Download C. difficile

Beyond the Target Pathogen:
Ecological Effects of the Hospital Formulary
Ellie J.C. Goldstein, MD, FIDSA
Clinical Professor of Medicine
David Geffen School of Medicine at UCLA
Director, R.M. Alden Research Laboratory
Santa Monica, California
Antimicrobial Stewardship and Infection Control Programs: Meeting New Challenges
Survival of the Fittest
Charles Darwin
Needed: Antibiotic Stewardship
Courtesy of Gary Doern, PhD
Antibiotics and Gram-negative
Organisms
Imipenem
Cephalosporins
Slower diffusion due to bulk
and ionic charges
Rapid diffusion due to small size
and zwitterionic +/- charge
OmpF
OmpC
Beta lactamases
(hydrolyzing enzymes)
Penicillin-binding proteins
PBP2
PBP1a
PBP3
PB1b
Resistant Organisms 2010:
When One is Targeted,
What is the Effect on the Non-Targets?
Current
Issues
•
•
•
•
•
Vancomycin MIC creep
MRSA
VRE
ESBL
P. aeruginosa
Acinetobacter
Increasing prevalence
Pan-resistance
Pan-resistance
Future
• E. coli
• Enterobacteriaceae
• K. pneumoniae
carbapenemase (KPC)
• ?
Integrons
What is the Breakpoint
and What Does it Mean ?
• Susceptible - level of antimicrobial activity associated with a high
likelihood of therapeutic success
• Intermediate - activity of uncertain therapeutic effect
– Infection may be appropriately treated in body sites where the
drugs are concentrated OR when a high dosage of drug can be
used
– It also indicates a buffer zone that should prevent small,
uncontrolled, technical factors from causing major
discrepancies in interpretations
• Resistant - activity associated with a high likelihood of
therapeutic failure
• Wild type (WT) - absence of acquired and mutational resistance
mechanisms to the drug in question
• Non-wild type (NWT) - presence of an acquired or mutational
resistance mechanism to the drug in question
What is “Collateral Damage”?
• A movie?
• Resistant fecal flora?
• C. difficile infection?
• Resistant isolates?
– Gram positive?
– Gram negative?
• Industry spin?
• Whatever you want it to be?
Potential “Collateral Damage” From Use
of Cephalosporins and Quinolones
• Class of agent, pathogen(s) selected for:
– Third generation cephalosporins
• Vancomycin-resistant enterococci
• ESBL Klebsiella species
• Beta-lactam–resistant Acinetobacter species
• Clostridium difficile
– Quinolones
• MRSA
• Quinolone-resistant gram-negative bacilli, including
Pseudomonas aeruginosa
Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-345.
The Diversity of the Fecal Flora
Courtesy of Sherwood Gorbach, MD
Microbial Populations Within the Human
Gastrointestinal Tract
Oral Cavity
Lactobacilli
Streptococci
Lactobacilli
Enterobacteriaceae
Aerobic
+
Anaerobic
Microbial
Populations
CFU=colony-forming unit
Edmiston CE, Jr, et al. Infect Dis Clin Pract. 1996;5(suppl 1):S16.
1.0–3.0 Log10 CFU/g
3.0–5.0 Log10 CFU/g
10.0–12.0 Log10 CFU/g
Rectum
Quorum Sensing
• Organism releases small amount of autoinducer or
transcription activator [small molecules]
• Concentration increases as cell density increases
until a minimal threshold concentration triggers a
shift in gene expression
• Associated with competence, conjugation, virulence
– eg, proteases, biofilm formation, antibiotic formation,
motility, and sporulation
Quorum Sensing in
Gram-negative Bacteria
LuxI – Enzymes that produce
AHL (acyl homoserine
lactone) autoinducer proteins
(AIP)
AHL
Luxl
LuxR
Genes xyz
Federle MJ, Bassler BL. J Clin Investig. 2003;112:1291-1299.
