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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. Beyond the Target Pathogen: Ecological Effects of the Hospital Formulary. - PowerPoint PPT Presentation
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Ellie J.C. Goldstein, MD, FIDSAClinical Professor of MedicineDavid Geffen School of Medicine at UCLADirector, R.M. Alden Research LaboratorySanta Monica, California
Beyond the Target Pathogen: Ecological Effects of the Hospital Formulary
Antimicrobial Stewardship and Infection Control Programs: Meeting New Challenges
Needed: Antibiotic StewardshipCourtesy of Gary Doern, PhD
Survival of the Fittest
Charles Darwin
Antibiotics and Gram-negative Organisms
Beta lactamasesBeta lactamases(hydrolyzing enzymes)(hydrolyzing enzymes)OmpFOmpF
OmpCOmpC
Penicillin-binding proteinsPenicillin-binding proteins
PB1bPB1bPBP3PBP3PBP1aPBP1aPBP2PBP2
CephalosporinsCephalosporinsSlower diffusion due to bulk Slower diffusion due to bulk and ionic chargesand ionic charges
ImipenemImipenemRapid diffusion due to small size Rapid diffusion due to small size and zwitterionic +/- chargeand zwitterionic +/- charge
Resistant Organisms 2010:When One is Targeted,
What is the Effect on the Non-Targets?
Current Issues• MRSA Vancomycin MIC creep• VRE• ESBL Increasing prevalence• P. aeruginosa Pan-resistance• Acinetobacter Pan-resistanceFuture• E. coli Integrons• Enterobacteriaceae• K. pneumoniae
carbapenemase (KPC)• ?
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
Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-345.
• 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
Courtesy of Sherwood Gorbach, MD
The Diversity of the Fecal Flora
CFU=colony-forming unit
Microbial Populations Within the Human Gastrointestinal Tract
1.0–3.0 Log10 CFU/g
3.0–5.0 Log10 CFU/g
10.0–12.0 Log10 CFU/g
Lactobacilli
StreptococciLactobacilli
Enterobacteriaceae
Aerobic+
AnaerobicMicrobial
Populations
Oral Cavity
RectumEdmiston CE, Jr, et al. Infect Dis Clin Pract. 1996;5(suppl 1):S16.
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
LuxlLuxl
AHLAHL
Genes Genes xyzxyz
Quorum Sensing in Gram-negative Bacteria
LuxI – Enzymes that produce AHL (acyl homoserine lactone) autoinducer proteins (AIP)
LuxR – binds AIP, then activates promoter segment of target gene
Federle MJ, Bassler BL. J Clin Investig. 2003;112:1291-1299.
• Advanced age• Hypoalbuminemia• Co-morbidities• Immunosuppression
Clinical Aspects of C. difficile Infection
During antibiotic (abx) therapy (usually after 4-5 days) 80%
Post-Abx therapy(usually within 4 weeks) 20%
No Abx therapy Rare
Time until onset
Risk Factors
C. difficile acquisition
Antimicrobial(s)
Hospitalization
Current Pathogenesis Model for C. difficile Infection (CDI)
C. difficile acquisition
Courtesy of Dale Gerding, MD
AsymptomaticC. difficile
colonization
CDI
Acquisition of a toxigenic strain of Acquisition of a toxigenic strain of C. difficileC. difficile and failure to mount and failure to mount an anamnestic Toxin A IgG antibody response results in CDIan anamnestic Toxin A IgG antibody response results in CDI
Loo VG, et al. N Engl J Med. 2005;353:2442-2449.
* 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
Age Number of Cases
Number of Cases/ 1000 Admissions*
Attributable 30-Day Mortality Rate
(%)**<40 76 3.5 2.6
41-50 85 11.2 1.251-60 191 20.0 3.261-70 272 24.4 5.171-80 523 38.3 6.281-90 458 54.5 10.2>90 114 74.4 14.0
Age-Specific Incidence and Mortality Attributed to Clostridium difficile-Associated Diarrhea
C. difficile acquisition
Antimicrobial(s)
Hospitalization
Current Pathogenesis Model for C. difficile Infection (CDI)
C. difficile acquisition
Courtesy of Dale Gerding, MD.
CDI
1. Keep 1. Keep patients out patients out
of the hospitalof the hospital
2. Barrier precautions 2. Barrier precautions and environmental and environmental
cleaningcleaning
3. Stop unnecessary 3. Stop unnecessary antimicrobial useantimicrobial use
4. 4. Restore flora Restore flora or or colonize with non-colonize with non-toxigenic toxigenic C. difficileC. difficile
5. Bolster immunity 5. Bolster immunity with vaccines or passive with vaccines or passive
antibody strategiesantibody strategies
6. Antibiotic 6. Antibiotic Rx vs non-Rx vs non-
antibiotic Rxantibiotic Rx
AsymptomaticC. difficile
colonization
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)
Forest Plot of 25 Randomized, Controlled Studies of Probiotics for Prevention of AAD and Pooled
Risk RatiosStudy 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, 2002Overall
0.020877 1Risk ratio
47.8984Favors probiotic Favors placebo
McFarland LV. Anaerobe. 2009;15:274–280.
