Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,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 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,Beta-lactams:,Penicillins,benzylpenicillin,flucloxacillin,ampicillin,piperacillin,Antimicrobials acting on the bacterial cell wall,Beta-lactams:,Cephalosporins,Orally active,cephradine,cephalexin,Broad spectrum,cefuroxime,cefotaxme,ceftriaxone,ceftazidime,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 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),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,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,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,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.,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?,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 failu