LuxR – binds AIP, then
activates promoter segment
of target gene
Clinical Aspects of C. difficile Infection
Time until onset
During antibiotic (abx) therapy
(usually after 4-5 days)
Post-Abx therapy
(usually within 4 weeks)
No Abx therapy
Risk Factors
• Advanced age
• Hypoalbuminemia
• Co-morbidities
• Immunosuppression
80%
20%
Rare
Current Pathogenesis Model for
C. difficile Infection (CDI)
C. difficile
acquisition
Antimicrobial(s)
Hospitalization
C. difficile
acquisition
Asymptomatic
C. difficile
colonization
CDI
Acquisition of a toxigenic strain of C. difficile and failure to mount
an anamnestic Toxin A IgG antibody response results in CDI
Courtesy of Dale Gerding, MD
Age-Specific Incidence and Mortality Attributed to
Clostridium difficile-Associated Diarrhea
Age
Number of
Cases
Number of Cases/
1000 Admissions*
Attributable 30-Day
Mortality Rate
(%)**
<40
41-50
51-60
61-70
71-80
81-90
>90
76
85
191
272
523
458
114
3.5
11.2
20.0
24.4
38.3
54.5
74.4
2.6
1.2
3.2
5.1
6.2
10.2
14.0
* Values are based on 1719 episodes of nosocomial C. difficile-associated diarrhea
** Values are based on data from 1703 patients with nosocomial C. difficile-associated
diarrhea
Loo VG, et al. N Engl J Med. 2005;353:2442-2449.
Current Pathogenesis Model for
C. difficile Infection (CDI)
2. Barrier precautions and
environmental cleaning
C. difficile
acquisition
Antimicrobial(s)
Hospitalization
1. Keep patients
out of the hospital
Courtesy of Dale Gerding, MD.
3. Stop unnecessary
antimicrobial use
C. difficile
acquisition
4. Restore flora or
colonize with nontoxigenic C. difficile
5. Bolster immunity
with vaccines or passive
antibody strategies
Asymptomatic
C. difficile
colonization
CDI
6. Antibiotic Rx vs
non-antibiotic Rx
Forest Plot of 25 Randomized, Controlled Studies
of Probiotics for Prevention of AAD and Pooled
Risk Ratios
Study
Adam, 1977
Surawicz, 1989
McFarland, 1985
Kotowska, 2005
Lewis, 1998
Cremonini, 2002
Arovala, 1999
Vanderhoof, 1999
Szajewska, 2001
Thomas, 2001
Cremonini, 2002
Armuzzi, 2001
Nista, 2004
Orrhage, 1994
Seki, 2003
Wunderlich, 1989
Borgia, 1982
Witsell, 1995
Gotz, 1979
Tankanow, 1990
Orrhage, 1994
Cremonini, 2002
Correa, 2005
LaRosa, 2003
Jirapinyo, 2002
Overall
Risk Ratio (95% CI)
0.26 (0.13, 0.53)
0.43 (0.21, 0.90)
0.49 (0.21, 1.17)
0.19 (0.07, 0.55)
1.53 (0.54, 4.35)
0.16 (0.02, 1.21)
0.32 (0.09, 1.11)
0.29 (0.13, 0.63)
0.20 (0.06, 0.66)
0.98 (0.68, 1.42)
0.17 (0.02, 1.27)
0.13 (0.03, 0.52)
0.88 (0.50, 1.57)
0.57 (0.24, 1.35)
0.12 (0.05, 0.28)
0.32 (0.07, 1.41)
0.28 (0.11, 0.72)
1.25 (0.81, 1.94)
0.40 (0.12, 1.36)
0.96 (0.61, 1.50)
0.29 (0.08, 1.05)
0.17 (0.02, 1.27)
0.51 (0.21, 1.23)
0.48 (0.29, 0.77)
0.47 (0.18, 1.21)
0.43 (0.31, 0.58)
0.020877
Favors probiotic
McFarland LV. Anaerobe. 2009;15:274–280.
1
Risk ratio
Favors placebo
47.8984
Antibiotics and ESBL
K. pneumoniae Colonization in Mice
• Ceftriaxone promoted overgrowth
• Ertapenem suppressed colonization
– Excreted into GI tract
• Imipenem – no promotion nor suppression
– Minimal excretion into GI tract
• Piperacillin/Tazo promoted overgrowth
of resistant but not susceptible strains
Pultz MJ, Donskey CJ. Antimicrob Agents Chemother. 2007;51:3044-3045.
OASIS I
• Design
– Prospective, multicenter, randomized, open-label trial (OASIS I)
• Patients
– 370 hospitalized adults with intra-abdominal infections requiring
surgery
• Therapy
– Ertapenem 1 g once daily versus piperacillin/tazobactam 3.375 g every
6 hours or 4.5 g every 8 hours
• Primary endpoint
– Proportion of microbiologically evaluable patients with favorable
clinical and microbiologic assessments at test of cure 2 weeks
after completion of therapy
OASIS = Optimizing Intra-Abdominal Surgery with INVANZ Studies
Adapted from Dela Pena AS, et al. J Gastrointest Surg 2006;10:567–574.
