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1、Antimicrobial Agents,Martin Votava Olga 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 t
2、o certain 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 ant
3、ibiotic might 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 species of microorganisms: bacteria, fungi, actinomycetes- to suppress the growth
4、 of other microorganisms 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., infec
5、tious bacteria, would 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
6、 colony is a clear zone where no bacteria are growing Zone 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
7、of other antibiotics from Streptomyces griseus.,Susceptibility vs. Resistance of 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
8、 MI effect is sufficient bacteriostatic agents (slow protein synthesis, prevent bacterial division) Host defenses impaired- bactericidal agents Complete ATB-mediated killing is necessary,Susceptibility vs. Resistance (cont.),Dose of drug has to be sufficient to produce effect inhibit or kill the mic
9、roorganism: However concentration of the drug must remain below those that are toxic to human cells If can be achieved microorganism susceptible to the ATB If effective concentration is higher than toxic- microorganism is resistant,Susceptibility vs. Resistance (cont.),Limitation of in vitro tests I
10、n vitro sensitivity tests are based on non-toxic plasma concentrations cut off Do not reflect concentration at the site of infection E.g.: G- aer.bacilli like Ps.aeruginosa inhibited by 2 4 ug/ml of gentamycin or tobramycin. Susceptible !?,Antibiotic Susceptibility Testing,Susceptibility vs. Resista
11、nce (cont.),Plasma concentration above 6-10 ug/ml may result in ototoxicity or nephrotoxicity Ration 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 b
12、e only marginally effective or ineffective even those in vitro 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 plasm
13、a , so resistant“ agents can be effective in infection limited to urine tract,Resistance,To be effective ATB must reach the target and bind to it. Resistance: Failure to reach the target The drug is inactivated The target is altered,Resistance (cont.),Bacteria produce enzymes at or within the cell s
14、urface inactivate drug Bacteria possess impermeable cell membrane prevent 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
15、by selection to daughter cells. More commonly horizontal transfer of resistance 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 itself Or genetic exchan
16、ge between resistant and further susceptible strains.,Resistance (cont.),Methicilin resistant strains of Staphylococcus aureus clonally derived from few ancestral strains with mecA gene Encodes low-affinity penicillin-binding protein that confers methicillin resistance. Staphylococcal beta-lactamase
17、 gene, which is plasmid encoded, presumambly transferred on numerous occasions. Because is 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
18、initial infecting organism not identified single broad spectrum agent Definitive therapy- microorganism 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 susceptibility Gr
19、am stain Pending isolation and identification of the pathogen Specimen for culture from site of infection 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 (e
20、specially in Gram-possitive organisms) Penicillins are bactericidal but can act only on dividing cells They are not toxic to animal cells which have no cell wall,Synthesis of Penicillin,b-Lactams produced by fungi, some ascomycetes, and several actinomycete bacteria b-Lactams are synthesized from am
21、ino acids valine and cysteine,b Lactam Basic Structure,Penicillins (cont.) Clinical Pharmacokinetics,Penicillins 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 unch
22、anged by the kidney, but the dose should be reduced in severe renal failure,Penicillins (cont.) Resistance,This is the result of production of b-lactamase in the bacteria which destroys the b-lactam ring It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrhoea,Penicil
23、lins (cont.) Examples,There are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach 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 labil
24、e and b-lactamase sensitive and is given only parenterally It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, Clostridia,Penicillins (cont.) Examples,Pheno
25、xymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections it is otherwise similar to benzylpenicillin,Penicillins (cont.) Examples,Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those
26、above) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains It is acid stable, is given orally or parenterally, but is b-laclamase sensitive,Penicillins (cont.) Examples,Amoxycillin is similar but better absorbed orally It is sometimes combined with clavulanic ac
27、id, 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 way It extends the spectrum of amoxycillin,Penicillins (cont.) Examples,Flucloxacillin is acid stable and is given orally or parenterally It is b-lactamase re
28、sistant It is used as a narrow spectrum drug for Staphylococcus aureus infections,Penicillins (cont.) Examples,Azlocillin is acid labile and is only used parenterally It is b-lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus species It is used intravenou
29、sly for life-threatening infections,i.e. in immunocompromised patients together with an aminoglycoside,Penicillins (cont.) Adverse effects,Allergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effects Superinfections(e.g.caused by Candida
30、 ) Diarrhoea : especially with ampicillin, less common with amoxycillin Rare: haemolysis, nephritis,Penicillins (cont.) Drug interactions,The use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation,Antistap
31、hylococcus penicillins,Oxacillin, cloxacillin Resistant against staphylococcus penicillinasis,Cephalosporins,They also owe their activity to b-lactam ring and are bactericidal. Good alternatives to penicillins when a broad -spectrum drug is required should not be used as first choice unless the orga
32、nism is known to be sensitive,Cephalosporins,BACTERICIDAL- modify cell wall synthesis CLASSIFICATION- first generation are early compounds Second generation- resistant to -lactamases Third generation- resistant to -lactamases & increased spectrum of activity Fourth generation- increased spectrum of
33、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 UTIs SECOND GENERATION- eg cefaclor and cefuroxime. Active vs enerobacteriaceae eg E. coli, Klebsiella spp,proteus sp
34、p. 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 +ve organisms. FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generat
35、ion. 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 acute renal failure Superinfections Gastrointestinal upsets when
36、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 complex (30S-mRNA-tRNA) so that no further initiation ca
37、n 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 destabilize bacterial membranes. Spectrum of A
38、ctivity -Many gram-negative and some gram-positive bacteria Resistance - Common Synergy - The aminoglycosides synergize with -lactam antibiotics. The -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.,Aminoglycosides Clinical pharmacokinetics,These are
39、 poorly lipid soluble and, therefore, not absorbed orally Parenteral 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 excreted unchanged by the kidney (w
40、here 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 bacterial enzymes whic
41、h 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 antibiotic com
42、bination 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 mainstay of
43、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. N
44、eomycin 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 ade
45、quate concentrations for bactericidal effects, while minimising adverse effects, every 2-3 days.,Aminoglycosides (cont.) Adverse effects,The main adverse effects are: Nephrotoxicity Toxic to the 8th cranial nerve (ototoxic), especially the vestibular division. Other adverse effects are not dose rela
46、ted, and are relatively rare, e.g. Allergies, eosinophilia.,Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin,Mode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunit Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legione
47、lla (intracellular bacterias) Resistance - Common,Macrolides (cont.) Examples and clinical pharmacokinetics,Erythromycin is acid labile but is given as an enterically coated tablet Absorption is erratic and poor. It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal trac
48、t (enterohepatic circulation). It may be given orally or parenterally,Macrolides (cont.) Examples and clinical pharmacokinetics,Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid The spectrum includes Staphylococcus aureus, Streptococcuss pyogenes, S. pneumonia
49、e, Mycoplasma pneumoniae and Chlamydia infections.,Macrolides (cont.) Examples and clinical pharmacokinetics,Newer macrolides such as clarithromycin and azithromycin may have fewer adverse effects.,Macrolides side effects,Nauzea, vomitus Allergy Hepatitis, ototoxicity Interaction with cytochrome P450 3A4 (inhibition),Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic),Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Spectrum of activity - Chloramphenicol - Broad range; Lincomycin a