抗生素ppt课件（英文精品）antibiotic resistant pathogens impact and control（104p）

ANTIBIOTIC RESISTANT PATHOGENS: IMPACT AND CONTROL David Jay Weber, M.D., M.P.H. Professor of Medicine, Pediatrics 348:651 PREVALENCE: ICU (EUROPE) Study design: Point prevalence rate n 17 countries, 1447 ICUs, 10,038 patients Frequency of infections: 4,501 (44.8%) n Community-acquired: 1,876 (13.7%) n Hospital-acquired: 975 (9.7%) n ICU-acquired: 2,064 (20.6%) u Pneumonia: 967 (46.9%) u Other lower respiratory tract: 368 (17.8%) u Urinary tract: 363 (17.6%) u Bloodstream: 247 (12.0%) Vincent J-L, et al. JAMA 1995;274:639 CHALLENGES IN THE PREVENTION AND MANAGEMENT OF HEALTHCARE-ASSOCIATED INFECTIONS Changing population of hospital patients n Increased severity of illness n Increased numbers of immunocompromised patients n Shorter duration of hospitalization n More and larger intensive care units Growing frequency of antimicrobial-resistant pathogens n Importation of antimicrobial-resistant pathogens from the community into the hospital Lack of compliance with hand hygiene Reduced infection control resources nationwide Future: Prion diseases, bioterrorism agents, gene therapy, xenotransplantation HEALTHCARE SYSTEM OF THE PAST Tranquil GardensNursing Home Home Care Acute Care Facility Outpatient/ Ambulatory Facility Long Term Care Facility CURRENT HEALTHCARE SYSTEM Tranquil GardensNursing Home Home Care Acute Care Facility Outpatient/ Ambulatory Facility Long Term Care Facility CURRENT STATE OF HEALTHCARE EPIDEMIOLOGY IN ACUTE CARE HOSPITALS Fewer hospitals Smaller hospitals More and larger intensive care units Greater patient severity of illness More immunocompromised patients Shorter stays Fewer nurses? Fewer infection control personnel? MECHANISMS OF ANTIBIOTIC RESISTANCE Intrinsic resistance Acquired resistance n Antibiotic modifying enzymes (e.g., penicillin resistance in S. aureus) n Target site alteration (e.g., methicillin resistance in S. aureus) n Permeability barriers (e.g., vancomycin tolerance in VISA) n Efflux pumps (e.g., erythromycin resistance in S. pneumoniae) Mechanisms of Resistance Eliopoulos. Infectious Diseases. 1992. IMPACT OF DRUG RESISTANT PATHOGENS Inappropriate therapy with worse outcome Prolonged hospitalization n Increased difficulty with placement in an extended care facility n Need of isolation precautions (may negatively impact on quality of patient care) Increased cost Higher mortality EMERGING DRUG RESISTANCE IN COMMUNITY PATHOGENS EMERGING RESISTANT PATHOGENS: COMMUNITY HIV: Multiple agents Pneumococcus: Penicillin/cephalosporins, erythromycin Group A streptococcus: Erythromycin Mycobacterium tuberculosis: INH, rifampin Neisseria gonorrhoeae: Penicillin, quinolones Staphyloccus aureus: Oxacillin Plasmodium falciparum: Chloroquine, mefloquine, others VA Feedlots Foreign Daycare Community Hospitals Tertiary Hospitals Nursing Homes Community Homecare Environments Where Antibiotic Resistance Develops and Their Relationships Adapted from B. Murray S. PNEUMONIAE: INCIDENCE, US Meningitis: 3,000 cases Bacteremia: 50,000 cases Pneumonia: 500,000 cases Otitis media: 7 million cases Deaths: 20,000 Source: Centers for Disease Control. MMWR 1997;46(RR-8) % of Isolates Resistant to Penicillin Year Breiman RF, et al. JAMA. 1994;271:1831-1835. Doern GV, et al. AAC. 1996;40:1208-1213. Thornsberry C, et al. DMID. 1997;29:249-257. Thornsberry C, et al. JAC. 1999;44:749-759. Thornsberry C, et al. CID 2002;34(S1):S4-S16. Karlowsky, et al. CID. 2003;36:963-970. Sahm, et al. IDSA 