OASIS I Therapy Resistant
Enterobacteriaceae Subanalysis
Ertapenem
14
Piperacillin/Tazobactam
12.2
12
Percent
10
8
6
4.5
4
2.6
2
0
0
n= 162
0.6
0
155
133
Resistant
Baseline
0.6
162
0
155
0.8
0.6
133
160
ESBL Producers
End of Therapy
DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis. 2005;24:443-449.
0.8
0.6
156
133
Resistant
160
156
133
ESBL Producers
2 Weeks Post Therapy
OASIS I VRE Subanalysis:
Minimal Risk of Colonization with VRE
Patients With VRE, %
10
8
6
4
2.4
2.7
2
0
0
0
Ertapenem
(n=37)
Piperacillin/Tazobactam
(n=42)
Baseline
VRE = vancomycin-resistant Enterococci
Adapted from DiNubile MJ, et al. Diagn Microbiol Infect Dis. 2007;58:491-494.
2 Weeks Post Therapy
OASIS II Therapy Resistant
Enterobacteriaceae Subanalysis
Ceftriaxone/Metronidazole
Ertapenem
25
22.4
20
17.2
Percent
17.1
15
9.3
10
4.0
5
0
n=
0.5
0.5
0
201
196
182
Resistant
Baseline
2.2
2.6
182
195
2.1
0
201
196
ESBL Producers
End of Therapy
193
174
Resistant
195
174
ESBL Producers
2 Weeks Post Therapy
Adapted from DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis 2005;24:443–449.
193
Tigecycline Fecal Concentrations,
mg/kg in 12 Healthy Subjects
Day 2
Day 5
Day 8
Day 10
Day 12
Day 15
Mean
4.7
5.0
6.0
4.1
2.4
0.1
SD
3.4
3.7
2.9
1.9
1.1
0.2
Median
4.5
3.5
5.6
3.7
2.8
0
Range
0-9.9
0-11.3
3-14.1
1.1-7.2
0.5-4.2
0-0.4
50 mg IV q 12 h x 10 days
Nord CE, et al. Antimicrob Agents Chemother. 2006;50:3375-3380.
Tigecycline Effect on Fecal Flora
By Day 8, 12 subjects
•
•
•
•
•
E. coli and enterococci reduced
Other enterobacteria and yeast increased
Lactobacilli and bifidobacteria decreased
Bacteroides no change
Resistance development [MIC ≥8 ug/ml]:
2 K. pneumoniae; 5 Enterobacter cloacae
Nord CE, et al. Antimicrob Agents Chemother. 2006;50:3375-3380.
Worldwide ESBL Prevalence
Europe
9-54%
Russia
40-90%
China
34-38%
USA
3-5%
Latin America
45%
India
30–80%
Africa
>20%
Taiwan
Philippines
Singapore
>20%
Effect of Ertapenem on the
Hospital Ecology
• Clinical Studies
–
–
–
–
–
Crank, 44th IDSA Annual meeting, Toronto, 2006. # 285.
Goff, J Infection. 2008;57:123-126.
Goldstein, AAC. 2009;53:5122-5126.
Carmeli, 47th ICAAC, Chicago, 2007. # K-396.
Eagye KJ, Nicolau DP, 49th ICAAC, San Francisco, 2009.
• Conclusions
– Use of ertapenem did not decrease susceptibilities of
Pseudomonas aeruginosa to carbapenems.
