CHEMOTHERAPY 1.Antibiotics 2.Classification of antibacterial agents 3.General principles of...
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Transcript of CHEMOTHERAPY 1.Antibiotics 2.Classification of antibacterial agents 3.General principles of...
CHEMOTHERAPY 1. Antibiotics2. Classification of antibacterial agents3. General principles of antibacterial therapy4. Antibiotic susceptibility testing 5. Bacterial resistance to antibacterial agents 6. 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 semi-synthetic 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 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, Sulfa-methoxazole-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 testingAntibiotic 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 antibio-tics 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
Interpretationof Disc Diffusion Test
Drug DiskInhibition zone diameter (in mm)
concent-ration
Resistant Intermediate Sensitive
Ampicillin 10 mcg <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
1. Intrinsic resistance
2. Alteration in the transport system, cell wall, or cell membrane
3. Enzymatic inactivation of the drug
4. 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 Enterobacteriaceae (plasmid-mediated)
Quinolones 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
B-Lactams S. aureus, Enterobacteriaceae, Haemophilus influenzae, Pseudomonas
(plasmid-mediated)
B. Acetyltransferases, phosphorylases, nucleotidases
Chloramphenicol S. aureus, Enterobacteriaceae (plasmid-mediated)
Aminoglycosides S. aureus, Streptococcus, Pseudomonas, Enterobacteriaceae
MECHANISMS OF RESISTANCE TO ANTIBIOTICS
ANTIBIOTICS RESISTANT BACTERIA
A. Alteration of DNA gyrase
Quinolones Enterobacteriaceae, Opportunistic Grame- negative 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 anti-
viral 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.
INTERFERONSType 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 AgentsCompound Indication Main Target for
Antiviral ActionANTI-MYXOVIRUS DRUGS
AmantadineRimantadine
Influenza A virus Penetration, uncoating and
assembly Zanamivir(Relenza)
Oseltamivir (Tamiflu)
Influenza A, Bviruses
Neuraminidase inhibitor
Ribavirin Influenza A, B virus, RSV, measles virus,
Lassa virus
Nucleic acid synthesis
Synthetic Antiviral AgentsANTI-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 AgentsANTI-RETROVIRUS DRUGS
Zidovudine HIV Viral reverse transcriptase, DNA chain terminationDidanosine HIV
Zalcitabine HIV
Stavudine HIV
Sanquinavir HIV Viral protease
Ritonavir HIV
Indinavir HIV
ANTI-HEPATITIS DRUGS
Ribavirin HCV Nucleic acid synthesis
Lamivudine HBV Viral reverse transcriptase, DNA chain termination
Foscarnet HBV DNA polymerase and reverse transcriptase