Antibioticos. Clasificación x Mecanismo de acción 50s30s 1) i síntesis de pared celular 5) Inh Síntesis y replicación del DNA x inh sub A y B de la girasa.

Presentación del tema: "Antibioticos. Clasificación x Mecanismo de acción 50s30s 1) i síntesis de pared celular 5) Inh Síntesis y replicación del DNA x inh sub A y B de la girasa."— Transcripción de la presentación:

1 Antibioticos. Clasificación x Mecanismo de acción 50s30s 1) i síntesis de pared celular 5) Inh Síntesis y replicación del DNA x inh sub A y B de la girasa Quinolonas 2) Membrana celular 6) Inh subunidad B de la RNA polimerasa Rifampicina 7) Antimetabolitos 3) Inh síntesis proteica (Ribos: i 30s) Aminoglucósidos Tetraciclínas 4) Inh Síntesis proteica (Ribos i 50 s) - MACRÓLIDOS-KETÓLIDOS - Union reversible a sitio P de subunidad 50s ribosomal LINCOSAMIDAS a sitio A Cloranfenicol y Tianfenicol Polimixina B Colistina, Nistatina y Anfoteric B -  -lactámicos Cicloserina - Vancomicina - Bacitracina – Fosfomicina Azoles Sulfas y Trimetoprim PABATHFA DHFA Acido Folico Purinas DNA RNAm Ribosomas

2 ANTIBIOTICOS MACROLIDOS Bacteriostaticos --- bactericidas. Eritromicina 1952. Alternativa en pctes alergicos a penicilina. Usos: infecciones respiratorias, de piel y tejidos blandos. ITS (Chlamydia y chancroide), pero…no activ N. gonorrhoeae, H. influenza. En Px de ruptura prematura de membranas (250 mg c/6h x7d o hasta parto). Pero…Absorcion G-I erratica y Ardor epigastico vida ½ corta, niveles sanguineos bajos e inestabilidad en medio acido=penicilinas.

3 2 G E N E R A C I O N E S 1º G. 2º G. Eritromicina  S. erytreus Oleandomicina  S. antibioticus Carbamicina Espiramicina  S. ambofaciens Josamicina Miocamicina Azitromicina Diritromicina Claritromicina Rokytamicina Roxitromicina Fidaxomicina xa C.difficile Naturales BACTERIOSTÁTICOS ↑ dosis + bacterias en crecimiento  BACTERICIDAS Semisinteticos BACTERICIDAS Efecto PostAntibióico prolongado

4 MACROLIDOS KETOLIDO$ Telitromicina (Ketex) y Cetromicina Derivados semisinteticos de eritromicina Gran actividad contra Neumococo-R a penic y a resto de macrolidos. EPA: 10 h contra Neumococo. Usos: Neumococo de comunidad, amigdalitis, bronquitis y otitis media. 400 mg, bid.

5 MACROLIDOS Espectro Actividad Anti-microbiana 1ra Generacion =bacteriostaticos pero dosis  =bactericidas. Activos xa Gram+. Sust naturales  Actinomycetos. 2da generacion =bactericidas. Activos Gram+ y algunos Gram- (Azitro y Claritro). Semisinteticas.

6 Espectro de actividad Neumococo Estreptococo Cl. tetani. Cl. perfringes. Mycoplasma Listeria Estafilococo ?

7 Coryn. difteriae Legionella Morax. catarralis Chlamydia Neisseria g. ? 2da generación (Elección) Mycoplasma pneumoniae Campylobacter  diarrea H. influenzae En ñ con diarrea del viajero la Azitromicina es de eleccion

8 MACROLIDOS 2da generacion Tienen EPA (Claritro 3v > Eritro)

9 Antagonismo competitivo!!! MEC ACCION: Unión reversible a sitio P de subunidad 50s ribosomal (33 proteinas diferentes y 2 moleculas de ARN).  bloquea transpeptidacion y translocacion y detiene la elongacion de cadena peptidica.

10 MACROLIDOS RESISTENCIA 1. Mutacion cromosomica en Recep ribosomal, x plasmidos, cruzada. Gram+, Gram-, Legionella y otros. 2. Impermeabilidad pared bacteriana (Enterobacteriaceas y S. epidermidis). 3. Enzimas (esterasas y fosforilasas) q’ hidrolisan a macrolidos. Enterobacteriaceas. Cruzada. (En Ags: 3 enzimas q`acetilan, adenilan y fosforilan) (cloranfenicol: acetil-transferasa).

