Impacto del gerenciamiento y control de antibióticos ( stewardship ) en hospitales Joseph L. Kuti, Pharm.D. Associate Director, Clinical and Economic Studies.

Presentación del tema: "Impacto del gerenciamiento y control de antibióticos ( stewardship ) en hospitales Joseph L. Kuti, Pharm.D. Associate Director, Clinical and Economic Studies."— Transcripción de la presentación:

1 Impacto del gerenciamiento y control de antibióticos ( stewardship ) en hospitales
Joseph L. Kuti, Pharm.D. Associate Director, Clinical and Economic Studies Center for Anti-Infective Research and Development Hartford Hospital

2 Consecuencias de Resistencia Bacteriana en desenlaces clínicos y costos financieros
Sample of 1391 high-risk hospitalized adult patients from Chicago hospitals Roberts RR, et al. Clin Infect Dis 2009;49:

3 Consumo de antibióticos
15 millones de kilos de antibióticos producidos cada año 30% a 50% de pacientes hospitalizados reciben al menos un antibiótico durante su estancia. Pacientes no hospitalizados reciben 160 millones de cursos de antibióticos cada año. Diferentes evaluaciones indican que la mitad de todos los antibióticos son usos inadecuados: Infecciones no bacterianas Inicio de antibióticos erróneos Antibióticos innecesariamente continuados por tiempos prolongados. Owens RC et al. Pharmacotherapy 2004;24:

4 Uso de antibióticos marca la resistencia
35 250 30 200 25 150 20 % of Strains Resistant to Ciprofloxacin Quinolone Use (kg x 103) 15 100 10 Pseudomonas Gram-Negative 50 5 Fluoroquinolone use Increased Antibiotic Use Drives Resistance Key point: Resistance is associated with increased antibiotic use. Increased antibiotic use is associated with increased resistance in Gram-negative bacteria1 Increased use of fluoroquinolones between 1994 and 2000 is commensurate with a substantial increase in the proportion of fluoroquinolone-resistant Gram-negative bacilli, especially Pseudomonas aeruginosa1 Resistance to one antibiotic class may be associated with resistance to other antibiotic classes, such as third-generation cephalosporins2 1994 1995 1996 1997 1998 1999 2000 Increasing fluoroquinolone resistance in Gram-negative bacilli correlates with increased fluoroquinolone use in patients from 43 states (numbers of isolates from =35,790). The 1990 to 1993 data points represent composite susceptibility and quinolone use for those 4 years. Neuhauser MM et al. JAMA. 2003;289: 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: 2. McGowan JE. Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Am J Infect Control. 2006;34:S29-S37.

5 imipenem resistance (%) imipenem consumption (DDDs)
La relación Susceptibilidad-Uso de antibióticos: Efecto de imipenem en la resistencia de Pseudomonas aeruginosa a los -Lactámicos Uso de Imipenem se correlaciona con resistencia de P aeruginosa 40 30 20 10 Jul 97 Jul 98 Jul 99 Jul 00 200 400 600 800 imipenem resistance (%) imipenem consumption (DDDs) consumption resistance Lepper et al looked at the effect of imipenem use on Pseudomonas resistance They found a partial correlation between imipenem consumption and percent resistance (cc 0.63) The investigators concluded that there was no apparent correlation between ceftazidime (cc 0.56) and piperacillin-tazobactam (cc 0.57) to Pseudomonas resistance Lepper et al. Antimicrob Agents Chemother. 2002;46:

6 Factores asociados al desarrollo de resistencia bacteriana
Mayor severidad de la enfermedad en los pacientes hospitalizados1 Uso inapropiado de antibióticos2 Uso prolongado o inadecuado de exposición a antimicrobianos. Factores institucionales3 Control de infecciones insuficiente (ej, higiene de manos)1 Movilización de pacientes al interior y entre instituciones4 Pobre adherencia a pautas de limpieza y desinfección ambiental4 Uso de antibióticos en animales4 * * Factors Encouraging the Development of Antimicrobial-Resistant Pathogens Key point: A combination of inadequate infection control, changing patient demographics, and inappropriate antibiotic use has contributed to rising antimicrobialresistance. Factors contributing to the emergence of antibiotic-resistant pathogens include the following High severity of illness in hospitalized patients1 Inappropriate antibiotic use Increased use of antimicrobial prophylaxis1 The use of antibiotics in cases where bacterial infection is unlikely (eg, the common cold)2 The use of antibiotics for bacterial infections that are likely to resolve on their own (eg, acute otitis media in children)2 Inappropriate dose or duration of antimicrobial use3 Institutional factors Inadequate infection control (eg, hand washing)1 Patient movement within and among medical institutions4 Poor adherence to environmental cleaning in high-risk venues4 Agricultural use of antimicrobials4 * Podemos ejercer cambio en estos puntos 1. Stein GE. Pharmacotherapy. 2005;25:44S-54S. 2. South M et al. Med J Aust. 2003;178: McGowan JE Jr. Clin Infect Dis. 2004;38: Levy SB. J Antimicrob Chemother. 2002;49:25-30. 1. Stein GE. Antimicrobial resistance in the hospital setting: impact, trends, and infection control measures. Pharmacotherapy. 2005;25(suppl):44S-54S. 2. South M, Royle J, Starr M. A simple intervention to improve hospital antibiotic prescribing. Med J Aust. 2003;178: 3. McGowan JE Jr. Minimizing antimicrobial resistance: the key role of the infectious diseases physician. Clin Infect Dis. 2004;38: 4. Levy SB. Factors impacting on the problem of antibiotic resistance. J Antimicrob Chemother. 2002;49:25-30.

