RESISTENCIA BACTERIANA

1. JUAN VILLENA VIZCARRA HNGAI UNMSM RESISTENCIA BACTERIANA

2. Fenotipo salvaje

3. Fenotipo Multi-drogo-resistente

5. Resistencia cromosomica Resistencia por plasmidios o transposomas ORIGEN DE LA RESISTENCIA ANTIBI�TICA

6. Emergencia de Resistencia Antimicrobiana Bacteria have evolved numerous mechanisms to evade antimicrobial drugs Chromosomal mutations are an important source of resistance to some antimicrobials Acquisition of resistance genes or gene clusters, via conjugation, transposition, or transformation, accounts for most antimicrobial resistance among bacterial pathogens These mechanisms also enhance the possibility of multidrug resistanceBacteria have evolved numerous mechanisms to evade antimicrobial drugs Chromosomal mutations are an important source of resistance to some antimicrobials Acquisition of resistance genes or gene clusters, via conjugation, transposition, or transformation, accounts for most antimicrobial resistance among bacterial pathogens These mechanisms also enhance the possibility of multidrug resistance

7. Selecci�n de Cepas Resistentes Once resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possibleOnce resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possible

8. P�rdida de la Resistencia a los Antibi�ticos Las bacterias resistentes a los antibi�ticos est�n en una desventaja selectiva - Pueden gastar mucha energia y recursos para sintetizar proteinas que confieren resistencia La prevalencia de resistencia bacteriana disminuye despu�s de disminuir el uso de antibi�ticos

9. Mecanismos deResistencia Antibi�tica

10. Produciendo enzimas que destruyan las mol�culas de antibi�ticos Alterando la permeabilidad de la pared celular Alterando los sitios de uni�n del antibi�tico, �BLANCOS� Resistencia Antibi�tica

11. MECANISMOS DE RESISTENCIABETALACT�MICOS Mutaci�n de blancos (PBPs) Permeabilidad disminuida Betalactamasas

12. Ej, TEM-1, TEM-2 y SHV-1 son las beta-lactamasas mediadas por pl�smidos predominantes en los bacilos Gram negativos . Su diseminaci�n es consecuencia de la presi�n selectiva ejercida por la introducci�n de ampicilina, carbenicilina y las primeras cefalosporinas en los a�os 60. �-lactamasas de amplio espectro:BLES Estas � -lactamasas son enzimas que se han originado desde las enzimas TEM-1, TEM-2 o SHV-1 luego de diversas mutaciones INHIBICI�N ENZIM�TICA

13. MECANISMOS DE RESISTENCIAAMINOGLIC�SIDOS Enzimas modificadoras (acetilaci�n, adenilaci�n, fosforilaci�n) Permeabilidad o captaci�n dependiente de energ�a disminuidas Menor fijaci�n a los ribosomas

14. MECANISMOS DE RESISTENCIAQUINOLONAS Mutaci�n de blancos (ADN girasa) Reducci�n de la Permeabilidad Eflujo activo

15. MECANISMOS DE RESISTENCIAGLUCOP�PTIDOS Mutaci�n en el sitio de fijaci�n al precursor de peptidoglicano

16. MicrorganismosEpidemiologicamente importantes Pseudomonas aeruginosa Acinetobacter baumannii Candida albicans

17. MicrorganismosEpidemiologicamente importantes Staphylococcus coagulasa negativo S. aureus resistente a oxacillina E. coli y K. pneumoniae productoras de betalactamasas de espectro extendido (ESBL o BLEE)

18. MicrorganismosEpidemiologicamente importantes Enterococcus spp resistente a Vancomicina (VRE) Enterobacter spp resistente a cefalosporinas Candida NO albicans

19. Resistencia Antimicrobiana entre los Pat�genos que causan Infecciones Intrahospitalarias The proportion of pathogens causing hospital-acquired infections that are resistant to target antimicrobial drugs continues to increase at an alarming rate Currently, more than 50% of Staphylococcus aureus isolates causing infections in intensive care units are resistant to methicillin; more than 40% are resistant in other hospital units Vancomycin-resistant enterococci (VRE) emerged in the late 1980s and are now endemic in many hospitals In many hospitals, more than 25% of enterococcal infections are caused by vancomycin-resistant strains The proportion of pathogens causing hospital-acquired infections that are resistant to target antimicrobial drugs continues to increase at an alarming rate Currently, more than 50% of Staphylococcus aureus isolates causing infections in intensive care units are resistant to methicillin; more than 40% are resistant in other hospital units Vancomycin-resistant enterococci (VRE) emerged in the late 1980s and are now endemic in many hospitals In many hospitals, more than 25% of enterococcal infections are caused by vancomycin-resistant strains

