Estrategias terapeuticas en el manejo de bacterias multiresistentes Maria Virginia Villegas, MD. MSc Internista Infectólogo Directora ejecutiva e Investigadora CIDEIM mariavirginia.villegas@gmail.com

Objetivos Gram (+) S.aureus Gram (-) K.pneumoniae y E.coli 1. Discutir las bacterias nosocomiales con mayor dificultad diagnostica e impacto terapeutico : Gram (+) S.aureus Gram (-) K.pneumoniae y E.coli P.aeruginosa A.baumannii

Objetivos 2. Escoger el antibiotico mas eficiente de acuerdo a: Epidemiologia en cada hospital Mecanismo de resistencia utilizado por la bacteria Menor Presion selectiva CIMs para esa Institucion y t> CIM del antibiotico(s)

Alvarez et al, Emerging Infect Dis. 2006;12:2000 MRSA en Colombia Alvarez et al, Emerging Infect Dis. 2006;12:2000

MRSA Asociado a la Comunidad Bogotá, Colombia % Alvarez et al, Emerging Infect Dis. 2006;12:2000

MRSA Asociado a la Comunidad, Houston TX %

MECANISMOS DE RESISTENCIA A OXACILINA DEL S.aureus Δ de las PUP

Mortalidad asociada al tto con Vancomicina en S Mortalidad asociada al tto con Vancomicina en S.aureus Sensible a Oxacilina Kim SH, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible S. aureus bacteremia. Antimicrob Agents Chemother 2008 January;52(1):192-7.

Gonzalez, et al. Clin Infect Dis. 1999;29:1171-1177. Neumonia bacteremica por SAMS: Mortalidad hospitalaria Vancomycin Oxacillin P<0.05 References: Gonzalez C, Rubio M, Romero-Vivas J, Picazo JJ. Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis. 1999;29:1171-1177. Gonzalez, et al. Clin Infect Dis. 1999;29:1171-1177.

Tratamiento Antimicrobiano Inadecuado por Inicio tardio en el tto de bacteremia por S aureus Early (n=119) Delayed (n=48) P value Infection-related mortality 19.3% 33.3% 0.05* OR 3.8 0.01† LOS after SAB 14.3 d 20.2 d 0.05† A retrospective cohort analysis of patients with S aureus bacteremia (SAB) showed that delayed antimicrobial treatment of infection significantly increases infection-related mortality and LOS after diagnosis of SAB. Patients included in the study had SAB diagnosed ≥2 days after admission to a level 1 trauma center. Classification and regression tree analysis (CART) identified a breakpoint of 44.75 hours from first positive blood culture to administration of appropriate treatment that differentiated early and delayed treatment based on the rate of infection-related mortality. [Lodise;1419] Of 167 patients with SAB, 48 received delayed treatment and 119 received early treatment. Univariate analysis showed nearly a twofold increase in infection-related mortality in the delayed over the early treatment group (33.3% and 20.2%, respectively; P=.05). [Lodise;1420] Multivariate analyses controlled for predictors of negative outcomes (APACHE II score ≥15.5, high-risk source of infection, mechanical ventilation, and presence of decubitus ulcers) found delayed treatment to be an independent predictor of infection-related mortality (OR 3.8; CI 1.3-11.0; P=.01). [Lodise;1420, 1421] Adjusted mean LOS after the onset of SAB was significantly longer in the delayed than in the early treatment group (20.2 days and 14.3 days, respectively; P=.05). [Lodise;1419,1421] Reference: Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003;36:1418-1423. Breakpoint between early and delayed treatment of SAB = 44.75 hours LOS=length of stay; SAB=S aureus bacteremia. *Unadjusted. †Adjusted. Lodise TP, et al. Clin Infect Dis. 2003;36:1418-1423.

Que hay nuevo y en estudio 1. Linezolid para neumonia por MRSA : Mayor penetracion Menor toxicidad Mayor eficacia, con menor mortalidad. 2. En sepsis por MRSA con Sind shock toxico: Bloquea toxina ( RNA ) Mayor ventaja que vancomicina u otra opcion terapeutica 3. MRSA de la comunidad !!!.....