7 Antimicrobial Agents Approved, N
“Bad Bugs, No Drugs” As Antibiotic Discovery Stagnates… A Public Health Crisis Brews Bars represent number of new antimicrobial agents approved by the FDA during each time frame. “The number of antibacterials in Phase 2 or 3 or clinical development remains disappointing, and the absence of agents designed to treat infections due to resistant gram-negative bacilli places patients with these infections in danger.” - Boucher, et al. Clin Infect Dis 2009 Antimicrobial Agents Approved, N Years

8 Antimicrobial Stewardship: Generalidades
Guías actualizadas en 2007 Consenso IDSA/SHEA* avalado por: American Academy of Pediatrics American Society of Health-System Pharmacists Infectious Diseases Society for Obstetrics and Gynecology Pediatric Infectious Diseases Society Society for Hospital Medicine Society of Infectious Diseases Pharmacists Objetivo primario: Optimizar desenlaces clínicos minimizando consecuencias no deseadas con el uso de antibióticos: Toxicidad Selección de bacterias patógenas (ej, Clostridium difficile) Emergencia de resistencia Objetivo secundario Reducción en costos en salud sin comprometer la calidad de la atención Antimicrobial Stewardship: Overview Key point: Antimicrobial stewardship is a program that combines judicious use of antibiotics with efforts to provide the best clinical outcome for the patient. The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing the unintended consequences of antibiotic use Toxicity Selection of pathogenic bacteria Emerging antibiotic resistance The secondary goal of antimicrobial stewardship is to reduce health care cost without compromising quality of care *Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). Dellit TH et al. Clin Infect Dis. 2007;44: Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

9 Stewardship NO es un concepto nuevo:
Muchas referencias desde los 80’s sobre programas de restricción de antibióticos. Pautas modernas incluyen recomendaciones de desescalonamiento y conformar un equipo de manejo de antibióticos. Tres fases descritas del proceso de la infección en las que el equipo puede interactuar: Estadío 1 – Tratamiento antibiótico empírico. Estadío 2 – Días 3-5: Disponibilidad de cultivos y datos de susceptibilidad para guiar tto antibiótico definitivo. Estadío 3 – Día 7 y posterior: Completar curso antibiótico, plan de salida, home care. Definir respuesta a la terapia. Quintiliani R, et al. Am J Med 1987;82:391-4. Briceland LL, et al. Arch Intern Med 1988;148:

10 Equipo de manejo de antibióticos
Hospital Administrator Hospital Epidemiologist Infectious Diseases Division Infection Control Director, Outcomes Research ASP Directors • ID PharmD • ID Physician Medical Information Systems Chairman, P&T Committee Partners in Optimizing Antimicrobial Use Such as Pulmonologists and Surgeons Antimicrobial Stewardship Teams Key point: A comprehensive program with collaboration among multiple disciplines is key to the success of antimicrobial stewardship. The core members of an antimicrobial stewardship team should include an infectious disease physician and a clinical pharmacist with infectious disease training Additional members will help the team function optimally Clinical microbiologist Information systems specialist Infection control professional Hospital epidemiologist The program should function under the auspices of quality assurance and/or patient safety Collaborations are crucial to the success of antimicrobial stewardship teams Teams should collaborate with hospital infection control and with the pharmacy/therapeutics committee Collaboration with hospital administrators, medical staff leaders, and local providers is also important Microbiology Laboratory Clinical Pharmacy Specialists Decentralized Pharmacy Specialist ASP = Antimicrobial Stewardship Program, ID = infectious disease, P&T = Pharmacy and Therapeutics. Dellit TH et al. Clin Infect Dis. 2007;44: and Fishman N. Am J Med. 2006;119:S53-S61. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

11 Equipo de manejo de antibióticos
Hospital Administrator Hospital Epidemiologist Infectious Diseases Division Infection Control Director, Outcomes Research ASP Directors • ID PharmD • ID Physician Medical Information Systems Chairman, P&T Committee Partners in Optimizing Antimicrobial Use Such as Pulmonologists and Surgeons Antimicrobial Stewardship Teams Key point: A comprehensive program with collaboration among multiple disciplines is key to the success of antimicrobial stewardship. The core members of an antimicrobial stewardship team should include an infectious disease physician and a clinical pharmacist with infectious disease training Additional members will help the team function optimally Clinical microbiologist Information systems specialist Infection control professional Hospital epidemiologist The program should function under the auspices of quality assurance and/or patient safety Collaborations are crucial to the success of antimicrobial stewardship teams Teams should collaborate with hospital infection control and with the pharmacy/therapeutics committee Collaboration with hospital administrators, medical staff leaders, and local providers is also important Microbiology Laboratory Pharmacy Decentralized Pharmacy Specialist ASP = Antimicrobial Stewardship Program, ID = infectious disease, P&T = Pharmacy and Therapeutics. Dellit TH et al. Clin Infect Dis. 2007;44: and Fishman N. Am J Med. 2006;119:S53-S61. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

