Chimioterapia antimicrobian

Bacterii gram pozitive aerobeCOCIgrmezi Staphylococcusn lanuri- streptocociDiplo i lanuri - - S. pneumoniae Enterococcus sp.

BACILIBacillus sp.Corynebacterium sp.Listeria monocytogenesNocardia sp.

Bacterii gram negative aerobeCOCIMoraxella catarrhalisNeisseria gonorrhoeaeNeisseria meningitidisHaemophilus influenzaeBACILIFam EnterobacteriaceaeEscherichia coli, Enterobacter sp.Citrobacter, Klebsiella sp.Proteus sp., SerratiaSalmonella, Shigella, YersiniaAcinetobacter,HelicobacterPseudomonas aeruginosa*

Germeni anaerobiSub diafragmClostridium perfringens, tetani, Cl. difficileBacteroides fragilis, disastonis, ovatus, thetaiotamicronFusobacterium

Deasupra diafragmuluiPeptococcus sp.Peptostreptococcus sp.PrevotellaVeillonellaActinomyces

Alte bacteriiBacterii atipiceLegionella pneumophilaMycoplasma pneumoniae sau hominisChlamydia pneumoniae, psittaci sau trachomatisRickettsia SpirocheteTreponema pallidum (syphilis)Borrelia burgdorferi (Lyme)

Bacteriile dupa sediul infecieiCavitate bucalaPeptococcusPeptosptreptococcusActinomycesPiele i esut subcutanatS. aureusStr.pyogenesS.epidermidisPasteurellaSistem osteoarticularS.aureusS.epidermidisStreptocociN.gonorrhoeaeBacili gram negativi

AbdomenE.coli, ProteusKlebsiellaEnterococcusBacteroides sp.Tract urinarE.coli, ProteusKlebsiellaEnterococcusS.saprophyticusTract respirator superiorS.pneumoniaeH.influenzeMoraxella catharrhalisStr.pyogenesTract respirator inferiorInfecii comunitareS.pneumoniaeH.influenzaeK.pneumoniaeLegionella pneumophylaMycoplasma, Chlamydia

Tract respirator inferiorInfecii nosocomialeK.pneumoniaePseudomonas aeruginosaEnterobacter sp.SerratiaS.aureusMeningiteStreptococcus pneumoniaeNeisseria meningitidisHaemophilus influenzaeStreptococ de grup BEscherichia coliListeria

Chimioterapice antiinfecioaseDefiniie: un grup de medicamente, cu toxicitate selectiv, capabile s distrug i s stnjeneasc multiplicarea unor anumite organisme patogene, implicate etiologic n variate infecii. ascomicete(Penicillium)actinomycete (Streptomyces, b.gr.+) genul Bacillus

Chimioterapice antimicrobieneAntibacterieneAntiviraleAntifungiceAntiprotozoareAntihelmintice

3 principii de baz ale chimioterapiei antiinfecioase1Toxicitatea selectiv exploatarea diferenelor de structur i metabolism a agenilor patogeni i a celulei gazd (a omor microorganismul i nu gazda uman!)2Atingerea unei concentraii inhibitorii la sediul infeciei3Penetrarea i ataarea de int, evitnd inactivarea i eliminarea

Spectrul de activitateSpectrul natural - cuprinde toate speciile bacteriene sensibile la un chimioterapic n momentul introducerii sale n terapie Pentru medicul bacteriolog, cunoaterea rezistenei naturale la antibiotice are valoare practic deosebit deoarece pe baza acestei rezistene se prepar mediile selective cu antibiotice, foarte utile izolrii n cultur pur a unor specii micobiene din produse intens contaminate.

Spectrul actual - cuprinde tulpinile microbiene sensibile la un anumit antibiotic, la un moment dat, ntr-o zon limitat i depinde n mare msur de antibioticele utilizate n zona respectiv. este mai restrns dect cel natural, deoarece n timpul scurs de la introducerea chimioterapicului n practic are loc apariia tulpinilor rezistente .

Lista neagrSe elaboreaz prin monitorizarea strict a sensibilitii la chimioterapice antiinfeciose a tuturor tulpinilor izolate intr-un spital ntr-un numr stabilit de ani (4-6). Antibioticele la care tulpinile arat un grad mare de rezisten se scot din uz pentru o perioad lung de timp, n care tulpinile i rectig sensibilitatea

Clasificarea chimioterapicelor antibacteriene:1. Dup origineAntibiotice - produi naturali ai fungilor, actinomycetelor i al bacteriilor ce omoar sau inhib creterea microbilor, ex. peniciline, cephalosporine, tetracycline, etcCompui sintetici, ex. trimethoprim,

Clasificarea chimioterapicelor antibacteriene: 2. aciunea bactericid sau bacteriostaticBactericid - omoar microorganismeleBacteriostatic oprete multiplicarea bacteriilor aprarea antiinfecioas este mai eficient cu o populaie static (este mai puin eficient la gazde immunocompromise)

Unii ageni, (ex.chloramphenicolul), pot fi bactericizi pentru unele specii (ex. H. influenzae), dar numai bacteriostatici pentru altele (ex. E. coli)

Clasificarea chimioterapicelor antibacteriene: 3. Dup structura chimic

Sinteza peretelui celular (PC lipsete la celulele eucariote)Sinteza proteic (ribozomi)Sinteza acizilor nucleiciInterferarea funciilor membranei citoplasmatice

Clasificarea chimioterapicelor antibacteriene: 4. Dup inta activitii (selectivitatea)

STRUCTURA CELULEI BACTERIENE Unitatea morfofuncional a bacteriilor este celula procariot , un complex autoorganizat de molecule organice care schimb energie cu mediul nconjur tor i este capabil s -i regleze n mod autonom funciile vitale.

