抗微生物药物（英文ppt）antimicrobial_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 to 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 antibiotic 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 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., infectious 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 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 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 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 microorganism: 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 In 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 8 4 02 1 Tetracycline (g/ml) MIC = 2 g/ml Determination of MIC Chl Amp Ery Str Tet Disk Diffusion Test Susceptibility vs. Resistance (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 be 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 plasma , 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 surface 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 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 exchange 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 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 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 Gram 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 (especially 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 amino 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 unchanged 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 Penicillins (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 labile 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 Phenoxymethylpenicillin (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 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 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 way It extends the spectrum of amoxycillin Penicillins (cont.) Examples Flucloxacillin is acid stable and is given orally or parenterally It 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 parenterally It is b-lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus species It 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% patients). Patient should be always asked about a history of previous exposure and adverse effects Superinfections(e.g.caused by Candida ) 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 Antistaphylococcus 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 organism 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 useful in UTIs SECOND GENERATION- eg cefaclor 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 +ve organisms. FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation. Also better vs gram -ve esp enterobacteriaceae Lincomycin and clindamycin - Restricted range Resistance - Common Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used 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 penetrates bone well) and anaerobic infections. Clindamycin Adverse effects Diarrhoea is common. Superinfection with a strain of Clostridium difficile which causes serious inflammation of the large bowel (Pseudomembranous colitis) Chloramphenicol This inhibits bacterial protein synthesis. It is well absorbed and widely distributed , including to the CNS. It is metabolized by glucoronidation in the liver. Although an effective broad-spectrum antibiotics, its uses are limitid by its serious toxicity. Chloramphenicol (cont.) The major indication is to treat bacterial meningitis caused by Haemophilus influenzae, or to Neisseria menigitidis or if organism is unknown.It is also specially used for Rikettsia (typhus). Chloramphenicol (cont.) Adverse effects A rare anemia, probably immunological in origin but often fatal Reversible bone marrow depression caused by its effect on protein synthesis in humans Liver enzyme inhibition Sulfonamides and trimethoprim Sulfonamides are rarely used alone today. Trimethoprim is not chemically related but is considered here because their modes of action are complementary. Sulfonamides, Sulfones (bacteriostatic) Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. Trimethoprim, Methotrexate, (bacteriostatic) Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. Spectrum of activity - Broad range activity against gram- positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains. p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides Sulfonamides and trimethoprim Mode of action Folate is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid. Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria. Sulfonamides and trimethoprim Clinical pharmacokinetics Most sulfonamides are well absorbed orally and they are widely distributed including to the CNS. Most are excreted by the kidney unchanged. They are effective against Gram-positive and many Gram-negative organism but are rarely used alone now. Sulfonamides and trimethoprim Clinical pharmacokinetics Trimethoprim is also well absorbed and excreted by the kidneys, with similar spectrum. Cotrimoxazole is widely used for urinary and upper respiratory tract infections but should not be the drug of choice because of its adverse effects. Sulfonamides and trimethoprim Clinical pharmacokinetics It is the drug of choice for the treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients. Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective. Sulfonamides and trimethoprim Adverse effects Gastrointestinal upsets Less common but more serious: -sulfonamides: allergy, rash, fever, agranulocytosis, renal toxicity -trimethoprim: macrocytis anemia, thrombocytopenia -cotrimoxazole: aplastic anemia Sulfonamides and trimethoprim Drug intereactions Sulfonamides can decrease metabolism of phenytoin, warfarin and some oral hypoglycaemics, increasing their effects. Quinolones (bactericidal) nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. Spectrum of activity - Gram-positive cocci and urinary tract infections Resistance - Common for nalidixic acid; developing for ciprofloxacin Quinolones The quinolones are effective but expensive antibiotics. With increased use, resistance to these drugs is becoming more common. They should in general be reverse drugs and not first-line treatment. Quinolones (cont.) Examples and clinical pharmacokinetics Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower urinary tract infections, as it has no systemic antibacterial effect. Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas, Quinolones (cont.) Examples and clinical pharmacokinetics It can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such as peritonitis and Salmonella. Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections. Quinolones (cont.) Adverse effects Gastrointestinal upsets Fluoroquinolones may block the inhibitory neurotransmitter GABA, and this may cause confusion in the elderly and lower the fitting threshold. They are also contraindicated in epileptics. Allergy and anaphylaxis Quinolones (cont.) Adverse effects Possibly damage to growing cartilage: not recommended for pregnant women and children Drug interaction Ciprofloxacin is a liver enzyme inhibitor and may cause life-threatening interaction with theophylline. Tetracyclines (bacteriostatic) tetracycline, minocycline and doxycycline Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. Spectrum of activity - Broad spectrum; Useful against intracellular bacteria Resistance - Common Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. Tetracyclines (cont.) Examples and clinical pharmacokinetics Tetracycline, oxytetracycline have short half -lives. Doxycycline has a longer half-life and can be given once per day. These drugs are only portly absorbed. They bind avidly to heavy metal ions and so absorption is greatly reduced if taken with food, milk, antacids or iron tablets. Tetracyclines (cont.) Examples and clinical pharmacokinetics They should be taken at least half an hour before food. Tetracyclines concentrate in bones and teeth. They are excreted mostly in urine, partly in bile. They are broad spectrum antibiotics, active against most bacteria except Proteus or Pseudomonas. Tetracyclines (cont.) Examples and cli