12 Vigilancia prospectiva con intervención y retroalimentación
Estrategias centrales para el gerenciamiento / stewardship de antibióticos Vigilancia prospectiva con intervención y retroalimentación Restricción en el formulario y autorización previa Core Strategies for Antimicrobial Stewardship Key point: Two core strategies and locally applicable supplemental strategies may be used for an optimal antimicrobial stewardship program. Facilities initiating an antimicrobial stewardship program will usually choose 1 of 2 core strategies This is an important first step if a formal stewardship program does not yet exist Each of the core strategies is based upon robust levels of evidence The choice will depend on local resistance patterns and which strategy will best impact the individual facility There may be cross-collaboration within or between the 2 strategies to optimize local stewardship programs A series of supplemental strategies may also be used These can be combined in several ways to tailor the antimicrobial stewardship program to individual situations For existing programs, tailoring substrategies or adding new strategies may help with ongoing success Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

13 Estrategia central 1: Vigilancia prospectiva con intervención y retroalimentación
Revisión concurrente de todos los pacientes en tto antimicrobiano Ordenes inapropiadas deben resultar en interacción entre el equipo de manejo de antibióticos y el formulador1 El objetivo es aumentar optimización de uso de antimicrobianos ( selección, dosis, duración, ruta) Ventajas Evita pérdida de la autonomía del formulador1 Crea incentivos a los médicos para mejorar adherencia Desventajas Adherencia es voluntaria1 Menos efectivo a menos distinga entre formulación apropiada e inapropiada.2 Core Strategy 1: Prospective Audit With Intervention and Feedback Key point: Prospective audit of antimicrobial use with direct interaction and feedback to the prescriber, usually performed by an infectious disease specialist or a clinical pharmacist with infectious disease training, can result in reduced inappropriate use of antimicrobials.1 Involves review of antimicrobial orders2 Inappropriate orders initiate contact between an antimicrobial team member and the prescriber Provides an opportunity to optimize therapy Advantages to prospective audit with intervention and feedback Prescribers still have autonomy in the antibiotics they prescribe2 This strategy can create incentives for physicians to improve their performance3 Disadvantages to conducting a prospective audit with intervention and feedback Compliance is voluntary2 This strategy must distinguish between appropriate and inappropriate prescribing to be effective3 1. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18: Available at: Accessed April 30, 2007. 1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44: 2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18: 3. Available at: Accessed April 30, 2007.

14 Programa global de un hospital para optimizar uso de antibióticos
Antibiotic Use Antimicrobial Treatment Committee ID, Microbiologists, Pharmacists, IM, IT Hospital-wide Program No restrictions on antibiotic use Antibiotic Order Form Feedback and education to prescribers Recommended substitutions 3rd-generation cephalosporins  cefepime Carbapenems  aminopenicillin/sulbactam The results reported by Bantar were: Overall reduction in antibiotic use Decreased resistance A significant cost reduction The article did not report on the cost to administer the program Decreased antibiotic use Decreased resistance Cost reduction: total savings of $913,236 over 18 months Consumption (DDD/1000 patient days) Bantar et al. Clin Infect Dis. 2003;37:

15 Efecto de esta estrategia en pacientes con neumonía adquirida en comunidad
Single Medical Center in Baltimore Quasi-experimental design Intervention Survey of prescriber knowledge Educational programs Daily Audits with Feedback Avdic E et al. Clin Infect Dis. 2012;54:

16 Empleando un modelo dinámico:
Medición de procesos para cambiar comportamiento: Oportunidad: Retroalimentación mensual o más frecuente resulta en mejor desempeño. Individualización: Retroalimentación individual más que grupal es mejor práctica para el éxito del programa. Sin culpa o castigo: Datos son confidenciales y ciegos, escarnio público resulta en rechazo al programa. Personalización: La retroalimentación debe tener sentido a los sujetos que se dirige. Patel SJ, et al. Inter Perspectives Infect Dis 2012;150367:1-6.

17 Estrategia central 2: Restricción de formulario o preautorización
Método efectivo para control de antibióticos y costos; resultados conflictivos en reducción de resistencia antimicrobiana.1 Ventajas Proporciona el control más directo en el uso de antimicrobianos2 Desventajas Los médicos pueden sentir pérdida de autonomía2 Miembros del equipo deben tener planes de contingencia para aprobaciones a toda hora1 Puede causar uso inapropiado de antibióticos3 Puede demorar inicio de tto AB adecuado Core Strategy 2: Formulary Restriction/Preauthorization Key point: Formulary restriction/preauthorization that limits use of antibiotics based on considerations of therapeutic efficacy, toxicity, and cost while limiting redundant new agents with no significant additional benefit, can reduce costs and decrease antibiotic resistance.1,2 Added step of restriction or preauthorization may be enough to limit antimicrobial use1 Advantages to formulary restriction/preauthorization This strategy provides the most direct control over antimicrobial use1 This is an alternative to providing incentives for appropriate prescribing3 Disadvantages to formulary restriction/preauthorization Prescribers may feel they have lost the autonomy to prescribe appropriate antibiotics1 Consultants may be needed at all hours to authorize appropriate antibiotics1 May discourage use of appropriate antibiotics3 May delay initiation of appropriate therapy May interfere with the relationship between physician and patient3 1. Dellit TH et al. Clin Infect Dis. 2007;44: MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18: Available at: Accessed April 30, 2007. 1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44: 2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18: 3. Available at: Accessed April 30, 2007.

