Bazele chimioterapiei antiinfecioase

Chimioterapice antiinfecioase

Definiie: un grup de medicamente, cu toxicitate selectiv, capabile s distrug i s stnjeneasc multiplicarea unor anumite organisme patogene, implicate etiologic n variate infecii.

Chimioterapice antiinfecioseAntibacterieneAntiviraleAntifungiceAntiprotozoareAntihelmintice

Spectrul de activitateSpectrul natural - cuprinde toate speciile bacteriene sensibile la un chimioterapic n momentul introducerii sale n terapie 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. Spectrul actual este mai restrns dect cel natural, deoarece n timpul scurs de la introducerea chimioterapicului n practic are loc apariia tulpinilor rezistente .

Clasificarea chimioterapicelor antibacteriene:1. Dup origineAntibiotice - produi naturali ai fungilor, i al bacteriilor (actinomycete)Chimioterapice: compui sintetici

Clasificarea chimioterapicelor antibacteriene: 2. aciunea bactericid sau bacteriostaticBactericid - distruge microorganismeleBacteriostatic oprete multiplicarea bacteriilor aprarea antiinfecioas este mai eficient cu o populaie static (este mai puin eficient la gazde imunocompromise)Aciunea depinde de doz

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

Inhibiia sintezei peretelui celular (PC lipsete la celulele eucariote)Inhibiia sintezei proteice (ribozomi)Inhibiia sintezei acizilor nucleiciLezarea membranei citoplasmatice

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

1. Inhibitori ai sintezei peretelui celularBeta-lactaminele Glycopeptidele (vancomycina, teicoplanina)CycloserinaBacitracina

Antibiotice beta-lactamicePename: peniciline naturale i semisinteticeCarbapenemeCephalosporine i CarbacefemeMonobactamiCephamycine

Aciunea beta-lactaminelorInhib sinteza peretelui celular prin legarea lor de enzimele care intervin n faza final a acestui proces (penicillin-binding proteins = PBP) cu blocarea activitii acestoraSpectrul de activitate a antibioticului este n funcie de capacitatea lui de a se leaga de PBPs coninute n microorganismul implicatBactericide

Peniciline naturale (V i G)GRAM POZITIVIS.aureus S.pneumoniaeStreptocociStreptococi viridansEnterocociGRAM NEGATIVINeisseriaBacili gram pozitiviGERMENI ANAEROBI(deasupra diafragmului)ClostridiumGERMENI AEROBIBacillus (sporulat, strict aeroci)

ALTIITreponema pallidum

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

CarbapenemeImipenem [Primaxim]Meropenam [Merrem IV]Cel mai larg spectru de aciune indicat in infecii mixteAdministrare parenteral

Toxicitatea beta-lactaminelor netoxice n general dar n doze ce depesc zeci de milioane de uniti:febr, diaree, vasculit, depresie medular, colit pseudomembranoas, neurotoxicitate alergizante, mai ales penicilinele

0.7% - 10% din alergiile la antibioticeoc anafilactic 0.004% - 0.04%Moarte: 0.001% (1/100000)

Efecte secundare ale beta-lactaminelor Rash cutanat

2. Inhibitori ai sintezelor proteiceAminoglicozideMacrolideTetraciclineCloramfenicolAcidul fusidic

Exemple de aminoglicozide:GentamicinaTobramicinaKanamicinaStreptomicinaAmikacinaNeomicinaSpectinomicina

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

Spectinomicina

Administrare unic n tratamentul uretritei gonococice

Spectru de aciune ngust - Neisseria gonorrhoeae rezistent la penicilin

Rezisten rar la Neisseria gonorrhoeae

MacrolideEritromicinAzitromicinClaritromicinaCH3CH3OHCH3OCH3OOH5C2H3CHOHOH3COOOHN(CH3)CH3OOCH3OCH3OHInhib subunitatea 50S

Macrolide - Proprieti generaleSpectru cuprindePatogeni respiratori: coci gram pozitivi (stafilococi, streptococi), Legionella sp., mycoplasme, Haemofilus, Bordetella pertussis, bacilul difteric, bacterii cu habitat intracelular (chlamydii, rickettsii), Campylobacter, Helicobacter, Borrelia burgdorferi, Neisseria, Treponema pallidum & ali patogeni genitali Azitromicina foarte activ pe Chlamydia trachomatis

Efecte secundare: gastrointestinale, hepatotoxice, Se administreaz oral, dar absorbia i timpul de njumtire variaz de la un macrolid la altulnlocuiete penicinilina la persoane alergicenlocuiete tetraciclina n tratamentul infeciilor chlamydiene la gravide i copiiRezistenaDescreterea permeabilitii la bacteriile gram negativeModificarea subunitii 50 S a ribozomilor prin mutaie

TetraciclineNaturale : clortetraciclina, oxitetraciclina, tetraciclina etcSemi-sintetice: doxiciclina, minociclina, etcInhib sinteza proteicmpiedicnd legarea amino-acil RNA de transfer de situsul corespunztor de pe ribozom

TetraciclineProprieti generaleSpectru bacteriile comune Gram (+) & (-),chlamydii, rickettsii, coxiella, spirochete, unele mycobacterii,E histolytica, & plasmodii.Absorbia pe cale digestiv este influenat de alimente (mai ales lactate) Penetrare intracelularRezistena dobndit codificat de tranpozoni

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

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

Sulfonamide proprieti generaleSpectru largUtilizarea restrns datorat rezisteneiMultiple interaciuni cu alte medicamente datorat legrii de proteinele plasmaticeUtilizate mai ales n infecii urinareIndicate n tratamentul leprei (Dapsona)

Sinteza acizilor nucleici:Inhibitori ai sintezei ADNQuinolonele (ex . ciprofloxacin - fluoroquinolone) sunt o familie mare de ageni sintetici ce afeacteaz DNA giraza necesar suprahelicrii DNA bacterian (important i n restaurarea ADN) i fr de care bacteria nu este capabil s-i mpacheteze ADNSpectru

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

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?

Rolul laboratorului n diagnsotic 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

Although 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 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 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) 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). 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