Antimicrobianos usados in vivoAgentes quimioteraputicosAntibiticos y agentes sintticos.

Paul Ehrlich.

Salvarsan (arsnico), Ehrlich, 1900.

Prontosil (sulfonamida), Gerard Domag, 1930.

Se establece el primer mecanismo de accin, Woods, 1935.

Penicilina, Alexander Fleming, 1939.

Florey, 1941. Optimizacin del cultivo y produccin

Mientras trabajaba con variantes de Staphylococcus sp. abandon sobre la mesa una serie de placas de cultivo y las fui examinando de vez en cuando. Para poder examinarlas, estas placas se exponan necesariamente al aire y se contaminaron con una serie de microorganismos. Observ que alrededor de una colonia grande de un hongo contaminante, las colonias de Staphylococcus se hacan transparentes y sufran una lsis obvia. Se hicieron siembras de este hongo y se realizaron experimentos encaminados a comprobar las propiedades de la sustancia que, era evidente, se haba formado en el cultivo del hongo y haba difundido al medio circundante.

Alexander Fleming, Premio Novel de Medicina.

antimicrobianosSon elementos qumicos naturales o sintticos que pueden reducir o eliminar (matar) el desarrollo de los microorganismos.

antimicrobianosBacteriosttico

antimicrobianosBacteriostticoBactericida

antimicrobianosBacteriostticoBacteriolticoBactericida

Bacteriosttico

Se inhibe el crecimiento microbiano pero la clula no muere.

En general son inhibidores de la sntesis proteica.

Se unen de manera reversible a ribosomas

Bactericida

Se mata a la clula bacteriana

No hay ruptura de la pared por tanto no hay lisis celular.

Se unen de manera covalente a sus dianas moleculares (enzimas de replicacin de ADN o ARN).

Bacterioltico

Se destruye a la clula bacteriana

Hay ruptura de la pared por tanto hay lisis celular.

Se afecta la estructura de la pared celular de clulas que estan creciendo.

La lisis celular puede ser observada por un cambio en la turbidez del medio de cultivo.Tiempo (hrs) 0 1 2 3 4No expuesto a ampicilinaExpuesto a ampicilina

CUANTIFICACIN DE LA ACTIVIDAD ANTIMICROBIANAConcentracin Mnima Inhibitoria(CIM)Mtodo de difusin en agar con discos de celulosa

Concentracin del qumicoIncubacin

Agentes QuimioteraputicosAgentes qumicos sintticos o naturales destinados a usarse internamente en el cuerpo humano para el control de microorganismos causantes de infecciones.

antimicrobianosSon elementos qumicos naturales o sintticos que pueden reducir o eliminar (matar) el desarrollo de los microorganismos.Independiente de donde se utilicen.

Agentes QuimioteraputicosAgentes qumicos sintticos o naturales destinados a usarse internamente en el cuerpo humano para el control de microorganismos causantes de infecciones.

Agentes QuimioteraputicosSe clasifican segnESTRUCTURAMECANISMO DE ACCINSintticosNaturales(Antibiticos)ORGENCarbohidratosLactosas macrocclicasQuinonasAminocidosHeterocclicos N, OAliciclosAromticosAlifticosQuinolonasOxazolidinonaSntesis de pared celularAnlogos de factores de crecimientoEstructura de la MB plasmticaSntesis de DNATranscripcinTraduccin

ETRUCTURAS REPRESENTATIVASEstreptomicina GlicsidoRifampicina lactosa macroccica

ETRUCTURAS REPRESENTATIVASMitomicina (Benzo Quinona)Polimixina B (nuclesido)

ETRUCTURAS REPRESENTATIVAScido nalidixico (quinolona)Lactona cclicaCicloheximidaGriseufulvina aromtico condensadoMonesina, heterociclo condensado

Sntesis de pared celularCicloserinaVancomicinaBacitarcinaPenicilinaCefalosporinaMonobactamasCarbapenemasMetabolismo del cido flicoTrimetropinaSulfonamidasPABAMEMBRANAEstructuras de la membranaPolimixinaPAREDElongacin de mRNAActinomicinaDNA girasaTrasncripcinRifampicinaEstreptovaricinasSntesis protica 50SEritromicinaCloranfenicolClindamicinaLincomicinaSntesis protica 30STetraciclinaEspectinomicinaGentamicinaKanamicinaNitrofuranos

Sntesis protica tRNAMupirocinaPuromicina

Macrlidos e interferencia con la sntesis protica.Bloqueo de la peptidil transferasaEritromicinaAzitromicina

Inhibicin del traspaso del peptidil tRNA al sitio P

Penicilina cefalosporina e interferencia con la sntesis de pared.

