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.

StreptomicinaStreptomicinaGentamicinaAmicacinaNetilmicina

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)

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 negativiP.aeruginosa: gentamicina,tobramicina, amikacina e netilmicina- Resistenti agli enterococchi e Micobatteri anaerobi: streptomycin, kanamycin

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

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

Formylmethionyl-tRNA, fMet-tRNA et, plays a key role in the initiation of bacterial protein synthesis, acting as the donor of the NH2-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.

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.

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

Resistenza batterica agli aminoglicosidi

1) OtotossicitàDanno cocleare: tinnito e perdita dell’uditoDanno 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

Fig. 1. Proposed mechanism of aminoglycoside (AG) toxicity atthe level of the hair cell in the cochlea and utricle of the innerear. After the AG enters the hair cell through mechano-electricaltransducer channels, it forms a complex with a transition metal,in this case iron (Fe). These redox active complexes generateROS/RNS including the superoxide anion radical, hydrogenperoxide, hydroxyl radical, peroxynitrite anion, etc. Thesereactants activate JNK (c-Jun N-terminal kinase) which thentranslocate (straus locates) to the nucleus to activate genes in thecell death pathway; these products are then transferred to themitochondria (mito) where they promote the release ofcytochrome c (Cyt c). In the cytosol, Cyt c triggers the activationof a series of caspases followed by apoptosis (programmed celldeath) via what is referred to as caspase-dependent cell death. Inaddition to this caspase-dependent apoptotic pathway, AG mayalso kill cells via caspase-independent mechanisms

Indian J Med Res 129, January 2009, pp 108-110

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 0-51.5 and 0-73.1 per cent, respectively during the period 1999-2002.

Cloramfenicolo

Il cloramfenicolo è un antibiotico a largo spettro d’azione che è usato

largamente in applicazioni topiche in oftalmologia e dermatologia.

Spettro d’azione

Meningiti

Psittacosi

Fibrosi cistica

Rickettiosi

Haemophilus influenzae

Limfogranuloma venereo

Salmonella

Febbre tifoide

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.

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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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 2004.

Resistenza batterica multipla

Indian J Med Res. 2008 May;127(5):478-82.

Trend of antibiotic resistance of Vibrio cholerae strains from East Delhi.Das S, Saha R, Kaur IR.Department of Microbiology, University College of Medical Sciences & Guru Teg Bahadur Hospital, Shahdara, Delhi, India. shukladas_123@yahoo.com

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.

J Infect Dev Ctries. 2009 Feb 28;3(1):35-40. Prevalence and antibiotic-resistance of Salmonella isolated from food in Morocco.Bouchrif B, Paglietti B, Murgia M, Piana A, Cohen N, Ennaji MM, Rubino S, Timinouni 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).

Magnitude of drug resistant Shigellosis: a report from Bangalore.Srinivasa H, Baijayanti M, Raksha Y.Department of Microbiology, St. John's Medical College, Bangalore - 560 034, 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.

BMJ. 2009 Jan 15;338:a2812. doi: 10.1136/bmj.a2812. LinksDoes 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 CF, Buettner PG, Cruickshank R, Graham D, Browning S, Pendergast J, Drobetz H, Gluer R, Lisec C.James Cook University, School of Medicine, Mackay Base Hospital, Queensland 4740, Australia. clare.heal@jcu.edu.au

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

Antimicrob Agents Chemother. 2008 Nov;52(11):4172-4. Inhibition of voriconazole metabolism by chloramphenicol in an adolescent with central nervous system aspergillosis.Hafner V, Albermann N, Haefeli WE, Ebinger 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