Structura celulei bacteriene

Structura peretelui celular la bacteriile gram pozitive

Structura peretelui celular la bacteriile gram negative

1. Sinteza peretelui celularCycloserinaGlycopeptidele (vancomycina, teicoplanina)BacitracinaBeta-lactaminele (penicilline, cephalosporine, carbapeneme, monobactami)

Cycloserina, isoniazida, etionamidaSunt chimioterapice utilizate n tratamentul TBC.Cicloserina inhib enzime care catalizeaz sinteza PCIsoniazida i etionamida interfereaz cu multiplicarea micobacteriilor la mai multe nivele. Etionamida (Nizotin) are efect tuberculostatic - indicatii in tuberculoza rezistenta in formele acute si grave reactii adverse: reactii alerice, hipoglicemie, cresterea transaminazelor serice, hepato si neurotoxice

Peptidoglicanul (murein) inta inhibitorilor sintezei peretelui celularCitoplasmsintezaprecursorilorPeretelui celularUDPNAGUDPUDPNAMCycloserinainhibit reaciile implicaten incorporarea D-ala-D-ala n catena lateral peptidic a NAMNAG N-acetilglucosaminNAM acid N-acetilmuramicD- alaD- alaL- alaninD- a.glutamicL- lisin

BacitracinaAntibiotic cu structur polipeptidic , care datorit toxicitii ridicate se utilizeaz doar n aplicaii locale n infecii cutanate.Este activ doar pe BGP prin multiple mecanismempiedic sinteza PCinhibiia enzimaticalterarea MC

Inihibitori ai sintezei peretelui celularMembrana citoplasmaticSinteza de noi subuniti a peretelui celular ataate de un carrier lipidicUDPGlycopeptidele Se leag de resturile terminale de D-ala-D-ala: previn incorporarea subunitilor n procesul de elongare a peptidoglicanuluiNAGNAMPPlipid C55Bacitracina Previne defosforilarea carrierului fosfolipidic, ce previne regenerarea carrierului necesar continurii sintezeiL- lisin

Activitatea glicopeptidelor (ageni activi pe peretele celular) asupra microorganismelor oblinuiteGlicopeptideVancomicinTeicoplanin

Stafilococi++E.coliRRStreptococi++Enterococi++PseudomonasRRGram (+)Gram (-) Molecule mari polare, se administreaz n general iv. Sunt active pe MRSA (Staphylococcus aureus meticilino R) Pe cale oral vancomocina este utilizat n tratmentul infeciilor produse de C. difficile (bacil G (+) ana) Vancomicina este nefrotoxic, teicoplanina mai puin

Antibiotice beta-lactamicePenicilineCephalosporineCarbapenemeMonobactamiCephamycineToate acioneaz prin legarea de proteine denumite penicillin-binding proteins (PBP)PBP sunt enzime implicate in sinteza compuilor de perete ce solidarizeaz transversal lanurile de peptidoglicanBacteriile au PBP diferiteSpectrul de activitate depinde de faptul dac antibioticul se leag de PBPs coninute n microorganismul implicat

Peniciline naturale: GP: Benzyl, Penicilina G potasic, sodic, Procain (Efitard), Benzantin peniciline(Moldamin, Retarpen) iVO (Ospen)GRAM POZITIVIS.aureus (peni-S)!!!Streptococcus pneumoniae!!!Streptococcus pyogenesStreptococi viridansEnterocociBacili Gram pozitivi (Bacillus)GRAM NEGATIVINeisseria meningitidisNeisseria gonorrhoeae!!!

GERMENI ANAEROBI(deasupra diafragmului)ClostridiumBacteroidesActinomycesALTII-Treponema pallidum-Borrelia burgdorferi

Coci Gram-positivi S. aureus (MSSA)Streptococcus pneumoniaeStreptococcus pyogenesstreptococci viridans

***Nafcilina-n infecii SNC!!(de elecie n meningite cu MSSA)i la cei cu funcie renal afectat ***Penicilinele orale indicate n infecii uoare de esuturi moi/alternativ cefalosporinele I.

Peniciline rezistente la penicilinazNafcilina, oxacilinaP,O, meticilina, cloxacilinaO, dicloxacilinaO

AminopenicilineampicilinIV,IM,O: Ampicilin, Pamecil, Standacillin, Ampidar, amoxicilinO: Amoxicilina, Dispamox, Duomox, Moxilen,Gram-positivi Gram-negativi !!!S.aureus Proteus mirabilisStreptococcus agalactiaeSalmonella, Shigella Streptococci viridans E. coliEnterococcus sp.L- H. influenzae Listeria monocytogenes

***Ampicilina: pneumonii comunitare, inf. enterococice, deseori n asociere cu aminoglicozidele***Amoxicilina: otita medie, sinizite,exacerbri ale bronitelor cronice, ITU

Peniciline cu spectru larg: Carboxypeniciline:carbenicillinIV,O, ticarcillinGram-negative Proteus mirabilisSalmonella, ShigellaE. coliL- H. influenzaeEnterobacter sp.Pseudomonas aeruginosa (AB de elecie) +/-Anaerobi (ca AB de a 2-a intenie n infecii abdominale)

Peniciline cu spectru larg: Ureidopeniciline: piperacillin, mezlocillin

Gram-positiveGram-negative strep. viridans Proteus mirabilisSalmonella, ShigellaEnterococcusE. coliL- H. influenzae Enterobacter sp. Pseudomonas aeruginosaSerratia marcescensKlebsiella sp.Anaerobi***Piperacilina preferat n locul ticarcilinei (activitate anti-Pseudomonas).

Inhibitori ai sintezei peretelui celularPerete celular Ataarea de noi subuniti pentru elongarea peptidoglicanuluiUDPL- lisinaD- ala

Antibiotice beta-lactamicePenicilineCephalosporineCarbapenemeMonobactamiCephamycineToate acioneaz prin legarea de proteine denumite penicillin-binding proteins (PBP)PBP sunt enzime implicate in sinteza compuilor de perete ce solidarizeaz transversal lanurile de peptidoglicanBacteriile au PBP diferiteSpectrul de activitate depinde de faptul dac antibioticul se leag de PBPs coninute n microorganismul implicat

Inelul beta-lactamicORSCOOHNRPenicilinele, ex, penicilina, cloxacilina,flucloxacilina, ampicilina, amoxicilina,carbenicilina, ticarcilina, azlocilina, mezlocilina, piperacilinaCephalosporine, ex, cephalexin, cefaclor, cefadrxil, cefuroxim, cefamandole, cefotaxim, ceftazidim,cetriaxon

