Treatment of Infection

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Treatment of Infection

• Professor Mark Pallen

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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

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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 spectrum)
• Vancomycin only Gram-positive bacteria
  (intermediate spectrum)
• Carbapenems many different bacteria (very broad
  spectrum)

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Treatment of Infection Anti-Microbial Drug
Targets
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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 synthesis
• aka penicillin-binding proteins

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Antimicrobials acting on the bacterial cell wall

• Beta-lactams Penicillins
• benzylpenicillin
• flucloxacillin
• ampicillin
• piperacillin

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Antimicrobials acting on the bacterial cell wall

• Beta-lactams Cephalosporins
• Orally active
• cephradine
• cephalexin
• Broad spectrum
• cefuroxime
• cefotaxme
• ceftriaxone
• ceftazidime

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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

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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

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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 polymerase
• flucytosine is incorporated into yeast mRNA

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Antimicrobials acting on protein synthesis

• Binding to 30s Subunit
• aminoglycosides (bacteriocidal)
• streptomycin, gentamicin, amikacin.
• tetracyclines
• Binding to the 50s subunit
• chloramphenicol
• fusidic acid
• macrolides (erythromycin, clarithromycin,
  azithromycin)

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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

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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

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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

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Mims C et al. Medical Microbiology. 1998.
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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

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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

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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

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Determination of MIC and MBC
Mims C et al. Medical Microbiology. 1998.
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Disk diffusion testing
Cohen Powderly 2004 http//www.idreference.com
/
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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 patient?
• Have you taken bacteriology specimens first?!

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Clinical use of antibiotics
Gillespie SH Bamford KB. 2003. Medical
microbiology infection at a glance.
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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 body

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Best antibiotic(s) for these organisms ?

• For some organisms sensitivities are entirely
  predictable
• 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

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Best antibiotic(s) for this site of infection ?

• Depends on penetration of antibiotic into tissues
• 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

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Are there any problems with this regimen in this
patient?

• Allergy
• usually only a problem with penicillins, and,
  less often, with cephalosporins (10 cross
  sensitivity)
• Ampicillin Rash
• develops if patient has glandular fever or
  lymphoma
• Not related to general penicillin allergy

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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
• VREs, MRSAs, Candida in ITU

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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 damage

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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!

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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