Micro 3053 - Topic 8
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- Antibiotics
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- metabolites produced by microorganisms that are inhibitory to other microbes in small amounts
- only good for treating BACTERIAL infections!!
- DO NOT work against viruses - What are antibiotics made by?
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1. Bacteria (Streptomyces & Bacillus)
2. Fungi (Penicillium & Cephalosporium) - It is difficult to find drugs to treat which microbes?
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1. Viruses - because they use our machinery and replicate inside our cells
2. Fungi - eukaryotes
3. Protozoa - eukaryotes
4. Helminths - eukaryotes - Narrow Spectrum Antibiotics
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- active against a select group of bacteria
- ex. Pen G (affects Gram positives)
- Gram negatives have outer membrane with LPS (penicillin does not enter) - Broad Spectrum Antibiotics
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- active against a wide range of bacteria
- ex. Gram positives and negatives
- can also kill normal microbiota which can cause SUPERINFECTION (ex. Candida albicans) - How are antimicrobial drugs classified?
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1. Bactericial or Bacteriostatic
2. Chemical Structure
3. MOA - Bacteriostatic
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- prevent growth allowing host defenses to work
- ex. phagocytosis; antibody production - What are the modes of action for antibiotics?
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1. Inhibit CELL WALL synthesis
2. Inhibit PROTEIN synthesis
3. Inhibit NA REPLICATION and TRANSCRIPTION
4. Inhibit ESSENTIAL METABOLITE synthesis
5. Injure PLASMA MEMBRANE - Which antibiotics inhibit cell wall synthesis?
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1. Penicillins
2. Vancomycin
3. Cephalosporins
4. Bacitracin
5. Isoniaszid, Ethambutol - What is Transpeptidation?
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- Final step in peptidoglycan synthesis
- involved formation of links between tetra peptides on adjacent strands
- Catalyzed by TRANSPEPTIDASE (enzyme) - How does Transpeptidase enzymes react with penicillin?
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- binds with penicillin or other Beta-lactam antibiotics
- therefore, also called PENICILLIN BINDING PROTEINS (PBPs)
- transpeptidases do not work in the presence of penicillin (cell membrane weakens and lyses - osmotic lysis) - Penicillin
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- beta-lactam antibiotics (beta-lactam ring in nucleus)
- differentiated by chemical side chain (confer different properties)
- may be natural or semisynthetic
- inhibit peptidoglycan synthesis by binding with and inactivating transpeptidase (inhibits cell wall synthesis)
- only effective against ACTIVE cells - What are Natural Penicillins?
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- extracted from cultures of mold Penicillium (ex. Pen G and Pen V)
- NARROW SPECTRUM
- susceptible to PENICILLINASES (Beta-lactamases) which are produced by some bacteria. They cleave to beta-lactam making bacteria RESISTANT - What are Semisynthetic Penicillins?
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- partly produced by mold and part is added synthetically
- ex. OXACILLIN (Penicillinase-resistant penicillins), AMPICILLIN (extended spectrum penicillins) - What is Methicillin?
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- penicillinase resistant
- methicillin-resistant S. aureus (MRSA) appeared (so prevalent that methicillin was discontinued) - What is MRSA?
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- can be carried for a long time without signs and symptoms
- can cause:
PNEUMONIA
CELLULITIS
ABSESSES
BACTEREMIA
- most cases are associated with healthcare - How to avoid spreading MRSA?
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1. Screening pts on admission
2. Isolate Pts
3. Hand hygiene
4. Gloves/Gowns
5. Masks (close contact with sputum)
6. Disinfecting hospital rooms - Extended-Spectrum Penicillins
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- effective against gram positives and negatives
- NOT resistant to penicillinases
- ex. AMINOPENICILLINS
CARBOXYPENICILLINS
UREIDOPENICILLINS - How to combat penicillinases (beta-lactamsases)
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- use penicillin + beta-lactamase inhibitors
(ex. Clavulanic acid) - non-competitive inhibitor
WITH
- broad spectrum penicillins (ex. amoxicillin)
- Amoxi-Clav - What are Cephalosporins?
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- similar ring structure to penicillins
- inhibit peptidoglycan synthesis in the same way as penicillins (inhibit cell wall synthesis)
- are susceptible to beta-lactamases called CEPHALOSPORINASES - What are the 4 generations of Cephalosporins?