Inelul beta-lactamicORNORCCOOHNORSCOOHNRCarbapeneme ex. imipenemCephamicine ex. cefoxitinOSO3Monobactami ex. aztreonamOCH3R

Spectrul de activitate al -lactaminelorPenicilinsBenzylpenicilinaFlucloxacilinaAmoxicilinaPiperacilinaCephalosporineCephalexinCefuroximCeftriaxonCeftazidimStafilococi++++E.coliRR++Streptococi++++EnterocociRR++PseudomonasRRR+

++RR

++++

RRRR

RRR+

Urin+++Gram (+)Gram (-)CarbapenemeImipenem

+

+

+

+

+

Inhibitori ai beta-lactamazelor

Cresc activitatea antibacterian a penicilinelor, doar atunci cnd rezistena bacterian este rezultat al producerii de beta-lactamaze. Sunt activi pe tupini secretoare de beta-lactamaze:S.aureusStreptococcus spp.(Unasyn)H.influenzaeBacteroides spp.E.coli, alte enterobacteriiPseudomonas aeruginosa (Timentin, Tazocin) ***Excepii: tulpini de Enterobacter, Citrobacter, Serratia, Morganella, Pseudomonas secretoare de beta-lactamaze.

Inhibitori ai beta-lactamazelorAcidul clavulanic : -utilizat cu amoxicilinO,P (Augmentin, Amoksiklav)-utilizat cu ticarcilinIV (Timentin)Sulbactam:-utilizat cu ampicilinP,O(Unasyn)Tazobactam - utilizat cu piperacilinP(Tazocin, Zosyn)***Indicaii: sinuzite, otite medii, ITU, inf. pulmonare, inf.polimicrobiene

Cefalosporine

Generaia IGeneraia IIGeneraia IIIGeneraia IVParenteraleCephalotin(Keflin)Cefamandol(Mandol)Cefotaxime (Claforan)Cefepime(Maxipime)Cefazolin (Ancef, Kefzol)Cefoxitin (Mefoxin)Cefoperazona (cefobid)CeftobiprolCepharidin (Cefadyl)Cefuroxime (Zinacef)Ceftizoxime (Cefizox)Cephradine (Velosef)Cefotetan (Cefotan)Ceftriaxona (Rocephin)Ceftazidime (Fortax)OraleCephalexin (Keflex)Cefuroxime (Ceftin)Cefixime (Suprax)Cephradine ((Velosef)Cefprozil (Cefzil)Cefpodoxime (Vantin)Cefadroxil (Duricef)Cefaclor (Ceclor)Ceftibuten (Cedax)Loracarbef (Lorabid)Cefdinir (Omnicef)

Cefalosporine

GeneraiaSpectrul de aciune1Cefalotinspectru larg, asemntor aminopenicilinelor, activ mai ales pe coci gram pozitivi (S. aureus, ); 2CefamandolCefuroximactive asupra unor bacili gr.neg. din familia Enterobacteriaceae, genul Haemophilus, anaerobi mai puin active faa de cocii gram pozitivi 3Cefotaxim Ceftriaxonaspectru foarte larg cu activitate foarte bun asupra baciilor gram negativi, inlusiv Pseudomonas aeruginosa; puin active aupra cocilor gram pozitivi 4CefepimSpectru foarte larg, antibiotic de rezerv, active pe bgn Pseudomonas i pe cocii gram pozitivi (S.aureus)Nu induce secreia de BLSE

CEFTOBIPROLUL

o nou cefalosporin cu spectru larg, cu activitate puternic bactericid mpotriva: MRSA, SCNStr.pneumoniae Penicilino-Rezistent Pseudomonas aeruginosa.se leag puternic de PBP al majoritii germenilor gram + /- i rezist la multiple -lactamaze;Calea de administrare: iv (ar putea fi disponibil i sub form oral)Mai multe trialuri clinice - utilitatea n infecii tegumentare i de tesuturi moi, precum i n cazul pneumoniilor nosocomiale Exist i alte cefalosporine noi care, fie nu sunt ntr-o faz att de avansat din punct de vedere al testrii, fie nu par att de eficiente ca Ceftobiprolul.

Carbapeneme: Imipenem P[Tienam, Primaxim]Meropenem IV[Meronem, Merrem]

Administrare parenteral, indicaii inclusiv n inf. oculare, pancreatite, IN severe, pacieni granulocitopenici Cel mai larg spectru de aciune indicat in infecii mixte produse de CGP, BGN, BGN non-fermentaivi:Streptococcus spp.,inclusiv Str. Pneumoniae intermediar rezistent la penicilinS.aureus (MSSA)Neisseria spp.H.influenzaeEnterobacteriiPseudomonas aeruginosa, S.maltophilia, Acinetobacter spp. Legionella pneumophilia

DORIPENEMUL

face parte din clasa Carbapenemelor - spectru foarte larg de aciune mpotriva multor bacterii aerobe i anaerobe, Gram +/ - cu multiple indicaii poteniale pneumonii nosocomiale i postventilaie asistat, infecii complicate de tract urinar, pielonefrite, infecii extinse intraabdominale.Comparndu-se eficiena Doripenem-ului versus Imipenem pe tulpinile de Enterobacteriaceae multirezistente, se observ c ambele preparate sunt inactive pe tulpinile de Proteus mirabilis productoare de carbapenemaz, n schimb Doripenemul este eficient mpotriva tulpinilor productoare de BLSE sau a altor germeni rezisteni.

