enteric bacteria with
beta-lactamases
Ceftriaxone – semisynthetic broad-spectrum drug for
treating wide variety of infections
пѓ� 4th generation - cefepime
пѓ� 5th generation - ceftobiprole
пѓ� Differ in spectrum, resistance to beta lactamases,
penetration into CNS
Vancomycin (Vancocin)
пѓ� Mechanism of action
пѓ� Inhibits bacterial cell
wall synthesis
пѓ� Bactericidal?
пѓ� Spectrum
– Gram positive bacteria
– Methicillin resistant
Staphylococcus
aureus
– Clostridium difficile
(oral)
Carbapenems
• Specific agents
– Imipenem
• With cilastin (Primaxin)
– Meropenem (Merrem)
– Ertapenem (Invanz)
– Doripenem (Doribax)
• Mechanism of action
– Inhibit bacterial cell wall synthesis
– Bactericidal
– Broad spectrum
• Gram positives
• Gram negatives
• Pseudomonas (except
ertapenem
Aminoglycosides
Cmposed of 2 or more amino sugars
and an aminocyclitol (6C) ring
пѓ� products of various species of soil
actinomycetes in genera
Streptomyces & Micromonospora
пѓ� Broad-spectrum, inhibit protein
synthesis, especially useful
against aerobic gram-negative
rods & certain gram-positive
bacteria
– Streptomycin – bubonic
plague, tularemia, TB
– Gentamicin – less toxic, used
against gram-negative rods
– Tobramycin & Amikacin
gram-negative bacteria
Macrolides
Mechanism of action
– Inhibit bacterial protein synthesis
– Bacteriostatic
• Mechanism of resistance
– Decreased permeability of drug
into the microbe
– Modification of target sites
– Hydrolysis of macrolide by
bacterial enzymes
Specific agents:
Erythromycin (attaches to ribosomal 50s subunit)
Azithromycin (Zithromax)
Clarithromycin (Biaxin)
Clindamycin
• Antimicrobial spectrum
– Anaerobes
– Some gram positives
• Inhibits bacterial protein
synthesis
• Bacteriostatic
• Adverse effects
– Nausea, diarrhea
– Clostridium difficile
Tetracycline antibiotics
пѓ� Broad-spectrum, block protein synthesis
пѓ� Specific agents; Aureomycin, Terramycin,
Tetracycline, Doxycycline and Minocycline
� Doxycycline & minocycline – oral drugs taken
for STDs, Rocky Mountain spotted fever, Lyme
disease, typhus, acne & protozoa
Chloramphenicol
пѓ� Isolated from Streptomyces venezuelae
пѓ� Potent broad-spectrum drug with unique nitrobenzene
structure
пѓ� Blocks peptide bond formation
пѓ� Very toxic, restricted uses, can cause irreversible damage
to bone marrow
пѓ� Typhoid fever, brain abscesses, rickettsial & chlamydial
infections
Quinolones
Spectrum of action
Broad spectrum (varies by agent)
пѓ� Inhibit DNA synthesis - Interact with
bacterial gyrase to prevent
supercoiling during DNA synthesis;
• Targets DNA gyrase (G-) and
topoisomerase IV (G+)
пѓ� Bactericidal
пѓ� Mechanisms of resistance
– Change in target enzyme
– Change in permeability of
organism
пѓ� Specific agents
– Norfloxacin
– Ciprofloxacin
– Levofloxacin (Levaquin)
– Gatifloxacin (Tequin)
– Moxifloxacin (Avelox)
– Nalidixic acid
Spectrum of Antimicrobial Activity
Considerations in Selecting an Antimicrobial Drug
Testing for Drug Susceptibility:
The MIC and Therapeutic Index
• In vitro activity of a drug is not always correlated with in
vivo effect.
– If therapy fails, a different drug, combination of
drugs, or different administration must be considered.
• Best to choose a drug with highest level of selectivity
but lowest level toxicity – measured by therapeutic
index – the ratio of the dose of the drug that is toxic to
humans as compared to its minimum effective dose
• High index is desirable.
Examination of bacteria
susceptibility to antibiotics
пѓ� Serial dilutions:
- in a liquid medium
- in a solid medium
пѓ� Disc diffusion method
пѓ� Rapid methods
Demands to nutrient media
пѓ� to be standard and provide optimal
conditions for microbial growth;
пѓ� do not have inhibitors of bacterial
growth and a lot of stimulators;
пѓ� do not have substances, which inhibit
antibiotic activity
The Kirby-Bauer Test
Serial dilution in liquid medium
• Minimum inhibitory concentration (MIC)smallest concentration of drug that visibly
inhibits growth
• Therapeutic index – the ratio of the dose of
the drug that is toxic to humans as
compared to its minimum effective dose
Serial dilution in solid medium
Rapid methods
пѓ� examination of changes of microbial enzymes activity
under the influence of antibiotics;
пѓ� examination of redox-indicators color;
пѓ� cytological evaluation of morphological changes;
пѓ� automatic
Measuring Antimicrobial
Sensitivity
E Test
MIC: Minimal inhibitory
concentration
Automatic method of examination of bacterial
susceptibility
Considerations in selecting an
antimicrobial drug
1. Nature of microbe causing infection
2. Ddegree of microbe’s sensitivity to
various drugs
3. Overall medical condition of patient
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
non-existent 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
Р†. Allergic reactions
пѓ� dangerous for life (anaphylactic shock, angioneurotic
oedema of larynx)
пѓ� -dangerous for life
(skin itching, urticaria, rash,
rhinitis,
glossitis,
conjunctivitis,
photodermatoses
(tetracyclines)
ІІ. Toxic reactions
пѓ� dangerous for life (agranulocytosis, aplastic anemia,
endotoxic shock)
пѓ� 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)
Teeth pigmentation
Rash after rifampin treatment
ІІІ. Dysbacteriosis
пѓ�
dangerous for life
(generalized candidiases sepsis,
staphylococcal enterocolitis, secondary pneumonia, which cause
gram-negative bacteria)
пѓ�
non-dangerous for life (local candidiases)
Candidiasis
Antibiotic Resistance – What is it?