18 P aeruginosa Resistant to Selected Antimicrobials, 1995-2001 (%)
Efecto de restricción de formulario en el perfil de resistencia de P aeruginosa: Resultados Resistance % Antimicrobial Before Program After Program P value ( ) ( ) Ceftazidime <.001 Piperacillin <.001 Imipenem-cilastatin Aztreonam P aeruginosa Resistant to Selected Antimicrobials, (%) Piperacillin Aztreonam Ceftazidime Imipenem-cilastatin Piperacillin-tazobactam Ciprofloxacin Tobramycin 35 25 30 Through an antimicrobial restriction program, a reduction in ceftazidime use was achieved with judicious use of other antipseudomonal antimicrobials, which resulted in reduced resistance of P aeruginosa to other beta-lactams 20 25 20 25 Resistance % Resistance % 15 10 10 Start of Program 5 Start of Program 5 1995 1996 1997 1998 1999 2000 2001 1995 1996 1997 1998 1999 2000 2001 Regal et al. Pharmacotherapy. 2003;23:

19 Uso racional de ABs en UCI en Francia:
Rational use protocol Antibiotic use controlled by 4 ICU physicians (members of ARC) Written algorithms for use Systematic reassessment at days 3, 7, 10 Twice-weekly meetings Results Antibiotic use  36% Resistant nosocomial infections  52% (P<10-5) MRSA  at yr 3; Enterobacteriaceae R at yr 4 No change in PSA resistance or ESBL producers Year 1994 1995† 1996 1997 1998 Total NI* Patients 99 97 105 116 109 Total Days of Antibiotic Use 3,658 3,314 2,974 2,496 2,311 Total Antibiotic Cost (Euro) 64,500 52,200 50,100 40,950 42,000 % Antibiotic Resistance 44% 53% 39% 31% 21% † Start of program * NI = Nosocomial infection This paper, by Geissler et al in France, described a Rational Antibiotic Use program, which involved: Antibiotic restrictions Systematic antibiotic control by 4 permanent ICU physicians Written algorithms Systematic reassessment on days 3, 7, and 10 Evaluated susceptibility, the possibility of oral use, and the possibility of discontinuing use Regular twice-weekly meetings on antibiotic use The results of the program, after several years, were: Overall antibiotic use decreased by 36% Total antibiotic costs decreased Antibiotic resistance decreased The authors did not report on the costs of operating the program The paper demonstrates what can be achieved with appropriate antibiotic use Geissler A et al. Inten Care Med. 2003;29:49-54.

20 Estrategias adicionales en Antimicrobial Stewardship
Protocolos clínicos y guías Estrechamiento / Desescalonamiento Optimización de dosis Terapia combinada Cambio de tto EV a oral Educación Formatos de formulación de ABs Ciclaje / cambio de antibióticos Trabajo coordinado con los microbiólogos Supplemental Strategies for Antimicrobial Stewardship Key point: Supplemental strategies can be used in combination with the core strategies to optimize antimicrobial stewardship. Dellit TH et al. Clin Infect Dis. 2007;44: Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

21 Optimización de dosis Tener en cuenta varios factores:
Características farmacocinética / farmacodinámica del antibiótico (PK/PD) Características del paciente ( Insuf. Renal, hepática, etc ) Organismo causante Sitio de infección Dose Optimization Key point: Dose optimization utilizes factors unique to each patient to achieve the best clinical outcome. Optimizing dosing of antibiotics based upon their pharmacokinetic/pharmacodynamic (PK/PD) properties can increase the likelihood of clinical success, pathogen eradication, and prevention of resistance. Dose optimization is dependent upon several other factors as well1 Patient characteristics (eg, age, weight, disease state, renal function) Causative organism Site of infection (eg, heart, lung) Dose optimization follows different pathways depending on whether the antibiotic exhibits concentration-dependent or time-dependent killing2 Concentration-dependent antibiotics show increased activity over a wide range of concentrations Maximizing the concentration can potentially improve bacteriologic response Time-dependent antibiotics show optimal activity over a narrower range of concentrations The focus for these drugs is maximizing the time the drug concentration is above the organism’s minimum inhibitory concentration (T>MIC) for optimal therapeutic benefit Dellit TH et al. Clin Infect Dis. 2007;44: 1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44: 2. Owens RC Jr, Ambrose PG. Antimicrobial stewardship and the role of pharmacokinetics-pharmacodynamics in the modern antibiotic era. Diagn Microbiol Infect Dis. 2007;57(suppl 3):S77-S83.

22 Protocolos y Guías prácticas
Deben ser desarrolladas con un equipo multidisciplinario. Ventajas Puede impactar comportamiento del formulador Mantiene la autonomía del formulador Desventajas Requiere intervención activa (el formulador es notificado cuando no hay adherencia a los protocolos y guías) para ser máximamente efectivo. Clinical Pathways and Guidelines Key point: Development of multidisciplinary, evidence-based practice guidelines utilizing local microbiology and resistance patterns can be an effective part of antimicrobial stewardship.1 Clinical guidelines should be developed within a multidisciplinary team, with input from as many members as possible Advantages to clinical pathways and guidelines2 Increased awareness of pathways and guidelines may alter prescribing behavior The prescriber still has autonomy to prescribe antibiotics Disadvantages to clinical pathways and guidelines2 Passive education (providing guidelines without active intervention and/or feedback) may not be as effective MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18: 1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44: 2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:

23 La implementación de guías prácticas reducen el uso inadecuado de antibióticos
† 18 Computer-Generated Regimen 16 Physician-Generated Regimen * * 14 12 10 * Number of Days 8 6 4 2 Duration of Length of ICU ICU Admission Total Length of Antibiotic Stay to Discharge Stay Reference: Evans RS, Pestotnik SL, Classen DC, et al. A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med. 1998;338(4): Therapy *P<0.001. †P<0.003. Evans RS et al. N Engl J Med. 1998;338(4):237.

