resistance
TRANSCRIPT
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
IMPACT OF NOSOCOMIAL INFECTIONS
IMPACT OF NOSOCOMIAL INFECTIONS
Incidence = 5-10% Incidence 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
Variable 1975 1995Admissions 37,700,000 35,900,000Patient-days 299,000,000 190,000,000Average length of stay 7.9 5.3Inpatient surgical procedures 18,300,000 13,300,000Nosocomial infections 2,100,000 1,900,000Incidence of nosocomial infections (Number per 1000 patient-days)
7.2 9.8
Burke JP. NEJM 2003;348:651
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 respiratory tract: 368 (17.8%) Urinary tract: 363 (17.6%) 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 Increased severity of illness Increased numbers of immunocompromised patients Shorter duration of hospitalization More and 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, gene therapy,
xenotransplantation
HEALTHCARE SYSTEM OF THE PAST
Tranquil GardensNursing Home
HomeCare
Acute CareFacility
Outpatient/Ambulatory
Facility
Long Term CareFacility
CURRENT HEALTHCARE SYSTEM
Tranquil GardensNursing Home
HomeCare
Acute CareFacility
Outpatient/Ambulatory
Facility
Long Term CareFacility
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
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. 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 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
CommunityHospitals
TertiaryHospitals
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: 20,000Source: Centers for Disease Control. MMWR 1997;46(RR-8)
0
2
4
6
8
10
12
14
16
18
1988 1990 1992 1994 1996 1998 2000 2002
% o
f Is
ola
tes
Res
ista
nt
to P
enic
illin
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
65.06 63.25
56.4953.52 52.03
75 75.673.2 72.5
76.4
70.565.8
30
40
50
60
70
80
year
% s
usc
epti
bilit
y
NC
US, ABC
US, Doern
CLINICAL SYNDROMES: STAPHYLOCOCCUS AUREUS
Skin Primary pyodermas: Impetigo, folliculitis, furuncles, carbuncles,
paronychia, cellulitis 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 Resistancein Gram-positive Cocci
S. aureusS. aureus
PenicillinPenicillin
[1940s][1940s] Penicillin-resistantPenicillin-resistantS. aureusS. aureus
MethicillinMethicillin
[1960s][1960s] Methicillin-resistantMethicillin-resistantS. aureus (S. aureus (MRSA)MRSA)
Vancomycin-resistantVancomycin-resistantenterococcus (VRE)enterococcus (VRE)
VancomycinVancomycin[1997][1997]
VancomycinVancomycin(glycopeptide)(glycopeptide)
intermediate-resistantintermediate-resistantS. aureusS. aureus
Vancomycin-resistantS. aureus
CiprofloxacinCiprofloxacin19871987
[2002][2002]
CLASSIFICATION OF S. AUREUS RESISTANCE
Type of S. aureus CommentOxacillin-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:
0 20 40 60 80 100
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%
ErythromycinErythromycin
Ciprofloxacin
GentamicinGentamicin
ClindamycinClindamycin
TMP-SMZTMP-SMZ
GatifloxacinGatifloxacin
Tetracycline 16%
Increasing Prevalence of MRSA in S. aureus Bloodstream Infections
0
10
20
30
40
50
60
70
80
Community Nosocomial
1997
1998
1999
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 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 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) Lack of rapid, accurate diagnostic tests to distinguish
between viral and bacterial infections Increased use of antibiotics in animals & agriculture
Source: Segal-Maurer S. ID Clin NA 1996;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
Pharyngitis 7,435 5,246 10
Bronchitis 6,418 4,664 9
Sinusitis 3,254 2,356 4
Nyquist 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
Pharyngitis 7,412 5,634 9
UTI 4,858 2,798 5Otitis media 4,226 2,003 3
Gonzoles 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
% N
onsu
scep
tib
le
Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC ‘98
= regional range
0
10
20
30
40
50A
tlan
ta
Bal
tim
ore
Con
n.
Met
roT
enn
.
Min
nea
pol
is
Por
tlan
d
San
Fra
n.