Problemas en la deteccion de Resistencia a Oxacilina en el laboratorio Sistemas Automatizados no son confiables para la identificacion de MRSA o MRS.coagulasa (-). Existen muchos metodos para confirmar si un S.aureus o coag (-) es realmente S/R a oxacilina. La prueba modificada del disco de cefoxitin es la mas barata y confiable

Detection of MRSA & MRSE Staphylococcus aureus & S. lugdunensis Do not trust automated systems (Vitek, MicroScan) Use 30 mcg Cefoxitin disk to screen for MRSA & MRSE Read after 24 hrs incubation at 35° C (sooner if Resistant) Cefoxitin zone 19 mm report as Oxacillin-resistant (Not Cefoxitin) For other coag neg staph (not lugdunensis) 24 mm = Ox Resist Oxacillin Cefoxitin

En resumen ●Mortalidad alta asociada a infecciones por S.aureus si Se inicia tardiamente Si se da tto con Vancomicina a un MSSA ● Recomendacion Todo S.aureus DEBE ser tamizado con disco de cefoxitin. Probablemente en una bacteremia en la que informen cocos Gram(+) la indicacion sea Vanco+Prosta/Beta-lactamico hasta S final.

Impacto clinico de las BLEE: Mortalidad entre 60 pacientes con bacteremia por Klebsiella productora de BLEE Paterson DL. CID 2004

Muerte en los 14 dias de bacteremia 33 (2/6) 100 (6/6) 8 0 (0/3) RESULTADOS EN PTES CON INFECCIONES SEVERAS POR BLEE Y CORRELACION CON LOS MIC EN EL LAB. % (No/total) de ptes quienes: MIC(mg/ml) Experimentan falla Tto con Cefalosporina Muerte en los 14 dias de bacteremia 8 4 2 £1 Total 100 (6/6) 67 (2/3) 33 (1/3) 27 (3/11) 54 (15/28) 33 (2/6) 0 (0/3) 18 (2/11) Paterson et al. J Clin Microbiol 2001;2200-2212

DETECCION INADECUADA DE BLEE POR EL LABORATORIO La utilizacion de inóculos bacterianos pequeños y tiempos de incubación cortos limitan el Dx de BLEE. Klebsiella, E.coli y Proteus con CIM ≤ 8 μg/ml DEBE descartarse una BLEE. Se DEBE utilizar simultaneamente el Test confirmatorio de BLEE

P.aeruginosa problema Dx y Terapeutico Falla en los sistemas automatizados para detectar S/R : La recomendación para las pruebas de sensibilidad en bacterias Gram negativas no fermentadoras, es confirmar la Sensibilidad por el método de difusión en agar.

Accuracy of Automated Systems: Susceptibility Testing P. aeruginosa Sader HS et al. Poster 105th Gen Mtg ASM, 2005 System/ Error type Aztreonam Cefepime Ceftaz. Imipen. Pip/Taz MSWA VM Maj Minor 28 3 32 13 2 10 19 1 - Vitek-L 26 11 21 Vitek 2 31 18 9 8 27

Escogencia del antibiotico DEBERA incluir la CIM y Dosificacion Utilizar puntos de corte adecuados Utilizar dosificacion adecuada para lograr un t>CIM del 40-70 % Ajustar dosis de acuerdo a la CIM Infusion del Beta-lactamico en 3 horas

Piperacillin-tazobactam Breakpoints Currently, NO intermediate category for P. aeruginosa Piperacillin-tazobactam MIC (µg/ml) S I R Enterobacteriaceae and other non-Enterobacteriaceae  16 32-64 128 P. aeruginosa  64 -- P. aeruginosa (Recommended)* * Under consideration by CLSI