Monobactami -Aztreonam(Azactam)BGN aerobi:Enterobacterii: E.coli, K. pneumoniae, P. mirabilis, S. marcescens, Enterobacter, Citrobacter, Providencia, Morganella, Salmonella, ShigellaPseudomonas aeruginosa (cca 12% din tulpini-rezistente) H. influenzae, (productor sau nu de beta-lactamaz), Neisseria spp. M. catarrhalisSlab aciune asupra CGP i anaerobi*** Indicaii: ITU, inf.intraabdominale, bacteriemii, pneumonii, inf.ale esuturilor moi, osoase, articulare cu BGN

Utilizarea beta-lactaminelorPenicilineBenzylpenicilinaFluclox/CloxacilinaAmp/AmoxicilinaAzlo/PiperacilinaCephalosporineCephalexinCefuroximCeftriaxonCeftazidimCefotaximFaringitie, Pneumonii, Men, EndocarditeI.cut., I.sc., artic., osoase [G (-)]ITU, Febre enterice, I.os.,Men., ITRsP. aeruginosa & ali bacili G (-)

IV IMIV IM OIV IM OIV

ITUITU, ITRiMeningite, Articulaii, OaseP. aeruginosa & ali bacili G (-)Men, ITRs, ITU, peritonit

OIV IMIV IMIV IMIV IMPrincipalele indicaii cliniceRouteCarbapenemeImipenemP. aeruginosa & i ali bacili G (-)

IV

Toxicitatea beta-lactaminelor n general netoxice, dar n doze ce depesc zeci de milioane de uniti: r. gastrointestinale, febr, diaree, vasculit, depresie medular, candidoz, colit pseudomembranoas (cefalosporinele), neurotoxicitateAlergizante, mai ales penicilinele. Alergia la penicilina G = presupus alergie la toate penicilinele derivate (cefalosporine, aztreonam, imipenem) i impune ntreruperea imediat a administrrii acestuia i nlocuirea cu alt AB alternativ0.7% - 10% din alergiile la antibioticeLa 1-10% din pacienioc anafilactic 0.004% - 0.04%Moarte: 0.001% (1/100000)

Efecte secundare ale beta-lactaminelor Rash cutanat

Rezistena bacteriilor la beta-lactaminesecreia de beta-lactamaze:Penicilinaza: fenotip Peni-R, PAZACefalosporinaze: fenotip CAZA BLSE - codificate plasmidic, dar i cromozomialModificarea intei: PBP (proteinelor de legare a P) MRSA, Pneumococ rezistent la Penicilin

Creterea rezistenei la beta-lactamineInfecii nosocomiale:SCN-infecii de cateter(60-90% rezistente la meticilin)MRSA (5-40%din totalul infeciilor nosocomiale din spital)MDR Pseudomonas aeruginosa i Acinetobacter spp.n secii de ATIKlebsiella pneumoniae -BLSE, selectate n urma tratamentului cu cefalosporine cu spectru larg, sensibile la imipenemBGN rezisteni la carbapenemeInfecii comunitare:Str. pneumoniae rezistent la penicilinH.influenzae i Branhamella catharalis - rezistente la AmpicilinMRSA comunitar

2. Inhibitori ai sintezelor proteiceSubunitile ribosomiale implicate n translaia mRNA sunt mai mici la bacterii (30S & 50S) dect la celulele eucariote (40S & 60S)Majoritatea antibioticelor active pe ribosomi sunt bacteriostatice, dar aminoglycosidele sunt bactericide

Inhibitorii sintezelor proteiceAminoglycosideMacrolideTetracycline ChloramphenicolAcidul fusidic

AminoglicozideDescoperite in 1940Produse de actinomycete (semisintez)2 zaharuri aminate legate de un inelaminociclitol printr-o legtur glicozidic

Proprieti generaleSpectru larg, active mai ales pe bacili gram negativiMijloace majore de tratament al septicemiilorLipoinsolubile deci nu se absorb pe cale digestivOto i nefrotoxice obligatorie monitorizarea nivelurilor sericeFlora anaerob este n general rezistent la aminoglicozide deoarece oxigenul este necesar absorbiei de antibiotic

Spectrul de aciuneGram-Positivi Aerobi S. aureus i staph coagulazo-negativistreptococci viridansEnterococcus sp.Gram-Negativi Aerobi (nu streptomycina)E. coli, K. pneumoniae, Proteus spAltii(, Citrobacter, Enterobacter sp.,Morganella, Providencia, Serratia, Salmonella, Shigella

Spectrul de aciuneNonfermentativi: Acinetobacter, Pseudomonas aeruginosa (amik>tobra>gent) Mycobacteriaceaetuberculoz - streptomycinatipic - streptomycina sau amikacina

Mecanisme de rezistenScderea permeabilitii pt aminoglicozideSinteze ce modific aminoglicozidele (plasmide)Alterarea intei de legare a aminoglicozidelor

AminoglicozideleGentamicinaTobramycinAmikacinNeomycin

StreptomycinPrimul aminoglicozid cu spectru largAcelai spectru ca gentamicinaDerivat semisintetic al kanamycinei, active fa de bacilii gram negativi rezisteni la gentamicinToxic- utilizat extern

Primul aminoglicozid utilizat la tratamentul TBC

Aminoglicozide - spectru de aciune

GentamicinaAmikacinaStreptomicina

Stafilococi+++Klebsiella+++Streptococi+++Enterococi+++Pseudomonas+++Gram (+)Gram (-)E.coli+++Proteus+++Bacter-oidesRRREntero-bacter+++

GentamicinaAmikacinaStreptomcinaGram (+)M. tbR++

Spectinomicina

Mecanism de aciune interfereaz interaciunea dintre ARNm cu unitatea 30S a ribozomilor

Spectru de aciune ngust - Neisseria gonorrhoeae rezistent la penicilin

Rezisten rar la Neisseria gonorrhoeae

Inhibitori ai sintezelor proteiceAminoglycozidMacrolideTetracycline ChloramphenicolAcid fusidic

MacrolideEritromicinAzitromicin !!!ClaritromicinaStructuri ciclice mari:

14- (Eritromicin & Claritromicina), 15- (Azitromicin)16-atomi de C CH3CH3OHCH3OCH3OOH5C2H3CHOHOH3COOOHN(CH3)CH3OOCH3OCH3OH

Macrolide - Proprieti generaleSe adsorb pe cale digestiv , se administreaz oral, dar absorbia i timpul de njumtire variaz de la un macrolid la altul i au o bun penetrare icse elimin mai ales pe cale biliaractive pe: CGP aerobi, anaerobi, spirocheteInactive asupra Mycobacteriilor, protozoarelor (T. gondii, E. histolytica, P. falciparum), Campylobacter, Helicobacter, Borrelia, Neisseria & ali patogeni genitali Eritromicina nlocuiete penicinilina la persoane alergice, Azitromicina - tetraciclina n tratamentul infeciilor chlamydiene la gravide i copiiProduc ef.sec. gastrointestinale-mai ales eritromicina