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
Adapted from Dela Pena AS, et al. J Gastrointest Surg 2006;10:567–574.
OASIS = Optimizing Intra-Abdominal Surgery with INVANZ Studies
OASIS I Therapy Resistant Enterobacteriaceae Subanalysis
DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis. 2005;24:443-449.
Baseline End of Therapy 2 Weeks Post Therapy
Ertapenem
0
2
4
14
6
8
10
12
Perc
ent
162
0
133
0
155
0
Resistant ESBL Producers Resistant ESBL Producers155
0.6
162
0.6
133
0.8
160
0.6
156
12.2
133
4.5
160
0.6
133
0.8
156
2.6
Piperacillin/Tazobactam
n=
OASIS I VRE Subanalysis: Minimal Risk of Colonization with VRE
Adapted from DiNubile MJ, et al. Diagn Microbiol Infect Dis. 2007;58:491-494.
Ertapenem(n=37)
Piperacillin/Tazobactam(n=42)
Patie
nts
With
VRE
, %
0
2
10
4
6
8
0 0
2.7 2.4
Baseline 2 Weeks Post TherapyVRE = vancomycin-resistant Enterococci
Adapted from DiNubile MJ, et al. Eur J Clin Microbiol Infect Dis 2005;24:443–449.
Ertapenem Ceftriaxone/Metronidazole
OASIS II Therapy Resistant Enterobacteriaceae Subanalysis
0
Perc
ent
0.5 0 0
Resistant ESBL Producers Resistant ESBL Producers
0.5
4.02.2 2.6
17.1
22.4
2.1
17.2
201 182 196196 201 182 195 193 174 195 174193
9.3
25
5
10
15
20
n=
Baseline End of Therapy 2 Weeks Post Therapy
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
USA 3-5%
Latin America 45%
Europe9-54%
Russia40-90%
Africa>20%
China34-38%
India 30–80%
TaiwanPhilippinesSingapore
>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 CenterSanta 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 Gram-negative Rods After 3 Years on Formulary
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
DesignDesign Retrospective analysis of hospital susceptibility data from June 2002 to December
SettingSetting 344-bed community teaching hospital in Santa Monica, California, US
MethodsMethods In vitro susceptibilities of gram-negative rods to formulary antibiotics determined
PrimaryPrimary endpointendpoint
Susceptibility of gram-negative rods to imipenem, ertapenem, levofloxacin, cefepime, gentamicin, and piperacillin/tazobactam
Usage of Antibiotics:3 Years of Formulary Inclusion
DDD/1000 Patient DaysErtapenem 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.
0 50 100 150 200 250Imipenem
Ertapenem
Metronidazole
Pip/Tazo
Amp/Sulbactam
Cefoxitin
Clindamicin
Levofloxacin
Cefepime
Gentamicin
20022005
Prevalence of ESBLs: 3 Years of Formulary Inclusion
Ertapenem added
2002 2004 2005
Isol
ates
, %
0
1
2
3
5
7
Ertapenem auto substitution
6
4
2003
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
E. coli ESBLs
Klebsiella spp ESBLs
Susceptibility of P. aeruginosa: 3 Years of Formulary Inclusion
Quarter
TobramycinLevofloxacin Piperacillin/Tazobactam Imipenem Cefepime
TobramycinLevofloxacin Piperacillin/Tazobactam
0
25
50
75
100
125150
175
200
225
250
DD
D/1
000
Patie
nt D
ays
0.0
20.0
40.0
60.0
80.0
100.0
Susceptible, %
Bar = Doses Line = %s
20021
20022
20023
20024
20031
20032
20033
20034
20041
20042
20043
20044
20051
20052
20053
20054
Ertapenem added Ertapenem auto substitution
Imipenem Cefepime
Ertapenem
Goldstein EJ, et al. Antimicrob Agents Chemother. 2009;53:5122-5126.
Univariate ARIMA ModelFitted to the Usage Series
MonthSusceptibility P. aeruginosa Imipenem (%)
Min Max Mean MedianStandard
Error
Before Ertapenem added
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
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.
Mean Carbapenem Use and P. aeruginosa Susceptibility at 25 Hospitals during 6 Years of
EURECA
Ertapenem Other Carbapenems Susceptibility
Eagye KJ, Nicolau DP. Presented at 49th ICAAC Meeting, San Francisco, CA, September 2009.
0
5
10
15
20
25
1 2 3 4 5 6Study Year
707580859095100
Perc
ent
Use
Den
sity
Rati
o
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 lowers mortality• De-escalation lowers resistance• Tailored therapy 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
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