Outcomes of Pseudomonas aeruginosa Bacteremia Treated with Piperacillin/Tazobactam Retrospective cohort study of pseudomonal bacteremia from 2002 to 2006 Primary outcome: 30-day mortality from first day of bacteremia 34 bacteremia episodes with reduced susceptibility to piperacillin/tazobactam (MIC 32 or 64 mg/L, reported as susceptible [CLSI breakpoint: ≤64 mg/L]) 30-day mortality (P = .004) 6 of 7 (85.7%) in the piperacillin/tazobactam group 6 of 27 (22.2%) in the control group Infection-attributed hospital mortality (P = .024) 5 of 7 (71.4%) in the piperacillin/tazobactam group Time to hospital mortality shorter in the piperacillin/tazobactam group (P < 0.001) Tam VH et al. Clin Infect Dis 2008;46:862-867

Outcomes in Gram-Negative Bacteremia Based on Cefepime Breakpoints 28-day mortality in patients with gram-negative bacteremia who received cefepime (typically 1 to 2 grams q12h) 23.3% 27.8% 27.3% 56.3% 53.3% n=116 n=18 n=11 n=16 n=15 P = 0.001 Susceptible* *CLSI susceptibility breakpoint for cefepime: ≤8 μg/mL Bhat SV et al. Antimicrob Agents Chemother 2007;51:4390-4395

J. Antimicrob Chemother. November 2005 Comparison of ß-lactam regimens for the treatment of Gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics J. Antimicrob Chemother. November 2005

Pseudomonas aeruginosa Unidades de Cuidado Intensivo

Impact of Dosing and Combination Therapy in the Evolution of Resistance in P. aeruginosa An Analysis Based on Pharmacodynamic Modeling 208 isolates of P. aeruginosa analyzed using pharmacokinetic properties, susceptibility results, and Monte Carlo simulation using 4 different dosing regimens of meropenem at pharmacodynamic endpoints 1 gram q8h 2 grams q8h 1 gram q8h infused over 3 hours 2 grams q8h infused over 3 hours “Meropenem 2 grams q8h with a 3-hour infusion in combination with an aminoglycoside provides the greatest likelihood of P. aeruginosa coverage, and may help to prevent development of resistance, although local MIC data are essential to inform therapeutic decisions.” Filho LS et al. Clin Microbiol Infect 2007;13:579-585

En resumen ●Mortalidad alta asociada a infecciones por P.aeruginosa si Se inicia tardiamente ( antibiotico inapropiado) Si se da dosificacion BAJA ● Recomendacion Toda SOSPECHA de P.aeruginosa ( UCI ) DEBERA iniciarse con dosis maximas del antibiotico en Infusion continua o por 3 horas. SOLO con CIM podra de-escalarse. El antibiotico empirico ideal sera el que tenga menor R y CIM menor !!

A.baumannii Problema terapeutico y epidemiologico Presencia de Acinetobacter panresistente. Adquisición de carbapenemasas ( OXA 23 ). Evidencia de transmision cruzada de clones en los hospitales, entre hospitales y ciudades. Multiresistencia deja muy pocas opciones terapeuticas : Sulbactam, Carbapenems Colistina y Tigeciclina . ●

Bad Bugs, No Drugs1 Declining research investments in antimicrobial development2 The Antimicrobial Availability Task Force of the IDSA identified, among others, Acinetobacter baumannii, ESBL-producing Enterobacteriaceae, vancomycin-resistant Enterococcus, & Pseudomonas aeruginosa as particularly problematic pathogens2 ESBL = extended spectrum b-lactamase 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.

Existen muy pocas opciones terapeuticas para Gram (-) Multiresistentes No vienen nuevos antibioticos para estas bacterias Gram (-) Multiresistentes existentes Tenemos que usar los antibioticos disponibles en forma adecuada: ¿ Como ? Evitando seleccion de Resistencia temprana = Disminuyendo Presion Selectiva

Presión selectiva • Ocurre cuando se aumenta el espectro de un antibiotico inecesariamente matando bacterias que NO estan generando infeccion en ese momento. • Cuando se usa un antibiotico existiendo un mecanismo de resistencia que permite la sobrevivencia de la bacteria.

