Treatment of Infection by yja71875


									Treatment of Infection

  Professor Mark Pallen
             Treatment of Infection
              How Do Antimicrobials Work?
• Key concept:
   selective toxicity
   – the antimicrobial
       agent blocks or
     inhibits a metabolic
     pathway in a micro-
     organism which is either
     absent or is radically
     different in the
     mammalian cells of the
     human host
          Principle of antibiotic spectrum

• Different antibiotics target different kinds of bacteria
   – i.e., different spectrum of activity
• Examples:
   – Penicillin G (= original pen.) mainly streptococci (narrow
   – Vancomycin only Gram-positive bacteria (intermediate
   – Carbapenems many different bacteria (very broad spectrum)
Treatment of Infection
Anti-Microbial Drug Targets
               Antimicrobials acting on
                the bacterial cell wall
• Interfere with synthesis
  of peptidoglycan layer in
  cell wall
   – eventually cause cell lysis
   – bind to and inhibit activity
     of enzymes responsible
     for peptidoglycan
       • aka “penicillin-binding
             Antimicrobials acting on
              the bacterial cell wall
• Beta-lactams:
                         a house with a garage
  –   benzylpenicillin    R
  –   flucloxacillin             
  –   ampicillin
  –   piperacillin                    beta-lactam
              Antimicrobials acting on
               the bacterial cell wall
• Beta-lactams:             Cephalosporins
  Cephalosporins          a house with a garage &
  – Orally active                basement
     • cephradine
     • cephalexin
  – Broad spectrum
     •   cefuroxime
     •   cefotaxme
     •   ceftriaxone
                            synthetic side chains
     •   ceftazidime
                            change the spectrum
                                  of action
              Antimicrobials acting on
               the bacterial cell wall
• Unusual beta-lactams
   – Carbapenems
       • Imipenem, meropenem
           – very wide spectrum
   – Monobactams
       • Aztreonam
           – only Gram-negatives
• Glycopeptides
   – only Gram-positives, but
     broad spectrum                    
   – vancomycin
   – teicoplanin
             Antimicrobials acting on
              nucleic acid synthesis

• Inhibitors Of Precursor Synthesis
   – sulphonamides & trimethoprim are synthetic,
     bacteriostatic agents
      • used in combination in co-trimoxazole
   – Sulphonamides inhibit early stages of folate synthesis
      • dapsone, an anti-leprosy drug, acts this way too
   – Trimethoprim inhibits final enzyme in pathway,
     dihydrofolate synthetase.
      • pyramethamine, an anti-toxoplasma and anti-PCP drug acts
        this way too
             Antimicrobials acting on
              nucleic acid synthesis
• Inhibitors of DNA replication
   – Quinolones (e.g ciprofloacin) inhibit DNA-gyrase
   – Orally active, broad spectrum
• Damage to DNA
   – Metronidazole (anti-anaerobes), nitrofurantoin (UTI)
• Inhibitors of Transcription
   – rifampicin (key anti-TB drug) inhibits bacterial RNA
   – flucytosine is incorporated into yeast mRNA
               Antimicrobials acting on
                  protein synthesis
• Binding to 30s Subunit                              30s subunit
   – aminoglycosides                 mRNA
       • streptomycin, gentamicin,
   – tetracyclines
• Binding to the 50s subunit
   – chloramphenicol
   – fusidic acid                                 50s subunit
   – macrolides (erythromycin,
     clarithromycin, azithromycin)          protein
          Antimicrobials acting on
            the cell membrane
• amphotericin binds to the sterol-containing
  membranes of fungi
• polymyxins act like detergents and disrupt
  the Gram negative outer membrane.
  – Not used parenterally because of toxicity to
    mammalian cell membrane
• fluconazole and itraconazole interfere with
  the biosynthesis of sterol in fungi
            Mechanisms of resistance

• Resistance can arise from chromosomal mutations, or from
  acquisition of resistance genes on mobile genetic elements
   – plasmids, transposons, integrons
• Resistance determinants can spread from one bacterial
  species to another, across large taxonomic distances
• Multiple resistance determinants can be carried by the same
  mobile element
   – Tend to stack up on plasmids
          Impact of antibiotic resistance

• Infections that used to be treatable with standard
  antibiotics now need revised, complex regimens:
   – e.g., penicillin-resistant Strep. pneumoniae now requires
     broad-spectrum cephalosporin
• In some instances, hardly any antibiotics left:
   – e.g., Multiresistant Pseudomonas aeruginosa
   – e.g., Vancomycin-resistant Staph. aureus
• Resistance rates worldwide increasing
Mims C et al. Medical Microbiology. 1998.
          Mechanisms of resistance

