Treatment of Infection Professor Mark Pallen. Treatment of Infection How Do Antimicrobials Work? Key...
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Transcript of Treatment of Infection Professor Mark Pallen. Treatment of Infection How Do Antimicrobials Work? Key...
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
Student
Bug
"magic bullet"
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– benzylpenicillin – flucloxacillin – ampicillin – piperacillin
Rβ
a house with a garage
beta-lactam ring
Antimicrobials acting on the bacterial cell wall
• Beta-lactams: Cephalosporins– Orally active
• cephradine• cephalexin
– Broad spectrum• cefuroxime • cefotaxme• ceftriaxone• ceftazidime
Cephalosporins
synthetic side chains change the spectrum
of action
β
a house with a garage & basement
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
β
β
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)• streptomycin, gentamicin,
amikacin.– tetracyclines
• Binding to the 50s subunit– chloramphenicol – fusidic acid – macrolides (erythromycin,
clarithromycin, azithromycin)
30s subunit
50s subunit
mRNA
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
Mim
s C
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998.
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?
– 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, 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 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
• 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