In vitro CMI50 (mg/L) a macrolidelor:patogeni respiratori

Clindamycina Lincomycina

Fig. 10 Structura chimic a LincosamidelorAntibiotice cu aiune bacteriostatic i bactericid:

Streptogramina A are un inel non-peptidic polinesaturat, iar Streptogramina B are structur peptidic ciclic.Streptogramina A: Pristinamycin VirginamycinaStreptogramina B: Quinupristin/ dalfopristin Fig. 14 Structura chimic a Streptograminei AFig. 15 Structura chimic a Streptograminei B

Inhibitori ai sintezelor proteiceAminoglicozideMacrolideTetracicline ChloramphenicolAcid fusidic

Chimioterapice active asupra ribozomilor TetraciclineNaturale clortetraciclina, oxitetraciclina, tetraciclinaSemi-sintetice ex. doxiciclina, minociclinaInhib sinteza proteicmpiedicnd legarea amino-acil RNA de transfer de situsul corespunztor de pe ribozom

Chimioterapice active asupra ribozomilor TetraciclineProprieti generaleSpectru larg: active fa de bacteriile comune Gram (+) & (-), chlamydii, rickettsii, coxiella, spirochete, unele mycobacterii, E histolytica, & plasmodii. Ptrunde intracelular.Absorbia pe cale digestiv este influenat de alimente (mai ales lactate)Toxicitate:frecvent intoleran gastrointestinalperturb flora normal a intestinuluiperturb metabolismul osos efecte secundare asupra dentaiei (chelator de Ca), CI la gravide i copii

Efecte secundareTulburri gastrointestinaleDiaree, Greuri i vrsturicrampeDentaieColorarea maronie a dinilorSuprainfecieC. difficileS.aureusCandidaHepatotoxicitateNefrotoxicitateNu se administreaz la copii i gravide

Inhibitori ai sintezelor proteiceAminoglycosideMacrolideTetracicline CloramfenicolAcid fusidic

Cloramfenicol proprieti generalenucleu nitrobenzen - blocheaz peptidiltransferaza, deci formarea legturilor peptidicebacteriostatic fa de G(+), o serie de Gram (-) (nu P. aeruginosa), leptospire, T. pallidum, chlamydii, mycoplasme, rickettsii, & unii anaerobi, (mai puin B. fragilis ) cu penetrare intracelularSe evit datorit efectelor toxice asupra mduvei hematogeneCOHHCH2OHCO2NHNHCOCHCl2

Cloramfenicol Proprieti generaleEfecte secundare:ImunodepresorToxicitate medularLegat de dozprin mecanism alergic care duce la anemie aplastic ireversibil (1/24.000). Rezistena dobndit:codificat de plasmide i const n sinteza unei acetiltransferaze intracelulare

Inhibitorii sintezei proteice AminoglicozideMacrolideTetracicline CloramfenicolAcid fusidic

Chimioterapice active pe ribozomi acidul fusidic- proprieti generaleActiv fa de majoritatea bacteriilor Gram (+) i cocilor Gram (-), MRSAOarecare activitate asupra G. lamblia, P. falciparumOarecare activitate asupra Mycobacteriilor Utilizat mai ales in infecii stafilococice (osteomielit) n aplicaii localeSe absoarbe bine pe cale oral

3. Inhibitorii sintezei acizilor nucleiciInhibiia sintezei precursorilorSulfonamideTrimetoprimInhibitori ai replicrii DNAQuinoloneInhibitori ai RNA polimerazeiRifampicin

3. Sinteza acizilor nucleici sinteza acidului folicTrimetoprim - inhib sinteza acidului folic necesar sintezei bazelor purinice i pirimidinice prin inhibiie enzimatic

Sulfonamidele la fel

Sinteza acidul tetrahidrofolic -1 Analogia de structura dintre PABA i sulphonamides duce la inhibiia dihidropteroate sintazei prin mecanism competitivNH2SO2NHacidulpara-aminobenzoicDapsonadihidropteroat sintetazaacidul para amino benzoic (PABA) + pteridinadihidropteroicNH2SO2NHNH2structurasulfamidelorXacid

Sinteza de acid tetrahidrofolic -2dihidrofolat sintetazaciddihidropteroicacid dihidrofolicL-glutamin

Sinteza de acid tetrahidrofolic -3 Analogia structural dintre Trimetoprim i acidul folic & inhibiia dihidrofolat reductazei prin structuri asemntoareX

Sinteza acidului tetrahidrofolic, a pirimidinelor i purinelor - 4acid tetrahidrofolic Pirimidine Purine

Sulfonamide proprieti generaleCotrimoxazolul (biseptolul) rezult din combinarea sulfametoxazolului cu trimetoprimul; au aciune sinergic, care depete suma aciunii celor 2 substane. Spectru larg (BGP, BGN), utilizate mai ales n infecii urinare, infecii cu Nocardia, & Toxoplasma gondii, Lepra (dapsona)Utilizarea restrns datorat rezisteneiMultiple interaciuni cu alte medicamente datorat legrii de proteinele plasmatice

3. Sinteza acizilor nucleici:Inhibitori ai sintezei ADNQuinolonele sunt o familie mare de ageni sintetici ce afecteaz DNA giraza necesar suprahelicrii DNA bacterian (important i n restaurarea ADN) i fr de care bacteria nu este capabil s-i mpacheteze ANDNegramul:prima, utilizare restrns datorit toxicitiiCiprofloxacin, Norfloxacin, Ofloxacin (fluoroquinolone) au activitate superioar i spectru larg (Stafilococi, BGN, inclusiv pe Pseudomonas sp.)Indicaii clinice: ITU, sistemice, febra tifoid

Antimicrobiene ce afecteaz ADN i ARN bacterianRifamicine (ex rifampicin) inhibitori specifici ai ARN-polimerazei ADN dependente blocheaz mARN; active pe CGP, MRSA, bKMetronidazol (un nitroimidazol) in stare redus poate reaciona cu ADN pe care l oxideaz producnd rupturi ale catenelor

4. Ageni care lezeaz MCPolimixinele: polimixina B i colistinulau structur polipeptidic i aciune bacteriostaticactive pe BGN (inclusiv Pseudomonas)se administreaz local n otite externe, infecii oculare, cutanatenu se adsorb pe cale digestivnu se mai administreaz pe cale sistemic datorit nefrotoxicitii.

