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1、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
2、,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 bac
3、teria (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
4、 “penicillin-binding proteins”,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 cefuroxim
5、e 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
6、 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
7、 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-
8、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, amikaci
9、n. tetracyclines Binding to the 50s subunit chloramphenicol fusidic acid macrolides (erythromycin, clarithromycin, azithromycin),Antimicrobials acting on the cell membrane,amphotericin binds to the sterol-containing membranes of fungi polymyxins act like detergents and disrupt the Gram negative oute
10、r 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 element
11、s 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 t
12、o 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 Res
13、istance 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 pum
14、ped 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 MRSAS. aureus resistance to mupiro
15、cin 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
16、 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 diffus
17、ion testing,Cohen http:/ 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?!,
