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1、Antimicrobial Agents,Martin VotavaOlga Kroftov,Overview,If bacteria make it past our immune system and start reproducing inside our bodies,they cause disease.Certain bacteria produce chemicals that damage or disable parts of our bodies.Antibiotics work to kill bacteria.Antibiotics are specific to ce
2、rtain bacteria and disrupt their function.,What is an Antibiotic?,An antibiotic is a selective poison.It has been chosen so that it will kill the desired bacteria,but not the cells in your body.Each different type of antibiotic affects different bacteria in different ways.For example,an antibiotic m
3、ight inhibit a bacterias ability to turn glucose into energy,or the bacterias ability to construct its cell wall.Therefore the bacteria dies instead of reproducing.,Antibiotics,Substances produced by various speciesof microorganisms:bacteria,fungi,actinomycetes-to suppress the growth of other microo
4、rganisms and to destroy them.Today the term ATB extends to include synthetic antibacterial agents:sulfonamides and quinolones.,History,The German chemist Paul Ehrlich developed the idea of selective toxicity:that certain chemicals that would be toxic to some organisms,e.g.,infectious bacteria,would
5、be harmless to other organisms,e.g.,humans.In 1928,Sir Alexander Fleming,a Scottish biologist,observed that Penicillium notatum,a common mold,had destroyed staphylococcus bacteria in culture.,Sir Alexander Fleming,Flemings Petri Dish,Zone of Inhibition,Around the fungal colony is a clear zone where
6、no bacteria are growingZone of inhibition due to the diffusion of a substance with antibiotic properties from the fungus,History,Penicillin was isolated in 1939,and in 1944 Selman Waksman and Albert Schatz,American microbiologists,isolated streptomycin and a number of other antibiotics from Streptom
7、yces griseus.,Susceptibility vs.Resistanceof microorganisms to Antimicrobial Agents,Success of therapeutic outcome depends on:Achieving concentration of ATB at the site of infection that is sufficient to inhibit bacterial growth.Host defenses maximally effective MI effect is sufficient bacteriostati
8、c agents(slow protein synthesis,prevent bacterial division)Host defenses impaired-bactericidal agentsComplete ATB-mediated killing is necessary,Susceptibility vs.Resistance(cont.),Dose of drug has to be sufficient to produce effect inhibit or kill the microorganism:However concentration of the drug
9、must remain below those that are toxic to human cells If can be achieved microorganism susceptible to the ATBIf effective concentration is higher than toxic-microorganism is resistant,Susceptibility vs.Resistance(cont.),Limitation of in vitro testsIn vitro sensitivity tests are based on non-toxic pl
10、asma concentrations cut offDo not reflect concentration at the site of infectionE.g.:G-aer.bacilli like Ps.aeruginosa inhibited by 2 4 ug/ml of gentamycin or tobramycin.Susceptible!?,Antibiotic Susceptibility Testing,Susceptibility vs.Resistance(cont.),Plasma concentration above 6-10 ug/ml may resul
11、t in ototoxicity or nephrotoxicityRation of toxic to therapeutic concentration is very low agents difficult to use.Concentration in certain compartments vitreous fluid or cerebrospinal fluid much lower than those in plasma.Therefore can be only marginally effective or ineffective even those in vitro
12、 test states sensitive.,Susceptibility vs.Resistance(cont.),Therefore can be only marginally effective or ineffective even those in vitro test states sensitive“.Conversely concentration of drug in urine may be much higher than in plasma,so resistant“agents can be effective in infection limited to ur
13、ine tract,Resistance,To be effective ATB must reach the target and bind to it.Resistance:Failure to reach the targetThe drug is inactivatedThe target is altered,Resistance(cont.),Bacteria produce enzymes at or within the cell surface inactivate drugBacteria possess impermeable cell membrane prevent
14、influx of drug.Transport mechanism for certain drug is energy dependent-not effective in anaerobic environment.ATB as organic acids penetration is pH dependent.,Resistance(cont.),Acquired by mutation and passed vertically by selection to daughter cells.More commonly horizontal transfer of resistance
15、 determinant from donor cell,often another bacterial species,by transformation,transduction,or conjugation.Horizontal transfer can be rapidly disseminated By clonal spread or resistant strain itselfOr genetic exchange between resistant and further susceptible strains.,Resistance(cont.),Methicilin re
16、sistant strains of Staphylococcus aureus clonally derived from few ancestral strains with mecA geneEncodes low-affinity penicillin-binding protein that confers methicillin resistance.Staphylococcal beta-lactamase gene,which is plasmid encoded,presumambly transferred on numerous occasions.Because is