Rezistena la chimioterapice antiinfecioase

Natural:caracter de specie, determinat geneticDobndit: n cadrul unor specii natural sensibile unele tulpini dezvolt sau achiziioneaz rezisten. Mecanismele rezistenei dobndite:A. genetice :1Mutaia2Infecia cu un plasmid

Diseminarea genelor de rezisten1. Rezisten mediat cromozomial: selecia mutantei2 Rezisten meditat de plasmide: diseminarea plasmidului de rezistenPlasmidele - molecule de DNACe se replic independent de cromozom. Acelai plasmid poate codifica rezistena fa de mai multe familii

donorreceptorconjugareantibiotic

Diseminarea genelor de rezisten3. Rezistena mediat de transpozonitranspozonii - genele sltreeElemente extracromozomiale (segmente circulare de ADN dublu catenar care asigur transferul unor secvene scurte de material genetic

Genele de rezisten de pe transpozoni se pot muta ntre plasmide i cromozomii de la un plasmid la cellalt

B. Mecanismele biochimice ale rezisteneiAlterarea intei a unei enzime sau a altui situs sau scderea afinitii pentru substana antibacterianAbsorbie sczut - prin creterea inpermeabilitii peretelui celular (pierderea unor proteine bacteriene porine), sau prin mrirea activ a efluxului de antibioticInactivarea antibioticului n exteriorul celulei bacteriene - prin producerea unor enzime care modific sau distrug agentul antibacterian (de ex. beta lactamazele, enzime de modificarea a aminoglicozidelor)

Niveluri de rezisten antibacterian Parial ( nivel sczut sau intermediar) - poate fi evitat prin creterea dozei de antibiotice sau prin combinarea cu un alt antibioticComplet

C. Cum este favorizat diseminarea rezistenei la antibiotice?Utilizarea unui antibiotic la care tulpinile sunt rezistente se vor selecta tulpinile rezistente Administrarea antibioticelor fr reetTratament greit, indicaii greiteCauza rezistenei este utilizarea incorect antibioticelor i utilizarea lor ca promotori de cretere a animalelor

Controlul diseminrii rezistenei

Supravegherea terapiei cu antibioticeAsociat cu supravegherea fenotipurilor de rezisten circulante ntr-o anumit zon

Enterobacterii secretoare de BLSE-test de sinergie

Antibioticoterapia raional

Terapia corect necesit un diagnostic1. Anamnez2.Istoricul bolii3.Este tratamentul esenial n aceast faz? 4.Dac da, atunci care este agentul etiologic posibil?5.Care este cel mai bun chimioterapic, lund n consideraie toi factorii de care dispunem?

Factori care influeneaz decizia terapeuticFactori importani de risc Imunosupresia patologic sau iatrogenHipotensiunea (TA diastolic 30/min, cianozFibrilaia atrialNivel de contienConvulsii, semne de focar neurologic

Rolul laboratorului n diagnostic i tratamentRecoltarea produsului biologic ct mai devreme, naintea instituirii antibioticoterapiei !!!!!!Transport i prelucrare rapid a produsuluiMicroscopie i teste rapide de identificareIzolare i identificareAntibiogramEfectuarea testelor sinergie (facultativ)Nivelul seric de antibioticeSE COMUNIC orice informaie pentru a corecta tratamentul

Factori care influeneaz alegerea chimioterapicului: interaciunea dintre chimioterapice

Factorii de influe a alegerii antibioticelor: Exemple de toxicitate medicamentoas

Factorii ce influeneaz riscul de toxicittate medicamentoas:exemple de efecte legate de vrst

Factorii ce influeneaz riscul de toxicittate medicamentoas : exemple de efecte n timpul sarcinii

Factorii ce influeneaz riscul de toxicittate medicamentoas : exemple de efecte n cursul alptrii

Factori ce influeneaz alegerea antimicrobienelor: disfuncia renal

Antibiotic Susceptibility Testing

Zone Diameter Standards for Disk Diffusion Tests

Antimicrobial agent

(amt. per disk)

and organism

Zone diameter (mm)

Approx. MIC (g/ml) for:

R

I

S

R

S

Ampicillin (10 g)

Enerobacteriacae

14

>32

4

16

Tetracycline (30 g)

19

>16

Legend: PRSP: pneumonie cu Str. Pneumoniae rezistent la penicilin, DFI: infecii diabetice ale piciorului, IAI:infecii intraabdominale, HAP: pneumonii nosocomiale, SSI: infecii cutanate i ale esuturilor moi, MRSA, BLSE, MDR, *investigat din mai 2006Tabel : Noi antibiotice

AntibioticClasaSpectruIndicaii cliniceComentariiLinezolidOxazolidinoneCGP inclusiv MRSA i PRSPHAP , SSI, inclusive DFIOral sau parenteralDaptomycinLipopeptid CyclicCGP inclusiv MRSASSI complicate1x ziQuinupristin-dalfopristinStreptograminCGP inclusiv MRSASSI complicateIndicat n bacteriemii produse de VRE (E.faecium)TigecyclineGlycylcyclinCGP inclusiv MRSAIAI i SSIPoate fi util mpotriva MDR ca Acinetobacter i secretori de BLSECeftobiprole*CephalosporinCGP inclusiv MRSA, PRSP i BGNPneumonii, SSI complicateRezistent la numeroase beta lactamazeDalbavancin*LipoglycopeptidCGP inclusiv MRSASSI complicate, bacteriemii de cateterTimp de njumtire prelungit, permite administrare sptmnalTelavancin*LipoglycopeptidCGP inclusiv MRSASSI complicate?Bactericid cu mechanism dual de aciune, 1 x pe zi