2003, abstract 201. Data on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results. Trend for Penicillin-Resistant (MIC 2 mg/ml) S. pneumoniae in the US (1988-2002) PENICILLIN SUSCEPTIBILITY CLINICAL SYNDROMES: STAPHYLOCOCCUS AUREUS Skin n Primary pyodermas: Impetigo, folliculitis, furuncles, carbuncles, paronychia, cellulitis n Toxin mediated syndromes: Toxic shock syndrome (TSS), scalded skin syndrome (SSS) Systemic: Sepsis, bacteremia, endocarditis Organ system: Meningitis, osteomyelitis, septic arthritis, paratitis, myositis Evolution of Antimicrobial Resistance in Gram-positive Cocci S. aureus Penicillin 1940s Penicillin-resistant S. aureus Methicillin 1960s Methicillin-resistant S. aureus (MRSA) Vancomycin-resistant enterococcus (VRE) Vancomycin1997 Vancomycin (glycopeptide) intermediate-resistant S. aureus Vancomycin- resistant S. aureus Ciprofloxacin 1987 2002 CLASSIFICATION OF S. AUREUS RESISTANCE Type of S. aureus Comment Oxacillin-susceptible (OSSA) Susceptible to oxacillin, nafcillin, cephalosporins, and -lactam inhibitor combinations. Borderline-resistant (BRSA) Borderline oxacillin MICs due to hyperproduction of -lactamase, abnormal PBPs, or heterogeneous mecA production. Oxacilin-resistant (ORSA) Oxacillin 4 ug/mL due to low affinity PBP (PBP- 2). Resistant to all penicillins, cephalosporins, carbapenems. Glycopeptide- intermediate (GISA) Vancomycin MIC 8-16 ug/mL; also intermediate to teicoplanin. Mechanism = thickened cell wall. Clinically resistant to vancomycin. Vancomycin-resistant (VRSA) Vancomycin MIC 32 ug/mL. Mechanism = vanA gene from VRE E. faecalis ORSA: Prevalence of co-resistance to other drugs, U.S., 1997-1999: MRSA with Co-Resistance Diekema DJ et al. CID. 2001;32:S114-S132. ORSA strains showed resistance to mean 3.5 (median 3) additional drug classes 36% 89% 93% 79% 26% 24% Erythromycin Ciprofloxacin Gentamicin Clindamycin TMP-SMZ Gatifloxacin Tetracycline 16% Increasing Prevalence of MRSA in S. aureus Bloodstream Infections Diekema DJ et al. CID. 2001;32:S114-S132. % MRSA United States, S aureus isolates (N=4405) EPIDEMIOLOGIC AND CLINICAL FEATURES Community-acquired strains demonstrate increased susceptibility to antibiotics and multiple clonal types Clinical features and epidemiologic features of community-acquired cases similar to healthcare associated n Skin and soft tissue infections predominate Familial transmission of MRSA described Outbreaks described (e.g., high school wresting team) ANTIBIOTIC RESISTANCE IN THE COMMUNITY: FACTORS CONTRIBUTING TO SPREAD IN THE COMMUNITY Factors contributing to spread of antibiotic resistance n Selection of antibiotic-resistance genes n Increase in “high-risk” (immunodeficient) population n Prolonged survival of persons with chronic diseases n Congregate facilities (e.g., jails, day care centers) n Lack of rapid, accurate diagnostic tests to distinguish between viral and bacterial infections n Increased use of antibiotics in animals 10:939-957. ANTIBIOTIC RESISTANCE: Physician practices contributing to inappropriate antibiotic use Providing antibacterial drugs to treat viral illnesses Using inadequate diagnostic criteria for infections that may have a bacterial etiology Providing expensive, broad-spectrum agents that are unnecessary Prescribing antibiotics at an improper dose or duration ANTIBIOTIC PRESCRIBING, CHILDREN Diagnosis Office Visits (x1000) Antibiotic Prescriptions (x1000) % Total Antibiotic Prescriptions Otitis media 20,820 16,150 30 URI 14,068 6,509 12 Pharyngiti s 7,435 