St Johns Health Center
Santa Monica, CA
• Community teaching
hospital
• 334 Licensed beds
• 200 Average daily census
• Active oncology ward
– 51 in-patient beds
– Research programs
• 32 ICU beds
• 32 Step-down beds
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Study of Susceptibility of Aerobic Gramnegative Rods After 3 Years on Formulary
Design
Retrospective analysis of hospital susceptibility data
from June 2002 to December
Setting
344-bed community teaching hospital in
Santa Monica, California, US
Methods
In vitro susceptibilities of gram-negative rods
to formulary antibiotics determined
Primary
endpoint
Susceptibility of gram-negative rods to imipenem,
ertapenem, levofloxacin, cefepime, gentamicin, and
piperacillin/tazobactam
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Usage of Antibiotics:
3 Years of Formulary Inclusion
Gentamicin
Cefepime
Levofloxacin
Clindamicin
Cefoxitin
Amp/Sulbactam
Pip/Tazo
Metronidazole
Ertapenem
2002
2005
Imipenem
DDD/1000 Patient Days 0
50
100
150
200
250
Ertapenem was added to formulary in 2002, and in 2003 an auto-substitution policy was established
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Prevalence of ESBLs:
3 Years of Formulary Inclusion
7
Isolates, %
6
Klebsiella spp ESBLs
5
4
3
2
E. coli ESBLs
1
0
2002
Ertapenem
added
2003
2004
Ertapenem auto
substitution
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
2005
Susceptibility of P. aeruginosa:
3 Years of Formulary Inclusion
Bar = Doses Line = %s
100.0
225
200
80.0
175
150
125
60.0
100
40.0
75
50
Susceptible, %
DDD/1000 Patient Days
250
20.0
25
0
0.0
2002
1
2002
2
Ertapenem added
2002
3
2002
4
2003
1
2003
2
2003
3
2003
4
2004
1
2004
2
2004
3
2004
4
2005
1
2005
2
2005
3
2005
4
Ertapenem auto substitution
Quarter
Levofloxacin
Piperacillin/Tazobactam
Imipenem
Cefepime
Tobramycin
Levofloxacin
Piperacillin/Tazobactam
Imipenem
Cefepime
Tobramycin
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Ertapenem
Univariate ARIMA Model
Fitted to the Usage Series
Susceptibility P. aeruginosa Imipenem (%)
Month
Min
Max
Mean
Median
Standard
Error
0-9
60.00
81.00
70.00
69.0
2.69
After Ertapenem was added,
Before the substitution
10-20
63.00
91.00
77.00
77.00
2.90
After the substitution
21-48
67.00
100.00
87.86
89.0
1.62
Before Ertapenem added
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Conclusions: Susceptibility
• No change in the susceptibility patterns of E. coli, P. mirabilis,
K. pneumoniae, K. oxytoca, Enterobacter species isolates to
imipenem since the inclusion of ertapenem on formulary
[100% susceptible to imipenem, ertapenem]
• P. aeruginosa improved activity of imipenem (0.38%) for every
unit decrease in DDD of imipenem usage (P=.008)
– Levofloxacin, cefepime and pip-tazo susceptibilities
improved
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Ertapenem Utilization and Resistance Emergence
among Collateral Antimicrobials (EURECA)
• Study Period:
– 3 year prior & 3 years after
ertapenem adoption
• Data Sources:
– USE: Commercial database
(Premier, Inc., Charlotte, NC)
– SUSCEPTIBILITY: Individual (25)
hospital antibiograms
• Antimicrobial use collected for:
– Ertapenem and other
carbapenems
– Aminoglycosides
– Fluoroquinolones
– Other Beta-lactams
• P. aeruginosa susceptibility:
– Combined %S of meropenem
and imipenem used for analysis
• Evaluation of drug use:
– Total grams & patient days
extracted from database
– DDDs as determined by WHO
– Use Density Ratio (UDR)
calculated for ertapenem plus
each antimicrobial class
• Statistical Analysis:
– GLM using repeated
measures ANOVA
– Dependent variable: 6-year
repeated carbapenem %S
– Explanatory variable:
ertapenem UDR in each year
– Controlled for UDR of other
carbapenems or other classes
Eagye KJ, Nicolau DP. Presented at 49th ICAAC Meeting, San Francisco, CA, September 2009.
Use Density Ratio
25
20
15
10
5
0
1
2
Ertapenem
3
4
Study Year
Other Carbapenems
5
6
Susceptibility
Eagye KJ, Nicolau DP. Presented at 49th ICAAC Meeting, San Francisco, CA, September 2009.
100
95
90
85
80
75
70
Percent
Mean Carbapenem Use and P. aeruginosa
Susceptibility at 25 Hospitals during 6 Years of EURECA
Association Between Antibiotic Use and
Resistance
• Decreasing susceptibility trends over time were not
statistically associated with the primary drug
– eg, organism susceptibility rate to imipenem with
imipenem usage
• Secondary drug use was associated with susceptibility rates
– eg, susceptibility of E. coli to cefepime with pip/tazo usage
• Conclusions: These results suggest that antibiotic use resistance relationships are influenced by the use of
secondary antibiotics. Thus, a resistance problem may not be
adequately addressed by simply altering the utilization of the
primary antibiotic.
Bosso J, et al. Presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting. Washington, DC, October 25-28, 2008.
Beyond the Target Pathogen
Collateral Benefits vs. Collateral Damage
• Initial aggressive therapy
• De-escalation
• Tailored therapy
lowers mortality
lowers resistance
lowers resistance
• Fecal Flora Changes and Colonization
– Resistant organism proliferation
– Transmission/outbreak due to inadvertent contact
• C. difficile infection
• Effects on non-target organisms
– Collateral resistance
– Integrons
– ESBLs
– P. aeruginosa