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
 GOALS OF LECTURE

 Review the mechanisms of resistance to antibacterial

 Review the growing problem of antibiotic resistant pathogens
 Review drug resistant Streptococcus pneumoniae infections
 Review drug resistant Staphylococcus aureus
 Review methods to control antibiotic-resistant pathogens
 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
Environments Where Antibiotic Resistance Develops
and Their Relationships

Daycare
Nursing
Homes

Homecare Foreign
Tertiary
Hospitals
Community
Hospitals
Community
VA Feedlots

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)
 RESPIRATORY PATHOGENS IN CAP
M pneumoniae Legionella spp
1%–6% 2%–8%

C pneumoniae
4%–6%

H influenzae
3%–10%

S aureus
3%–5%

Others
3%i–10%

S pneumoniae
Viruses 20%–60%
2%–15%

1. Bartlett JG, Mundy LM. N Engl J Med. 1995;333:1618–1624.

ETIOLOGIC AGENTS OF BACTERIAL MENINGITIS

Schuchat A, et al. NEJM 1997;337:970

 Trend for Penicillin-Resistant (MIC  2 mg/ml)
S. pneumoniae in the US (1988-2002)
18
% of Isolates Resistant

16
14
to Penicillin

12
10
8
6
4
2
0
1988 1990 1992 1994 1996 1998 2000 2002
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.
 PENICILLIN SUSCEPTIBILITY

80
76.4 75 75.6
73.2 72.5
70 70.5
% susceptibility

65.06 65.8
63.25
60 NC
56.49
53.52 52.03 US, ABC
50
US, Doern
40

30
95

96

97

98

99

00
19

19

19

19

19

20
year
 ERYTHROMYCIN SUSCEPTIBILITY

100

90 89.7
% susceptibility

85 84.9
80 80.8 NC
77.83 79.5 78.3
US, ABC
73.8
70 68.7 Doern
64.03
60 61.4 60.59

50
1995

1996

1997

1998

1999

2000
year
 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
 RELATIVE FREQUENCY OF S. AUREUS AS A
CAUSE OF COMMUNITY ACQUIRED INFECTION

 Pneumonia requiring hospitalization 4%

 Pneumonia after influenza 20%
 Hematogenous endophthalmitis 10%
 Meningitis 1-9%
 Septic bursitis 90%, nongonococcal septic arthritis 60%
 Cavernous sinus thrombosis 66%
 Spinal epidural abscess 62%
 Vertebral osteomyelitis 60%
 Pleural empyema 33%
 Endocarditis 10-27%, prosthetic valve endocarditis 14%
 Evolution of Antimicrobial Resistance
in Gram-positive Cocci

Penicillin Methicillin

[1940s] Penicillin-resistant [1960s] Methicillin-resistant

S. aureus S. aureus S. aureus (MRSA)
Vancomycin
[1997]
[2002] Ciprofloxacin
Vancomycin- 1987
resistant
S. aureus Vancomycin Vancomycin-resistant
(glycopeptide) enterococcus (VRE)
intermediate-resistant
S. aureus
 ORSA: Prevalence of co-resistance to
other drugs, U.S., 1997-1999:

 ORSA strains showed resistance to mean

Tetracycline 16% 3.5 (median 3) additional drug classes
Gatifloxacin 24%
TMP-SMZ 26%
Gentamicin 36%
Clindamycin 79%
Ciprofloxacin 89%
Erythromycin 93%
0 20 40 60 80 100
MRSA with Co-Resistance

Diekema DJ et al. CID. 2001;32:S114-S132.

 Increasing Prevalence of ORSA in
S. aureus Bloodstream Infections

80 United States, S aureus isolates 1997

70 (N=4405)
1998
60 1999

% ORSA 50
40
30
20
10
0
Community Nosocomial

Diekema DJ et al. CID. 2001;32:S114-S132.

 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 ORSA 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 viral etiology
 Providing expensive, broad-spectrum agents that are
unnecessary
 Prescribing antibiotics at an improper dose or duration
 ANTIBIOTIC PRESCRIBING, CHILDREN

Diagnosis Office Visits Antibiotic Prescriptions % Total Antibiotic

(x1000) (x1000) 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 Antibiotic Prescriptions % Total Antibiotic

(x1000) (x1000) 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 5
Otitis 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%

Nyquist A-C, et al. JAMA 1998;279:875

Gonzoles R, et al. JAMA 1997;278:901
 Streptococcus Pneumoniae:
Regional Trends in Antibiotic Resistance

50 = regional range Beta-lactam

% Nonsusceptible

Macrolide
40
30
20
10
0
Conn.
Atlanta

Portland

San Fran.
Minneapolis
Metro
Baltimore

Tenn.
Region
Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC ‘98
 Streptococcus Pneumoniae:
Risk for Antibiotic Resistance is Greater with
Increased Outpatient Antibiotic Use

