Antibióticos. Clasificación x Mecanismo de acción 1) Inh síntesis de la pared celular --lactámicos: 4 Cicloserina .1 Vancomicina 4 Bacitracina 2 Antimic.imidazoles Fosfomicina.1 6) Inh síntesis y replicación del DNA Quinolonas 5) Inh RNA polimerasa Rifampicina DNA PABA THFA Ribosomas RNAm 7) Antimetabolitos 50s 3) Inh íntesis proteica (Ribos 30s) Aminoglucósidos Tetraciclínas DHFA Sulfas y Trimetoprim 30s 4) Inh síntesis proteica (Ribos 50s) Macrólidos -Ketólidos Cloranfenicol Lincomicinas Acido Folico Purinas 2) Membrana celular POLIPEPTIDOS (polimixina B Colistin, Capreomicina (Tb). ANTIBIOT POLIENOS: Anfoteric B y Nistatina

ANTIBIOTICOS BETALACTAMICOS CEFALOSPORINAS De Cephalosporium acremonium. Bactericidas (=penicilinas) Escasa toxicidad (=Penic) Amplio espectro antibacteriano (?generac) Pero,… caros y ya resistencia bacteriana !!

Estructura química (7-ACA) similar a penicilinas (6-APA). CEFALOSPORINAS Estructura química (7-ACA) similar a penicilinas (6-APA).

CLASIFICACION CEFALOSPORINAS 1ra G.: Cefalexina, cefalotina, cefalopirina, cefadroxilo, cefazolina, cefaloridina, etc. 2da G.: cefoxitina, cefaclor, cefuroxima, etc. 3ra G.: ceftazidima, ceftriaxone, cefamandol, moxalactam. 4ta G.: cefepime, cefpiroma, cefdinir, cefditoren.

1ra GENERACIÓN Cefazolina Cefalexina Cefalotina Cefadroxilo

2da GENERACIÓN Cefoxitina Cefonicid Cefuroxima (v.o. y parenteral)

3ra GENERACIÓN Ceftriaxona Cefotaxima Ceftazidima Cefoperazona Ceftibuteno (v.o.)

4ta GENERACIÓN Cefepime cefpiroma, cefdinir, cefditoren

CEFALOSPORINAS ESPECTRO ANTIBACTERIANO 1ra Generación Gram+ (incluso Stafilococo productor penicilinasa). Streptococo pyogens (A y B-hemolitico, agalactiae, viridans, pneumoniae). No Staf meticilino-R ni Strept. faecalis < Gram- (E.coli, Kliebsiella y P. mirabilis) NO anaerobios. NO Pseudomonas NO penetran al SNC.

2da Generación CEFALOSPORINAS Gram- (x mejor estabilidad a B-lactamasas) N.gonorroheae, N. meningitidis, H. influenza (R-ampic), Citrobacter, Proteus y Serratia. Gram+. NO Pseudomonas, NO Acinetobacterias Anaerobios: Cefoxitina + xa Bact fragilis No a SNC (SI en meninges inflamadas)

3ra Generación +++actividad Gram- (N. gonorrhoeae y N. meningitidis). +Enterobacteriaceas: E.coli, Klebsiella, Enterobacter, Proteus, Morgagnella, Providencia, Serratia, Salmonella, Shigella. Activas xa Pseudomona (+Ceftazidima). Activas xa anaerobios. SI penetran SNC.

4ta Generación +Amplio espectro y +activas q` 3ra. Stafilococo (no St-meticilino-R) y enterococo. Xa Gram-R a 3ra generación (+estables contra B-lactamasas). En Pseudomona-R a ceftazidima

MECANISMO de ACCIÓN: Inhiben la síntesis de la pared bacteriana (PBP) La transpeptidación es inhibida por las Cefalosporinas (peptidoglucano o mureina da la estructura rígida a la pared).