OrgenSintticosNaturalesAnlogos de factores de crecimientoSulfamidas, Isoniazina, Mycobacterium tuberculosis

QuinolonasInteraccin con DNA girasa.cido nalidixico.Norfloxacino, ciprofloxacino.Antibiticos -lactmicosPenicilinas y Cefalosporina

De origen procariotaAminoglicsidosMacrlidosTetraciclinas

SINTTICOS

SINTTICOS

ciprofloxacin, una quinolonaSINTTICOS

NATURALES OSEMI SINTTICOS

Resistencia a los antibiticos Capacidad presente en una poblacin bacteriana que es seleccionada por la presencia del antibitico

Est presente habitualmente en genes que son transmitidos horizontalmente a otros microorganismos.

MECANISMOS DE RESISTENCIACarencia de la diana en el microorganismos, ejemplo: pared celular

Impermeabilidad al antibitico

Biotransformacin del compuesto qumico antimicrobiano, ejemplo beta lactamasas

Modificacin metablica. Sulfonamidas

Modificacin de la diana

Bombas de eflujo de antibiticos

Diseminacin de la resistenciaUso inadecuado excesivo en la prctica clnica

Uso inadecuado de dosis y duracin de tratamientos

Falta de seguimiento teraputico

Antibiticos ms utilizados en clnica

AmoxicilinaAbiolex, Amobiotic, Amoval

Beta-lactmico

Comprimidos y jarabe

0.5 mg/12h

ClaritromicinaClarimax, Infex, Euromicina

Macrlido

Comprimidos, IV, jarabe

250-300 mg/12 h

CeftriaxonaAcantex

Cefalosporina de 3 generacin, beta- lactmico.

Administracin parenteral

1-2 g/24 h

Trimetoprim + sulfametoxazolClotrimoxazol, Bacterol, Septrin

Inhiben sntesis de THF (precursor cido flico)

Comprimidos, suspensin oral.

800/160 mg cada 12 h.

CiprofloxacinoBaycip, Ciproval, Cifloxin

Inh. DNA girasa

Comprimidos, IV

2x 500mg/da

Va de Administracin de ABTpica Neomicina

Oral Claritromicina

EV, IM Penicilina

Ocular Ciprofloxacino

AmoxicilinaClaritromicinaCeftriaxonaClasificacinPenicilinas (- lactam)MacrlidoCefalosporina(- lactam)Mecanismo de accinInh. Sntesispared celular: Unin a transpeptidasas (PBPs). Inh. Sntesis proteca: Unin a subunidad 50SInh. Sntesis pared celular: Unin a PBPs.Dosis adulto500 mg/12h1g/24 h250-500 mg/12h1-2 g/24hPresentacinComprimidosJarabeComprimidosSol. EV Solucin EVVas de adm.OralOral y EV EVNombrecomercialAbiolex, Amobiotic, AmovalClarimax, Infex,EuromicinaAcantex

Trimetoprim+SulfametoxazolCiprofloxacinoClasificacinDihidropirimidina/SulfonamidaQuinolonaMecanismo de accinInh. De la sntesis de cido flico. Inh dihidro folato reductasa/ Anlogo de PABAInh. DNA girasaDosis adulto800/160 mg cada 12 h125-250 mg/12hPresentacinComprimidos, PSOComprimidos, Solucin OftlmicaVas de administracinOralOral, OcularNombre ComercialCotrimoxazol,Bacterol, Septrin Baycip, Ciproval,Ciprodex (ocular)

ClaritromicinaNitrofurantonaClasificacinMacrlidoNitrofuranosMecanismo de accinIhn sntesis protenas: Unin subunidad 50S del ribosoma.Antisptico

Dosis adulto250 mg/12 h 500 mg/12 h50-100 mg/6-8 hPresentacinComprimidosComprimidos, solucin oralVas de administracinOralOralNombre ComercialInfex, Euromicina, ClarimaxMacrodantina, Macrosan

VancomicinaLincomicinaClasificacinGlicopeptidoLincosamidasMecanismo de accinInhibicin de transglicosilasa (pared celular)Ihnibicribosomain de la subunidad 50S del Dosis adulto500 mg/ 6 h 1 g/ 12h500 mg/ 8 hPresentacinIVComprimido, AmpollasVas de administracinIVOral, IVNombre ComercialKovanLincocin

IsoniazidaRifampicinaClasificacinHidrazidaMecanismo de accinDesconocidoInhibicin de la RNA polimerasa DNA dependiente.Dosis adulto300 mg/da600 mg/daPresentacinComprimidoComprimidoVas de administracinOralOralNombre ComercialRifadin

ImipenemCilastatinaClasificacinCarbapenemMecanismo de accinInhibicin sntesis de pared celularInhibidor de la dihidropeptidasa IDosis adulto500 mg-500 mg/ 8 hPresentacinAmpolla

Vas de administracinIVNombre ComercialINEM, TIENAM

ClarotromicinaIsoniacida+rifampicinaMertopenem + cilastinoNitrofurantoinaLincosamina: Lincomicina, clindamicinaVancomicina

****Figure: 20-14-01UN

Caption:Salvarsan

************Figure: 20-10

Caption:Antibiotic assay by tube dilution, permitting detection of the minimum inhibitory concentration (MIC). A series of increasing concentrations of antibiotic is prepared in the culture medium. Each tube is inoculated, and incubation is allowed to proceed. Growth (turbidity) occurs in those tubes with antibiotic concentrations below the MIC.