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1. 1st Generation: NARROW spectrum (gram positives)
2. 2nd Generation: more extended (includes some gram negatives)
3. 3rd Generation: further increased activity against gram negative
4. 4th Generation (most EXTENDED spectrum) - What is Bactracin?
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- SOURCE: Bacillus strain from a wound on a girl named Tracy
- POLYPEPTIDE antibiotic
- effective against: GRAM POSITIVES (ex. Staphylococcus & Streptococcus)
- interferes with peptidoglycan carbohydrate backbone
- TOPICAL applications - What is Vancomycin?
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- NARROW SPECTRUM (gram positives)
- GLYCOPEPTIDE antibiotic (complex structure of SUGARS & AAs)
- inhibits peptidoglycan synthesis by BLOCKING formation of peptide cross-links
- drug of last resort for MRSA
- widespread use led to VRSA and VRE - resistant to Vancomycin - What is VRE?
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- Vacomycin resistant enterococci
- GRAM POSITIVE (+)
- can persist in hospitals for long periods (ex. hands, bedding)
- OPPORTUNISTIC PATHOGENS - can cause serious diseases in other parts of the body (ex. lungs, blood) - How to control VRE (vancomycin resistance enterococci)?
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1. Isolate Pt
2. Hand washing
3. ANTISEPTIC SOAP
4. Gloves/gown
5. Disinfection of hospital rooms
6. Extreme care of contaminated linen and equipment - What are Antimycobacterial Drugs?
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- Mycobacterium species: acid-fast (my colic acids in cell wall - waxy lipids)
- ex. M. tuberculosis & M. leprae
- ISONIAZID (INH): treats TB (inhibits mycolic acid synthesis)
- ETHAMBUTOL (EMB): prevents mycolic acids from entering cell wall
- drug combinations used to minimize development of drug resistance - What are 6 Antibiotics that inhibit Protein Synthesis?
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1. Chloramphenicol
2. Aminoglycosides (ex. Streptomycin)
3. Tetracyclines
4. Macrolides (ex. Erythromycin)
5. Streptogramins (ex. Synercid)
6. Oxazolidinones - What is Chloramphenicol?
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- inhibits protein synthesis by combining with 50S ribosomal subunit and INHIBITING PEPTIDE BOND FORMATION
- BROAD SPECTRUM
- SERIOUS side effects (ex. suppression of bone marrow activity --> affects blood cell formation) - What antibiotics bind to 50S ribosomal subunit?
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- Chloramphenicol
- Clindamycin - treats acne
- Metronidazole
*inhibit peptide bond formation - What are Aminoglycosides?
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- ex. STREPTOMYCIN
- BROAD SPECTRUM (significant activity against gram negatives)
- 1st antibiotic treatment for TB
- CHANGES SHAPE OF 30S subunit so mRNA (read incorrectly)
- no longer used because of resistance, NEUROtoxicity (auditory nerve) and NEPHROtoxicity (kidney) - What are examples of Aminoglycosides?
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1. Streptomycin
2. Neomycin - topical treatment
3. Gentamycin - useful against PSEUDOMONAS (ex. CF Pts)
4. Tobramycin administered as AEROSOL (control CF infections) - What are Tetracyclines?
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- BROAD SPECTRUM
- penetrate tissues
- interfere with attachment of tRNA to mRNA - ribosome complex
- effective against CHLAMYDIA
- Several forms - What are the disadvantages of Tetracyclines?
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1. Suppress normal microbiota of intestine - superinfections (ex. Candida albicans)
2. discolour children's teeth
3. Pregnant women should avoid (LIVER damage) - What are Macrolides?
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- contains Macrocyclic lactone ring
- ex. ERYTHROMYCIN
- similar activity spectrum as penicillin (often used when people have penicillin allergies)
- INHIBITS PROTEIN SYNTHESIS (by binding to 50S subunit & preventing aminoacyl TRANSLOCATION
- AZITHROMYCIN, CLARITHROMYCIN (semi-synthetic, broader spectrum)
- KETOLIDES - new generation (semi-synthetic mycolides) - What are Streptogramins?
