Date post: | 23-Dec-2015 |
Category: |
Documents |
Upload: | lillian-lewis |
View: | 216 times |
Download: | 4 times |
prepared by Miss Rashidah Hj Iberahim
ANTIMICROBIAL THERAPHY
prepared by Miss Rashidah Hj Iberahim
Antimicrobial theraphy in daily life
prepared by Miss Rashidah Hj Iberahim
Content
• Overview of the mechanism of action of antimicrobial drugs
• Antimicrobial sensitivity test• Mechanism of antibiotic resistance
prepared by Miss Rashidah Hj Iberahim
Introduction
Discovered by Paul Ehrlich (chemical killing pathogenic m/org wtout injuring the host)
Antimicrobial theraphy ChemotheraphyAntibiotic (antibiosis) – chemical (against life)2 types synthetic
semisynthetic
prepared by Miss Rashidah Hj Iberahim
prepared by Miss Rashidah Hj Iberahim
General properties
• Selective toxicity• The spectrum of activity • Modes of action• Side effects• Resistance of m/org
prepared by Miss Rashidah Hj Iberahim
PART 1 – GENERAL PROPERTIES
prepared by Miss Rashidah Hj Iberahim
Selective toxicity
• To way of actions
internal (eat) external (topical)• Internal – should be selective toxicity (harm to
microbes not the host cell)• Most of the antibiotic act depending on 2 levels - toxic dosage level (cause host damage) - therapeutic dosage level ( eliminates the pathogenic organism)
prepared by Miss Rashidah Hj Iberahim
Relationship of antibiotic and host
• Measured by chemotherapeutic index –
max dose ÷ min dose = range 1 till 8 kg bw kg bw
• 8 = > effective, < toxic• 1 = > toxic, < effective• Eg. arsenic, mercury, antimony = toxic and effective towards
pathogen• Eg. Treatment for worm infection = damage to parasites and host
prepared by Miss Rashidah Hj Iberahim
The spectrum of activity
prepared by Miss Rashidah Hj Iberahim
Modes of action
1. Inhibition of cell wall synthesis2. Disruption of cell membrane function3. Inhibition of protein synthesis4. Inhibition of nucleic acid synthesis5. Action as antimetabolites
prepared by Miss Rashidah Hj Iberahim
1. Inhibition of cell wall synthesis• Normal mechanism, the peptidoglycan can helps to
maintain the osmotic pressure of the cell• Allow the membrane of the effected microbe to
rupture and release the cell content• Usually affecting Gram positive bacteria• Examples – penicillin, bacitracin, vancomycin and
cephalosporin• All the respective antibiotic contain β-lactam ring that
attach to enzyme and cross-link with peptidoglycan• However, those lack with peptidoglycan (Fungi and
Archaea) were unaffected
prepared by Miss Rashidah Hj Iberahim
2. Disruption of cell membrane function
• Dissolve the membrane of interfere with the movement of substances into or out of the cells
Polypeptide antibiotic (Polymyxins)• act on bacteria as detergent and distort
bacterial cell membranes by binding with the phospholipid bilayer
• Effects on Gram negative bacteria (rich with phospholipids)
prepared by Miss Rashidah Hj Iberahim
Cont.
Polyene antibiotic (amphotericin B)• Bind to particular sterols, present in the
membranes of fungal and animal cell
• Polymyxins – do not act on fungi• Polyenes - do not act on bacteria
prepared by Miss Rashidah Hj Iberahim
3. Inhibition of protein synthesis
• Basically protein synthesis requires DNA, RNA and ribosomes (bacterial – 50S + 30S / animal – 60S + 40S)
• Prevent the growth of microbes by disrupting ribosomes or otherwise, interfering with the process of translation
• Thru selective toxicity (respective attack)Examples: • Streptomycin – from amino acids and glycosidic bonds that
act on 30S portion interfering the translation process• Tetracycline • Erythromycin, chloramphenicol – act on 50S portion and
interfering the growing of polypeptide
prepared by Miss Rashidah Hj Iberahim
4. Inhibition of nucleic acid synthesis
• Interfere with the synthesis RNA (transcription) or DNA (replication) and disrupt the formation these molecules contain
• The enzyme used by bacterial and animal cells to synthesize nucleic acids provide a means selective action of antimicrobial agents
• Example: rifamycin family (transcription), quinolones (DNA replication) and metronidazole
• Bind to a bacterial RNA polymerase and inhibit RNA synthesis
prepared by Miss Rashidah Hj Iberahim
5. Action as antimetabolites
• Affect normal metabolites by competitively inhibiting microbial enzymes or by being erroneously incorporated into important molecules such as nucleic acids
prepared by Miss Rashidah Hj Iberahim
Side effects
• Most of the host will show adverse effects such as toxicity, allergy and disruption of normal microflora
• Most of the antibiotic acts on pathogen, and also the normal flora
• Leads to superinfections will happens where the normal flora will demolished and no host defends in particular area
prepared by Miss Rashidah Hj Iberahim
Resistance of m/org
• Antibiotic resistance can be a result of horizontal gene transfer, and also of unlinked point mutations in the pathogen genome and a rate of about 1 in 108 per chromosomal replication.