11 MACROLIDOS FARMACOCINETICA Eritromicina-base se destruye en medio acido (Tab cubierta enterica, sales de Eritro: estolato, etilsuccinato, estearato). 2da G.: +resistentes a medio acido.  biodisp. Absorcion retardada por alimentos. Adm i.v. lactobionato (10 mcg/ml)

12 →PLASMA Lactobionato IV +++ Macrólidos de 2º G ++ Eritromicina + Unen a alfa-glicoproteina (40-90%) Distribuye en tejidos y fluidosConcentra residuos SNC incipiente (No Ags, No Tetra, Si Clor, No lincosamidas). Eritro desmetilada en higado (inactiva)  orina 5% v.o. y 15% de parenteral. Claritro (metab activo y  vida ½ 6h). Azitro 40h Tejidos y fluidos corporales +prostata, pleural y sinovial, humores. Placenta 10%, leche materna.

13 Eliminación Eritro—filtracion glomerular y reabsorbe parcialmente en zona tubular, Claritromicina es=eritro Azitro 10% orina y resto x heces. bilis 30% y enterohepatica. ELIMINACION

14 FARMACOPATOLOGIA MACROLIDOS FARMACOPATOLOGIA Seguros y eficaces y > 2da generacion. +++G-intestinal: n-v, ardor epigastrico, diarrea, regurgitaciones acidas. I.M. dolorosa. I.v. tromboflebitis.

15 Superinfecciones x Cándida o Cl. difficile Racciones alergicas (raras) exantema, fiebre, eosinofilia, urticaria.

16 MACROLIDOS FARMACOPATOLOGIA Eritro: colestasis intraHep, inicia en 2-3 sem: dolores colicos, n-v, fiebre e ictericia, x hipersensibilidad. En ñ no Htoxicidad pero, estenosis hipertrofica de piloro. Eritro dosis  i.v. = ototoxicidad (reversible)

17 Usos Clínicos Elección en: –Legionella pneumofilica –Campylobacter jejuni –Bordetella pertussis –Corynebacterium diphtheriae –Micoplasma pneumoniae –Chlamydia trachomatis Alternativas en alergia a penicilina: infecciones x Estrepto y Estafilo. -Px fiebre reumatica -Tx de trepanomatosis.

18 Traveler's diarrhea: updates for pediatricians Pediatr Ann. 2008 Dec;37(12):814-20. Ang JY, Mathur A. Ang JYMathur A Children who travel are at risk of developing the same illnesses that affect adult travelers. Treatment, etiology and actual risk of TD in children are not well defined. Prevention and self-treatment of TD should be discussed in great detail during pre-travel counseling. This includes information and instructions on various preventive measures as well as when to use medications and the potential adverse effects associated with these medications. A TD that is mild can be managed effectively by appropriate use of oral rehydration solutions. Families should be advised to carry ORS packets and start treatment in children as soon as the diarrhea begins. Self treatment with antibiotics such as azithromycin may be considered in children if diarrhea is moderate to severe.

19 Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment ofClostridium difficile Infection Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D Posted: 06/18/2012; Am J Health Syst Pharm. 2012;69(11):933-943. © 2012 Abstract Purpose The pharmacology, clinical efficacy, safety, dosage and administration, and place in therapy of fidaxomicin for the treatment of Clostridium difficile infection (CDI) are reviewed. Summary Fidaxomicin, a macrocyclic antibiotic, has a narrow spectrum of activity against gram-positive anaerobes and is bactericidal against C. difficile. It has no activity against gram-negative bacteria. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against C. difficile ranged from 0.0078 to 2 μg/mL in in vitro studies. After oral administration, fecal concentrations are detected and are directly proportional to the dose administered. Fidaxomicin resistance in vivo has not been reported. In clinical trials, fidaxomicin has been shown to be noninferior to vancomycin in the management of mild- to-moderately severe CDI. The adverse-effect profile of fidaxomicin is comparable to that of vancomycin. The recommended dosage for treatment of CDI is fidaxomicin 200 mg orally twice daily for 10 days. Fidaxomicin should be considered for patients who previously received treatment with metronidazole or vancomycin for CDI and who are diagnosed with recurrent CDI in which a non-NAP1/BI/027 strain is isolated. At institutions where strain typing is not available, fidaxomicin may be considered in patients with recurrent CDI who have not responded to treatment with the regimen used for the first episode of CDI. Conclusion Fidaxomicin is a well-tolerated agent for the treatment of CDI and has been shown to be noninferior to vancomycin in the management of mild-to-moderately severe CDI.