n mod ideal antibioticul ar trebuie s acioneze ntr-un situs prezent n microorganismul infectant dar absent n organismul gazd. Acest lucru se petrece mai adesea la procariote (bacterii) dect la eucariote (organisme care au nucleu, membran nuclear, organite celulare nespecifice cum sunt mitocondriile,aparatul Golgi, RE). Peptidoglicanul, componenta vitala peretelui celular este unic la bacterii motiv pentru care constituie o int optim pentru toxicitatea selectiv. Peptidoglicanul (sau ureina), este un polimer de dizaharide aminate: N-acetil-glucozamina i acidul N-acetilmuramic la care se adaug peptidele transversale formate din amoniacizi.La bacteriile gram-pozitive, peptidoglicanul formeaz un strat mai gros (20-80nm) la exterior de membrana citoplasmatic. La bacterille Gram-negative stratul de peptidoglican este subire (5-10nm) i este acoperit la bacteriile gram-negative de o membran extern ce conine un LPZ.Sinteza precursorilor peptidoglicanului ncepe n citoplalsm. Cyclloserina inhib reaciile implicate n incorporarea de alanin n precursorii peretelui celular.Subunitile peretelui celular sunt transportate prin membrana citoplasmatic n asociere cu un carrier lipidic. Bacitracina previne defosforilarea carierullui fosfolipidic ceea ce mpiedic regenerarea carrierului, neceasr sintezei.Glicopeptidele (vancomicina i teicoplanina) se leag de alanina terminal mpiedicnd astfel incorporarea subunitii n peptidoglicanul n curs de elongaie.Bacitracina este foarte activ fa de un numr de germeni gram pozitivi i fa de Neisserii. Nu se absoarbe pe cale oral. Se utilizeaz n aplicaii locale iar pe cale oral pentru a inhiba flora intestinal, inclusiv Clostridium difficile. Vancomicina este un produs de fermentaie al actinomicetelor. Are o structur complex i activitatea ei se restrnge asupra florei gram pozitive. Este n general bactericid dar bacteriostatic pe Enterococcus i unii streptococi viridans. Vancomicina se absoarbe greu pe cale digestiv i nu traverseaz bariera hematoencefalic. Se elimin pe cale renal. Administrarea rapid iv poate duce la elliberarea crescut de histamin din bazofile i mastocite producnd prurit, angioedem i rar colaps caridovascular.Este nefrotoxic i ototoxic necesitnd monitorizarea nivelurilor serice. Vancomicina pe cale oral se utilizeaz n tratamentul Colitei pseudomembranoase i stafilococice. Teicoplanina nu produce degranularea bazofilelor, este mai puin toxic i necesit administrare o dat pe zi. Betalactaminele constituie o mare familie ce conine grupe de compui ce au n structura lor inelul beta-lactamic. Ele includ peniciline, cefalosporine, cefamicine, monobactami i carbapeneme care se leag i inhib o enzim, PBP (penicillin binding protein). Aceasta catalizeaz legtura dintre L-lysin and D-alanin. Fiind blocat sinteza lanurilor transversale, se vor acumula subuniti de murein care derepreseaz un sistem enzimatic autolitic care va declana liza celulei bacteriene.

Aceasta este structura de baz a inelului beta-lactamic. Diferitele grupe de beta-lactamine se deosebesc prin structurle ataate de inelul beta-lactamic: - in penicillins, it is a 5-membered ring, in cephalospoirins a six-membered ring and by the side-chains attached to these rings. The penicillins and cephalosporins are the major members of the family.

The ring structure is common to all beta-lactams and must be intact for antibacterial action. Enzymes that catalyse the hydrolysis of the beta-lactam ring, are known as beta-lactamases, and render the agents inactive. De reinut c majoritatea beta-lactaminelor uzuale sunt inactive fa de Enterococcus i PseudomonasAlthough protein synthesis proceeds in essentially the same way in prokaryotes and eukaryotes, some differences can be exploited to achieve selective toxicity. The ribosomal units involved in mRNA translation in bacterial systems are smaller than in eukaryotes. A range of antibacterial agents act as inhibitors of protein synthesis, but knowledge of the mechanisms of action is incompletely understood. The aminoglycosides can be divided up into several different chemical groups. None are absorbed from the gut; they do not penetrate well into tissues and bone; and they do not cross the blood-brain barrier. The aminoglycosides are potentially nephrotoxic and ototoxic, and the therapeutic window, i.e., difference in concentation required for therapeutic activity and that which is toxic is small. Blood concentrations need monitoring regularly.

Gentamicin - bactericidalDespite their potential toxicty they represent a useful addition to the clinicians armamentarium. They are especially useful for the treatment of serious Gram-negative infections, including those caused by Pseudomonas aeruginosa used in renal infections

In severe sepsis of unknown origin, Gentamicin could be used with an agent active against Gram positive and Gram negative organisms eg piperacillin, or metronidazole if anaerobes were thought likely.

They are not active against anaerobes. They are not active against Streptococci or Enterococci, but have activity against Staphylococci. The family of macrolides all share a large macrocyclic lactone ring, to which typically two sugars, one an amino sugar, are attached.The clinically important drugs are erythromycin, azithromycin and clarithromycin. They share overlapping binding sites on ribosomes with the lincosamides (clindamycin) and streptogramins (group currently under development), and resistance to macrolides confers resistance to the other two groups. The macrolides have a spectrum of activity against a number of respiratory pathogens, including the newly emergent Legionella spp. Eryhtromycin is therefore an important drug in the treatment of atypical pneumonia. In addition to Legionella, macrolides have activity against several other intracellular pathogens including Chlamydia and Rickettisia species. They are active against several another newly emergent pathogens Campylobacter spp, Helicobacter pylori, and the spirochaete Borrelia burgdorferi (the agent causing Lyme disease). The activity against Chlamydia make them useful in the treatment of urogenital infections (the macrolides are active against Neisseria gonorrhoeae the agent causing gonorrhoea). The newer agents also have a place in treating some Mycobacteria.