Region
Beta-lactamMacrolide
1
1.2
1.4
1.6
1.8
2
2.2
Rel
ativ
e R
isk
0-24 25-49 50-74 75-100 %
Antibiotic Use Quartile
B-lactamsMacrolides
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
00.5
11.5
22.5
33.5
44.5
5
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
S. p
neum
o. w
ith R
educ
edSu
scep
tibili
ty to
Flu
oroq
uino
lone
s (%
)
0
1
2
3
4
5
6
# of
Pre
scrip
tions
/ 10
0 Pe
rson
s
15 - 64 y.o
> 64 y.o
# of Rx/100 persons
• 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. CDC. Am J Infect ControlAm J Infect Control. 1997;25:477-487.. 1997;25:477-487.
0
20
40
60
Bloodstream Infection
CoNS*S. aureusEnterococcusC. albicansEnterobacterOther
**CoNS = coagulase-negative staphylococciCoNS = coagulase-negative staphylococci
0
20
40
60
Pneumonia
P. aeruginosaS. aureusEnterobacterK. pneumoniaeH. influenzaeOther
0
20
40
60
Surgical Site Infection
EnterococcusCoNS*S. aureusP. aeruginosaEnterobacterOther
Per
cen
t
Per
cen
t
Per
cen
t
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 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%) Bloodstream: 247 (12.0%)
Vincent J-L, et al. JAMA 1995;274:639
RISK FACTORS FOR ICU ACQUIRED INFECTIONS
0 0.5 1 1.5 2 2.5
Trauma on Admission
Mechanical Ventilation
Urinary Catherization
Stress Ulcer Prophylaxis
CVP Line
PA Catherization
Odds Ratio
(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
0 10 20 30 40 50 60 70 80
>21
14-20
7-13
5-6
3-4
1-2
Leng
th o
f Sta
y, d
Odds Ratio
(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 1997–2001)
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 (%)Jan–Dec 20021997–2001 (± sd)
Ceph = cephalosporin;NNIS = National Nosocomial Infections Surveillance System; CNS = coagulase-negative staphylococci
NNIS. Am J Infect Control 2003;31:481–98
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
0
2
4
6
8
10
12
14
58 70 75 80 85 89 90 91 92 93 94
FY97
% VRE in ICU % VRE Non-ICU
Increasing VRE Over Time
VancomycinVancomycinIntroducedIntroduced
C. difficileC. difficiledescribeddescribed
“PROBLEM” GRAM-NEGATIVE PATHOGENS
P. aeruginosa ESBL-producing GNR
E. coli Klebsiella pneumoniae Enterobacter spp.
Acinetobacter spp. Stenotrophomonas maltophila
P. AERUGINOSA SUSCEPTIBILITYUS, 1999 (SENTRY)
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%
Amikacin
Tobramycin
Ciprofloxacin
Ceftazidime
Cefepime
Piperacillin
Meropenem
Imipenem
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.Rice LB. Pharmacotherapy. 1999;19(8 Pt 2):120S-128S.
Evolution of -Lactamase
Plasmid-Mediated TEM and SHV Enzymes
Ampicillin
19651965
TEM-1E. coliS. paratyphi
1970s1970s
TEM-1Reported in 28 gram-negativespecies
1983 1983
ESBL in Europe
19871987
ESBL inUnitedStates
20012001
>150 ESBLsworldwide19631963
Third-generation cephalosporins
1980s1980s
ESBLs Detection Methods: Inhibition by Clavulanic Acid
© Ronald J. Jones (Reprinted with Permission of Author).© Ronald J. Jones (Reprinted with Permission of Author). ESBL ESBL ® ® Etest Prescribing Information – AB BIODISKEtest Prescribing Information – AB BIODISK
ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 – JUNE 2003
0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%
Quinolone-E. coli
Cef3-E. coli
Cef3-Klebsiella
Carbapenem-Klebsiella
Cef3-Enterobacter
% Resistant
ICU
Non-ICU Inpatient
CDC. AJIC 2003;31:881-98.