20 DIFICID ACTS LOCALLY IN THE GASTROINTESTINAL TRACT 1 1 DIFICID is the first bactericidal therapy in more than 25 years that targets C. difficile 1 1 DIFICID has primary activity against species of clostridia, including C. difficile, in vitro 1 1 Bactericidal against C. difficile in vitro 1 1 Acts locally in the gastrointestinal tract against C. difficile 1 1 Demonstrates no cross-resistance with other classes of antibacterial drugs in vitro 1 1 Inhibits bacterial RNA polymerase 1 1

21 DIFICID delivers powerful efficacy comparable to vancomycin for first-line treatment of Clostridium difficile-associated diarrhea (CDAD) in adults≥18 years of age 1 1 COMPARABLE CLINICAL RESPONSE RATE AT THE END OF 10-DAY TREATMENT VERSUS VANCOMYCIN (PRIMARY ENDPOINT) 1 1

22 Claritromicina en

23 MACROLIDOS PRECAUCIONES No en infecciones graves (Sepsis, osteomielitis). Contraindicado estolato de Eritro en Enf Hep. No asociar alcaloides cornezuelo de centeno  ergotismo con necrosis de extremidades.

24 ORIGINAL ARTICLE Azithromycin and the Risk of Cardiovascular Death Wayne A. N Engl J Med 2012; 366:1881-1890. May 17, 2012 DISCUSSION We found that a 5-day course of azithromycin was associated with a small absolute increase in the risk of cardiovascular death, which was most pronounced for patients in the highest decile of the baseline risk of cardiovascular disease. There was no increased risk of death from noncardiovascular causes among patients who took azithromycin, but there was an increase in the risk of death from any cause. The risk of cardiovascular death was significantly greater with azithromycin than with either amoxicillin or ciprofloxacin but did not differ significantly from the risk with levofloxacin.

25 CDC July 15, 2013 Two New Promising Treatment Regimens for Gonorrhea Additional Options Urgently Needed Two new antibiotic regimens using existing drugs—injectable gentamicin in combination with oral azithromycin and oral gemifloxacin in combination with oral azithromycin—successfully treated gonorrhea infections in a clinical trial. The trial was conducted by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH). The study was conducted to identify new treatment options in the face of growing antibiotic resistance. The findings will be presented July 16 by CDC’s Robert Kirkcaldy, M.D., at the 20th Meeting of the International Society for Sexually Transmitted Diseases Research (ISSTDR) in Vienna, Austria. Dr. Kirkcaldy served as the clinical trial’s principal investigator. All drugs studied in the trial were Food and Drug Administration-approved and are available in the United States. This is the first clinical trial to evaluate them as combination therapy for gonorrhea. Researchers found 100 percent effectiveness of the injectable gentamicin/oral azithromycin combination in curing genital gonorrhea infections, and 99.5 percent effectiveness of the oral gemifloxacin/oral azithromycin combination. Both combinations cured 100 percent of infections of the throat and rectum. However, many trial participants reported adverse effects from the drugs, mostly gastrointestinal issues.

26 LINCOSAMIDAS Quimicamente diferentes a los macrolidos pero semejantes x: mec accion, espectro antibacteriano y farmacocinetica.

27 LINCOSAMIDAS ESPECTRO ANTIBACTERIANO Sensibles, =Eritro: Gram+. No sensibles, Gram- aerobios (C. difficile, Neisseria, Enterobacter y H. influenza). Resistentes: Enterococos. +++Anaerobios: Bacteroides, Fusobacterium, Actinomyces, C. perfringis, Peptoestreptococos y Campylobacter.

28 Antagonismo competitivo!!! MEC ACCION Bacteriostaticas. Unen sitio A de 50s ribosomal=inh sintesis proteinas = macrolidos-ketolidos y cloranfenicol.

29 Mecanismos de resistencia -x plasmidos = macrolidos, resist cruzada. -5% Estafilococos y 0-10% de B. fragilis son R a clindamicina.