24

25 Estrechamiento o desescalonamiento:
Estudio prospectivo de antes y después en una UCI Implementación de una guía clínica de admón de AB inicial adecuado y subsecuente reevaluación para el potencial para desescalonamiento en pacientes con NAV Clinical Outcome Measures Before Period (n=50) After Period (n=52) Outcome P Value Mortality, no. (%) ICU length of stay, days Hospital length of stay, days Secondary VAP, no. (%) 21 (42.0) 23.1 ± 17.4 39.3 ± 33.1 12 (24.0) 27 (51.9) 21.7 ± 12.9 34.2 ± 26.2 4 (7.7) .102 .987 .379 .030 Streamlining/De-escalation: Example Key point: Although initial experiences with streamlining/de-escalation are limited, available data suggest that outcomes can be improved with its use, including decreased antibiotic use, fewer secondary episodes of pneumonia, decreased resistance, shorter duration of therapy, and decreased mortality. A study of patients with VAP attempted to reduce unnecessary antibiotic administration1 Antibiotic treatment was modified based on culture results and patient clinical outcome Antibiotics were discontinued after 7 days if patients met clinical criteria Duration of antibiotic therapy was decreased from 15 days to 9 days (P<.001) No significant difference in mortality was observed Implementation of the clinical guidelines, which included de-escalation therapy, resulted in patients being less likely to have a recurrence of pneumonia In a review of de-escalation therapy in VAP2 De-escalation was defined as using antimicrobiologic and clinical data to change from an initial broad-spectrum, multidrug, empiric therapy to therapy with fewer antibiotics and agents of narrow spectrumAvailable data suggest that it is a promising strategy for optimizing responsible use of antibiotics while allowing delivery of prompt appropriate empiric VAP therapy Ibrahim EH et al. Crit Care Med. 2001;29: 1. Ibrahim EH, Ward S, Sherman G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001;29: 2. Niederman MS. De-escalation therapy in ventilator-associated pneumonia. Curr Opin Crit Care. 2006;12:

26 Evaluando programas de control de ABs:
Comparación entre equipos de manejo de Abs vs Fellows de infectología: Patients Whose Treatment Was Managed By Outcome AMT (n=87) ID Fellows (n=93) Unadjusted OR (95% CI) P Value Appropriate 76 44 7.7 ( ) <.001 Cure* 49 35 2.4 ( ) .007 Failure 13 26 0.5 ( ) .03 Evaluating Stewardship Programs: Example 1—Clinical Outcomes Key point: Implementation of antimicrobial stewardship programs can optimize the use of antimicrobials and significantly improve clinical outcomes. A study at the Hospital of the University of Pennsylvania compared the effectiveness of antimicrobial management by the antimicrobial management team (AMT) versus antimicrobial management by infectious disease (ID) fellows Compared antimicrobial use and clinical outcomes Outcome measures included Appropriateness of antimicrobial agents Cure with first regimen Failure of first regimen Failure defined as change/addition of secondary antimicrobial agent to target isolated pathogens resistant to initial treatment Cost of care Better performance for all measured outcomes was observed in cases managed by the AMT compared with those managed by ID fellows AMT = antimicrobial management team; ID = infectious disease. *Ten subjects in each group for whom antimicrobial agents were requested for prophylaxis or in whom no evidence of infection was seen when the request was reviewed were excluded. Gross R et al. Clin Infect Dis. 2001;33: Gross R, Morgan AS, Kinky DE, et al. Impact of hospital-based antimicrobial management program on clinical and economic outcomes. Clin Infect Dis. 2001;33:

27 The California Antibiotic Stewardship Program Initiative
Part of California Department of Public Health California Senate Bill 739 mandated that by Jan 1, 2008, all general acute hospitals must monitor and evaluate the utilization of antibiotics and charge a quality improvement committee responsible for oversight of antibiotics As of March 2011: Survey of 229 acute care facilities 48% with stewardship program in place 28% planning one

28 Intervenciones en Gram-Negativos:
Reducir sobreuso de fluoroquinolonas: Daño colateral sustancial; asociado a brotes de infección por Clostridium difficile Wong-Beringer A, et al. Pharmacotherapy 2009;29: Programas de educación/intervención exitosos resultaron en disminución en 30% del uso de FQ, mejoraron susceptibilidad de P. aeruginosa en 10%, y disminución en la mortalidad asociada. Reducir uso betalactámicos anti-Pseudomónicos para infecciones por BGN fermentadores Piperacilina-tazobactam para infecciones de piel y TB Uso de carbapenems del grupo 1 y no del grupo 2 para el tratamiento de las infecciones por gérmenes BLEE+

29 Efecto de restricción de cefalosporinas en Klebsiella
Cambio en el formulario: Restricción de ceftazidime, prelación uso de imipenem Median Monthly Use (g) P 1995 (Before Program) 1996 (After Program) Ceftazidime 383 66 <.005 All cephalosporins 5,558 1,106 <.001 Imipenem 197 474 <.05 Results  Ceftazidime resistance  Imipenem resistance An intervention program was implemented in response to high levels of ceftazidime-resistant Klebsiella Ceftazidime was restricted and imipenem use was encouraged Ceftazidime use as well as all cephalosporin use went down a significant amount Ceftazidime resistance occurred less often However, imipenem-resistant Pseudomonas aeruginosa increased significantly No. of resistant isolates 1995 (Before Program) 1996 (After Program) Change (%) P Ceftazidime-resistant Klebsiella Hospital-wide (per 1000 ADC) 150 84 -44.0 <.01 All ICUs (per 100 ADC) 55 16 -70.9 <.001 Imipenem-resistant P aeruginosa 67 113 68.7 20 35 75.0 <.05 Rahal et al. JAMA. 1998;280:

30 Ertapenem para bacteremias por microorganismos BLEE+:
Retrospective cohort study from January 2005 – June 2010 at single center in Detroit, MI, USA 261 unique patients with BSI due to ESBL-producing Enterobacteriaceae (41% Urine Source) Treatment with a carbapenem was favorable to survival compared with other antibiotic therapies (ertapenem, n = 72; group 2 carbapenems, n=132) Sub-analysis performed on patients treated with a carbapenem after excluding patients who received both: Collins VL et al. Antimicrob Agents Chemother 2012;56:

31 Ertapenem no induce resistencia a los carbapenems del grupo 2
Nicolau DP, et al. Int J Antimicrob Agents 2012;39:11-15.

32 52% disponían de programa implementado
Barreras para implementar un programa de manejo de antibióticos ( Stewardship ) Encuesta de 3500 hospitales americanos desde Enero 2007 a Junio 2008: 357 respuestas 52% disponían de programa implementado Escasez de personal (55%) Consideraciones financieras (36%) Oposición del formulador (27%) Resistancia administrativa (14%) Otras: No estándares de mediciones de desempeño Los programas deben ser específicos para el hospital ( trabajo de novo de alta energía ) Falta de programas de entrenamiento Dificultad en proporcionar nuevos ahorros en costos luego de que el programa ya ha sido efectivo. Pope SD, et al. Infect Control Hosp Epidemiol 2009;30:97-98. George P et al. Crit Care 2010;14:205.

33 Cómo medir desenlaces clínicos y económicos para justificar su programa de control / manejo / stewardship de antimicrobianos

34 “Un programa de regulación de antibióticos sin medición de indicadores NO es un programa de regulación ( stewardship ) de antimicrobianos” Yours Truly, Joseph Kuti (y probablemente un grupo grande de personas inteligentes)

35 Cuando hacer medición en un programa de manejo de antibióticos
Pre-intervención: Cuál y dónde es el problema en su institución? Alta resistencia, abuso de ciertos antibióticos, pobres desenlaces para ciertas infecciones. Qué datos se requieren para definir correctamente un protocolo para solucionar un problema? Post-intervención Qué tan adherentes son los trabajadores de salud con el programa de control de antibióticos? La intervención alcanzó los resultados deseados? Se requieren nuevas modificaciones? Ayudar a soportar y justificar los recursos para el programa de manejo de ABs?

36 Medición de procesos vs desenlaces
… de desenlaces … de procesos Based on the primary goal of ASP May not always measure quality of care Often affected by multiple variables Examples: Mortality Clinical success/failure Resistance Superinfections (C.difficile) Healthcare costs Length of Stay Useful only if have a link to the outcome Examples: Compliance Reductions in antibiotic utilization Antibiotic cost Frequency/time to appropriate antibiotic therapy Number of suggestions implemented

37 Evaluando consumo de antibióticos: Dosis Diaria Definida (DDD)
Promocionado por la OMS Asume una dosis promedio diaria de mantenimiento por cada antibiótico para su indicación principal, en adultos. Gramos totales sumados durante el período de interés y se dividen por la DDD asignada por la OMS (gramos/día). Expresada más usualmente como DDDs por 1000 días paciente para comparación con otras instituciones. Limitaciones: Subestima exposición a Abs en pactes con insufic. Renal. No está validada para población pediátrica. Si la dosis real administrada es diferente a la DDD de OMS, no podrá correlacionarse con el número de días de tratamiento.

38 Evaluando consumo de antibiótico: Días de tratamiento (DDT)
Medición directa del número de días de tratamiento. Una dosis de un AB en un día dado queda registrado. Expresado más usualmente como DDT x 1000 días paciente para comparación con otras instituciones. Puede usarse para comparar uso relativo entre clases ( ej. Cefalosporinas ) de ABs y en pediatría. Limitaciones: Sobreestima uso de ABs dados en múltiples dosis x día. Difícil de medir sin registros computarizados de farmacia.

39 DDD versus DOT Polk R, et al. Clin Infect Dis 2007;44:

40 Neumonía asociada a VM en el Hospital Hartford
Problema identificado por los intensivistas Sospecha de pobres desenlaces clínicos en estos pacientes e inseguros de cuál antibiótico empírico utilizar. Cada médico tuvo diferente enfoque para tratar NAV Se implementó programa de intervención de NAV para documentar etiología y definir tx empírico.

