1、ANTIBIOTIC RESISTANT PATHOGENS: IMPACT AND CONTROL,David Jay Weber, M.D., M.P.H. Professor of Medicine, Pediatrics & Epidemiology University of North Carolina at Chapel Hill, USA,SOURCES OF SLIDES,Thanks are given to the following persons who provided slides for this lecture William Jarvis, CDC Mari
2、n Kollef, Washington Universitiy, St. Louis Christopher Ohl, Wake Forest University Jan Patterson, University of Texas, San Antonio Michael Pfaller, University of Iowa Louis Rice, VA Medical Center, Cleveland,IMPACT OF NOSOCOMIAL INFECTIONS,IMPACT OF NOSOCOMIAL INFECTIONS,Incidence = 5-10% Incidence
3、 rising with time 2,000,000 patients develop a healthcare-associated infection each year Healthcare-associated infections result in 90,000 death Cost estimated at $4.5 to $5.7 billion dollars per year,NOSOCOMIAL INFECTIONS IN THE UNITED STATES,Burke JP. NEJM 2003;348:651,PREVALENCE: ICU (EUROPE),Stu
4、dy design: Point prevalence rate 17 countries, 1447 ICUs, 10,038 patients Frequency of infections: 4,501 (44.8%) Community-acquired: 1,876 (13.7%) Hospital-acquired: 975 (9.7%) ICU-acquired: 2,064 (20.6%)Pneumonia: 967 (46.9%)Other lower respiratory tract: 368 (17.8%)Urinary tract: 363 (17.6%)Bloods
5、tream: 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 Increased severity of illness Increased numbers of immunocompromised patients Shorter duration of hospitalization More and
6、 larger intensive care units Growing frequency of antimicrobial-resistant pathogens 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, g
7、ene therapy, xenotransplantation,HEALTHCARE SYSTEM OF THE PAST,Home Care,Acute Care Facility,Outpatient/ Ambulatory Facility,Long Term Care Facility,CURRENT HEALTHCARE SYSTEM,Home Care,Acute Care Facility,Outpatient/ Ambulatory Facility,Long Term Care Facility,CURRENT STATE OF HEALTHCARE EPIDEMIOLOG
8、Y 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 resist
9、ance Antibiotic modifying enzymes (e.g., penicillin resistance in S. aureus) Target site alteration (e.g., methicillin resistance in S. aureus) Permeability barriers (e.g., vancomycin tolerance in VISA) Efflux pumps (e.g., erythromycin resistance in S. pneumoniae),Mechanisms of Resistance,Eliopoulos
10、. Infectious Diseases. 1992.,IMPACT OF DRUG RESISTANT PATHOGENS,Inappropriate therapy with worse outcome Prolonged hospitalization Increased difficulty with placement in an extended care facility Need of isolation precautions (may negatively impact on quality of patient care) Increased cost Higher m
11、ortality,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 Stap
12、hyloccus 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: INCIDE
13、NCE, US,Meningitis: 3,000 cases Bacteremia: 50,000 cases Pneumonia: 500,000 cases Otitis media: 7 million casesDeaths: 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:
14、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 n
15、ecessarily 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 Primary pyodermas: Impetigo, folliculitis, furuncles, carbuncles, paronychia, cellulitis Toxin mediate
16、d 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,CLASSIFICATION OF S. AUREUS RESISTANCE,ORSA: Pre
17、valence 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,Tet
18、racycline,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 c
19、lonal types Clinical features and epidemiologic features of community-acquired cases similar to healthcare associated Skin and soft tissue infections predominate Familial transmission of MRSA described Outbreaks described (e.g., high school wresting team),ANTIBIOTIC RESISTANCE IN THE COMMUNITY: FACT
20、ORS CONTRIBUTING TO SPREAD IN THE COMMUNITY,Factors contributing to spread of antibiotic resistance Selection of antibiotic-resistance genes Increase in “high-risk” (immunodeficient) population Prolonged survival of persons with chronic diseases Congregate facilities (e.g., jails, day care centers)