Como disminiur la Presion selectiva Estratificar la infeccion para no cubrir Pseudomona inecesariamente.!! Siendo mas selectivos : No usando drogas con actividad antipseudomona para Enterobacteriacea !! De-escalando : iniciar en UCI cubrimiento antipseudomona y con cultivo que descarte Pseudomona de-escalar a otro antibiotico sin actividad contra Pseudomona.

Antibioticos con la mayor Presion selectiva sobre la flora intestinal del paciente Cefalosporinas de 3ra generacion : Seleccionan para BLEEs y AmpC Estudio OASIS I y II ● Mortalidad asociada del 32 al 45 % Estudios Sciappa, Rice, Chow etc

Presion selectiva de Ceftriaxone vs. Ertapenem durante y pos tto Draft: Not Approved for Use OASIS II Therapy-Resistant Enterobacteriaceae Subanalysis Source: IVZ 2005-W-226381-SS (Slide 32) 1/DiNubile EJCMID 2005, p 446, Table 3, L1, C1, 5-7 L2, C1-4 L3, C1-7 Presion selectiva de Ceftriaxone vs. Ertapenem durante y pos tto 25 Baseline End of Therapy 2 Weeks Posttherapy 22.4% 20 The OASIS II therapy-resistant Enterobacteriaceae subanalysis examined the selection of therapy-resistant Enterobacteriaceae with ertapenem versus ceftriaxone/metronidazole.1 As shown on the left side of the slide, less than 1% of evaluable patients in the ertapenem treatment group had evidence of ertapenem-resistant Enterobacteriaceae at baseline, at the end of therapy, and 2 weeks after therapy. At baseline, 4% of patients in this treatment group had isolates that produced ESBLs; this percentage decreased to zero during ertapenem therapy and was 2.2% two weeks after therapy.1 As shown on the right, bacterial resistance was more common in the ceftriaxone/metronidazole treatment group. At baseline, more than 2% of patients in this group had isolates that were either resistant to this regimen or produced ESBLs. After therapy with this regimen, 17.1% of patients were found to have treatment-resistant isolates and 9.3% of isolates produced ESBLs. Two weeks after therapy, 22.4% of patients treated with ceftriaxone/metronidazole had Enterobacteriaceae that were resistant to this regimen and 17.2% of patients had isolates that produced ESBLs.1 The emergence of resistance to study therapy and the emergence of ESBL-producing Enterobacteriaceae occurred at significantly higher rates in the piperacillin/tazobactam treatment group than in the ertapenem treatment group at the end of therapy and 2 weeks posttherapy (P<0.001 for all comparisons).1 The OASIS II therapy-resistant Enterobacteriaceae subanalysis in intra-abdominal infections showed that bowel colonization with therapy-resistant gram-negative bacilli was less likely with ertapenem than with ceftriaxone/metronidazole.1 1/DiNubile EJCMID 2005, p 448, C1, ¶2, L1-4 1/DiNubile EJCMID 2005, p 446, Table 3, L2, C1-4, L3, C1-4 L1, C1, 5-7, L3, C1, 5-7 L1, C1, 5-7, L2, C1-4, L3, C1-7, Last footnote 1/DiNubile EJCMID 2005, p 448, C2, ¶3, L1-5 17.1% 17.2% 15 Percent 9.3% 10 4.0% 5 2.6% 2.2% 2.1% 0.5% 0.5% 0% 0% (n=201) (n=196) (n=182) (n=201) (n=196) (n=182) (n=195) (n=193) (n=174) (n=195) (n=193) (n=174) Resistant, % ESBL Producers, % Resistant, % ESBL Producers, % Ertapenem Ceftriaxone/Metronidazole Adapted from DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis 2005;24:443–449. Reference DiNubile MJ, Friedland I, Chan CY, et al. Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy. Eur J Clin Microbiol Infect Dis. 2005;24:443–449. IVZ 2007-W-1242823-SS