41 Percentage of Isolates at each MIC
El empleo de distribuciones locales de MICs en estrategias de dosificación optimizada de ABs empíricos Pseudomonas aeruginosa (n=50) MIC Distributions: MICU 2006 5 10 15 20 25 30 35 0.13 0.25 0.5 1 2 4 8 16 32 64 128 256 MIC (mcg/ml) Percentage of Isolates at each MIC cefepime piperacillin/tazobactam meropenem Kuti JL, et al. Abstract th IDSA, San Diego, CA. October 2007. 41

42 Fracción acumulativa de respuesta (CFR) contra P. aeruginosa
Antibiotic Regimen (infusion duration) CFR (%) MICU SICU NTICU Cefepime 2g q 12 hr (0.5 hr infusion) 2g q 8 hr (0.5 hr infusion) 2g q 8 hr (3 hr infusion) 46.5 58.8 61.2 50.0 60.8 63.6 86.4 96.8 98.7 Ciprofloxacin 0.4g q 12 hr (1 hr infusion) 0.4g q 8 hr (1 hr infusion) 24.3 32.1 7.8 22.1 41.3 66.1 Meropenem 0.5g q 6 hr (0.5 hr infusion) 49.0 58.5 69.1 44.5 53.6 58.4 89.1 91.5 92.1 Piperacillin/tazobactam 4.5g q 6 hr (0.5 hr infusion) 4.5g q 6 hr (3 hr infusion) 18g q 24 hr (24 hr infusion) 55.5 60.7 43.3 50.2 50.3 85.0 91.7 Tobramycin 7mg/kg added Pharmacokinetic (PK) parameters provided by published population PK studies MICU = medical ICU; SICU = surgical ICU; NTICU = neurotrauma ICU Nicasio AM, et al. J Crit Care 2010;25:69-77. 42

43 43

44 Mediciones de procesos y desenlaces de la intervención:
Measurement Historic Control N=74 Clinical Pathway n = 94 P-value Mortality, n (%) Infection-Related 28-Day Crude 16 (21.6) 26 (35.1) 8 (8.5) 21 (22.3) 27 (28.7) 0.029 0.940 0.471 Appropriate Antibiotic Therapy, n (%) 36 (48.6) 53 (71.6) 0.007 Time to Appropriate Antibiotic, days Mean (SD) 1.73 (2.64) 0.76 (0.77) 0.065 Length of Stay, mean days (SD) ICU after VAP Ventilator Duration after VAP Total Hospital Length of Stay 26.1 (18.5) 24.6 (19.0) 20.8 (16.6) 43.3 (23.6) 11.7 (8.1) 20.2 (15.9) 18.3 (15.7) 37.9 (20.1) <0.001 0.128 0.119 0.113 Superinfections, n (%) All pathogens MDR-pathogens 20 (27.0) 15 (16.0) 9 (9.6) 0.006 Infection-related mortality: death within 24 hours after completion of antibiotic therapy. MDR: multidrug resistant Nicasio AM, et al. J Crit Care 2010;25:69-77.

45 Resultados económicos del protocolo de NAH
Variable Control (n=73) Pathway (n=93) P-value LOTVAP 27.1±18.5 12.7±8.1 <0.001 LOS 35.0±22.0 28.9±17.3 0.076* COSTVAP $75K $35K COSTafter $95K $76K 0.077* Antibiotic Cost $934±1533 $766±755 0.45 Hospital costs similar for pathway ($24,501) and control ($28,13,817) over first week of VAP, but significantly lower for clinical pathway during week 2 ($12,231 vs $20,947, p<0.001). * Treatment on Clinical Pathway was independently associated with lower total LOS after VAP (p=0.012) and lower total hospital costs after VAP (p=0.033) in multivariable models. LOTVAP = length of VAP treatment; LOS = total length of hospital stay after identification of VAP; COSTVAP = hospital costs (2007$) of treating VAP; COSTafter = total hospital costs (2007$) of treating VAP after VAP identification; Antibiotic Cost = acquisition cost of antibiotics used to treat VAP Nicasio AM, et al. Pharmacother ;30:

46 Se requiere monitoría continua de los programas para mantener su utilidad:
Cuando los recursos se desvían y baja el cumplimiento, se observa una disminución en el éxito del programa. La adherencia al programa de NAH se redujo de 100% a 44%. Porcentaje de pacientes tto antibiótico adecuado bajó de 70.8% a 56.3% (36.1% en pacientes en pacientes por fuera del protocolo, p<0.001). Tto antibiótico triple disminuyó del 79.2% a 32.8% (p<0.001) El tiempo para inicio de tto AB apropiado aumentó un día. La mortalidad durante hospitalización aumentó del 32% a 42% (p=0.603) Wilde AM, et al. Pharmacother 2012;32:

47 IMPLEMENTACIÓN DE UN PROGRAMA DE USO REGULADO DE ANTIBIÓTICOS PURA EN DOS UNIDADES DE CUIDADO INTENSIVO (UCI) MEDICO-QUIRÚRGICO EN UN HOSPITAL UNIVERSITARIO DE TERCER NIVEL EN COLOMBIA Christian José Pallares Gutiérrez, MD Ernesto Martínez Buitrago, MD Infectólogo Epidemiología Hospitalaria, Comité de Infecciones

48 Prevalencia de Microorganismos Causantes de Infección UCI 1 Y UCI 2 Periodo 2008-2009
FUENTE: - Epidemiología H.U.V - PURA

49 PROGRAMA USO REGULADO DE ATB IMPLEMENTACIÓN
Software para almacenamiento y análisis de datos Perfil Microbiológico de la Resistencia Bacteriana Formato FORMULACIÓN Guía de Uso de Antibióticos IMPLEMENTACIÓN Seguimiento y Vigilancia Prueba Piloto Asesoría por Infectología

50 Adherencia a las Guías de Uso de Antibióticos Periodo: Marzo a Septiembre del 2009
UCI 1 n= 442 UCI 2 n= 407 FUENTE: - Epidemiología H.U.V - PURA