ACINETOBACTER SUSCEPTIBILITYUS & CANADA, 1997-1999 (SENTRY)
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%
Imipenem
Meropenem
Ticar/Clav
Pip/Tazo
Ceftazidime
Cefepime
Ciprofloxacin
Gentamicin
Tobramycin
Amikacin
All isolates
Nosocomialisolates
Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113
STENOTROPHOMONAS RESISTANCEUS, 1997-1999 (SENTRY)
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%
Tetracycline
Gatifloxacin
Ciprofloxacin
Tobramycin
Amikacin
Ceftazidime
Pip/tazo
Ticar/clav
TMP-SMX
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 & 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.
PRINCIPLES OF ANTIBIOTIC RESISTANCE(Levy SB. NEJM, 1998)
1. Given sufficient time and drug use, antibiotic resistance will emerge.2. Resistance is progressive, evolving from low levels through
intermediate to high levels.3. Organisms resistant to one antibiotic are likely to become resistant
to other antibiotics.4. Once resistance appears, it is likely to decline slowly, if at all.5. 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-teaching 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
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0%
Cefotax-Pneumococcus
Pen-Pneumococcus
Vanco-Enterococcus
Ox-Coag Neg Staph
Ox-S. aureus
% Resistant
ICU
Non-ICU Inpatient
Outpatient
CDC. AJIC 2003;31:881-98.
ANTIMICROBIAL RESISTANCE RATES-GNR, ICARE/AUR, JANUARY 1998 – JUNE 2003
0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%
Quinolone-E. coli
Cef3-E. coli
Cef3-Klebsiella
Carbapenem-Klebsiella
Cef3-Enterobacter
% Resistant
ICU
Non-ICU Inpatient
Outpatient
CDC. AJIC 2003;31:881-98.
ICU (NNIS, 1989-99): Primary Bloodstream Infection
Black bar = pooled percentage resistance during hospitalizationOpen bars <7 days hospitalization Closed 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 hospitalizationOpen bars <7 days hospitalization Closed 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
Duration mechanical ventilation >7d, OR=6.0 Prior antibiotic use, OR=13.5 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 < 0.02 versus Groups 2, 3, or 4† † p < 0.0001 versus Group 4p < 0.0001 versus Group 4 Adapted from Trouillet JL, et al. Adapted from Trouillet JL, et al. Am J Respir Crit Care MedAm J Respir Crit Care Med. 1998;157:531-539. 1998;157:531-539
IMPACT OF DRUG 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: TWO META-ANALYSES
*Cosgrove SE et al. CID. 2003;36:53-59. †Whitby M et al. MJA. 2001;175:264-267.
1980–2000*n=3963
1990–2000†
n=2209
0
10
20
30
40
50 ORSA
OSSA
% M
ort
alit
y 36%
29%23%
12%
P<.001
P<.001
EXCESS MORTALITY ASSOCIATED WITH VRE
37%
16%
0%
10%
20%
30%
40%
50% VRE
VSE
% M
ort
alit
y
p<0.001
CDC. MMWR 1993;42:597-599
FAILURE OF CEPHALOSPORINS (by MIC) WITHESBL+ E. coli AND K. pneumoniae BACTEREMIA
Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212.
Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212.