Draft: Not Approved for Use OASIS I Therapy-Resistant Enterobacteriaceae Subanalysis Source: IVZ 2005-W-226381-SS (Slide 31) 1/DiNubile EJCMID 2005, p 446, Table 2, L1, C1, L5-7, L2, C1-4, L3, C1-7 Minimal Risk of Resistance Development With Ertapenem 14 Baseline End of Therapy 2 Weeks Posttherapy 12.2% 12 1/DiNubile EJCMID 2005, p 448, C1, ¶2, L1-4 1/DiNubile EJCMID 2005, p 446, Table 2, L2, C1-4, L3, C1-4 L1, C1, 5-7, L3, C1, 5-7 L1, C1, 6, L2, C1, 3 Footnote b 1/DiNubile EJCMID 2005, p 448, C2, ¶3, L1-5 The OASIS I therapy-resistant Enterobacteriaceae subanalysis examined the selection of therapy-resistant Enterobacteriaceae with ertapenem versus ceftriaxone/metronidazole.1 As shown on the left side of the slide, less than 1% of evaluable patients in the ertapenem treatment group had evidence of Enterobacteriaceae that were either resistant to ertapenem or producers of ESBLs at baseline, at the end of therapy, and 2 weeks after therapy.1 As shown on the right, less than 1% of patients in the piperacillin/tazobactam treatment group had isolates that were either resistant to this regimen or producers of ESBLs at baseline. After therapy with the latter regimen, however, 12.2% of patients were found to have treatment-resistant isolates and 2.6% of isolates produced ESBLs. Two weeks after therapy, 4.5% of patients treated with piperacillin/tazobactam still had Enterobacteriaceae that were resistant to this regimen.1 The emergence of resistance to study therapy occurred at a significantly higher rate in the piperacillin/tazobactam treatment group than in the ertapenem treatment group at the end of therapy (P<0.001).1 The OASIS I therapy-resistant Enterobacteriaceae subanalysis showed that bowel colonization with resistant gram-negative bacilli was less likely after treatment of intra-abdominal infections with ertapenem than with piperacillin/tazobactam.1 10 8 Percent 6 4.5% 4 2.6% 2 0.6% 0.6% 0.8% 0.6% 0.6% 0.8% 0% 0% 0% (n=162) (n=155) ( n=133) (n=162) (n=155) (n=133) (n=160) (n=156) (n=133) (n=160) (n=156) (n=133) Resistant, % ESBL Producers, % Resistant, % ESBL Producers, % Ertapenem Piperacillin/Tazobactam Adapted from DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis 2005;24:443–449. Reference DiNubile MJ, Friedland I, Chan CY, et al. Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy. Eur J Clin Microbiol Infect Dis. 2005;24:443–449. IVZ 2007-W-1242823-SS

Antibioticos con la mayor Presion selectiva sobre la flora intestinal del paciente Quinolonas: Antibiotico con la mayor resistencia en la comunidad y hospitalaria para E.coli. Presenta un aumento dramatico de resistencia frente a P.aeruginosa

Resistencia E. coli en UCI

P. aeruginosa† : Neuhauser JAMA 2/19/03 †: 1990-1993 vs. 1994-1998: Ciprofloxacin 11% to 21%, p=0.001, OR=2.2

Resistance Associated With Fluoroquinolone Usage 35 250,000 30 200,000 25 Graph: Neuhauser/ pg 887/ B Strains resistant to ciprofloxacin, % 150,000 20 Fluoroquinolone use, kg 15 100,000 10 The development of antibacterial resistance in P aeruginosa and Gram-negative bacilli appears to be correlated with the use of fluoroquinolones [Neuhauser/ pg 887/ A, B]. This slide illustrates the increasing resistance rates from 1994-2000 for P aeruginosa and shows the correlation with fluoroquinolone usage [Neuhauser/ pg 887/ B].1 The most troubling trend observed in the current study was the dramatic decline in the activity of ciprofloxacin against some key gram negative pathogens, particularly P. aeruginosa [Neuhauser/ pg 887/ A]. 1 The percent of strains susceptible declined dramatically in this species, from 89% in 1990-93 to 68 % in 2000. This decline in activity was associated with a 2.5 fold increase in total quinolone use over that same time period [Neuhauser/ pg 887/ A]. 1 References: 1. Neuhauser MM, Weinstein RA, Rydman R, et al. Antibiotic resistance among Gram-negative bacilli in US intensive care units: implications for fluoroquinolone use.JAMA. 2003;289:885–888. 50,000 5 1994 1995 1996 1997 1998 1999 2000 P aeruginosa Gram-negative bacilli Fluoroquinolone use Neuhauser MM et al. JAMA. 2003;289:885–888.

