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AMINOGLICOSIDI Tra gli aminoglicosidi la Streptomicina fu il primo antibiotico ad essere impiegato nel trattamento terapeutico della tubercolosi. La streptomicina.

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Presentazione sul tema: "AMINOGLICOSIDI Tra gli aminoglicosidi la Streptomicina fu il primo antibiotico ad essere impiegato nel trattamento terapeutico della tubercolosi. La streptomicina."— Transcript della presentazione:

1 AMINOGLICOSIDI Tra gli aminoglicosidi la Streptomicina fu il primo antibiotico ad essere impiegato nel trattamento terapeutico della tubercolosi. La streptomicina è prodotta da un actinobatterio. Essa è battericida nei confronti di batteri sensibili. Streptomicina Gentamicina Amicacina Netilmicina

2 Struttura e caratteristiche chimiche Sono delle basi deboli solubili in acqua. Sono policationi a pH corporeo e passano in quantità ridotte la membrana cellulare. Provengono da: Micromonospora actinomyctes Gentamicina (gentamicin and netilmicin) Streptomyces griseus Streptomicina (streptomicina e diidrostreptomicina) Kanamicina (kanamycina, amikacina, e tobramicina) Neomicina (neomicina) Apramicina (farmaco veterinario)

3 For Waksman the discovery of streptomycin in 1944 and its effect on the tubercle bacillus accomplished with the collaboration of A. Schatz and confirmation by E. Bugie was a rich and satisfying fulfillment of many of his personal and altruistic aims. Ever practical, he established effective and congenial relations with Merck and Company, which developed liquid culture methods for production of bulk quantities of the microbial products during World War II. Patenting and licensing the promising ones, notably streptomycin, provided funds, 80 percent of which was assigned to Rutgers University to support research and eventually an associated Institute of Microbiology. He also soon arranged to have animal tests and clinical trials carried out at the Mayo Clinic to expedite the possible use in treating tuberculosis. Of the 20 percent of license funds accruing in his own name, one-half was later consigned to a foundation for research support.

4 The first clinical trial with a randomized intake in the history of medicine was started in 1946 by the British Medical Research Council (13). Because only a limited amount of SM was available in the United Kingdom, patients with advanced pulmonary disease could ethically be randomized to treatment with bed rest alone or bed rest plus 2 g SM daily. The results (Table 1) showed a substantial immediate advantage to the SM arm, but most patients developed Sm/resistant strains, and the results of a 5-year follow-up indicated that they had little eventual benefit compared with the control arm.

5 The major historical landmarks of tuberculosis (TB) therapy include: the discovery of effective medications (streptomycin and para-aminosalicylic acid) in 1944; the revelation of "triple therapy" (streptomycin, para-aminosalicylic acid and isoniazid) in 1952, which assured cure; recognition in the 1970s that isoniazid and rifampin could reduce the duration of treatment from 18 to 9 months; and the observation in the 1980s that adding pyrazinamide to these drugs allowed cures in only 6 months.

6 Spettro d’azione - Altamente efficaci nei confronti di bacilli gram negativi - Efficaci (Netilmicina) contro lo stafilococco meticillino resistente - Meno efficaci nei confronti dei cocchi gram negativi P.aeruginosa: gentamicina,tobramicina, amikacina e netilmicina - Resistenti agli enterococchi e Micobatteri anaerobi: streptomycin, kanamycin

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9 Aerobic. Most common cause of urinary tract infection in young women. Causes cystitis, pyelonephritis, sepsis, neonatal meningitis, and enteric diseases. Enterohemorrhagic E. coli causes hemolytic uremic syndrome, and enterotoxigenic E. coli causes travelers diarrhea. E.Coli aerobic (faculatative anaerobe) encapsulated Causes pneumoniae (thick bloody sputum) and urinary tract infection.The autoimmune disease, ankylosing spondylitis, is thought to be a possible sequela of Klebsiella infection. Klebsiella

10 Gli aminoglicosidi inibiscono la sintesi proteica legandosi alla porzione 16S rRNA del ribosoma batterico interferendo con il legame della FORMIL- METHIONYL-tRNA nelle subunità 30S. Questo impedisce l’inizio della sintesi proteica portando a morte le cellule batteriche. Meccanismo di azione

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12 Formylmethionyl-tRNA, fMet-tRNA et, plays a key role in the initiation of bacterial protein synthesis, acting as the donor of the NH 2 -terminal amino acid of the nascent polypeptide chain. A regulatory function for this tRNA was recently suggested by the observation of its binding to Escherichia coli RNA polymerase holoenzyme; this is a specific interaction that requires both the formyl and tRNA moieties.