30 LINCOSAMIDAS FARMACOCINETICA CLINDA. Oral 75% pasa a sangre y es independiente de alimentos. Palmitato (v.o, 1h 2.8mcg/ml) y fosfato (i.v. 5mcg/ml). LINCO, 75% en ayunas y 25% con alimentos. Atraviesan la placenta NO llegan a LCR

31 LINCOSAMIDAS FCOPATOLOGIA Clinda y Linco, 10% diarrea y > colitis pseudomembranosa (diarrea muco-sanguinolenta, dolor abdominal, n-v)  C. difficile (toxina). i.m.=dolor e i.v.=tromboflebitis. Rapida=colapso cardio-vascular (K). Clinda, no Hepatoxica, pero  transaminasas.

32 Farmacopatología Colitis pseudomembranosa Agrava miastenia gravis  bloqueo neuromuscular de Aminoglucosidos e inh placa neuromotriz (no juntas!).

33 LINCOSAMIDAS FARMACOPATOLOGIA Reacciones alergicas (raras) erupciones cutaneas, fiebre, urticaria. Eritema multiforme, anafilaxia, Sd Stevens Johnson.

34 USOS CLINICOS Tx germenes ANAEROBIOS. +Aminogs en abscesos, e infecciones abdominales severas, peritonitis, EPI. Alternativa a penicilinas en osteomielitis x Staf aureus. Gardnerella vaginalis (vaginosis bact ← ovulos)

35 LINCOSAMIDAS USOS CLINICOS Px quirurgica abdominal Px infecciones estreptococicas clinda+pirimetamina=encefalitis x T.gondii (SIDA) clinda+quinina = Malaria-R /

36 TELITROMICINA Y CETROMICINA Derivados sintéticos

37 Usos Clínicos de Telitromicina y Cetromicina Amigdalitis Bronquitis Neumonía

38 Nature Reviews Drug Discovery 9, 260 (April 2010) | Trial watch: Phase III success for novel Clostridium difficile antibiotic Abstract The results of the second of two Phase III trials evaluating the macrocyclic antibiotic fidaxomicin (OPT-80, PAR-101), developed by Optimer Pharmaceuticals, confirm that it is as efficacious as vancomycin for treating patients with Clostridium difficile infection (CDI). It is also associated with a lower incidence of recurrence of CDI.

39 C difficile organism (National Institutes of Health) February 4, 2011 — Compared with vancomycin, fidaxomicin (Optimer Pharmaceuticals, Inc) produces noninferior rates of clinical cure in adults with Clostridium difficile infection. In addition, for some strains, fidaxomicin is associated with a significantly lower rate of recurrence, according to the findings of a randomized trial. Thomas J. Louie, MD, with the University of Calgary, in Calgary, Alberta, Canada, reported the study findings of the randomized phase 3 trial in the February 3 issue of theNew England Journal of Medicine. According to the researchers, fidaxomicin is a macrocyclic antibiotic that is more active in vitro than vancomycin in clinical isolates of C difficile, including the NAP1/BI/027 strain. "This activity, in combination with minimal systemic absorption, high fecal concentrations, and limited activity in vitro and in vivo against components of the normal gut flora, makes fidaxomicin a promising candidate that may provide highly active but more selective therapy for C. difficile infection," the study authors write. The current study included 629 adults with acute symptoms of C difficile infection, with a positive result on a stool toxin test. Patients were randomly assigned to receive fidaxomicin at a dose of 200 mg twice daily or vancomycin at a dose of 125 mg 4 times daily. Both medicines were taken orally for 10 days. Of the patients, 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those observed with vancomycin in both the modified intent-to-treat analysis (88.2% vs 85.8% with fidaxomicin vs vancomycin, respectively) and the per- protocol analysis (92.1% and 89.8%, respectively).

40 The Year in Medicine 2013: News That Made a Difference December 10, 2013 Major Drug Alerts Several drug warnings were important for clinicians this year. The popular antibiotic azithromycin (Zithromax and Zmax, Pfizer) poses the risk for torsades de pointes, which therefore warrants careful screening of patients for this drug. [12] The antibiotic clarithromycin prescribed for patients already taking antihypertensive calcium-channel blockers is associated with increases in hospitalization for acute kidney injury, hypotension, and death. [14] The fluoroquinolone class of antibiotics increases the risk for permanent peripheral neuropathy, a risk that now appears on updated labels for the drugs. [13] And last, the use of statins appears to be associated with an increased risk for musculoskeletal injuries, including an increased risk for dislocations, strains, and sprains. [15]

41 Other Major Alerts Healthcare professionals also heard warnings about some commonly used nutrients, drinks, and more. Calcium supplement use is associated with higher all-cause and cardiovascular death rates but not with deaths from stroke, but the finding is controversial. [16] Heavy coffee consumption, defined as more than 28 cups of coffee per week, is associated with an increased risk for all-cause mortality among men. [17] Consumption of noncaloric, artificially sweetened beverages may increase the risk for excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. [18] And last, a new hypothesis proposes that antioxidant levels within cancer cells are responsible for resistance to treatment. [19] The theory destroys any reason for taking antioxidative nutritional supplements, because they are more likely to cause than prevent cancer.