20. Resistencia Antimicrobiana entre los Pat�genos que causan Infecciones Intrahospitalarias The problem of antimicrobial resistance also includes Gram-negative organisms Klebsiella and many other Enterobacteriaceae have acquired extended-spectrum beta-lactamases (ESBLs) that confer resistance to cephalosporins Resistance to fluoroquinolones is also emerging, a situation attributable to the expanding use in the past decade of this class of antimicrobialsThe problem of antimicrobial resistance also includes Gram-negative organisms Klebsiella and many other Enterobacteriaceae have acquired extended-spectrum beta-lactamases (ESBLs) that confer resistance to cephalosporins Resistance to fluoroquinolones is also emerging, a situation attributable to the expanding use in the past decade of this class of antimicrobials

21. Prevalencia de Pat�genos-Resistentes (R) Que causan infecciones adquiridas en las Unidades de Cuidados Intensivos 1999 versus 1994-1998 Organismos # Aislamientos % Incremento* Fluoroquinolonas-R Pseudomonas spp. 2,657 49% 3ra generaci�n cefalosporinas-R E. coli 1,551 48% Meticilino-R Staphylococcus aureus 2,546 40% Vancomicina-R enterococci 4,744 40% Imipenem-R Pseudomonas spp. 1,839 20% The rate of increased prevalence of resistance for some organisms is alarming For example, the prevalence of fluoroquinolone resistance among Pseudomonas spp. increased by almost 50% in 5 years Likewise, ESBL-producing Gram-negative pathogens, MRSA, and VRE continue to account for an increasing proportion of hospital-acquired infections Imipenem resistance is still not common, but has emerged in some locales The rate of increased prevalence of resistance for some organisms is alarming For example, the prevalence of fluoroquinolone resistance among Pseudomonas spp. increased by almost 50% in 5 years Likewise, ESBL-producing Gram-negative pathogens, MRSA, and VRE continue to account for an increasing proportion of hospital-acquired infections Imipenem resistance is still not common, but has emerged in some locales

22. Evoluci�n de la Resistencia en S. aureus Introduction of every new class of antimicrobial drug is followed by emergence of resistance By the 1950s, penicillin-resistant S. aureus were a major threat in hospitals and nurseries By the 1970s, methicillin-resistant S. aureus had emerged and spread, a phenomenon that encouraged widespread use of vancomycin In the 1990s, vancomycin-resistant enterococci emerged and rapidly spread; most of these organisms are resistant to other traditional first-line antimicrobial drugs At the end of the century, the first S. aureus strains with reduced susceptibility to vancomycin were documented, prompting concerns that S. aureus fully resistant to vancomycin may be on the horizon Introduction of every new class of antimicrobial drug is followed by emergence of resistance By the 1950s, penicillin-resistant S. aureus were a major threat in hospitals and nurseries By the 1970s, methicillin-resistant S. aureus had emerged and spread, a phenomenon that encouraged widespread use of vancomycin In the 1990s, vancomycin-resistant enterococci emerged and rapidly spread; most of these organisms are resistant to other traditional first-line antimicrobial drugs At the end of the century, the first S. aureus strains with reduced susceptibility to vancomycin were documented, prompting concerns that S. aureus fully resistant to vancomycin may be on the horizon

26. Antibi�ticos y probabilidad de seleccionar resistencia durante el tto frente a P. aeruginosa Ceftazidime y cefepime : 0.8 Piperacillin y Pip/taz : 5.2 Ciprofloxacin: 9.2 (similar para otras quinolonas ) Imipenem: 44

27. Resistencia durante tratamiento Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies.Fish DN, Piscitelli SC, Danziger LH.University of Colorado Health Sciences Center, Department of Pharmacy Practice, School of Pharmacy, Denver 80262, USA.The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem-cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance.Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies.

28. De-escalonamiento Con cultivo positivo se cambia de un amplio espectro a un antibiotico de espectro reducido. Se disminuye dosis ? despues de tto por 72 hrs y signos de mejoria en el pte se puede bajar la dosificacion ( ej : de 6 gm/d a 4 gm /d ). EXCEPTO en P.aeruginosa

29. Quinolonas y Resistencia cruzada en P. aeruginosa CIPRO- S Gent 22% Caz 14% Imi 11 % Amik 5% No hay v�nculo con otros mecanismos como pl�smidos llevando otros genes (BLEES) o enzimas modificadoras de aminoglicosidos. CIPRO-R Gent 66% Caz 40% Imi 38% Amik 26% Probablemente es por adquisici�n sequencial de mutaciones m�ltiples bajo presi�n selectiva. Neuhauser JAMA 2/19/03 1990-1993 vs. 1994-1998: Ciprofloxacin 11% to 21%, p=0.001, OR=2.2

30. Colistina: resurrecci�n en el siglo XXI�Qu� hizo necesario el �revivir� de las polimixinas? Multirresistencia de BGN NF a todos los ATB incluyendo carbapenemes En Ps.aeruginosa En complejo Acinetobacter baumannii-calcoaceticus Futuro en enterobacterias?