51 COMPORTAMIENTO DEL CONSUMO ANTIBIÓTICO EN UCI 1 PRE Y POST INTERVENCIÓN
% REDUCCIÓN UCI 1 P* % REDUCCIÓN UCI 2 Meropenem 30% 0,0092 68% 0,0000 Vancomicina 34% 0,0180 Ceftriaxona 45% 0,0157 75% Ciprofloxacino 32% 0,0277 Piperacilina/Tazobactam 5% NS - 95% 0,0176 Cefepime - 100% 0,0280 - 36% 0,0044 * Test no paramétrico de Wilcoxon Mann Whitney

52 COMPORTAMIENTO DE LA INFECCIÓN POR MICROORGANISMO ESPECÍFICO EN UCI 1 /UCI 2 PRE Y POST INTERVENCIÓN
AISLAMIENTO UCI 1 UCI 2 IA* PRE-PURA IA* PURA REDUCCIÓN E.coli y K.pneumoniae BLEE 16,67 2,83 83% 21,28 4,69 78% P.aeruginosa R/CIPRO 21,91 87% 14,89 2,73 82% P.aeruginosaR/Cef 3ra 14,76 2,43 3,90 76% S.aureus OXA R 5,24 4,04 23% 8,15 52% A.baumannii MDR 17,14 8,09 53% 16,31 16,0 2% *IA: incidencia acumulada en seis meses x 100 pacientes

53 Costo Promedio Mensual PRE PURA Costo Promedio Mensual PURA
COMPARACIÓN DEL COSTO DE ANTIBIÓTICO PRE Y POST INTERVENCIÓN DEL PURA UCI 1 ANTIBIÓTICO Costo Promedio Mensual PRE PURA Costo Promedio Mensual PURA AHORRO MENSUAL MEROPENEM $ $ $ TIGECICLINA $ $ $ VANCOMICINA CIPROFLOXACINO Y CEFTRIAXONA $ $ $ LINEZOLID $ $ $ GENERALES* $ $ $ PIP/TAZO $ $ - $ CEFEPIME $ $ - $ TOTAL $ $ $ * Amikacina, Gentamicina, Clindamicina, Metronidazol, Amp/Sulb

54 Costo Promedio Mensual PRE PURA Costo Promedio Mensual PURA
COMPARACIÓN DEL COSTO DE ANTIBIÓTICO PRE Y POST INTERVENCIÓN DEL PURA UCI 2 ANTIBIÓTICO Costo Promedio Mensual PRE PURA Costo Promedio Mensual PURA AHORRO MENSUAL MEROPENEM $ $ $ TIGECICLINA $ $ $ VANCOMICINA CIPROFLOXACINO Y CEFTRIAXONA $ $ $ LINEZOLID $ $ $ GENERALES* $ $ $ PIP/TAZO $ $ - $ CEFEPIME $ $ - $ TOTAL $ $ $ * Amikacina, Gentamicina, Clindamicina, Metronidazol, Amp/Sulb

55 Conclusiones Incremento de prevalencia de resistencia bacteriana es un problema emergente de salud pública Actualmente, “Stewardship” es más arte que ciencia: Disminuye uso inapropiado de antimicrobianos y desarrollo de resistencia bacteriana a nivel hospitalario. Puede resultar en mejores desenlaces clínicos y ahorros financieros institucionales Deben ser ajustados al nivel local. Sea inteligente pero prudente en el uso de nuevos antibióticos donde probablemente sean de alto beneficio. Reducciones en uso de anibióticos anti-pseudomónicos puede resultar en mejoría de susceptibilidades sin compromiso en el éxito terapéutico. Conclusions Nosocomial, or health care–associated, infections are a common complication in US hospitals Many are due to resistant organisms, and mortality rates correlate with presence of multidrug-resistant organisms Rising prevalence of resistance is therefore recognized as an emerging public health threat Antimicrobial stewardship can minimize inappropriate antimicrobial use These programs can also reduce the development of antibiotic resistance in hospitals Local antimicrobial stewardship programs can improve appropriateness of antibiotic use

56 Conclusiones Evaluación con indicadores es parte vital de un programa de control / stewardship de antimicrobianos La medición puede realizarse previo a la intervención para guiar recomendaciones o posteriormente para monitorizar continuamente el progreso. Idealmente, los indicadores deberían evaluar tanto desenlaces como procesos. No evaluar sólo costo de antibióticos… Por favor! Use sus datos para mejor sus resultados, aún si al comienzo el programa no parece funcionar como se esperaba! Conclusions Nosocomial, or health care–associated, infections are a common complication in US hospitals Many are due to resistant organisms, and mortality rates correlate with presence of multidrug-resistant organisms Rising prevalence of resistance is therefore recognized as an emerging public health threat Antimicrobial stewardship can minimize inappropriate antimicrobial use These programs can also reduce the development of antibiotic resistance in hospitals Local antimicrobial stewardship programs can improve appropriateness of antibiotic use

57 Resources for Stewardship
Adult Infectious Diseases Fellowships (MD, DO) 136 programs listed on IDSA website across United States Antibiotic Utilization/Restriction is considered a core competency Infectious Diseases PGY-2 Residencies in Pharmacy 43 ASHP accredited programs Certification Programs Society of Infectious Diseases Pharmacists (SIDP) Making a Difference (MAD-ID) Stewardship Certification State Specific Programs (e.g., New York) Other Resources MedScape CME/CE Program ASHP Advantage SHEA Online Education Course

58 G r a c i a s p o r s u a t e n c i ó n . . .