• 54% (15/28) failure when organism susceptible54% (15/28) failure when organism susceptible
• 100% failure when organism intermediate100% failure when organism intermediate
% (no./total) of patients who% (no./total) of patients who
MIC (MIC (g/mL)g/mL) Failed on cephalosporin therapyFailed on cephalosporin therapy Died <14 days of bacteremiaDied <14 days of bacteremia
88 100 (6/6)100 (6/6) 33 (2/6)33 (2/6)
44 67 (2/3)67 (2/3) 0 (0/3)0 (0/3)
22 33 (1/3)33 (1/3) 0 (0/3)0 (0/3)
11 27 (3/11)27 (3/11) 18 (2/11)18 (2/11)
WHY ANTIBIOTICS ARE USED AND OVERUSED
IMPACT OF ANTIMICROBIALSIMPACT OF ANTIMICROBIALS
0
10
20
30
40
50
60
Hospital Mortality
%
All Cause Infection-related
Inadequate Therapy n = 169
Adequate Therapy n = 486
Kollef Chest 115:462, 1999
HAP: The Importance of Initial Empiric Antibiotic Selection
16.2
41.5 3833.3
24.7
63
81
61.4
0102030405060708090
Alvarez-Lerma Rello Luna Kollef
% m
ort
ali
ty
Adequate init. antibiotic Inadequate init. antibiotic
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 Strategiesfor the New Millennium
• Handwashing/Infection Control
• Antimicrobial Use
Control of Antibiotic Resistance
InfectionInfectionControlControl
AntibioticAntibioticControlControl
VREVREMRSAMRSAESBL ESBL
K. pneumoniaeK. pneumoniae
KEY INTERVENTIONS IN INFECTION CONTROL FOR RESISTANT PATHOGENS
Hand hygiene Surveillance Contact precautions
Gloves when entering the room Gown for close contact with patient or environment Environmental disinfection
EFFECTIVENESS OF HAND HYGIENE
Pittet D, et al. Lancet 2000;356:1307-12.
Efficacy of Hand Hygiene Agents in the Log Reductions of Gram-negative Bacteria (S. marcescens )
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Episode 1 Episode 3 Episode 5 Episode 7 Episode 10
Lo
g R
ed
uc
tio
n
60% Ethyl Alcohol (N=5) 61% Ethyl Alcohol (N=5)62% Ethyl Alcohol (N=5) 61% Ethyl Alcohol/1% CHG (N=5)70% Ethyl Alcohol/0.005% Silver Iodide (N=5) 0.4% Benzalkonium Chloride (N=5)0.5% PCMX/40% SD Alcohol (N=5) 0.75% Chlorhexidine Gluconate (N=5)2% Chlorhexidine Gluconate (N=5) 4% Chlorhexidine Gluconate (N=5)1% Triclosan (N=5) 0.2% Benzethonium Chloride (N=5)Non-antimicrobial Control (N=5) Tap Water Control (N=5)
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 antimicrobial resistance
Optimize selection, dose and duration of Rx Reduce morbidity and mortality Reduce length of stay Reduce health care expenditures Reduce adverse drug events
ANTIMICROBIAL STEWARDSHIP:GOALS
PRSP: Interventions to Improve Antimicrobial UseRural Alaska Villages
Studied children <5 yrs old, 3400 persons
3 rural regions: 1 study 2 control Educational intervention to
parents and providers on judicious antibiotic use in study region
Focused on respiratory tract infections
Peterson, ICCAC, 1999
-30
-20
-10
010
2030
% C
han
ge
Intervention Control
Rx’s Resp PNSP PRSP visits NP carriage
KEY INTERVENTIONS IN ANTIOBIOTIC CONTROL FOR RESISTANT PATHOGENS
Don’t treat non-bacterial infections or non-infectious diseases with antibiotics
Don’t prolong the duration of beyond what is needed Avoid prophylactic antibiotics unless benefit demonstrated Use the narrowest spectrum agent available
RISK STRATIFICATIONRISK STRATIFICATION•Prior Tx with ABX while in HospitalPrior Tx with ABX while in Hospital•Prolonged LOSProlonged LOS•Presence of In-Dwelling DevicePresence of In-Dwelling Device
HIGH RISK PTS WITH SERIOUS HIGH RISK PTS WITH SERIOUS INFECTIONSINFECTIONS
•Hospital-Acquired PneumoniaHospital-Acquired Pneumonia•Bloodstream infectionsBloodstream infections
-Lactam -Lactam ++