31. Nuevos agentes (1)

32. An experimental study has been performed to compare the in vitro activity and the in vivo efficacy of tachyplesin III, colistin, and imipenem against a multiresistant Pseudomonas aeruginosa strain. In vitro experiments included MIC determination, time-kill, and synergy studies. For in vivo studies, a mouse model of sepsis has been used. The main outcome measures were bacterial lethality, quantitative blood cultures, and plasma levels of lipopolysaccharide, tumor necrosis factor alpha, and interleukin-6. The combination of tachyplesin III or colistin with imipenem showed in vitro synergistic interaction. A significant increase in efficacy was also observed in vivo: combination-treated groups had significantly lower levels of bacteremia than did groups treated with a single agent. Tachyplesin III combined with imipenem exhibited the highest efficacy on all main outcome measurements. These results highlight the potential usefulness of these combinations and provide therapeutic alternatives for serious infections caused by gram-negative bacteria in the coming years.An experimental study has been performed to compare the in vitro activity and the in vivo efficacy of tachyplesin III, colistin, and imipenem against a multiresistant Pseudomonas aeruginosa strain. In vitro experiments included MIC determination, time-kill, and synergy studies. For in vivo studies, a mouse model of sepsis has been used. The main outcome measures were bacterial lethality, quantitative blood cultures, and plasma levels of lipopolysaccharide, tumor necrosis factor alpha, and interleukin-6. The combination of tachyplesin III or colistin with imipenem showed in vitro synergistic interaction. A significant increase in efficacy was also observed in vivo: combination-treated groups had significantly lower levels of bacteremia than did groups treated with a single agent. Tachyplesin III combined with imipenem exhibited the highest efficacy on all main outcome measurements. These results highlight the potential usefulness of these combinations and provide therapeutic alternatives for serious infections caused by gram-negative bacteria in the coming years.

41. Resistencia a vancomicina : Europa-EEUU

42. Importancia de la resistencia Brotes intrahospitalarios Dificultad en su detecci�n por el laboratorio Problemas de tratamiento Posibilidad de extenderse a otros gram +

44. Resistencia de Acinetobacter a Sulbactam 1997 8 % 1998 23% 1999 36% 2000 48% 2001 54% 2002 60% 2003 63% Datos: Sociedad Argentina de Bacteriolog�a Clinica (SADEBAC) 2003 43% Disco sulbactam-cefoperazona 46% (25% intermedio) Disco ampicilina sulbactam Datos del Laboratorio de Microbiolog�a del Hospital de Cl�nicas.

45. Actividad de Sulbactam (SB) contra Acinetobacter SB es intr�nsecamente activo contra Acinetobacter spp. Se comercializa combinado con ampicilina � cefoperazona. OJO dosis de SB es de 4 gr por d�a. Villar et al (2) : public� acerca de la actividad bactericida contra Acinetobacter spp y del excelente futuro de esta droga para este prop�sito Casellas et al(3) public� acerca de que la actividad bactericida no era real y observ� un aumento de la resistencia a SB si era usado solo para las infecciones por este microorganismo. 1.- Livermore DM. Clin Microbiol Rev (1995) 8: 557 2.- Villar He et al. Enf Infecc Microbiol Clin (1996) 14: 524 3.- Casellas JM and Dana R. Enf Infecc Microbiol Clin (1997) 15: 335

46. Acinetobacter sp.Sensibilidad a ATB de cepas aisladas en CTI Abril - Diciembre 2003Gentileza de Dras. V. Seija y C. Bazet. Dpto. Microbiolog�a PIPERACILINA-TAZOBACTAM 11 % IMIPENEM 96 % MEROPENEM 96 % SULBACTAM CEFOPER. (? 21 mm) 57 % AMPICILINA SULBACTAM 54 % (25% - I) CEFTAZIDIME 26 % CIPROFLOXACINA 0 % CEFEPIME 8 % AMIKACINA 27 % Estudio por disco difusi�n de 72 aislamientos consecutivos. Aislamiento de 4 cepas (pac: CF, MM, JM y WS) resistentes a carbapenem; enzim�tica (en estudio).

47. Ante la multiresistencia incluyendo carbapenemes se han intentado otras soluciones: Sulbactam a dosis altas Mantener concentraci�n elevada de carbapenem (prolongando su tiempo de infusi�n): utilidad cl�nica limitada. Combinaciones con rifampicina de sulbactam y minociclina (bacteriost�tica y no hay en Uruguay). Tratamiento con nebuliz. en inf pulmonar. Ninguna de ellas ha resultado plenamente satisfactoria Resistencia de Acinetobacter

48. Acinetobacter MR Algunos pacientes tratados con f�rmacos no activos en estudios �in vitro�, han tenido una respuesta cl�nica satisfactoria, esto enfatiza acerca de la baja virulencia de este g�rmen en hu�sped normal o poco grave. Clinton K. Curr.Opin.Infect Dis 2005; 18:502 Experiencia personal �Qu� podemos hacer?: Prevenir la colonizaci�n y subsecuente infecci�n. Aislamiento: precauciones de contacto Otras estrategias preventivas (estudios genot�picos de las clonas) Limitar el uso de carbapenems para tratar otras infecciones bacterianas. Polimixinas

49. Otras alternativas terap�uticas en Acinetobacter Futuro tigeciclina? 98% activa Aerosolizaci�n preventiva con colistina (+ RFP?).