42 Probiotics and the Brain, Cinnamon and Diabetes Meds Two studies released this year generated a lot of interest, despite being preliminary. First, a new study provided the first evidence in humans that probiotics in the diet can modulate brain activity: Using functional MRI, researchers found that women who regularly consumed probiotic-containing yogurt showed altered activity of brain regions that control central processing of emotion and sensation. [20] Whether the effects are clinically beneficial will require further study, researchers said. And in a separate meta- analysis, patients with type 2 diabetes who took cinnamon supplements had improved fasting blood glucose and cholesterol levels but not glycated hemoglobin (HbA 1c ) levels. [21] The researchers don't currently recommend cinnamon instead of diabetes medication, but cinnamon might someday play a role as an adjunct to traditional medicine.

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44 Azitromicina: FDA alerta sobre el riesgo de alteraciones en el ritmo cardíaco potencialmente mortales PROBLEMA: La FDA advierte al público que la azitromicina (Zithromax o Zmax) puede causar cambios anormales en la actividad eléctrica del corazón, que pueden ocasionar irregularidades en el ritmo cardíaco potencialmente fatales. Los pacientes particularmente a riesgo de presentar esta condición incluyen aquellos con factores de riesgo conocidos como prolongación del intervalo QT, niveles sanguíneos bajos de potasio o magnesio, un ritmo cardiaco más lento de lo normal, o el uso concomitante de ciertos medicamentos utilizados para tratar las alteraciones en el ritmo cardiaco o arritmias. Esta alerta es resultado del análisis de dos estudios, de los cuales uno de ellos fue realizado por el fabricante del producto, que tenian como fin establecer el efecto del consumo de azitromicina en la actividad eléctrica del corazón. La FDA emitió un comunicado el 17 de mayo de 2012, sobre un estudio que comparó los riesgos de muerte cardiovascular en los pacientes tratados con los antibióticos azitromicina, amoxicilina, ciprofloxacina (Cipro) y levofloxacina (Levaquin), o ningún fármaco antibacteriano. El estudio reportó un incremento en las muertes por causa cardiovascular, y en el riesgo de muerte por cualquier causa, en personas tratadas por 5 días con azitromicina (Zithromax) en comparación con las personas tratadas con amoxicilina, ciprofloxacino, o ningún fármaco. Los riesgos de muerte cardiovascular asociados con el tratamiento con levofloxacino fueron similares a los asociados con el tratamiento con azitromicina. ANTECEDENTES: La azitromicina se comercializa en EE.UU. bajo los nombres de marca Zithromax y Zmax.. En Colombia existen varias presentaciones genéricas. Las indicaciones de la azitromicina aprobadas por la FDA incluyen: exacerbaciones bacterianas agudas de la enfermedad pulmonar obstructiva crónica, sinusitis bacteriana aguda, neumonía adquirida en la comunidad, faringitis / amigdalitis, infecciones cutáneas no complicadas, uretritis y cervicitis y úlceras genitales. RECOMENDACIÓN: Los profesionales de la salud deben considerar el riesgo de torsades de pointes y de alteraciones fatales en el ritmos cardiaco con azitromicina y evaluar otras opciones de tratamiento para los pacientes con un riesgo elevado de eventos cardiovasculares. La FDA señala que el posible riesgo de prolongación del intervalo QT con azitromicina debe ser colocado en un contexto apropiado la hora de elegir un medicamento antibacteriano ya que medicamentos alternativos de la clase de los macrólidos, o no macrólidos como las fluoroquinolonas, también aumentan el riesgo de prolongación del intervalo QT u otros efectos colaterales que se deben considerar al seleccionar un fármaco antibacteriano.

45 MACRÓLIDOS Y LINCOSAMIDAS

46 Mecanismo de Resistencia

47 Mecanismo de acción