17、widely distributed among unrelated strains,identified also in enterococci,Selection of the ATB,Requires clinical judgment,detailed knowledge of pharmacological and microbiological factors.Empirical therapy initial infecting organism not identified single broad spectrum agentDefinitive therapy-microo
18、rganism identified a narrow spectrum low toxicity regiment to complete the course of treatment,Empirical and Definite Therapy,Knowledge of the most likely infecting microorganism and its susceptibilityGram stainPending isolation and identification of the pathogenSpecimen for culture from site of inf
19、ection should be obtain before initiation of therapy Definite therapy,Penicillins,Penicillins contain a b-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls(especially in Gram-possitive organisms)Penicillins are bactericidal but can act only on dividing cell
20、sThey are not toxic to animal cells which have no cell wall,Synthesis of Penicillin,b-Lactams produced by fungi,some ascomycetes,and several actinomycete bacteriab-Lactams are synthesized from amino acids valine and cysteine,b Lactam Basic Structure,Penicillins(cont.)Clinical Pharmacokinetics,Penici
21、llins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed(so they are effective in meningitis)They are actively excreted unchanged by the kidney,but the dose should be reduced in severe renal failure,Penicillins(cont.)Resistance,This
22、is the result of production of b-lactamase in the bacteria which destroys the b-lactam ringIt occurs in e.g.Staphylococcus aureus,Haemophilus influenzae and Neisseria gonorrhoea,Penicillins(cont.)Examples,There are now a wide variety of penicillins,which may be acid labile(i.e.broken down by the sto
23、mach acid and so inactive when given orally)or acid stable,or may be narrow or broad spectrum in action,Penicillins(cont.)Examples,Benzylpenicillin(Penicillin G)is acid labile and b-lactamase sensitive and is given only parenterallyIt is the most potent penicillin but has a relatively narrow spectru
24、m covering Strepptococcus pyogenes,S.pneumoniae,Neisseria meningitis or N.gonorrhoeae,treponemes,Listeria,Actinomycetes,Clostridia,Penicillins(cont.)Examples,Phenoxymethylpenicillin(Penicillin V)is acid stable and is given orally for minor infectionsit is otherwise similar to benzylpenicillin,Penici
25、llins(cont.)Examples,Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including(in addition in those above)Strept.faecalis,Haemophilus influenza,and some E.coli,Klebsiella and Proteus strainsIt is acid stable,is given orally or parenterally,but
26、 is b-laclamase sensitive,Penicillins(cont.)Examples,Amoxycillin is similar but better absorbed orally It is sometimes combined with clavulanic acid,which is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this wayIt extends
27、 the spectrum of amoxycillin,Penicillins(cont.)Examples,Flucloxacillin is acid stable and is given orally or parenterallyIt is b-lactamase resistant It is used as a narrow spectrum drug for Staphylococcus aureus infections,Penicillins(cont.)Examples,Azlocillin is acid labile and is only used parente
28、rallyIt is b-lactamase sensitive and has a broad spectrum,which includes Pseudomonas aeruginosa and Proteus speciesIt is used intravenously for life-threatening infections,i.e.in immunocompromised patients together with an aminoglycoside,Penicillins(cont.)Adverse effects,Allergy(in 0.7%to 1.0%patien
29、ts).Patient should be always asked about a history of previous exposure and adverse effectsSuperinfections(e.g.caused by Candida)Diarrhoea:especially with ampicillin,less common with amoxycillinRare:haemolysis,nephritis,Penicillins(cont.)Drug interactions,The use of ampicillin(or other broad-spectru
30、m antibiotics)may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation,Antistaphylococcus penicillins,Oxacillin,cloxacillinResistant against staphylococcus penicillinasis,Cephalosporins,They also owe their activity to b-lactam ring and are bactericidal.Good alter
31、natives to penicillins when a broad-spectrum drug is requiredshould not be used as first choice unless the organism is known to be sensitive,Cephalosporins,BACTERICIDAL-modify cell wall synthesisCLASSIFICATION-first generation are early compoundsSecond generation-resistant to-lactamasesThird generat
32、ion-resistant to-lactamases&increased spectrum of activityFourth generation-increased spectrum of activity,Cephalosporins,FIRST GENERATION-eg cefadroxil,cefalexin,Cefadrine-most active vs gram+ve cocci.An alternative to penicillins for staph and strep infections;useful in UTIsSECOND GENERATION-eg ce
33、faclor and cefuroxime.Active vs enerobacteriaceae eg E.coli,Klebsiella spp,proteus spp.May be active vs H influenzae and N meningtidis,Cephalosporins,THIRD GENERATION-eg cefixime and other I.V.s cefotaxime,ceftriaxone,ceftazidine.Very broad spectrum of activity inc gram-ve rods,less activity vs gram