Persistencia de cepas resistentes atraves del tiempo Persistence of colonization with Escherichia coli isolates with reduced susceptibility to fluoroquinolones for a median duration following hospital discharge was 80 days (range, 8 to 172 days) Lautenbach E et al. Antimicrob Agents Chemother 2006;50: 3939–3943

Lower Respiratory Tract Infection Caused by P Lower Respiratory Tract Infection Caused by P. aeruginosa and Treated with Ciprofloxacin With regimen of 200 – 300 mg IV every 12 hours, an emergence of resistance rate ≥70% during therapy (as compared to 75% by prediction model) With a regimen of 400 mg IV every 8 hours, emergence of resistance in 33% of cases (as compared to 38% by prediction model) Drusano GL et al. Clin Infect Dis 2006;42:525-532

Antibioticos con la mayor Presion selectiva sobre la flora intestinal del paciente Imipenem y meropenem: No para Enterobacteriaceas sino para P.aeruginosa multiresistente ( UCI ). Su uso en Enterobacteriaceas selecciona P.aeruginosa multiresistente !! Mayor costo tto/dia !!

Antibióticos y probabilidad de seleccionar resistencia durante el tto frente a P.aeruginosa Cox proportional hazard ratios for development of resistance during therapy (mainly respiratory isolates in ICU) Ceftazidime y cefepime : 0.8 Piperacillin y Pip/taz : 5.2 Ciprofloxacin: 9.2 (similar para otras quinolonas ) Imipenem: 44 ( similar para Meropenem) Carmeli. Antimicrob Agents Chemother. 1999.

Cual debe ir primero Pip/taz o Cefepime en UCI para P.aeruginosa ? Estara basado en: Epidemiologia local Incluir la distribucion de P.aeruginosa vs. MICs de cada antibiotico Considerar dosificacion adecuada para alcanzar el target ( 60 % t>MIC): 4.5 gm c/4-6 hrs Pip/taz vs. 2gm c/8hrs Cefepime 4. Costo tto /dia

Cual debe ir primero Imipenem o Meropenem en UCI para P.aeruginosa ? Estara basado en: Epidemiologia local que muestra Resistencia de P.aeruginosa a Cefepime o Pip/taz 2. Incluir la distribucion de P.aeruginosa vs. MICs de cada antibiotico. Considerar dosificacion adecuada para alcanzar el target Costo tto /dia: 500mg a 1 gm de Imi c/6hrs vs. mero 1-2 gm c/8hrs

Porque Ertapenem debe ir primero que Pip/taz o Cefepime para Enterobacteriaceas ? Mayor actividad contra Enterobacteriaceas ( todas !!) Estable frente a B-lactamasas que Inactivan a Pip/taz y Cefepime !! No ejerce presion selectiva contra P.aeruginosa ni Acinetobacter. Menor costo tto/dia !!

Porque Ertapenem debe ir primero que Imipenem o Meropenem para Enterobacteriaceas multiresistentes ? Igual actividad contra Enterobacteriaceas ( raras excepciones ) Actividad similar para anaerobios y Gram (+) NO ejerce Presion selectiva contra P.aeruginosa y Acinetobacter. Menor costo tto/dia !!

Porque Ertapenem debe ir primero queTigeciclina para Enterobacteriaceas Mayor evidencia en estudios clinicos frente a Enterobacteriaceas multiresistentes ( BLEE, AmpC) Cubre Providencia y Proteus que no cubre Tigeciclina. Alcanza mayores concentraciones en sangre ( para bacteremia e infecciones moderadas-severas). Menor costo y tto EV/IM una vez/dia !

