Antimicrobial usage

Antimicrobial usage

1. Genetic components of bacteria and their interactions

   • Plasmids
     • Conjugation
       • Bacterial mating - transfer of plasmid
       • Plasmid transferred through pillus
       • Quick spread of antibiotic resistance
       • Occurs often in enterobacteriaceae
     • Extra-chomosomal circular DNA
       • Easily transmissible between bacteria
     • Independent replication
       • Use host cell machinery
     • Usually auxiliary genes, addiction mechanisms exist
     • Types of plasmid
       • Resistance
       • Virulence
       • Colicin
       • Fertility
       • Degradative
       • >1 type per cell
         • Often v high copy no.s
     • Are essentially parasitic
       • Energy burden on cell

2. Linkage of resistance

   • Plasmid can carry resistance to 2 or more antibiotics
     • Usage of one selects resistance to the other
       • e.g. tetracycline and cephalosporins
         • Beta lactamase production
         • Tetracycline resistance often carried on a plasmid
           • Pump to pump drug out of cell
             • Unable to reach effective concentration
         • Stop use of cephalosporins, but continue with tetracycline
           • Selection pressure still there, plasmid will persist
     • Difficult to lower levels of resistance to an antibiotic by stopping usage without knowing underlying molecular biology
   • Streptomycin
     • Mutation of target
       • Not carried on a plasmid
   • Complete absence of plasmid in cell - replicates faster
     • Absence of selection pressure
     • Bacteria without plasmids outcompete those with plasmids
   • Best treatment of animal
     • Understand metagenome
       • Whole population
       • Switch from antibiotic with plasmid-borne resistance to one with chromosomal resistance
         • Target ribosomes
         • Plasmids will drop out as they are of no benefit with streptomycin selective pressure
   • Clinical audit
     • Is there an alternative?
       • e.g. Chloramphenicol?
   • Rotate antibiotic usage
     • WHO suggestion to stop cephalosporin usage
   • Examples of resistance
     • Cross-resistance
       • Detection
         • Culture more bacteria
           • Too much data
         • Look at complete bacterial flora
         • Wait for treatment failure
           • Process of elimination of antibiotics
         • Change antibiotics and let resistance decline in the population
           • Need to switch to an equally efficacious drug, otherwise farmers won’t comply with non-usage
     • Disc tests
     • PCR not useful
       • Prone to false -ves
       • Need understanding of ecology of individual species
       • End up selecting for resistant bacteria
     • Proteomics
       • Mass spectrometry
       • Total protein population
       • Still in its infancy as a technique
     • Extended Spectrum Beta Lactamases (ESBLs)
       • Produced by enterobacteria
       • Secreted - so will target penicillins/cephalosporins used to target eg MRSA
       • Produced by non-target species
         • Protective resistance
       • Use clavulanic acid in combination
         • Inhibits beta lactamases

3. Treatment strategies

   • Don't use unneccessarily
     • BUT
       • Too little antibiotic will encourage maintenance of resistance as immune system will not have time to clear infection
         • Low dose
         • Short course
         • Can't just give ever higher doses due to side effects
     • Too frequently may encourage resistance
       • Propagation of infection
   • Increase dose enough to overcome resistant bacteria
     • Bacteria are just resistant to dosing levels that are currently available – they will not be resistant to far higher drug levels
   • Increase duration?
   • Resistance only occurs up to a threshold
     • Generally, increase dose, decrease resistance
       • BUT cephalosporin – increase the dose, increase the resistance (only slightly)
         • Don't use often, but use of tetracycline means that this has persisted
   • Therapeutic dose
     • Level of CTA needed for clinical treatment of an infection in a specific host
   • Toxic dose
     • Level of the same CTA which is too toxic for use in that host
   • Toxic dose / Therapeutic dose = Therapeutic index
     • High index - selectively toxic; useful
     • Low index - toxic to host; side effects
   • Can we deliver antibiotic more directly?
     • Can start repurposing and reusing antibiotics
     • Antibiotic encapsulation
       • e.g. very resistant strain of TB – can’t get drug dosage high enough systemically to treat without killing the host
       • Targeted treatment
   • Remember ecology and target
     • Remember what individual antibiotics do
       • e.g. metronidazole inhibits anaerobic respiration
         • Will kill eneterobacteria in gut
         • Will not kill then once they have left the intestine
           • Wound infections and sepsis
           • No longer an anaerobic environment
           • Are now respiring aerobically, anaerobic pathways are no longer being used – targeting these is now futile
       • Penicillins only kill actively dividing bacteria
         • No effect on chronic infections

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