AminoglycosideAminoglycosideoror
FluoroquinoloneFluoroquinolone++
VancomycinVancomycinor or
LinezolidLinezolid
Modify Regimen as NecessaryModify Regimen as Necessary
Select Appropriate Empiric TherapySelect Appropriate Empiric Therapy•Pseudomonas aeruginsoaPseudomonas aeruginsoa•AcinetobacterAcinetobacter spp. spp.•Methicillin-resistant Methicillin-resistant Staphylococcus aureusStaphylococcus aureus
Specimens Specimens for Culturefor Culture
Clinical Re-assessmentClinical Re-assessment Microbiological DataMicrobiological Data
DURATION OF THERAPY:STUDY DESIGN
Authors: Chastre J, et al. JAMA 2003;290:2988 Study goal: Compare 8 vs 15 days of therapy for VAP Design: Prospective, randomized, double-blind (until day 8),
clinical trial VAP diagnosed by quantitative cultures obtained by bronchoscopy
Location: 51 French ICUs (N=401 patients) Outcomes: Assessed 28 days after VAP onset (ITT analysis)
Primary measures = death from any cause Microbiologically documented pulmonry infection recurrence Antibiotic free days
DURATION OF THERAPY:RESULTS
Primary outcomes (8 vs 15 days) Similar mortality, 18.8% vs 17.2% Similar rate of recurrent infection, 28.9% vs 26.0%
MRSA, 33.3% vs 42.9% Nonfermenting GNR, 40.6% vs 25.4% (p<0.05)
More antibiotic free days, 13.1% vs 8.7% (p<0.001) Secondary outcomes (8 vs 15 days)
Similar mechanical ventilation-free days, 8.7 vs 9.1 Similar number of organ failure-free days, 7.5 vs 8.0 Similar length of ICU stay, 30.0 vs 27.5 Similar frequency death at day 60, 25.4% vs 27.9% Multi-resistant pathogen (recurrent infection), 42.1% vs 62.0% (p=0.04)
MORTALITY
ANTIMICROBIAL STEWARDSHIP:INTERVENTIONS
Antimicrobial restrictions and controls Assistance in antimicrobial dosing
Feedback to MD to optimize therapy Immediate feedback when informatics detects antimicrobial/pathogen
mismatch Identify candidates for early IV to PO switch
Automatic Stop Orders Therapeutic Substitutions Cycling (Benefit unproven)
Restriction of 3rd Generation Cephalosporins
Bradley, et al - 1998 Goal - to reduce the risk of VRE in patients in leukemia units. Situation - 50% VRE carriage in oncology units. Methods
Phase I - no interventions - ceftazidime used as empiric therapy for febrile neutropenic patient
Phase 2 a and b - 2- 4 month intervals substituting piperacillin/tazobactam for ceftazidime as empiric therapy for the febrile neutropenic patient.
Phase 3 - 4 months validation substituting ceftazidime for piperacillin/tazobactam as in Phase I
J Antimicrob Chemother. 1999.
Restriction of 3rd Generation Cephalosporins
Bradley, et al. - 1998 (continued) Results
Phase 1 - 57% VRE colonization with 6 weeks of admission - 5 clinical infections.
Phase 2 - rate of colonization fell gradually to 29% in phase 2a. Last 3 months (phase 2b) the colonization rate was 8% with no clinical infections. Phase 1 vs 2b - p< 0.0001
Phase 3 - VRE colonization increased back to 36% with 3 clinical infections.
J Antimicrob Chemother. 1999.
Increasing ESBL-Mediated Resistance
Data from Rice LB et al. Clin Infect Dis. 1996;23:118-124.Data from Rice LB et al. Clin Infect Dis. 1996;23:118-124.
00
1010
2020
3030
4040
Jan-Mar 1993Jan-Mar 1993 Jan-Mar 1994Jan-Mar 1994
Per
cen
t C
efta
zid
ime
Per
cen
t C
efta
zid
ime
Res
ista
nce
Res
ista
nce
Prevalence of Ceftazidime-Resistant Prevalence of Ceftazidime-Resistant K. pneumoniaeK. pneumoniae
Piperacillin/tazobactam is not appropriate Piperacillin/tazobactam is not appropriate therapy for the treatment of known ESBL therapy for the treatment of known ESBL infections.infections.
