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 microorganism 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
spectrum)
– Vancomycin only Gram-positive bacteria (intermediate
spectrum)
– 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
synthesis
• aka “penicillin-binding
proteins”
Antimicrobials acting on
the bacterial cell wall
• Beta-lactams:
Penicillins
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benzylpenicillin
flucloxacillin
ampicillin
piperacillin
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R
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beta-lactam
ring
Antimicrobials acting on
the bacterial cell wall
• Beta-lactams:
Cephalosporins
– Orally active
• cephradine
• cephalexin
– Broad spectrum
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cefuroxime
cefotaxme
ceftriaxone
ceftazidime
Cephalosporins
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basement
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synthetic side chains
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
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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
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
Antimicrobials acting on
protein synthesis
• Binding to 30s Subunit
– aminoglycosides
(bacteriocidal)
30s subunit
mRNA
• streptomycin, gentamicin,
amikacin.
– tetracyclines
• Binding to the 50s subunit
– chloramphenicol
– fusidic acid
– macrolides (erythromycin,
clarithromycin, azithromycin)
50s subunit
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;
http://www.idreference.com/
Questions to ask
before starting antibiotics
• Does this patient actually need antibiotics?
• What is best treatment?
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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?!
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
body
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
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
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
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, MRS A s, 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
damage
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
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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