13 USI “STORICI” DELLA STREPTOMICINA Nella tubercolosi viene usata in combinazione con altre farmaci anti- TB. Non è il trattamento di scelta. Nella peste (Yersinia pestis), è stata storicamente trattata con la streptomicina che è il farmaco di scelta e approvata per questa finalità dalla FDA americana. Nelle endocarditi infettive causate da enterococchi quando l’organismo non è sensibile alla Gentamicina. Nella medicina veterinaria, la streptomicina è il primo antibiotico usato contro i batteri gram negativi in grandi animali come cavalli, pecore e bovini. E’ comunemente combinata alla penicillina-g per iniezioni intramuscolo. Generalmente la streptomicina viente somministrata per via intramuscolare (in molti paesi è auturozzata la sola somministrazione intramuscolo). Il farmaco però può essere somministrato anche per via endovenosa.

14 Meccanismi di resistenza 1)Produzione di enzimi che inattivano gli aminoglicosidi per adenililazione, acetilazione e fosforilazione 2)Incapacità di entrare nella cellula batterica 3)Target proteico alterato

15 Resistenza batterica agli aminoglicosidi

16 The aminoglycosides can be ranked in order of decreasing toxicity: neomycin> amikacin > gentamicin > tobramycin > netilmicin. Differences in nephrotoxic potential are related to increased ability to bind to the brush border membranes of the renal tubule. Experimental and clinical studies have shown that the relative risk of developing auditory toxicity from gentamicin and tobramycin is generally considered to be equivalent. Tossicita’

17 1)Ototossicità Danno cocleare: tinnito e perdita dell’udito Danno vestibolare: vertigini atassia e perdita della postura 2) Nefrotossicità (si manifesta attraverso la proteinuria) 3) Blocco neuromuscolare (in particolare dato dall’associazione con la neostigmina e gluconato di calcio) 4) Reazioni allergiche Effetti collaterali

18 Fig. 1. Proposed mechanism of aminoglycoside (AG) toxicity at the level of the hair cell in the cochlea and utricle of the inner ear. After the AG enters the hair cell through mechano-electrical transducer channels, it forms a complex with a transition metal, in this case iron (Fe). These redox active complexes generate ROS/RNS including the superoxide anion radical, hydrogen peroxide, hydroxyl radical, peroxynitrite anion, etc. These reactants activate JNK (c-Jun N-terminal kinase) which then translocate (straus locates) to the nucleus to activate genes in the cell death pathway; these products are then transferred to the mitochondria (mito) where they promote the release of cytochrome c (Cyt c). In the cytosol, Cyt c triggers the activation of a series of caspases followed by apoptosis (programmed cell death) via what is referred to as caspase-dependent cell death. In addition to this caspase-dependent apoptotic pathway, AG may also kill cells via caspase-independent mechanisms

19 Indian J Med Res 129, January 2009, pp Correspondence Sir, Streptomycin (SM) has been used in the treatment of tuberculosis (TB) for more than 50 years and is an important part of current treatment regimens for category II pulmonary TB cases. Due to its usage over a period of time and even as a monotherapy, resistance to streptomycin has increased. Globally, the range of initial and acquired streptomycin resistance has been reported to be and per cent, respectively during the period

20 Cloramfenicolo Il cloramfenicolo è un antibiotico a largo spettro d’azione che è usato largamente in applicazioni topiche in oftalmologia e dermatologia.

21 Spettro d’azione Meningiti Psittacosi Fibrosi cistica Rickettiosi Haemophilus influenzae Limfogranuloma venereo Salmonella Febbre tifoide

22 Meccanismo di azione Il cloramfenicolo è un farmaco liposolubile ed entra bene nella membrana batterica legandosi irreversibilmente alla subunità 50s dei ribosomi batterici dove impedisce il trasferimento di un aminoacido nella crescita proteica sia negli organismi procariotici che nei mitocondri.