2.2
Controlled for region
2

1.8
Relative Risk

1.6
B-lactams
1.4 Macrolides
1.2

1
0-24 25-49 50-74 75-100 %
Antibiotic Use Quartile
Data: B. Schwartz, Emerging Infections Program, CDC; ICAAC ‘98
 Decreased Susceptibility of S. pneumoniae to
Fluoroquinolones in Canada:
Relationship of Resistance to Antibiotic Use

5 15 - 64 y.o 6 • Overall prevalence of

Susceptibility to Fluoroquinolones (%)

4.5 > 64 y.o FQRSP 1.0%

# of Prescriptions / 100 Persons

4 # of Rx/100 persons 5
S. pneumo. with Reduced

• No reduced susceptibility
3.5 4 in children
3 • FQRSP prevalence
2.5 3 higher in the elderly and in
2
2 Ontario
1.5
• Highest FQ use in the
1 1 elderly and in Ontario
0.5
0 0
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

Chen et. al., NEJM 1999;341:233-9

 ANTIBIOTICS FOR TREATMENT OF
RESISTANT GRAM POSITIVE COCCI

 “Old” therapy
 Glycopeptide class: Vancomycin (IV)
 Quinolone class: Levofloxacin, moxifloxacin, gatifloxacin (IV, PO)
(pneumococcus only)
 “New” therapy
 Oxazolidone class: Linezolid (IV, PO)
 Cyclic lipopeptide class: Daptomycin (IV)
 Streptogramin class: Quinupristin/dalfopristin (IV)
 Ketolide class: Telithromycin (PO)
 TREATMENT OF ORSA AND OTHER ANTIBIOTIC-
RESISTANT GRAM POSITIVE COCCI

MRSA MRSE VRE VRE DR-SP

Antibiotic E. facium E. faecalis
Ciprofloxacin (IV/PO) 0 0 0 0 0 to +
Levoflloxacin (IV/PO) 0 0 0 0 ++
Vancomycin (IV) ++ ++ 0 0 ++
Linezolid (IV/PO) ++ ++ ++ ++ ++
Daptomycin (IV) ++ ++ ++ ++ ++
Quinupristin-dalfopristin (IV) ++ ++ ++ 0 ++
Telithromycin (PO) ? ? ? ? ++
++ Drug covers >90% isolates, + drug covers 50-90% of isolates,
0 drug covers <50% of isolates
 TREATMENT OF ORSA: ORAL THERAPY

 Oral regimens (use only after susceptibility testing)

 Linezolid (expensive)
 Quinolone
 Clindamycin (use only if erythromycin susceptible)
 Trimethoprim-sulfamethoxazole
 Minocycline plus rifampin
 Monitoring
 Daptomycin: CPK each week; stop if CPK >5x abnormal (symptomatic)
or >10x abnormal (asymptomatic)
 Linezolid: CBC with platelets each week
 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 1995

Admissions 37,700,000 35,900,000
Patient-days 299,000,000 190,000,000
Average length of stay 7.9 5.3
Inpatient surgical procedures 18,300,000 13,300,000
Nosocomial infections 2,100,000 1,900,000
Incidence of nosocomial infections 7.2 9.8
(Number per 1000 patient-days)
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

KEY NOSOCOMIAL PATHOGENS
 National Nosocomial Infections Surveillance
(NNIS) Report: ICU Infections 1986 - 1997
60
CoNS*
S. aureus

Percent
40
Enterococcus
C. albicans
20 Enterobacter
Other
0
Bloodstream Infection

60
P. aeruginosa
60
Enterococcus
Percent

Percent
S. aureus CoNS*
40 40
Enterobacter S. aureus
K. pneumoniae P. aeruginosa
20 H. influenzae 20 Enterobacter
Other Other
0 0
Pneumonia Surgical Site Infection

*CoNS = coagulase-negative staphylococci CDC. Am J Infect Control. 1997;25:477-487.