5,246 10 Bronchitis 6,418 4,664 9 Sinusitis 3,254 2,356 4Nyquist A-C, et al. JAMA 1998;279:875 ANTIBIOTIC PRESCRIBING, ADULTS Diagnosis Office Visits (x1000) Antibiotic Prescriptions (x1000) % Total Antibiotic Prescriptions Sinusitis 13,369 7,494 12 Bronchitis 10,235 6,762 11 URI 11,033 5,842 10 Pharyngiti s 7,412 5,634 9 UTI 4,858 2,798 5 Otitis media 4,226 2,003 3Gonzoles R, et al. JAMA 1997;278:901 FREQUENCY OF ANTIBIOTIC USE Diagnosis Children Adult Common cold 44% 51% URI 46% 52% Bronchitis 75% 66% Streptococcus Pneumoniae: Regional Trends in Antibiotic Resistance % Nonsusceptible Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC 98 = regional range 0 10 20 30 40 50 Atlanta Baltimore Conn. MetroTenn. Minneapolis Portland San Fran. Region Beta-lactam Macrolide Streptococcus Pneumoniae: Risk for Antibiotic Resistance is Greater with Increased Outpatient Antibiotic Use Controlled for region Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC 98 Decreased Susceptibility of S. pneumoniae to Fluoroquinolones in Canada: Relationship of Resistance to Antibiotic Use Overall prevalence of FQRSP 1.0% No reduced susceptibility in children FQRSP prevalence higher in the elderly and in Ontario Highest FQ use in the elderly and in Ontario Chen et. al., NEJM 1999;341:233-9 KEY NOSOCOMIAL PATHOGENS National Nosocomial Infections Surveillance (NNIS) Report: ICU Infections 1986 - 1997 CDC. Am J Infect Control. 1997;25:477-487. Bloodstream Infection CoNS* S. aureus Enterococcus C. albicans Enterobacter Other *CoNS = coagulase-negative staphylococci Pneumonia P. aeruginosa S. aureus Enterobacter K. pneumoniae H. influenzae Other Surgical Site Infection Enterococcus CoNS* S. aureus P. aeruginosa Enterobacter Other Percent Percent Percent RISK FACTORS FOR HEALTHCARE- ASSOCIATED INFECTIONS HAZARDS IN THE ICU Weinstein RA. Am J Med 1991;91(suppl 3B):180S PREVALENCE: ICU (EUROPE) Study design: Point prevalence rate n 17 countries, 1447 ICUs, 10,038 patients Frequency of infections: 4,501 (44.8%) n Community-acquired: 1,876 (13.7%) n Hospital-acquired: 975 (9.7%) n ICU-acquired: 2,064 (20.6%) u Pneumonia: 967 (46.9%) u Other lower respiratory tract: 368 (17.8%) u Urinary tract: 363 (17.6%) u Bloodstream: 247 (12.0%) Vincent J-L, et al. JAMA 1995;274:639 RISK FACTORS FOR ICU ACQUIRED INFECTIONS (1.01-1.43) (1.16-1.57) (1.20-1.60) (1.19-1.69) (1.51-2.03) (1.75-2.44) (95% CI) RISK FACTORS FOR ICU ACQUIRED INFECTIONS (1.56-4.13) (5.51-14.70) (9.33-24.14) (19.43-48.67) (37.90-96.25) (48.18-120.06) (95% CI) EMERGING DRUG RESISTANCE IN NOSOCOMIAL PATHOGENS EMERGING RESISTANT PATHOGENS: HEALTH CARE FACILITIES Staphylococcus aureus: Oxacillin, vancomycin, linezolid Enterococcus: Penicillin, aminoglycosides, vancomycin, linezolid, dalfopristin-quinupristin Enterobacteriaceae: ESBL producers, carbapenems Candida spp.: Fluconazole Mycobacterium tuberculosis: INH, rifampin Current status of resistance in the ICU: (NNIS, 2002 vs 19972001) Resistance (%) 0 10 20 30 40 50 60 70 80 90 Vancomycin/Enterococci Methicillin/S. aureus Methicillin/CNS 3rd Ceph/E. coli 3rd Ceph/K. pneumoniae Imipenem/P. aeruginosa Quinolone/P. aeruginosa 3rd Ceph/P. aeruginosa 3rd Ceph/Enterobacter spp. +11 +13 +1 +14 2 +32 +27 +22 5 Change in resistance (%)JanDec 200219972001 ( sd) Ceph = cephalosporin; NNIS = National Nosocomial Infections Surveillance System; CNS = coagulase-negative staphylococci NNIS. Am J Infect Control 2003;31:48198 ORSA, SENTRY, 1997-1999 Diekema D, et al. CID 2001;32(S-2):S114 ENTEROCOCCAL RESISTANCE