*Figure: 20-11

Caption:Agar diffusion method for assaying antibiotic activity.

*****Figure: 20-14

Caption:Annual worldwide production and use of antibiotics. Each year more than 500 metric tons of chemotherapeutic agents are manufactured.

**Figure: 20-12a

Caption:Classification of antibacterial chemotherapeutic agents according to chemical structure. A representative example is shown for each group.

*Figure: 20-12b

Caption:Classification of antibacterial chemotherapeutic agents according to chemical structure. A representative example is shown for each group.

*Figure: 20-12c

Caption:Classification of antibacterial chemotherapeutic agents according to chemical structure. A representative example is shown for each group.

****Figure: 20-15

Caption:Antimicrobial spectrum of action for selected chemotherapeutic agents.

*

----- Notas de la reunin (5/20/11 10:52) -----

*Figure: 20-16

Caption:(a) The simplest sulfa drug, sulfanilamide. (b) Sulfanilamide is an analog of p-aminobenzoic acid, which itself is part of (c) the growth factor folic acid (Section 5.1 discusses growth factors).

*Figure: 20-17

Caption:Growth factors and structurally similar analogs.

*Figure: 20-18

Caption:The structure of ciprofloxacin, a quinolone. Fluorinated derivatives of nalidixic acid (Figure 20.12) are more soluble than nalidixic acid and reach clinically therapeutic levels in blood and tissues. Ciprofloxacin is used to treat urinary tract infections and anthrax caused by penicillin-resistant Bacillus anthracis.

***Figure: 20-25

Caption:The emergence of antimicrobial drug-resistant bacteria. (a) Relationship between antibiotic use and the percentage of bacteria isolated from diarrheal patients resistant to the antibiotic. Those agents that have been used in the largest amounts, as indicated by the amount produced commercially, are those for which drug-resistant strains are most frequent. (b) Percentage of reported cases of gonorrhea caused by drug-resistant strains. The actual number of reported drug-resistant cases in 1985 was 9000. This number rose to 59,000 in 1990. Greater than 95% of the reported drug-resistant cases are due to penicillinase-producing strains of Neisseria gonorrhoeae. Since 1990, penicillin has not been recommended for treatment of gonorrhea because of emerging drug resistance. (Source: Centers for Disease Control, Atlanta, GA).

*Figure: 20-26

Caption:The appearance of antimicrobial drug resistance in some human pathogens. The *symbol indicates that some multi-drug resistant strains of these organisms are now untreatable with known antimicrobial drugs.

*Figure: 20-27ab

Caption:Computer-generated antiviral drugs. (a) The HIV protease homodimer. Individual polypeptide chains are shown in green and blue. A peptide (yellow) is bound by the catalytic site. This protease cleaves an HIV precursor protein, a necessary step in virus maturation (Section 16.14). Blocking of the protease site by the peptide shown inhibits precursor processing and HIV maturation. This structure is derived from information in the Protein Data Bank. (b) These anti-HIV drugs are peptide analogs that were designed by computer to block the active site of HIV protease. The areas highlighted in orange show the regions analogous to peptide bonds. Binding of these compounds by the HIV protease prevents HIV precursor processing and virus maturation. These compounds are representative of a class of therapeutic drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTI). The concentration of these compounds in HIV-infected cells, coupled with their strong affinity for HIV reverse transcriptase, makes them very potent competitive inhibitors for the active sites of the transcriptase and prevents viral replication. These protease inhibitors are widely used for treatment of HIV infection (see Table 20.5 and Section 26.14).

****************Figure: 20-17

Caption:Growth factors and structurally similar analogs.

*Figure: 20-19

Caption:The structures of some important penicillins. The red arrow (top panel) is the site of action for most b-lactamases.

*Figure: 20-20

Caption:Structure of kanamycin, an aminoglycoside antibiotic. The amino sugars are in yellow. The site of modification by an N-acetyltransferase, encoded by a resistance plasmid, is indicated.

*Figure: 20-21

Caption:Structure of erythromycin, a macrolide antibiotic.

*Figure: 20-22

Caption:Structure of tetracycline and important semisynthetic analog

*Figure: 20-24

Caption:Sites at which antibiotics are attacked by enzymes encoded by R plasmid genes. In aminoglycoside antibiotics related to streptomycin, those with a free amino group may be inactivated by N-acetylation (see also Figure 20.20).