Etapas de formacion de peptidoglicanos: Inhiben Sintesis de pared bacteriana, especificamente la Transpeptidacion o 4ta etapa (B-lactamicos, vancom). Etapas de formacion de peptidoglicanos: 1. Sintesis ( Inh x fosfomicina y cicloserina); 2.Transporte (x bacitracina); 3. Polimerizacion 4. Transpeptidacion (x Peni y Cefalosp) PEPTIDOGLICANO: Complejo peptidico formado x 2 tipos de moleculas: alternadas unidas a través de puentes peptidicos. En Gram+ es el 90% de la pared. Unen a PBP en m.c.

RESISTENCIA a CEFALOSPORINAS mecanismos: 1. Por enzimas:Producción de B-lactamasas: Gram-, mediada cromosómicamente ó x plasmidos. Cefalosporinasas no dañan a 3ra y 4ta G. 2. Alteraciones de PBP (mutaciones): natural (enterococo, Legionella, Candida, Clostridium). Adquirida: Gram+, E. coli, N.gonorroheae. 3. ▼permeabilidad de pared a Cefalosp---Incapacidad de transitar por las porinas. x: # o mutaciones q alteran la conformación estructural: Pseudomonas. 1 2 PBP 3

CEFALOSPORINAS FARMACOCINETICA X v.o.: 1ra y 2da generación (xq´son acido-resistentes). Otras acido-lábiles x vía parenteral excepto: Ceftibuteno y cefpodoxima de 3ra G. v.o. En 60-90 m, plasma 15-20mcg/mL Alimentos o leche retardan absorción.

CEFALOSPORINAS FARMACOCINETICA Transporte y Distribución 1ra G. Ligan a proteínas (exc. cefazolina) distribución amplia, No a LCR. 2da G. a proteínas (exc cefuroxima) difusion tejidos (pleural, sinovial, bronquial). LCR x cefuroxima y x meninges inflamadas.

CEFALOSPORINAS FARMACOCINETICA 3ra G. ligadura proteica, buena distribución tejidos y fluidos. LCR y membranas inflamadas (+cefamandol y ceftriaxone). 4ta G. Cefepime. 20% ligadura, buena distribución. Pasa barrera hematomeníngea en inflamaciones.

CEFALOSPORINAS METABOLISMO y EXCRECION 1ra G. metabolizan parcialmente o nada. Eliminan casi 100% x orina y poco x bilis. x filtración y secreción (Probenecid ?).

CEFALOSPORINAS METABOLISMO y EXCRECION 2da G. = 1ra G. Exc ceforanida no x sec tubular. Ceforanida y cefonicida tienen vida ½ prl, bid. 3ra G. NO metabolismo H (excepto cefotaxima). Excreción diferente, filtración y secreción o solo filtración o x bilis. Ceftriaxona vida ½ prl QD. 4ta G. NO se metabolizan, eliminan x riñón sin cambio. Pasan la leche materna.

CEFALOSPORINAS FARMACOPATOLOGIA 1. REACCIONES de HIPERSENSIBILIDAD +++ Rash maculopapular. Tipo inmediato (fiebre, anafilaxia, broncoespasmo, urticaria, oesinofilia). Reacciones de sensibilidad cruzadas con Penicilinas 5%. Raros: leucopenia, trombocitopenia y anemia hemolítica x mec inmunológicos. Coombs directa +

CEFALOSPORINAS FARMACOPATOLOGIA 2. REACCIONES HEMATOLOGICAS Hemorragia e hipoProtrombinemia x 3ra G (cefamandol, cefoperazona y moxalactam (trast plaqueta) x grupo metiltiotetrazol) x interferencia en metab de Vit K. 3. ▲TOXICIDAD RENAL Necrosis tubular renal (dosis alta o pctes disfunción o ancianos o + Ags). Cefalotina y cefaloridina.