• Enzymes modify antibiotic
  – widespread, carried on mobile elements
     • beta-lactamases
     • chloramphenicol-modifying enzymes
     • aminoglycoside-modifying enzymes
• Permeability
  – antibiotic cannot penetrate or is pumped out
     • chromosomal mutations leads to changes in porins
     • efflux pumps widespread and mobile
            Mechanisms of resistance

• Modification or bypass of target
   – by mutation or acquisition of extrinsic DNA
   – S. aureus resistance to flucloxacillin
      • acquires an extra PBP2 to become MRSA
   – S. aureus resistance to mupirocin
      • Chromosomal mutations in low-level resistance
      • Plasmid-borne extra ILTS gene in high-level resistance
   – Rifampicin resistance in M. tuberculosis
      • Point mutations in RNA polymerase gene
     Antibiotic susceptibility testing
            in the laboratory

• Bacterial cultures tested on artificial media
• Tests the ability to grow (or: be killed) in the
  presence of defined antibiotics
• Provides guidance for ongoing therapy
• Provides resistance rates for empiric therapy
• Problems: not all results correspond with clinical
  success or failure
Determination of MIC and MBC

      Mims C et al. Medical Microbiology. 1998.
Disk diffusion testing

                   Cohen & Powderly 2004;
                Questions to ask
            before starting antibiotics
• Does this patient actually need antibiotics?
• What is best treatment?
   –   What are the likely organisms?
   –   Where is the infection?
   –   How much, how often, what route, for how long?
   –   How much does it cost?
   –   Are there any problems in using antibiotics in this
• Have you taken bacteriology specimens first?!
                      Clinical use of antibiotics

Gillespie SH & Bamford KB. 2003.
Medical microbiology & infection at a glance.
                       Does this patient
                       need antibiotics?
• Is the patient even infected?
    – e.g. urethral syndrome vs UTI
• Is it a viral infection?
    – e.g. the common cold
• Is the infection trivial or self-limiting?
    – most diarrhoea
• Are there more appropriate treatments?
    – physiotherapy for bronchitis
    – treatment of pus is drainage
    – treatment of foreign body infection is removing the foreign
                   Best antibiotic(s)
                for these organisms …?
• For some organisms sensitivities are entirely
   – e.g. Streptococcus pyogenes always penicillin-sensitive
• For most organisms, sensitivity tests contribute to
  rational therapy
   – e.g. coliforms in UTI
• Knowledge of local resistance problems contributes to
  choice of empirical therapy
              Best antibiotic(s)
         for this site of infection …?
• Depends on penetration of antibiotic into
  – e.g. gentamicin given iv does not enter CSF or gut
  – E.g. azithromycin accumulates in cells even though
    levels low in serum
• Depends on mode of excretion
  – e.g. amoxycillin excreted in massive amounts in urine
       Are there any problems with
       this regimen in this patient?
• Allergy
  – usually only a problem with penicillins, and, less
    often, with cephalosporins (~10% cross
• Ampicillin Rash
  – develops if patient has glandular fever or
  – Not related to general penicillin allergy
       Are there any problems with
       this regimen in this patient?
• Side Effects
• some occur with almost any antibiotic
  – Gastric upset
  – Antibiotic-associated diarrhoea
     • C. difficile infection
     • pseudo-membranous colitis an be fatal
  – Overgrowth of resistant organisms
     • “Thrush” in the community
     • VRE’s, MRSAs, Candida in ITU
         Are there any problems with
         this regimen in this patient?
• Organ-specific side effects
• damage to kidneys, ears, liver, bone marrow
   – chloramphenicol produces rare aplastic anaemia
   – vancomycin can cause "red man syndrome"
   – rifampicin discolours tears, urine contact lenses, can
     cause "flu-likesyndrome"
   – erythromycin causes gastric irritation
   – ethambutol can cause ocular damage
   – Aminoglycosides and vancomycin can cause ear and kidney
         Are there any problems with
         this regimen in this patient?
• Care needed in patients with metabolic problems
   – renal failure
   – liver failure
   – genetic diseases
• Drug interactions
   – e.g. gentamicin and frusamide
• Use in pregnancy, breast feeding, children
• Check in the BNF!
              Other Questions to Ask

•   How much?
•   How long for?
•   How frequently?
•   What route?
    – In general, you should avoid “overdoing it”
      Microbiologists spend as much time telling people when to
      stop antibiotics as when to start!
    – Switch from i-v to oral therapy as soon as you can
    – Treat UTIs for just three days

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