The macrolides have a spectrum of activity against a number of respiratory pathogens, including the newly emergent Legionella spp. Erythromycin is therefore an important drug in the treatment of atypical pneumonia. Besides Legionella, macrolides have activity against several other intracellular pathogens including Chlamydia and Rickettisia species. They are active against several another newly emergent pathogens Campylobacter spp, Helicobacter pylori, and the spirochaete Borrelia burgdorferi (the agent causing Lyme disease). The activity against Chlamydia make them useful in the treatment of urogenital infections (the macrolides are active against Neisseria gonorrhoeae the agent causing gonorrhoea). The newer macrolides also have a place in treating some Mycobacteria (MAI). The tetracyclines represent a family of large cyclic structures (four rings) derived from streptomyces species that have several sites for possible chemical substitutions. There are natural products and semi-synthetic derivatives. They Inhibit protein synthesis by preventing amino-acyl transfer RNA from entering the acceptor sites on the ribosome. This activity is not selective for prokaryotes, but uptake of tetracylines by bacterial cells is much greater than human cells. They are active against many common Gram (+)ve & (-)ve bacteria, chlamydiae, rickettsiae, coxiellae, spirochaetes, some mycobacteria, E histolytica, & plasmodia.

Although active against a wide range of bacteria, their use is restricted by a wide range of resistance, due in part to the widespread use of these drugs in man and also to their use as growth promoters in animal feed.

In man tetracyclines are used primarily in the treatment of infections due to mycoplasmas (lack cell wall), chlamydia, coxiellae, and rickettisiae (Gram-negative). Additional uses of tetracyclines include malaria, Lyme disease (Borrelia spirochaete stains with acridine orange), brucellosis (Gram-negative rods) Chloramphenicol was isolated from streptomycetes and was the first broad-spectrum antibiotic to be discovered. It is a relatively simple molecule consisting of a nitrobenzene nucleus, which is responsible for some of its toxicity. The most important toxic effect of chloramphenicol is on the bone marrow. It can cause an idiosyncratic reaction causing aplastic anaemia which is not dose dependent and is irreversible, occurring at a rate of about 1 in 30 000 patients treated. It also causes a dose-dependant bone marrow suppression. Babies may be unable to conjugate (glucoronidation) chloramphenicol, and high plasma conxcentrations are associated with gray baby syndrome with associated circulatory collapse.

Metronidazole in combination with beta-lactam antibiotics is now preferred in the treatment of brain abscess. In the developing world chloramphenicol is still used for the treatment of typhoid fever. It is otherwise little used nowadays, reference being made to its use in cholera, plague, tularemia, bartonellosis, and meliodosis.

Its bacteriostatic effect may inhibit the action of penicillins and other beta-lactam antibiotics against certain bacteria, eg, Klebsiella pneumoniae and other enterobacteria in vitro, but the clinical significance of this is uncertain Fusidic acid is one of a group of naturally occurring antibiotics (Fusidanes). It is active against most Gram (+)ves and Gram (-)ve cocci, including MRSA; has some activity against G. lamblia, P. falciparumand Mycobacteria.

Mostly used for staphylococcal infections (osteomyelitis) and topically. Fusidic acid is well absorbed orally. Sulphonamides and trimethoprim both interfere in the synthesis of tetrahydrofolic acid by interacting with key enzymes in the pathway. The sulphonamides act at an early stage.

Sulphonamides are structural analogues of and act in competition with para-amino benzoic acid. There are a large number of molecules in this group and they are produced entirely by chemical synthesis, ie, they are antibacterials, not antibiotics.Trimethoprim is one of a group of pyrimidine like structures analagous in structure to the aminohydroxypyriomidine moiety of folic acid and in this way antagonizes the enzyme dihydrofolate reductase. Nalidixic acid is one of the earlier prototypes.The newer quinolones have a greater degree of activity against Gram-negative rods than nalidixic acid. Ciprofloxacin is also active against P. aeruginosa. In addition to the treatment of urinary tract infections, the newer quinolones are also useful for treating systemic Gram-negative infections.They also have activity against chlamydial and rickettsial infections and other intracellular oragnisms such as Legionella & S. typhi, and in combination with other drugs are used for treatment of atypical mycobacteria.

They have activity against staphlylococci, but are less active against streptococci; enterococci are resistant. Rifamycins (eg rifampacin) specific inhibitors of bacterial DNA-dependent RNA polymerase. Rifampicin, for example, binds to RNA polymerase and thus blocks the synthesis of mRNA. Selective toxicity depends on its greater affinity for bacterial polymerases than equivalent human enzymes.Principal use of rifampicin and rifabutin is in the treatment of mycobacterial infection. Rifampicin drug of choice for prophylaxis of meningococcal and Haemophilus meningitisRifampicin is also useful in conjunction with other agents in treatment of severe staphylococcal infections eg endocarditis. Also used to treat Legionella

Metronidazole (a nitroimidazole) When reduced it can react with DNA, oxidizing it and causing strand breaks. Metronidazole is useful only against anaerobic bacteria, because only these can produce the low redox potential necessary to reduce the parent drug.Metronidazole is also useful in the treatment of E histolytica, G. lamblia, Balantidium coli, and Trichomonas vaginalis Resistance can be defined as an organism that cannot be inhibited or killed by an antimicrobial agent at concentrations that are achievable in the body after normal dosage. Some bacteria are innately resistant, others acquire resistance. Gram negative rods with their outer membrane layer exterior to the cell wall peptidoglycan are less permeable to large molecules than Gram positive oragnisms.

Resistance may arise from:A single chromosomal mutation resulting in the synthesis of an altered protein, orA series of mutations

Resistance genes may also be acquired from resistance genes on transmissible plasmids (extrachromasomal DNA carried in small circular plasmids) Resistance can occur in three ways:First by the acquisition of chronmosomal mutationsSecondly by plasmids. Plasmids may code for resistance determinants to several families of unrelated antibiotics, therefore a cell may acquire resistance to many different drugs at once.And thirdly, resistance genes may also occur on transposons; the so-called jumping genesAnd thirdly, resistance genes may also occur on transposons; the so-called jumping genes. Transposons are extrachromosomal elements consisting of circular segments of double-stranded DNA which sponsor transfer of small lengths of genetic material into the chromosome or plasmids. The chromosome provides a more secure position for the genes, but they will be dissseminated only as rapidly as the cell divides. Transposons moving from the chromosome to plasmids allow chromosomal genes to be disseminated more rapidly. Transposons can also move between plasmids.

Resistance mechanisms can be classified into three main types: