CHEMOTHERAPY
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Antibiotics
Classification of antibacterial agents
General principles of antibacterial therapy
Antibiotic susceptibility testing
Bacterial resistance to antibacterial agents
Interferon and antiviral agents
ANTIBIOTICS (DEFINITIONS)
• Antibiotics (anti-against,
bios-life)
are
the
substances able to inhibit
microorganisms.
• Antibacterial agents are
any compounds natural,
synthetic,
or
semisynthetic that are clinically
useful in the treatment of
bacterial infections.
Antibiotics acting
on bacteria
causing them to
expand and burst
ANTIBIOTICS
• Bacteriostatic
agents
(sulfonamides,
chloramphenicol) inhibit bacterial growth
• Bacteriocidal
agents
(penicillin,
streptomycin) significantly reduce the
number of viable bacteria in the culture.
Bactericidal agents generally kill only
growing organisms
ANTIBIOTICS
• Narrow spectrum antibacterial agents are
preferentially active against other Gram +
or Gram- bacteria
• Broad-spectrum antibacterial agents are
active against Gr+ and Gr- bacteria
THE ACTIVITY OF ANTIBIOTICS
• The activity of antibiotics is expressed in
international unit (IU). IU of penicillin (oxford unit) is
the smallest amount of preparation inhibiting the
growth of a standard S. aureus strain.
• One unit of activity (A.U.) corresponds to the
activity of 0.6 micrograms (mg) of the chemically pure
crystalline sodium salt of benzylpenicillin.
Classification of antibacterial agents
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1. According to origin
Antibiotics produced by:
– Fungi - Penicillins
– Actinomycetes – Streptomycin, Erythromycin,
Tetracycline
– Bacteria - Gramicidins
Semisynthetic antibiotics: Ampicillin, Oxicillin
Sulfonamides
Derivatives of imidazoles: Metronidazole
Quinolones: Norfloxacin, Abactal, Ofloxacin
Derivative of pyrimidine: Trimethoprim
Derivatives of Arsenic (As), Bismuth (Bi), Mercury
(Ar), Acridine.
Classification of antibacterial agents
2. On the of chemical composition
• Beta-lactams: Penicillins, Cephalosporins
• Derivatives of dioxiaminophenilpropan:
Levomycetin (Chloramphenicol)
• Tetracyclines
• Aminoglycosides: Gentamicin
• Macrolides: Erythromycin
• Acyclic antibiotics: Nistatin
• Lincosamides: Lincomycin
Classification of antibacterial agents
A. Inhibitors cell wall synthesis
• B-lactams (Penicillins, Cephalosporins)
• Other inhibitors of bacterial cell wall
synthesis: Cycloserine, Vancomycin,
Bacitracin
B. Inhibitors nucleotide synthesis
• Sulfonamides: Trimethoprim, Sulfamethoxazole-trimethoprim.
Classification of antibacterial agents
C. Inhibitors nucleic acid synthesis
• DNA synthesis inhibitors: Novobiocin,
Quinolones, Nitroimidazoles (Metronidazole)
• RNA synthesis inhibitors: Rifampin
D. Inhibitors protein synthesis
• Inhibitors of the 30 s ribosomal unit:
Aminoglycosides, Tetracyclines
• Inhibitors of the 50 s ribosomal unit:
Chloramphenicol, Macrolide (Erythromycin,
Clarithromycin), Lincomycin
General principles of effective
antibacterial therapy
1.The choice of antibacterial agent should
be based on susceptibility
2.When the infection is life-threatening or
when early treatment is extremely
important, treatment is initiated with
broad-spectrum
antibiotics
without
detection susceptibility
General principles of effective
antibacterial therapy
3. Early treatment usually involves
short-term therapy, which has the
advantage
of
reducing
the
possibility of superinfection.
4. Infections of poorly vascularized
tissues
(e.g.
Endocarditis,
Osteomyelitis) should be treated
with bactericidal antibiotics.
Antibiotic susceptibility testing
Antibiotic susceptibility testing allows the
choice of the best antibiotic with the
narrowest
spectrum
and
highest
effectiveness against the isolated bacteria
1. Tube dilution test
2. The agar diffusion test (Bauer-Kirby
test)
3. E-test method
4. Automated tests
Definition of MIC by Tube Dilution Test
• Minimal inhibitory concentration (MIC) is the
lowest concentration of an antibiotic that will inhibit
the growth of a microorganism.
Interpretation of Tube Dilution Test
• A bacterium is considered clinically
susceptible to a given antibiotic if a blood
level 2-4 times the MIC can be attained with
the usual dosages and no appreciable side
effects
Kirby - Bauer technique
• Broth culture of an isolated bacterium is spread
into an agar plate and paper disks impregnated
with known concentration of different antibiotics are dropped on the surface of the seeded
plate
Antibiotic susceptibility testing plate
• You should measure the diameter of zones of
inhibition in millimeters. The zone seen here
measures 20 mm in diameter
Interpretation
of Disc Diffusion Test
Inhibition zone diameter (in mm)
Drug
Ampicillin
Disk
concentration
10 mcg
Resistant Intermediate Sensitive
<20
21-29
>30
Erythromycin
15 mcg
<13
14-17
>18
Kamamycin
30 mcg
<13
14-17
>18
Methicillin
5 mcg
<9
10-13
>14
Penicillin
10 units
<20
21-29
>30
E-test method
• Applying the plastic
strip impregnated with
different concentrations
of antibiotic onto the
surface of the agar plate
• Incubating
plates.
Plates should be read
as early as possible
after
24
hours
incubation and results
recorded
in
the
susceptibility book.
• Measure
MIC
of
antibiotic as shown in
Figure.
E-test method
Definition of
susceptibility of
microorganisms
to antibiotics by
E-test
Automated tests
• These tests measure the inhibitory effect of the
antimicrobial agents in a liquid medium by
using light scattering to determine growth of the
test organism. Results can be obtained within a
few hours.
Bacterial Resistance
The two
basic
mechanisms
of bacterial
resistance
• Mutation
• Transfer of
resistance
genes
through
plasmids
MECHANISMS OF RESISTANCE TO
ANTIBIOTICS
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2.
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4.
Intrinsic
resistance
Alteration in
the transport
system, cell
wall, or cell
membrane
Enzymatic
inactivation
of the drug
Target
alteration
Why has antibiotic resistance occurred?
• Pressure on doctors, by patients,
to prescribe antibiotics even
when they are not needed.
• Patients being prescribed
antibiotics without the doctor
knowing the cause of the
infection.
• Use of antibiotics in animals for
growth promotion and
prophylaxis, which allows
them to enter the human food
chain.
MECHANISMS OF RESISTANCE TO
ANTIBIOTICS
ANTIBIOTICS
RESISTANT BACTERIA
B-lactams
Pseudomonas, Enterobacter
Aminoglycosides
Pseudomonas, Streptococcus
faecalis, Serratia
Chloramphenicol
Pseudomonas
MECHANISMS OF RESISTANCE TO
ANTIBIOTICS
ANTIBIOTICS
RESISTANT BACTERIA
A. Decreased uptake or increased removal
Tetracyclines
Quinolones
Enterobacteriaceae (plasmidmediated)
Escherichia coli (plasmid-mediated)
B. Poor transport of enzymatically modified drug
Aminoglycosides
Enterobacteriaceae, Pseudomonas
Chloramphenicol
Pseudomonas
MECHANISMS OF RESISTANCE TO
ANTIBIOTICS
ANTIBIOTICS
RESISTANT BACTERIA
A. B-lactamases
S. aureus, Enterobacteriaceae,
Haemophilus influenzae, Pseudomonas
(plasmid-mediated)
B. Acetyltransferases, phosphorylases, nucleotidases
B-Lactams
S. aureus, Enterobacteriaceae
(plasmid-mediated)
Aminoglycosides S. aureus, Streptococcus, Pseudomonas,
Enterobacteriaceae
Chloramphenicol
MECHANISMS OF RESISTANCE TO
ANTIBIOTICS
ANTIBIOTICS
RESISTANT BACTERIA
A. Alteration of DNA gyrase
Quinolones
Enterobacteriaceae, Opportunistic Gramenegative organisms (Chromosomal mutation)
B. Alteration of the B subunit of RNA polymerase
Rifampin
Enterobacteriaceae, (Chromosomal mutation)
C. Alteration of the 50S ribosomal unit
Erythromycin
S. aureus, E. coli (plasmid-mediated)
D. Alteration of the 30S ribosomal unit
Streptomycin
Enterobacteriaceae (chromosomal mutation)
SIDE EFFECTS OF ANTIBIOTICS
• 1. Organotoxic action:
neurotoxic
(Streptomycin);
toxic
action
on
the
haematopoietic system
(Tetracyclines).