34、+ve organisms.FOURTH GENERATION-cefpirome better vs gram+ve than 3rd generation.Also better vs gram-ve esp enterobacteriaceae&pseudomonas aerugenosa.I.V.route only,Cephalosporins(cont.)Adverse effects,Allergy(10-20%of patients wit penicillin allergy are also allergic to cephalosporins)Nephritis and
35、acute renal failureSuperinfectionsGastrointestinal upsets when given orally,Aminoglycosides(bactericidal)streptomycin,kanamycin,gentamicin,tobramycin,amikacin,netilmicin,neomycin(topical),Mode of action-The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation comp
36、lex(30S-mRNA-tRNA)so that no further initiation can occur.They also slow down protein synthesis that has already initiated and induce misreading of the mRNA.By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity.May also
37、 destabilize bacterial membranes.Spectrum of Activity-Many gram-negative and some gram-positive bacteriaResistance-CommonSynergy-The aminoglycosides synergize with-lactam antibiotics.The-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.,Aminoglycosides
38、Clinical pharmacokinetics,These are poorly lipid soluble and,therefore,not absorbed orallyParenteral administration is required for systemic effect.They do not enter the CNS even when the meninges are inflamed.They are not metabolized.,Aminoglycosides(cont.)Clinical pharmacokinetics,They are excrete
39、d unchanged by the kidney(where high concentration may occur,perhaps causing toxic tubular demage)by glomerular filtration(no active secretion).Their clearance is markedly reduced in renal impairment and toxic concentrations are more likely.,Aminoglycosides(cont.)Resistance,Resistance results from b
40、acterial enzymes which break down aminoglycosides or to their decreased transport into the cells.,Aminoglycosides(cont.)Examples,Gentamicin is the most commonly used,covering Gram-negative aerobes,e.g.Enteric organisms(E.coli,Klebsiella,S.faecalis,Pseudomonas and Proteus spp.)It is also used in anti
41、biotic combination against Staphylococcus aureus.It is not active against aerobic Streptococci.,Aminoglycosides(cont.)Examples,In addition to treating known sensitive organisms,it is used often blindly with other antibiotics in severe infections of unknown cause.Streptomycin was formerly the mainsta
42、y of antituberculous therapy but is now rarely used in the developed world.,Aminoglycosides(cont.)Examples,Tobramycin:used for pseudomonas and for some gentamicin-resistant organisms.Some aminoglycosides,e.g.Gentamicin,may also be applied topically for local effect,e.g.In ear and eye ointments.Neomy
43、cin is used orally for decontamination of GI tract.,Aminoglycosides(cont.)Adverse effects,Although effective,aminoglycosides are toxic,and this is plasma concentration related.It is essential to monitor plasma concentrations(shortly before and after administration of a dose)to ensure adequate concen
44、trations for bactericidal effects,while minimising adverse effects,every 2-3 days.,Aminoglycosides(cont.)Adverse effects,The main adverse effects are:NephrotoxicityToxic to the 8th cranial nerve(ototoxic),especially the vestibular division.Other adverse effects are not dose related,and are relativel
45、y rare,e.g.Allergies,eosinophilia.,Macrolides(bacteriostatic)erythromycin,clarithromycin,azithromycin,spiramycin,Mode of action-The macrolides inhibit translocation by binding to 50 S ribosomal subunitSpectrum of activity-Gram-positive bacteria,Mycoplasma,Legionella(intracellular bacterias)Resistanc
46、e-Common,Macrolides(cont.)Examples and clinical pharmacokinetics,Erythromycin is acid labile but is given as an enterically coated tabletAbsorption is erratic and poor.It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract(enterohepatic circulation).It may be given
47、orally or parenterally,Macrolides(cont.)Examples and clinical pharmacokinetics,Macrolides are widely distributed in the body except to the brain and cerebrospinal fluidThe spectrum includes Staphylococcus aureus,Streptococcuss pyogenes,S.pneumoniae,Mycoplasma pneumoniae and Chlamydia infections.,Mac
48、rolides(cont.)Examples and clinical pharmacokinetics,Newer macrolides such as clarithromycin and azithromycin may have fewer adverse effects.,Macrolides side effects,Nauzea,vomitusAllergyHepatitis,ototoxicityInteraction with cytochrome P450 3A4(inhibition),Chloramphenicol,Lincomycin,Clindamycin(bact
49、eriostatic),Mode of action-These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity.Spectrum of activity-Chloramphenicol-Broad range;Lincomycin and clindamycin-Restricted rangeResistance-CommonAdverse effects-Chloramphenicol is toxic(bone marrow suppression)but is used
50、 in the treatment of bacterial meningitis.,Clindamycin,Clindamycin,although chemically distinct,is similar to erythromycin in mode of action and spectrum.It is rapidly absorbed and penetrates most tissues well,except CNS.It is particularly useful systematically for S.aureus(e.g.osteomyelitis as it p