Porque sulbactam debe ir primero que Tigeciclina para Acinetobacter multiresistente Existe mayor evidencia ( estudios clínicos) para iniciar con Sulbactam ( con amp o cefoperazona ) Excepto en la presencia de OXA-23 favorecería el uso de Tigeciclina : en infecciones moderadas cuando no hay bacteremia. En caso de sepsis y sensibilidad a los Carbapenems SON los antibioticos mas activos o usar Polimixina B si hay resistencia

Sulbactam en el tto de Acinetobacter multiresistente Wood et al reported successful use of sulbactam to treat 14 patients with multidrug- resistant Acinetobacter ventilator-associated pneumonia, finding no difference in clinical outcomes between sulbactam-treated patients and 63 patients who received imipenem. Wood GC, Hanes SD, Croce MA, Fabian TC, Boucher BA. Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of Acinetobacter ventilator-associated pneumonia. Clin Infect Dis 2002; 34:1425–30.

Sulbactam vs, tigeciclina en el tto de Acinetobacter multiresistente “Tigecycline, has bacteriostatic activity against multidrug-resistant Acinetobacter sp. High-level resistance to tigecycline has been detected among some multidrug-resistant Acinetobacter isolates ( by upregulating chromosomally mediated efflux pumps.) Concern about adequate peak serum concentrations → reserved for salvage therapy, with administration determined in consultation with an infectious diseases specialist “. Maragakis LL and Perl TM.Clinical Infectious Diseases 2008; 46:1254–63

Propuesta para el uso adecuado de antibioticos 1. Enterobacteriaceas multirresistentes Ertapenem para BLEEs y AmpC ( 1ra opcion) Tigeciclina si hay alergia o infeccion mixta con MRSA, EVR. Restringir al máximo Cefalosporinas de 3ra generación para algunos usos en la comunidad ( Meningitis, NAC, Pielonefritis ) y solo a nivel hospitalario en indicaciones restringidas.

Propuesta para el uso adecuado de antibioticos 2. Para P. aeruginosa Existe una limitación dramática de nuevos antibióticos para P. aeruginosa y Acinetobacter por lo tanto : No usarlas para Enterobacteriaceas Reservarlas para infecciones con riesgo de P. aeruginosa ( esp. UCI !! ) y con cultivo (+) Iniciar con Cefepime o Pip/taz ( CGN ) → carbapenems para paso posterior

Propuesta para el uso adecuado de antibioticos 3. Para MRSA : Sospecha de MRSA de la comunidad sin sepsis: Bactrim o Clindamicina Sospecha de MRSA de la comunidad con sepsis o shock toxico o compromiso pulmonar : Linezolid Sospecha de MRSA nosocomial: Vancomicina ( de-escalar )

Y finalmente…… 1. Protocolos basados en la Epidemiologia local : Mecanismos de resistencia de las bacterias en esa Institucion, CIM de las bacterias para las diferentes opciones terapeuticas, Dosificacion y Tiempo de administracion adecuado 2. Medicamentos de calidad !!! Si con los originales apenas tenemos niveles….

MUCHAS GRACIAS ☺

Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam 40 patients with nosomial infections caused by multidrug- resistant Acinetobacter baumannii were treated with intravenous ampicillin/sulbactam. The infections were primary bloodstream (32.5%), pneumonia (30%), urinary tract (15%), peritonitis (7.5%), surgical site (7.5%), meningitis (5%) and sinusitis (2.5%). Most were severe infections with underlying conditions (median APACHE II score: 14.5) and 72.5% occurred in the ICU. Levin et al. Inter Journ of Antim Agents; 2003 (21) : 58-62.

Severe nosocomial infections with imipenem-resistant Acinetobacter baumannii treated with ampicillin/sulbactam Twenty-seven (67.5%) were improved/cured, Seven (17.5%) were failures and Six (15%) were considered to have an indeterminate outcome because patients died within the first 48 h of treatment. The median daily dose of ampicillin/sulbactam was 6 g/3 g and six patients received 12 g/6 g. No adverse effects were observed. This study indicates that ampicillin/sulbactam may be a good and safe therapeutic option to treat severe nosocomial infections caused by multi-drug resistant A. baumannii.