• 2. Allergic reactions:
angioneurotic oedema,
anaphylactic
shock,
allergic asthma, contact
dermatitis (Penicillin).
SIDE EFFECTS OF ANTIBIOTICS
• 3. Development of resistant strains of
microorganisms which cause various
complications
• 4. Dysbacteriosis - disorders of normal flora
of intestine and appears of infections.
• 5. Immunosupression action.
INTERFERONS
Interferons - are natural substances that have antiviral properties. Interferons are synthesized by
cells infected an virus.
Type I
-Interferon-α (IFN-α) has maximal antiviral activity
-Interferon-β (IFN-β) has intermediate antiviral
activity.
Mechanism of action IFN-α and IFN-β:
1. Inhibit viral protein synthesis.
2. May block other stages of viral replication,
including budding.
INTERFERONS
Type II
-Interferon-α (IFN-α) is more active as a lymphokyne than as
an antiviral agents.
Type III
Mechanism of action Interferon-γ (IFN γ)
1. Inhibits viral replication by increasing intracellular nitric
oxide levels;
2. Activates cytotoxic T cells, monocytes, macrophages, and
natural killer cells, which are able to kill virus-infected cells.
• IFN-α is used in the treatment of Hepatitis B, C Herpes
simplex virus, cytomegalovirus, AIDS - associated
Kaposi’s sarcoma.
• IFN-γ is used as an immunostimulant in the treatment of
oncologic disorders and some immunodeficiency
diseases.
Synthetic Antiviral Agents
Compound
Indication
Main Target for
Antiviral Action
ANTI-MYXOVIRUS DRUGS
Amantadine
Rimantadine
Influenza A virus
Zanamivir
(Relenza)
Oseltamivir
(Tamiflu)
Ribavirin
Influenza A, B
viruses
Influenza A, B virus,
RSV, measles virus,
Lassa virus
Penetration,
uncoating and
assembly
Neuraminidase
inhibitor
Nucleic acid
synthesis
Synthetic Antiviral Agents
ANTI-HERPESVIRUS DRUGS
Acyclovir
HSV, VZV
DNA chain termination
Famcyclovir
HSV, VZV
DNA chain synthesis
Gancyclovir
HSV, VZV,
CMV, EBV
DNA chain synthesis
Valacyclovir
HSV, VZV
DNA chain synthesis
Foscarnet
HSV, VZV,
CMV, EBV
DNA polymerase and
reverse transcriptase
Trifluridine
HSV, VZV
Thymidilate synthesis
Synthetic Antiviral Agents
Zidovudine
Didanosine
Zalcitabine
Stavudine
Sanquinavir
Ritonavir
Indinavir
ANTI-RETROVIRUS DRUGS
HIV
Viral reverse transcriptase, DNA chain
termination
HIV
HIV
HIV
HIV
Viral protease
HIV
HIV
ANTI-HEPATITIS DRUGS
Ribavirin
HCV
Lamivudine HBV
Foscarnet
HBV
Nucleic acid synthesis
Viral reverse transcriptase, DNA chain
termination
DNA polymerase and reverse
transcriptase