Intrinsic Resistance Semisynthetic penicillins Cephalosporins Clindamycin Trimethoprim-Sulfamethoxazole Monobactams Aminoglycosides Carbapenems (E. faecium) Acquired Aminoglycosides (High Level) Chloramphenicol Erythromycin Penicillin Tetracycline Vancomycin and Teicoplanin Linezolid Synercid Increasing VRE Over Time Vancomycin Introduced C. difficile described “PROBLEM” GRAM-NEGATIVE PATHOGENS P. aeruginosa ESBL-producing GNR n E. coli n Klebsiella pneumoniae n Enterobacter spp. Acinetobacter spp. Stenotrophomonas maltophila P. AERUGINOSA SUSCEPTIBILITY US, 1999 (SENTRY) Gales A, et al. CID 2001;32(S-2);146 What is an Extended-Spectrum -Lactamase (ESBL)? Variant of standard TEM and SHV -lactamases Result of point mutations in TEM-1 and SHV-1 genes Alters active binding site of enzyme Extends spectrum of the mutated -lactamase Allows effective hydrolyzation of third-generation cephalopsorins Transmitted via plasmids Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S-128S. Evolution of -Lactamase Plasmid-Mediated TEM and SHV Enzymes Ampicillin 1965 TEM-1 E. coli S. paratyphi 1970s TEM-1 Reported in 28 gram-negative species 1983 ESBL in Europe 1987 ESBL in United States 2001 150 ESBLs worldwide1963 Third-generation cephalosporins 1980s ESBLs Detection Methods: Inhibition by Clavulanic Acid Ronald J. Jones (Reprinted with Permission of Author). ESBL Etest Prescribing Information AB BIODISK ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 JUNE 2003 CDC. AJIC 2003;31:881-98. ACINETOBACTER SUSCEPTIBILITY US 32(Suppl 2):S104-113 STENOTROPHOMONAS RESISTANCE US, 1997-1999 (SENTRY) Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113 ANTIBIOTIC RESISTANCE IN HOSPITALS: FACTORS CONTRIBUTING TO SPREAD IN HOSPITALS Greater severity of illness of hospitalized patients More severely immunocompromised patients Newer devices and procedures in use Increased introduction of resistant organisms from the community Ineffective infection control 25:684-99. PRINCIPLES OF ANTIBIOTIC RESISTANCE (Levy SB. NEJM, 1998) Given sufficient time and drug use, antibiotic resistance will emerge. Resistance is progressive, evolving from low levels through intermediate to high levels. Organisms resistant to one antibiotic are likely to become resistant to other antibiotics. Once resistance appears, it is likely to decline slowly, if at all. The use of antibiotics by any one person affects others in the extended as well as the immediate environment. FACTORS ASSOCIATED WITH RESISTANT PATHOGENS All resistance is local Hospital demographics n Size n Teaching versus non-teaching n Location Care in an intensive care unit Duration of hospitalization and use of an invasive medical device (central venous catheter, endotracheal tube for mechanical ventilation, urinary catheter) Prior antimicrobial use ANTIMOCROBIAL RESISTANCE, US, 1999-2000 Diekema DJ, et al. Clin Infect Dis 2004;38:7885 ANTIMOCROBIAL RESISTANCE, US, 1999-2000 Diekema DJ, et al. Clin Infect Dis 2004;38:7885 ANTIMICROBIAL RESISTANCE RATES-GPC, ICARE/AUR, JANUARY 1998 JUNE 2003 CDC. AJIC 2003;31:881-98. ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 JUNE 2003 CDC. AJIC 2003;31:881-98. ICU (NNIS, 1989-99): Primary Bloodstream Infection Black bar = pooled percentage resistance during hospitalization Open bars 7 days hospitalization ICU (NNIS, 1989-99): Ventilator-Associated Pneumonia Fridkin SK. Crit Care Med 2001;29:N67 Black bar = pooled percentage resistance during hospitalization Open bars 7 days hospitalization ICU (NNIS, 1989-99): Urinary Tract Infection Fridkin SK. Crit Care Med 2001;29:N67 RESISTANACE AS A FUNCTION OF PRIOR ANTIBIOTIC USE AND DURATION OF HOSPITALIZATION 135 consecutive cases of VAP, French ICUs Potentially “resistant” bacteria higher mortality: P. aerugninosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, ORSA Risk factors for resistant bacteria n Duration mechanical ventilation 7d, OR=6.0 n Prior antibiotic use, OR=13.5 n Broad spectrum antibiotic, OR=4.1 Source: Troullet, AJRCCM 1998;157:531 PATHOGENS AS A FUNCTION OF DURATION OF VAP Trouillet J, et al. Am J Respir Crit Care Med 1998;157:608-613. Effect of Mechanical Ventilation and Prior Antibiotic Use on Development of Multiresistant Pathogens Numbers and percentages of microorganisms responsible for 135 VAP episodes classified according to duration of mechanical ventilation (MV) and prior antibiotic therapy (ABT) Organisms Group 1 (n=22) MV 7 ABT = no Group 2 (n=12) MV 7 ABT = yes Group 3 (n=17) MV 7 ABT = no Group 4 (n=84) MV 7 ABT = yes Multiresistant bacteria 0* 6 (30) 4 (12.5) 89 (58.6) P. aeruginosa 0 4 (20) 2 (6.3) 33 (21.7) A. baumannii 0 1 (5) 1 (3.1) 20 (13.2) S. maltophilia 0 0 0 6 (3.9) MRSA 0 1 (5) 1 (3.1) 30 (19.7) Other bacteria 41 (100) 14 (70) 28 (87.5) 63 (41.4) * p 0.02 versus Groups 2, 3, or 4 p 0.0001 versus Group 4 Adapted from Trouillet JL, et al. Am J Respir Crit Care Med. 1998;157:531-539 IMPACT OF DRUG RESISTANT PATHOGENS IMPACT OF DRUG RESISTANT PATHOGENS Prolonged hospitalization n Increased difficulty with placement in an extended care facility Need of isolation precautions (may negatively impact on quality of patient care) Increased cost Higher mortality EXCESS MORTALITY ASSOCIATED WITH ORSA: TWO META-ANALYSES *Cosgrove SE et al. CID. 2003;36:53-59. Whitby M et al. MJA. 2001;175:264-267. 19802000* n=3963 19902000 n=2209 % Mortality 36% 29% 23% 12% P.001 P.001 EXCESS MORTALITY ASSOCIATED WITH VRE % Mortality p0.001 CDC. MMWR 1993;42:597-599 FAILURE OF CEPHALOSPORINS (by MIC) WITH ESBL+ E. coli AND K. pneumoniae BACTEREMIA Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212. 54% (15/28) failure when organism susceptible 100% failure when organism intermediate % (no./total) of patients who MIC (g/mL) Failed on cephalosporin therapy Died 14 days of bacteremia 8 100 (6/6) 33 (2/6) 4 67 (2/3) 0 (0/3) 2 33 (1/3) 0 (0/3) 1 27 (3/11) 18 (2/11) WHY ANTIBIOTICS ARE USED AND OVERUSED IMPACT OF ANTIMICROBIALS Kollef Chest 115:462, 1999 HAP: The Importance of Initial Empiric Antibiotic Selection Alvarez-Lerma F. Intensive Care Med 1996 May;22(5):387-94. Rello J, Gallego M, Mariscal D, et al. Am J Respir Crit Care Med 1997 Jul;156(1):196-200. Luna CM, Vujacich P, Niederman MS et al. Chest 1997;111:676-685. Kollef MH and Ward S. Chest 1998 Feb;113(2):412-20. Prevention and Control Strategies for the New Millennium Handwashing/Infection Control Antimicrobial Use Control of Antibiotic Resistance Infection Control Antibiotic Control VREMRSA ESBL K. pneumoniae KEY INTERVENTIONS IN INFECTION CONTROL FOR RESISTANT PATHOGENS Hand hygiene Surveillance Contact precautions n Gloves when entering the room n Gown for close contact with patient or environment n Environmental disinfection EFFECTIVENESS OF HAND HYGIENE Pittet D, et al. Lancet 2000;356:1307-12. ANTIMICROBIAL STEWARDSHIP A system of informatics, data collection methods, personnel, and policy / procedures which promotes the optimal selection, dosing, and duration of therapy for antibiotics Prevent or slow the emergence of antimicrobi