• The antibiotic action against the pathogen can be seen as an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce.
• They will then pass this trait to their offspring, which will result in a fully resistant colony.
prepared by Miss Rashidah Hj Iberahim
prepared by Miss Rashidah Hj Iberahim
The four main mechanisms:1. Drug inactivation or modification: e.g. enzymatic deactivation of
Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
2. Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins—in MRSAand other penicillin-resistant bacteria.
3. Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux(pumping out) of the drugs across the cell surface.
prepared by Miss Rashidah Hj Iberahim
Diagram of resistance
prepared by Miss Rashidah Hj Iberahim
History of resistance• The first antibiotic,
penicillin, was discovered in 1929 by Sir Alexander Fleming, who observed inhibition of Staphylococci on an agar plate contaminated by aPenicillium mold
prepared by Miss Rashidah Hj Iberahim
In simple words..
• Hereditary drug resistance (R) factors are carried by plasmids and transposons
• Resistance may be due to enzymatic destruction of a drug, prevention of penetration of the drug to its target site, cellular or metabolic changes at target sites, or rapid efflux of the antibiotic
• Resistance can be minimized by the discrimination use of drugs in appropriate concentrations and dosages
prepared by Miss Rashidah Hj Iberahim
Examples
• Staphylococcus aureus• Pseudomonas aeruginosa• Streptococcus and Enterococcus• Clostridium difficile• Salmonella and E. Coli• Acinetobacter baumannii
prepared by Miss Rashidah Hj Iberahim
PART 2 – DETERMINING MICROBIAL SENSITIVITY
prepared by Miss Rashidah Hj Iberahim
1. The Disk Diffusion Method
• Also known as Kirby-Bauer method• The sensitivity compared by size of inhibition
zone around the disk referred to a table of standard measurements
prepared by Miss Rashidah Hj Iberahim
The sensitivity level
prepared by Miss Rashidah Hj Iberahim
2. The Dilution Method
• Constant inoculum is placed into broth cultures or well wt differing known quantities of chemotherapeutic agents
2 level of determination:• MIC (minimum inhibitory concentration) - lowest
concentration of growth / no growth at all• MBC (minimum bactericidal concentration) –
lowest cont. in which subculturing of broth yields no growth
prepared by Miss Rashidah Hj Iberahim
prepared by Miss Rashidah Hj Iberahim
3. Serum Killing Power
• To determine the capability of antibiotic in killing the pathogen
• By adding bacterial suspension to the patient’s serum that already taken the antibiotic for certain period of time
prepared by Miss Rashidah Hj Iberahim
4. Automated Methods
prepared by Miss Rashidah Hj Iberahim
Antibacterial agents
• Refer to : slide on modes of action
prepared by Miss Rashidah Hj Iberahim
Antifungal
• Imidazoles and Triazoles• Polyenes• Griseofulvin• Other agents
prepared by Miss Rashidah Hj Iberahim
Antiviral agents
• Purine and Pyrimidine Analogs• Amantadine• Interferons and Immunoenhancers
prepared by Miss Rashidah Hj Iberahim
Antiprotozoan agents
• Quinine• Chloroquine and Primaquine• Metronidazole• Other agents
prepared by Miss Rashidah Hj Iberahim
Antihelminthic agents
• Niclosamide• Mebendazole• Other agents
prepared by Miss Rashidah Hj Iberahim
Homeworks
• Please study regarding each of the antimicrobial agents listed in this lecture.
• Focus on the mechanism of actions, resistances and laboratory diagnostic.
prepared by Miss Rashidah Hj Iberahim
THE END