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- Synercid - use of 2 different antibiotics: staphylococci and vancomycin-resistant (combination is SYNERGISTIC)
- combination of 2 cyclic peptides: quinupristin, and dalfopristin
- INTERFERE with 2 different steps in PROTEIN SYNTHESIS
- NARROW SPECTRUM
- many adverse effects - What are Oxazolidinones?
-
- synthetic (developed because of vancomycin resistance)
- INTERFERE with PROTEIN SYNTHESIS
- NARROW SPECTRUM
- active against: enterococci (not sensitive to Synercid)
- Linezolid - used to combat MRSA - What drugs inhibit Plasma Membrane?
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- Polymyxin B: bactericidal (kills)
- BROAD SPECTRUM (including Pseudomonas)
- interacts with LPS and Phospholipids (damages outer membrane and plasma membrane)
- used together with BACITRACIN (ex. Polysporin) - What is RIFAMYCIN?
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- ex. Rifampin
- treats TB
- INHIBIT SYNTHESIS of mRNA
- can penetrate tissues, CSF, and abscesses
- side effects: red urine, saliva, sweat and tears - What drugs are inhibitors of DNA/RNA Synthesis?
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1. Rifamycins (Rifampin)
2. Quinolones (Naldixic acid) - INHIBITS DNA REPLICATION and treatment of UTIs
3. Fluoroquinolone (Ciprofloxacin) - What are Sulfonamides (Sulfa drugs)?
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- BROAD SPECTRUM
- used for UTIs
- structurally similar to PABA
- many bacteria use PABA as precursor for the synthesis of the essential co-enzyme THFA
- COMPETITIVE inhibitor: competes with PABA
- BLOCKS SYNTHESIS of THFA so DNA cannot be SYNTHESIZED - What is drug synergism?
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- use of 2 drugs (produce a result that is not attainable independently)
- ex. TMP-SMZ
- can use LOWER levels
- BROADER spectrum
- REDUCE emergence of RESISTANCE - What is Susceptibility testing?
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- to determine which chemo agent will be effective against a specific pathogen
1. Diffusion Methods (Disk Diffusion Method & E Test)
2. Broth Dilution Test - What is Disk Diffusion Method (Kirby-Bauer Test)?
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- type of diffusion method
- swab test organism
- antibiotic-impregnated disks are placed on the surface
- measure ZONES OF INHIBITION
- ***cannot determine if it is bactericidal or bacteriostatic - What is an E test?
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- type of diffusion method
- enables an estimate of the MINIMUM INHIBITORY CONCENTRATION (MIC) - lowest antibiotic concentration that prevents visible growth - What is MINIMUM INHIBITORY CONCENTRATION (MIC)
- - lowest antibiotic concentration that prevents visible growth
- What is Broth Dilution Test?
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- can determine MIC and MBC (Minimum bactericidal concentration) of an ANTIMICROBIAL drug
- MBC: lowest antibiotic concentration that kills bacteria
- test bacteria is inoculated into broth tubes which contain decreasing concentrations of antibiotic
- after incubation, tubes are observed for growth or no growth (MIC)
- tubes with no growth can be subcultured in broth WITHOUT antibiotic: MBC - MBC (Minimum bactericidal concentration)
- - lowest antibiotic concentration that kills bacteria
- What is Resistance?
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- genes that make bacteria resistant
- random mutations occur
- Plasmid (R factors), transposons also carry resistance genes
- can be transferred between different bacteria
- some have INTRINSIC resistance (Outer membrane, mycoplasmas, resistance to vancomycin if no target peptides in peptidoglycan) - What are "superbugs"?
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- some multiple-drug resistant pathogens resistant to 3 or more drugs
- ex. Staphylococcus, Streptococcus, Psuedomonas, Mycobacterium, TB, Plasmodium - What are 4 mechanisms of resistance?
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1. Blocking entry into cell (ex. modified porins in gram (-)s
2. Enzymatic destruction or inactivation (ex. penicillinase)
3. Alteration of drug target site (ex. modified PBPs in MRSA)
4. Rapid efflux (flowing out) of drug - How to prevent resistance?
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1. Continue antibiotic for the full treatment period
2. Never use leftover antibiotics to treat new illnesses
3. Never use antibiotics prescribed to someone else
4. Health-care workers should avoid unnecessary prescriptions (ensure choice and dosage is appropriate for the situation)