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
(95% CI)
PA Catherization (1.01-1.43)
CVP Line (1.16-1.57)
Stress Ulcer Prophylaxis (1.20-1.60)
Urinary Catherization (1.19-1.69)
Mechanical Ventilation (1.51-2.03)
Trauma on Admission (1.75-2.44)

0 0.5 1 1.5 2 2.5

Odds Ratio
RISK FACTORS FOR ICU ACQUIRED INFECTIONS
(95% CI)
1-2 (1.56-4.13)
3-4 (5.51-14.70)
Length of Stay, d

5-6 (9.33-24.14)

7-13 (19.43-48.67)
14-20 (37.90-96.25)
>21 (48.18-120.06)

0 10 20 30 40 50 60 70 80
Odds Ratio
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)
Change in
1997–2001 (± sd) Jan–Dec 2002 resistance (%)
Vancomycin/Enterococci +11
Methicillin/S. aureus +13
Methicillin/CNS +1
3rd Ceph/E. coli +14
3rd Ceph/K. pneumoniae –2
Imipenem/P. aeruginosa +32
Quinolone/P. aeruginosa +27
3rd Ceph/P. aeruginosa +22
3rd Ceph/Enterobacter spp. –5
0 10 20 30 40 50 60 70 80 90
Ceph = cephalosporin; Resistance (%)
NNIS = National Nosocomial Infections NNIS. Am J Infect
Surveillance System; CNS = coagulase-negative staphylococci Control 2003;31:481–98
 ENTEROCOCCAL RESISTANCE

Intrinsic Resistance Acquired

 Semisynthetic penicillins  Aminoglycosides (High Level)
 Cephalosporins  Chloramphenicol
 Clindamycin  Erythromycin
 Trimethoprim-Sulfamethoxazole  Penicillin
 Monobactams  Tetracycline
 Aminoglycosides  Vancomycin and Teicoplanin
 Carbapenems (E. faecium)  Linezolid
 Synercid
 Increasing VRE Over Time
14
12 Vancomycin
Introduced
10
8 C. difficile
6 described

0
58 70 75 80 85 89 90 91 92 93 94
FY97

% VRE in ICU % VRE Non-ICU

 “PROBLEM” GRAM-NEGATIVE PATHOGENS

 P. aeruginosa
 ESBL-producing GNR
 E. coli
 Klebsiella
pneumoniae
 Enterobacter spp.

 Acinetobacter spp.
 Stenotrophomonas maltophila
 P. AERUGINOSA SUSCEPTIBILITY
US, 1999 (SENTRY)
Imipenem
Meropenem
Piperacillin
Cefepime
Ceftazidime
Ciprofloxacin
Tobramycin
Amikacin

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0
%
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 Third-generation
cephalosporins
1965 1970s 1980s 1983 1987 2001

TEM-1 TEM-1 ESBL in ESBL >150 ESBLs

1963 E. coli Reported in Europe in worldwide
S. paratyphi 28 gram-negative United
species States
 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

Cef3-Enterobacter

Carbapenem-Klebsiella

Cef3-Klebsiella
ICU
Cef3-E. coli
Non-ICU Inpatient
Quinolone-E. coli

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%

% Resistant
CDC. AJIC 2003;31:881-98.
 ACINETOBACTER SUSCEPTIBILITY
US & CANADA, 1997-1999 (SENTRY)
Amikacin
Tobramycin
Gentamicin
Ciprofloxacin All isolates
Cefepime
Nosocomial
Ceftazidime isolates
Pip/Tazo
Ticar/Clav
Meropenem
Imipenem

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%
Gales AC, et al. Clin Infect Dis 2001;32(Suppl 2):S104-113
 STENOTROPHOMONAS RESISTANCE
US, 1997-1999 (SENTRY)
TMP-SMX

Ticar/clav

Pip/tazo

Ceftazidime

Amikacin

Tobramycin

Ciprofloxacin

Gatifloxacin

Tetracycline

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%
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

ICU (NNIS, 1989-99): Primary Bloodstream Infection

Black bar = pooled percentage resistance during hospitalization

Open bars <7 days hospitalization Closed bars >7 days hospitalization
ICU (NNIS, 1989-99): Ventilator-Associated Pneumonia

Black bar = pooled percentage resistance during hospitalization

Open bars <7 days hospitalization Closed bars >7 days hospitalization
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 Group 2 Group 3 Group 4
(n=22) (n=12) (n=17) (n=84)
MV < 7 MV < 7 MV  7 MV  7
ABT = no ABT = yes ABT = no 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
 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

50 ORSA
OSSA
40

30 P<.001
% Mortality

36%

29% P<.001
20
23%
10
12%
0
1980–2000* 1990–2000†
n=3963 n=2209
*Cosgrove SE et al. CID. 2003;36:53-59. †Whitby M et al. MJA. 2001;175:264-267.
EXCESS MORTALITY ASSOCIATED WITH VRE

50% p<0.001 VRE

37% VSE
40%

30%
% Mortality

16%
20%

10%

0%

CDC. MMWR 1993;42:597-599

 FAILURE OF CEPHALOSPORINS (by MIC) WITH
ESBL+ E. coli AND K. pneumoniae BACTEREMIA
% (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)

• 54% (15/28) failure when organism susceptible

• 100% failure when organism intermediate

Modified from Paterson DL et al. J Clin Microbiol. 2001;39:2206-2212.