23 Effetti tossici Gli effetti tossici possono ssere di natura: 1) Neurologica: Confusione, mal di testa 2) Oftalmici: Bruciore agli occhi 3) Psichiatrici: Depressione 4) Cardiaci: sindrome grigia del neonato, anemia aplastica

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25 A conjugative plasmid, pMRV150, which mediated multiple-drug resistance (MDR) to at least six antibiotics, including ampicillin, streptomycin, gentamicin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole, was identified in a Vibrio cholerae O139 isolate from Hangzhou, eastern China, in Resistenza batterica multipla

26 Indian J Med Res May;127(5): Trend of antibiotic resistance of Vibrio cholerae strains from East Delhi. Das SDas S, Saha R, Kaur IR.Saha RKaur IR Department of Microbiology, University College of Medical Sciences & Guru Teg Bahadur Hospital, Shahdara, Delhi, India. Multiple antibiotic resistance (MAR) V. cholerae O1 Inaba isolates exhibited increased resistance to ciprofloxacin with MIC >4 microg/ml, but largely all remained susceptible to other antibiotics like, gentamicin, tetracycline and chloramphenicol.

27 J Infect Dev Ctries Feb 28;3(1): Prevalence and antibiotic-resistance of Salmonella isolated from food in Morocco. Bouchrif BBouchrif B, Paglietti B, Murgia M, Piana A, Cohen N, Ennaji MM, Rubino S, Timinouni M.Paglietti BMurgia MPiana ACohen NEnnaji MM Rubino STiminouni M Laboratoire de Microbiologie et d'Hygiène des aliments et des eaux, Institut Pasteur du Maroc, Morocco. Salmonellosis remains one of the most frequent food-borne diseases worldwide, especially in developing countries. The emergence of antimicrobial resistance in Salmonella isolates from food can potentially compromise the treatment of these infections. Resistance to tetracycline was the most common finding (21%), followed by resistance to ampicillin (13%), amoxicillin+clavulanic acid (9%), streptomycin (7%), chloramphenicol (4%) and nalidixic acid (3,8%). None of the isolates was resistant to 3rd-cephalosporin and fluoroquinolones (i.e. ciprofloxacin).

28 Magnitude of drug resistant Shigellosis: a report from Bangalore. Srinivasa HSrinivasa H, Baijayanti M, Raksha Y.Baijayanti MRaksha Y Department of Microbiology, St. John's Medical College, Bangalore , India. Shigella is an important cause of acute invasive diarrhea in children and others. The results also suggest that Ampicillin, Co-trimoxazole, Chloramphenicol, Nalidixic acid and Ciprofloxacin should not be used empirically as the first line drugs in the treatment of Shigellosis. Periodic analysis and reporting of antibiotic susceptibility is an important measure to guide antibiotic treatment.

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30 BMJ Jan 15;338:a2812. doi: /bmj.a2812. Links Does single application of topical chloramphenicol to high risk sutured wounds reduce incidence of wound infection after minor surgery? Prospective randomised placebo controlled double blind trial. Heal CFHeal CF, Buettner PG, Cruickshank R, Graham D, Browning S, Pendergast J, Drobetz H, Gluer R, Lisec C.Buettner PGCruickshank RGraham DBrowning SPendergast J Drobetz HGluer RLisec C James Cook University, School of Medicine, Mackay Base Hospital, Queensland 4740, Australia. Application of a single dose of topical chloramphenicol to high risk sutured wounds after minor surgery produces a moderate absolute reduction in infection rate that is statistically but not clinically significant

31 Antimicrob Agents Chemother Nov;52(11): Inhibition of voriconazole metabolism by chloramphenicol in an adolescent with central nervous system aspergillosis. Hafner VHafner V, Albermann N, Haefeli WE, Ebinger F.Albermann NHaefeli WEEbinger F Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. For an adolescent with bacterial meningitis and subsequent cerebral aspergillosis, intravenous voriconazole dose requirements substantially decreased during coadministration with intravenous chloramphenicol and considerably rose after discontinuation of the antibiotic. In agreement with in vitro evidence, these data suggest that chloramphenicol is a rather significant inhibitor of hepatic CYP3A4 and/or CYP2C19. Interazione tra antibiotici


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