RESULTS OF INTERVENTIONRESULTS OF INTERVENTION
Reprinted from Rice LB. Pharmacotherapy. 1999;19:120S-128S.Reprinted from Rice LB. Pharmacotherapy. 1999;19:120S-128S.
% R
esis
tan
ceA
ntib
iotic U
se
Intervention
Piperacillin/tazobactam is not appropriate Piperacillin/tazobactam is not appropriate therapy for the treatment of known ESBL therapy for the treatment of known ESBL infections.infections.
Resistance Rates and Usage
Strategies to Reduce ESBLs
Year Author Agent Reduction in Ceph Use
Replacement Agent
Intervention Successful
(Yes/No) 1993 Meyer CTZ 73% I/C Yes
1996 Rice CTZ 50% P/T Yes
1998 Pena 3GC 83% P/T I/C
Yes
1998
Rahal All Cephs
80% I/C Yes
1999 Landman CTX CTZ
89% 66%
A/S P/T
Yes
2000 Patterson CTZ Hosp. A-71% Hosp. B-27%
P/T Yes
Meyer KS et al. Ann Intern Med. 1993;119:353-359.
Rice LB et al. Clin Infect Dis. 1996;23:118-124.Pena C et al. Antimicrob Agents Chemother. 1998;42:53-58.
Rahal JJ et al. JAMA. 1998;280:1233-1237.Landman D et al. Clin Infect Dis. 1999;28:1062-1066.
Patterson JE et al. Infect Control Hosp Epidemiol. 2000;21:455-458.
Meyer KS et al. Ann Intern Med. 1993;119:353-359.Rice LB et al. Clin Infect Dis. 1996;23:118-124.
Pena C et al. Antimicrob Agents Chemother. 1998;42:53-58.Rahal JJ et al. JAMA. 1998;280:1233-1237.
Landman D et al. Clin Infect Dis. 1999;28:1062-1066.Patterson JE et al. Infect Control Hosp Epidemiol. 2000;21:455-458.
Correlation Between Consumption of Imipenem and Resistance of P. aeruginosa
Lepper PM, et al.Lepper PM, et al. Antimicrob Agents ChemotherAntimicrob Agents Chemother. 2002;46:2920-2925.. 2002;46:2920-2925.
Relationship Between Imipenem Consumption and New Patients Colonized or Infected with Acinetobacter baumannii
Relationship Between Imipenem Consumption and New Patients Colonized or Infected with Acinetobacter baumannii
Reprinted from Corbella X, et al. Reprinted from Corbella X, et al. J Clin MicrobiolJ Clin Microbiol. 2000;38:4086-4095.. 2000;38:4086-4095.
DDD = Defined daily doses of.DDD = Defined daily doses of.
Order entry-program recommended antibiotic, dose and length of therapy
Clinicians were not required to follow program recommendations
Data on indices of quality of care were compared between computer regimen and non-regimen patients pre and post implementation.
Antimicrobial StewardshipComputer-assisted Order Entry
IMHS: Evans et. al.; NEJM 1998
Antimicrobial StewardshipComputer-assisted Order Entry (n=545)
IMHS: Evans et. al.; NEJM 1998
Allergy ordersExcess dosagesDays of excess dosageSusceptibility MismatchAdverse EventsCost of agentsTotal Hospital CostsLength of Hospital Stay
35872.7124
$102$26,31510.0 days
146
405
5.9
206
28
$340
$35,238
12.9 days
$427
$44,865
16.7 days
Outcome Study Group Non-Study Group Pre-interventionPost-intervention
CONCLUSIONS The changing healthcare environment is diminishing the boundaries
between traditional community and hospital-acquired infections. Inappropriate antimicrobial use and failure to fully implement
infection control recommendations are leading to the emergence of antimicrobial-resistant pathogens.
Increased collaboration between clinicians, infectious disease, infection control and microbiology personnel, Federal and State public health authorities, and private industry will be needed to reduce antimicrobial use, improve infection control, and prevent the further emergence of antimicrobial-resistant pathogens.