Antibiotic resistance – when bacteria
change eliminating the effectiveness of
the drug designed to cure or prevent
infection
– How it happens?
• Bacteria survive antibiotic control and continue
to multiply into resistant strains
• Sensitive “S”
• Resistant “R”
- microbe is inhibited.
- microbe unaffected.
Timeline of Antibiotic Resistance
� 1929 – Alexander Fleming
discovers the first antibiotic,
Penicillin
� 1942 – Penicillin available through
mass production
� 1954 – 2 million pounds of
antibiotics produced in the United
States annually
� 1960’s – Various resistant strains
emerging due to abused antibiotic
use
� Today – 50 million pounds of
antibiotics produced in the United There is probably no
States annually
chemotherapeutic drug to which in
suitable circumstances the bacteria
cannot react in some way acquiring
fastness (resistance)
Alexander Fleming
Antibiotic Resistance
пѓ� Innate resistance
пѓ� Acquired resistance (primary or secondary):
пѓ� Mutations of existing genes (stepwise)
пѓ� Acquisition of foreign DNA
• Plasmid exchange (conjugation, transduction)
• Transformation
• Transposons
пѓ� Clonal spread
пѓ� All promoted by antibiotic use!
Resistance Mechanisms
пѓ� Microbe lacks structure the antibiotic
attaches to
пѓ� Microbe impermeable to antibiotic
пѓ� Microbe can modify antibiotic to inactive
form (Drug inactivation – penicillinases)
пѓ� Microbe may modify the target of the
antibiotic
пѓ� Microbe may develop a resistant
biochemical pathway Microbe may pump
out an antibiotic entering the cell
Mechanisms drug resistance
Microbial Factors Selective pressure
• Mutations that render bacteria resistant to
antibiotics are random, BUT antibiotic use
provides the selective pressure that allows
mutants to become dominant.
No antibiotics
Resistance by Replication
• Resistant bacteria usually have a gene that makes
the antibiotic ineffective
– Surviving bacteria will replicate
• Bacteria have plasmids that allow genes to move
between different types of bacteria
– Bacteria that was previously susceptible to antibiotic
now have the resistant gene
• Dead bacterial cells give off DNA that can be
incorporated into living bacteria allowing it to
become resistant (transformation)
R-Plasmids
Transposons
Staphylococci, Enterobacteria – transposon Tn551
(erythromycin),
Tn552
(penicillin),
Tn554
(erythromycin, spectinomycin). They can integrate
with R-plasmids and phages
Overcoming Antibiotic Resistance
пѓ� Altering the use of existing antibiotics:
– Decrease the duration of the antibiotic so the organism
does not create resistance
– Increase the dosage of the antibiotic for a higher
concentration of drug
– Discontinue use of an antibiotic for a period of time
пѓ�Rotation of antibiotics used in treatment
– Especially useful when used with last resort treatments
пѓ�Combination of antibiotics in a treatment
– Minimizes possibility of resistance since the organism
needs two ways to get rid of antibiotics
http://www.pharmacist.com/pdf/combating_antibiotic_res_sr.pdf
Prevention of Antibiotic Resistance
пѓ� Only use an antibiotic when they are likely to be
beneficial
пѓ� Do not take an antibiotic for a viral infection like a
cold, most sore throats or flu
пѓ� Do not save any of your antibiotic prescription
пѓ� Take an antibiotic exactly as the doctor tells you
пѓ� Do not take an antibiotic that is prescribed for
someone else
Alternative Treatments for
Antibiotics
� Inhibitors that will neutralize the organism’s
ability to become resistant
пѓ� Antibiotic will attack a different site of bacteria
than normal that allows it to be effective
пѓ� Chemicals with antibiotic qualities are being
used to kill organisms
пѓ� Current antibiotics are made from microbes and fungi
пѓ� Bacteriophages (virus that attacks bacteria) are
being altered
http://www.pharmacist.com/pdf/combating_antibiotic_res_sr.pdf
The Future of Chemotherapeutic Agents
Antisense agents
– Complementary DNA or peptide
nucleic acids that binds to a
pathogen's virulence gene(s) and
prevents transcription
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