June 2012. FDA is reminding health care professionals about the need to adjust the dosage of the antibacterial drug cefepime in patients with renal (kidney) impairment. There have been cases of a specific type of seizure called nonconvulsive status epilepticus associated with the use of cefepime, primarily in patients with renal impairment who did not receive appropriate dosage adjustments of cefepime. Cases of nonconvulsive status epilepticus associated with cefepime are documented in the medical literature and have been identified in FDA’s Adverse Event Reporting System (AERS) database. Most cases occurred in patients with renal impairment who did not receive appropriate dosage adjustment; however, some cases occurred in patients receiving dosage adjustment appropriate for their degree of renal impairment. In the majority of cases, the seizures were reversible and resolved after discontinuing cefepime and/or after hemodialysis.

CEFALOSPORINAS FARMACOPATOLOGIA 4. REACCIONES G-INTESTINALES n-v, pirosis, anorexia. Diarrea severa x C. difficile (vancomicina o metronidazol). Candida. 6. EFECTOS TERATOGENICOS? No reportes de teratogenicidad o embriotoxicidad.

CEFALOSPORINAS FARMACOPATOLOGIA REACCIONES LOCALES i.m=dolor; i.v.=tromboflebitis.

USOS CLINICOS APARATO Respiratorio: -Sinusitis, -amigdalitis, -faringitis, -bronquitis y -neumonía neumocócica (VO. 1ra G). -Neumonía x Klebsiella y nosocomiales (3ra) (2da Cefuroxima).

INFECCIONES G-INTESTINALES e INTRABDOMINALES USOS CLINICOS INFECCIONES DEL SNC. meningitis x H. influenzae, N. meningitidis y S. pneumoniae =2da G. cefuroxima i.m. LCR, Meningitis x bacilos entericos Gram-= 3ra G Ceftazidima xa P. aeruginosa. INFECCIONES G-INTESTINALES e INTRABDOMINALES -F. tifoidea = Ceftriaxona y cefoperazona. -Intraabdominal traumática o quirúrgica = cefoxitina. 3raG.= B. fragilis -Infecc Hepatobiliares= Cefoperazona y Ceftriaxona. - Septicemia por Gram+ o Gram- (cura 90%). + Ags.

-EPI= Neisseria g (ceftriaxona),chancro. USOS CLINICOS I. Ginecológicas -EPI= Neisseria g (ceftriaxona),chancro. T. urinario: -Simples =1ra G. orales. -Hospitalarias=3ra Cefepime: Tx neutropenia febril e infecciones intrabdominales complicadas. Otras infecciones: piel, tejidos blandos, huesos, endocarditis, úlcera de decúbito, celulitis.

CEFALOSPORINAS 6. PROFILAXIS 1ra G. parenterales = quimioPx de interv quirúrgicas: inserción de prótesis vasculares en corazón, cirugía G-duodenal y biliar, histerectomía abdominal y vaginal, cesárea, resección pulmonar, intervenciones de larga duración. Cefazolina 1 amp i.v. al inicio de anestesia

Obstet Gynecol. 2010;116:791-792 Antimicrobial prophylaxis for cesarean delivery typically employs narrow-spectrum antibiotics, such as a first-generation cephalosporin, effective against gram-positive bacteria, gram-negative bacteria, and some anaerobic bacteria. A single 1-g intravenous dose of cefazolin usually results in a therapeutic level for 3 to 4 hours, but obese women may need larger doses. Clindamycin with gentamicin is a reasonable option for women with a significant allergy to β-lactam antibiotics, such as cephalosporins and penicillins. Studies to date suggest that preoperative antimicrobial prophylaxis does not appear to have any harmful effects on the mother or infant, nor is it associated with an increase in neonatal infectious morbidity or selection of antimicrobial-resistant bacteria causing neonatal sepsis. However, additional prospective evaluation is needed because these studies lacked sufficient power to assess those outcomes. "The Committee on Obstetric Practice recommends antimicrobial prophylaxis for all cesarean deliveries unless the patient is already receiving appropriate antibiotics (eg, for chorioamnionitis) and that prophylaxis should be administered within 60 minutes of the start of the cesarean delivery," the committee concludes. "When this is not possible (eg, need for emergent delivery), prophylaxis should be administered as soon as possible."

