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Antibiotic therapy - Treatment

Chemotherapy - treatment of disease with a chemical compound dircted against invading mcrobes or abnormal cells

Antimicrobial - agent which kill or inhibit growth of suseceptible organism:

  • antibiotics - microbial product which kills or inhibits susceptible organisms. Administer outside the body
  • disinfectant - apply to non living or surfaces 
  • antiseptic - splly to living tissue

Characteristics of antimicrobial drugs

a, selective toxicity - agent must kill the or inhibit the microbes while damaging the host as little as possible: therapeutic dose and toxic dose

b, range of effectiveness - narrow or broad spectrum

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c, pharmacokinetic and pharmacodynamic properties:

  • location of infection
  • absorption into various body compartment
  • route of antibiotic administeration
  • dose
  • frequency and duration of treatment

d, killing Vs. inhibiting:

  • bacteriocidal compounds - antimicrobes which kill the bacteria
  • bacteriostatic compounds - antimicrobes that inhibit or reduce the rate of microbial growth

Susceptibility to antibiotics 

Method: gar diffusion method

Minimum inhibitory concentration (MIC) - is the lowest dosage that can be administered that will inhibit the growth of bacteria. 

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Mechanisms of antibiotics action 

Prerequisite - unique characteristics of the microorganisms that is different from the host:

  • inhibiting cell wall synthesis
  • contain DNA gyrase, RNA elongation and they don't undergo translation
  • folic acid metabolisms 

Antibiotic resistance 

Intrinsic resistac, natural - occur naturall in all strains. It is chromosomally encoded

Extrinisic resistance, acquired - results of a mutation of the DNA or acquisition of new DNA 


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Spread of antimicrobial resistance

Niche competition - result of natural selection

The problem arises under these conditions:

  • overuse of antibiotics
  • incomplete or incorrect use of therapy
  • failure on hospital infection control
  • antibiotics as growth enhancer
  • global dissemination of resistance strains increases the chnace of spreading 

Mechanisms :

  • efflux pump
  • reduces uptake
  • metabolic bypass
  • antibiotic degadation enzyme
  • antiobiotic alteration enzyme 
  • biofilm
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In S. aureus...MRSA 

The hospital strain quickly develop resistance o vairiety of antibiotics. 

β-lactam antibiotics are structualy analogues of D-alanyl-D-adenine dipeptides. They are the temineral AA on precursor disaccharide NAM/NAG subunit of the PH layer. NAM and NAG is cross-linked by transpeptidases in a transpeptidation reaction. β-lactams irreversibly bind to PBP active site → inhibit the transpeptidation reaction. 

Resistance to β-lactam antibiotics:

  • production of β-lactamase 
  • Penicillin binding protein - onto a large mobile Staaphylococcal chromosomal cassette mec and other several different types. 

Treatment with Vancomycin 

It binds to two types of D-adenyl-D-adenine residues of the PG: 1, periplasmic-located residue 2, cytoplasmic membrane anchor monomers called lipid II.

Bindind to lipid II inhibits the transglycosylation reaction - bactericidial.

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Resistance to Vanomycin 

Acquired by mechanisms:

1, thickening of the cell wall

  • non-specific substate thta traps vanomycin in the cell wall
  • protect the lipid II at the cell membrane 
  • multiple gene and pathway alterations

2, synthesis of D-alanyl-D-lactate peptidoglycan precusor 

  • low affinity for vancomycin
  • modified lipid II 
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Drug discovery 

Combinatorial chemistry - analogue of existing antimicrobial compounds.  Rational drug design - production of synthetic inhibitory chemicals Traditional methods - serach for a novel natural compounds from environment  Anti-infectives 

  • issolation of anti-bacterials that target virulence determinants 
  • specific for pathogenic bacteria
  • least likey to evolve a resistace mechanisms 

Urinary Tract Infection

Caused by Uropathgenic E.coli. A recurrent infections is common and it is increasingly ressiatance to antibiotics. 

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Screen: biofilm inhibitor 

  • formation of biofilm o PVC plate, 24h @ 37c
  • stain with crystal violet
  • screen for inhibit biofilm 

Vaccines 

  • a strategies used to reduce the risk of illness while retaining the ability to induce beneficial immune response
  • a biological preparation to improve immunity against a particular disease
  • stimulates body to recognise infectious agent
  • develop memory - faster recognition and destroy the infectious agent at latter encounters
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Screen: biofilm inhibitor 

  • formation of biofilm o PVC plate, 24h @ 37c
  • stain with crystal violet
  • screen for inhibit biofilm 

Vaccines 

  • a strategies used to reduce the risk of illness while retaining the ability to induce beneficial immune response
  • a biological preparation to improve immunity against a particular disease
  • stimulates body to recognise infectious agent
  • develop memory - faster recognition and destroy the infectious agent at latter encounters
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Types:

  • Kill - microorganisms which have been killed or destroyed
  • Attenuated - live microorganisms with no virulence properties
  • Toxoid - inactiviated compounds
  • Subunit - a protein fragment that is immunoreactive
  • Conjuagate - combination of polysaccharides linked to immunogenic proteins

Search for new vaccines

1, infection with Tb does not protect against adult TB → new vaccines is needed to confer stronger immune response

2, one third of population is already infected → vaccines that erradiacte the disease

3, co infection with HIV → vaccine must be safe to used in immuno supressed patients 

4, larger percetage of population has been infected with BCG → new vaccine must work in this population

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Vaccine development 

Problems: antigenically hypervariable and a need to block bloodstream dissemination of pathogen in asymptomatic carriers. 

A new concenpt of reverse vaccinology made it possible by genome sequencing revolution. 

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