21、Lack of rapid, accurate diagnostic tests to distinguish between viral and bacterial infections 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 inad
22、equate 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,Nyquist A-C, et al. JAMA 1998;279:875,ANTIBIOTIC PRESCRIBING, ADULTS,G
23、onzoles R, et al. JAMA 1997;278:901,FREQUENCY OF ANTIBIOTIC USE,Streptococcus Pneumoniae: Regional Trends in Antibiotic Resistance,Streptococcus Pneumoniae: Risk for Antibiotic Resistance is Greater with Increased Outpatient Antibiotic Use,Controlled for region,Data: B. Schwartz, Emerging Infections
24、 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 childrenFQRSP prevalence higher in the elderly and in OntarioHighest FQ use in the elderly and in
25、 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-neg
26、ative 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 M
27、ed 1991;91(suppl 3B):180S,PREVALENCE: ICU (EUROPE),Study design: Point prevalence rate 17 countries, 1447 ICUs, 10,038 patients Frequency of infections: 4,501 (44.8%) Community-acquired: 1,876 (13.7%) Hospital-acquired: 975 (9.7%) ICU-acquired: 2,064 (20.6%)Pneumonia: 967 (46.9%)Other lower respirat
28、ory tract: 368 (17.8%)Urinary tract: 363 (17.6%)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),(
29、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
30、-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
31、 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 2002,19972001 ( sd),Ceph = cephalosporin; NNIS = National Nosocomial Infections Surveillance System
32、; 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
33、 Carbapenems (E. faecium),Acquired Aminoglycosides (High Level) Chloramphenicol Erythromycin Penicillin Tetracycline Vancomycin and Teicoplanin Linezolid Synercid,Increasing VRE Over Time,“PROBLEM” GRAM-NEGATIVE PATHOGENS,P. aeruginosa ESBL-producing GNR E. coli Klebsiella pneumoniae Enterobacter sp
34、p. 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 s
35、ite 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. parat
36、yphi,1970s,TEM-1 Reported in 28 gram-negative species,1983,ESBL in Europe,1987,ESBL in United States,2001,150 ESBLs worldwide,1963,Third-generation cephalosporins,1980s,ESBLs Detection Methods: Inhibition by Clavulanic Acid, Ronald J. Jones (Reprinted with Permission of Author).ESBL Etest Prescribin
37、g Information AB BIODISK,ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 JUNE 2003,CDC. AJIC 2003;31:881-98.,ACINETOBACTER SUSCEPTIBILITY US & CANADA, 1997-1999 (SENTRY),Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113,STENOTROPHOMONAS RESISTANCE US, 1997-1999 (SENTRY),Gales AC
38、, 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 org
39、anisms from the community Ineffective infection control & isolation practices (esp. compliance) Increased use of antimicrobial prophylaxis Increased use of polymicrobial antimicrobial therapy High antimicrobial use in intensive care units,Source: Shales D, et al. Clin Infect Dis 1997;25:684-99.,PRIN
40、CIPLES 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 antibiot
41、ics. 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 Size Teaching versus non-te
42、aching 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 Di
43、s 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 (
44、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 Op
45、en 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. aerugnin
46、osa, Acinetobacter baumannii, Stenotrophomonas maltophilia, ORSA Risk factors for resistant bacteria Duration mechanical ventilation 7d, OR=6.0 Prior antibiotic use, OR=13.5 Broad spectrum antibiotic, OR=4.1Source: Troullet, AJRCCM 1998;157:531,PATHOGENS AS A FUNCTION OF DURATION OF VAP,Trouillet J,
47、 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,* 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 D
48、RUG RESISTANT PATHOGENS,IMPACT OF DRUG RESISTANT PATHOGENS,Prolonged hospitalization 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
49、: 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,
