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