WHY ANTIBIOTICS ARE USED
AND OVERUSED
 IMPACT OF ANTIMICROBIALS

60 Inadequate Therapy n = 169

Adequate Therapy n = 486
50

40
Hospital
Mortality 30
%
20

10

0
All Cause Infection-related

Kollef Chest 115:462, 1999

 HAP: The Importance of Initial Empiric
Antibiotic Selection
Adequate init. antibiotic Inadequate init. antibiotic

90 81
80
70 63 61.4
% mortality

60
50 41.5
38
40 33.3
30 24.7
20 16.2
10
0
Alvarez-Lerma Rello Luna Kollef

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

ESBL
MRSA VRE K. pneumoniae

Infection Antibiotic
Control Control
 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 )
4.5
4
3.5
3
Log Reduction

2.5
2
1.5
1
0.5
0
-0.5 Episode 1 Episode 3 Episode 5 Episode 7 Episode 10

60% Ethyl Alcohol (N=5) 61% Ethyl Alcohol (N=5)

62% Ethyl Alcohol (N=5)
70% Ethyl Alcohol/0.005% Silver Iodide (N=5)
0.5% PCMX/40% SD Alcohol (N=5)
2% Chlorhexidine Gluconate (N=5)
1% Triclosan (N=5)
Non-antimicrobial Control (N=5)
61% Ethyl Alcohol/1% CHG (N=5)
0.4% Benzalkonium Chloride (N=5)
0.75% Chlorhexidine Gluconate (N=5)
4% Chlorhexidine Gluconate (N=5)
0.2% Benzethonium Chloride (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
 ANTIMICROBIAL STEWARDSHIP:
GOALS
 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
 PRSP: Interventions to Improve Antimicrobial Use
Rural Alaska Villages

Intervention Control
 Studied children <5 yrs old,
30

3400 persons
20

 3 rural regions: 1 study

% Change
10

2 control
 Educational intervention to
0

parents and providers on

-30 -20 -10

judicious antibiotic use in

study region
Rx’s Resp PNSP PRSP  Focused on respiratory tract
visits NP carriage
infections
Peterson, ICCAC, 1999
 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 antibiotics beyond what is needed
 Avoid prophylactic antibiotics unless benefit demonstrated
 For surgical prophylaxis provide only a single dose
(intraoperative doses may be indicated for prolonged surgery)
 Use the narrowest spectrum agent available
 RISK STRATIFICATION HIGH RISK PTS WITH SERIOUS
INFECTIONS
•Prior Tx with ABX while in Hospital
•Hospital-Acquired Pneumonia
•Prolonged LOS
•Bloodstream infections
•Presence of In-Dwelling Device

Specimens
for Culture Select Appropriate Empiric Therapy
•Pseudomonas aeruginsoa
•Acinetobacter spp.
•Methicillin-resistant Staphylococcus aureus

-Lactam
+
Aminoglycoside
or
Fluoroquinolone
+
Vancomycin
or
Linezolid
Clinical Re-assessment Microbiological Data

Modify Regimen as Necessary

 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)
Correlation Between Consumption of Imipenem and
Resistance of P. aeruginosa

Lepper PM, et al. Antimicrob Agents Chemother. 2002;46:2920-2925.

 Relationship Between Imipenem Consumption and New Patients
Colonized or Infected with Acinetobacter baumannii

DDD = Defined daily doses of.

Reprinted from Corbella X, et al. J Clin Microbiol. 2000;38:4086-4095.

 Strategies to Reduce ESBLs
Year Author Agent Reduction in Replacement Intervention
Ceph Use Agent Successful
(Yes/No)
1993 Meyer CTZ 73% I/C Yes
1996 Rice CTZ 50% P/T Yes

1998 Pena 3GC 83% P/T Yes

I/C
1998 Rahal All 80% I/C Yes
Cephs
1999 Landman CTX 89% A/S Yes
CTZ 66% P/T
2000 Patterson CTZ Hosp. A-71% P/T Yes
Hosp. B-27%

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.
 Antimicrobial Stewardship
Computer-assisted Order Entry

 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.

IMHS: Evans et. al.; NEJM 1998

 Antimicrobial Stewardship
Computer-assisted Order Entry (n=545)
Post-intervention
Outcome Study Group Non-Study Group Pre-intervention
Allergy orders 35 146
Excess dosages 87 405
Days of excess dosage 2.7 5.9
Susceptibility Mismatch 12 206
28
Adverse Events 4
Cost of agents $102 $427 $340
Total Hospital Costs $26,315 $44,865 $35,238
Length of Hospital Stay 10.0 days 16.7 days 12.9 days
IMHS: Evans et. al.; NEJM 1998
 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.