Interacciones Medicamentosas -Anfotericina B -Aminoglucósidos -Acido etacrínico, -Furosemida y -Vancomicina + Cefalotina y Cefaloridina ↑ NEFROTOXICIDAD Alcohol Reacción de tipo Disulfirán -Aspirina, -Anticoagulantes orales -Heparina Cefamandol ↑ riesgo de hemorragia.



Annals of Clinical Microbiology and Antimicrobials New Antibiotics for Bad Bugs: Where Are We? Matteo Bassetti, Maria Merelli, Chiara Temperoni, Augusta Astilean DisclosuresAnn Clin Microbiol Antimicrob. 2013;12(22) Cephalosporins The cephalosporin class of antimicrobial agents is known for its broad spectrum of activity, proven efficiency and favorable safety profile, making it the most commonly prescribed class of antimicrobials. There are four recognized class generations of cephalosporins based on their activity spectrum. Now with ceftaroline-fosamil and ceftobiprole, a new subclass of antimicrobials, cephalosporins with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity has been introduced. Ceftaroline and ceftobiprole have also been described in the literature as 'fifth-generation' cephalosporin; however, such classification suggests a broader Gram-negative profile whereas ceftaroline and ceftobiprole spectrum of activity is truly unique for its expanded Gram-positive activity beyond all other presently available cephalosporins (i.e. MRSA).

Curr Opin Infect Dis. 2014;27(1):62-67 Curr Opin Infect Dis. 2014;27(1):62-67. Global Resistance of Neisseria gonorrhoeae David A. Lewis. Recent findings The estimated incidence of new gonorrhoea cases is increasing, and the antimicrobial resistance profile ofN. gonorrhoeae is worsening. The most significant recent finding has been the emergence of extensively drug-resistant (XDR) N. gonorrhoeae characterized by very high ceftriaxone minimum inhibitory concentrations. A national switch from cefixime to high-dose ceftriaxone as first-line antigonococcal therapy in England and Wales, as well as parts of Japan, has been accompanied by a reduction in the prevalence of oral ESC-resistant gonococci. Azithromycin given in combination with either gentamicin or gemifloxacin has been shown to be an effective alternative antigonococcal therapy. Both ertapenem and solithromycin have good in-vitro activity against ESC-resistant N. gonorrhoeae strains. Summary Current strategies to control gonococcal AMR should focus on the use of higher doses of ceftriaxone given as part of dual therapy and further evaluation of alternative drug combinations. The emergence of XDR gonorrhoea argues for enhanced efforts to develop novel antimicrobial agents and a gonococcal vaccine.

Medscape Medical News Ceftriaxone Linked to Renal Failure in Children Veronica Hackethal, MD March 24, 2014 Ceftriaxone used at therapeutic doses is linked to renal stones and pediatric acute renal failure (PARF), with recovery possible on early treatment, according to a retrospective studypublished online March 24 in Pediatrics. "Ceftriaxone therapy in children may cause PARF," the authors note, "Early diagnosis and prompt pharmacological therapy are important in relieving the condition. Retrograde ureteral catheterization is an effective treatment for those who fail to respond to pharmacotherapy." Ceftriaxone, an antibiotic commonly used to treat childhood infections, has been linked to biliary pseudolithiasis, nephrolithiasis, and bladder sludge, according to background information described in the article. Formation of urine crystals that cling to renal tubular cells has been observed during ceftriaxone treatment, with the potential for causing acute renal failure. Few studies have reported on ceftriaxone-associated PARF, however, and its incidence is presumably rare, according to the authors.