ESBL

Jasmin FauteuxMarch 29th 2012

PLC Intake

• 66 yo female with dysuria and pelvic pain

• Just returned from visit to Pakistan

• VS Normal

• Physical exam: Mild right CVA tenderness

• Seen 2d ago and given Cipro for UTI

UA: WBC-21-30 Nitrites +

E. Coli > 8 x 106

• Ampicillin R• Ceftriaxone R• Pip/tazo S• Cipro R• Nitrofurantoin S• TMP/SMX S

Disposition?

Goals

• Definition• Microbiology• Incidence• Risk factors• Morbidity• Management• Prevention

A new problem?

• 1940s: First β-lactamase in E. coli

• 1980s: Introduction of Cefotaxime in Europe

• 1984: First reported case of ESBL in France and Germany

• 1988: First case in US

Definitions

• Beta-lactams– Beta-lactam ring that inhibits cell wall synthesis– Penicillins, cephalosporins, carbapenems and

monobactams

• Beta-lactamase– Bacterial enzymes that open the beta-lactam ring,

inactivating the antibiotic– Currently over 600 β-lactamases

Extended spectrum β-lactamase

• Activity against oxyimino-cephalosporins (3rd generation) and monobactams but not the cephamycins

• Inhibition by beta-lactam inhibitors

• AmpC– Resitant to cephamycins and beta-lactam inhibitors

• Carbapenemase– Resistant to carbapenems

Extended spectrum β-lactamase

• Heterogeneous group

• Testing of various oxyimino-β-lactams required

Which bugs?

• All Gram-negative bacterias– Klebsiella species– E. coli– Pseudomonas– Acinetobacter– Burkholderia– Citrobacter– Enterobacter– Morganella– Proteus– Salmonella– Serratia– Shigella

Detection

• 2010 CLSI– New MIC criterias

– Correlates with clinical outcome

CLSI SensitivityESBL Cefotaxime Ceftriaxone Cefpodoxime Ceftazidime Cefepime

Se 99,2% 99,2% 98,3% 65,3% 11,9%

Sp 40,7% 41,5% 44,9% 55,9% 99,2%

AmpC Cefotaxime Ceftriaxone Cefpodoxime Ceftazidime Cefepime

Se 100% 100% 100% 84,6% 7,7%

Sp 34,6% 41% 32,1% 39,7% 100%

• Any gram-negative bacteria

• Resistance to a single 3rd generation cephalosporin

KlebsiellaE. Coli

12,8% 4,7% 26,6%

13,9%

35,5%26,3%

45,5%25,9%

33,8%32,4%

54,9%12,9%

Canada

ESBL Amp C Carbapenem R

E. Coli 4,4% *2,6%K. Pneumoniae 1,3%Pseudomonas 7,2% 5,6%

CANWARD 2008*CANWARD 2007-2009

Calgary E. coli

Molecular Epidemiology over an 11-Year Period (2000 to 2010) of Extended-Spectrum -Lactamase-Producing Escherichia coli Causing Bacteremia in a Centralized Canadian Region, Peirano et al, Journal of Clinical microbiology

Calgary E. Coli

• 2008-2010 Antibiograms– Sensitivity to Ceftriaxone

ACH PLC FMC RGH

E. Coli 93% 87% 90% 87%

Calgary K. pneumoniae

Molecular epidemiology of extended-spectrum-b-lactamase-producing Klebsiella pneumoniae over a 10 year period in Calgary, Canada, Peirano, G. Journal of Clinical Microbiology

Calgary Klebsiella

• 2008-2010 Antibiograms– Sensitivity to Ceftriaxone

ACH PLC FMC RGH

Klebsiella species 95% 94% 97% 98%

Calgary P. aeruginosa

• 2008-2010 Antibiograms

ACH PLC FMC RGH

Ceftazidime 93% 94% 87% 96%

Meropenem - 94% 91% 90%

RiskFactors

Colonization is the main risk factor

Carrier

-24-33% still colonized at 6mo-10-12% still colonized at 3+ years

Prior antibiotic use CONSISTENTLY increases your risk

• All antibiotics

• 3rd generation cephalosporins– Restriction of use caused reduction in ESBL infection

88% of healthy travelers returning from India were colonized with ESBL E.coli

KlebsiellaE. Coli

12,8% 4,7% 26,6%

13,9%

35,5%26,3%

45,5%25,9%

33,8%32,4%

54,9%12,9%

- Hospital stay and contact- Health care workers contact- Long term care

Instrumentation

• Central or arterial line• Urinary catheter• Mechanical ventilation• G/J-tube• Hemodialysis

• Severity of illness

• Comorbidities

• Low birth weight (NICU)

Who cares?

Hospital cost and length of stay roughly double

-OR for mortality = 2,35-Adjusted for sepsis severity and with appropriate initial therapy = 1,37

Inappropriate therapy increases mortality by 2-10 fold

Back to our patient…

Management

• High bacterial inoculum

• Uncomplicated UTI

Everything but uncomplicated UTI

• Carbapenems–Need to speak to ID– Ertapenem 1g IV q 24hrs– In patient vs outpatient

Serious bacterial infectionsTreatment

• Even with In Vitro susceptibility, we should not use:

– 3rd generation cephalosporins– 4th generation cephalosporins*– Cephamycins– Pip/tazo– Fluoroquinolones– Aminoglycosides

* Might change with 2010 CLSI, potential future therapy

What if…

Speak to ID-Amikacin-Tigecycline-Colistin

Uncomplicated UTI

• If sensitive-Nitrofurantoin - 5 days-Fosfomycin* - 3g PO once

-Fluroquinolones – May be considered

*Not available in Canada

Prevention

• Isolation of ESBL

• Responsible antibiotic use

• Avoiding unnecessary procedures

Contact Isolation

• Reduces incidence of ESBL by 55%

• In Calgary: - no isolation- no screening

Antibiotic stewardship

• Use of narrower spectrum antibiotics– Avoiding cephalosporins and fluroquinolones

• Minimizing days of therapy

Avoid unnecessary procedures

Carbapenem resistance

Carbapenem resistance

• Pseudomonas: 3,3%• A. Baumannii: 2,7%• E. Coli & Klebsiella: 0,1%

• Mortality:40-60%

• Contact ID & contact isolation

Thanks to• Dr. Michael Parkins

• Dr. Shawn Dowling

Thank you!

Bibliography (1/4)• Mandell, Douglas, and Bennett, Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed., 2010• Munoz-Price, Jacoby, “Extended spectrum beta lactamase”, Up to Date Online, Jan 20th 2012, http://www.uptodate.com/contents/extended-spectrum-

beta-lactamases?source=search_result&search=esbl&selectedTitle=1~39• Pitout JD, “Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices”, Drugs.

2010 Feb 12;70(3):313-3• Fraimow HS, Tsigrelis C, “Antimicrobial resistance in the intensive care unit: mechanisms, epidemiology, and management of specific resistant pathogens”,

Crit Care Clin. 2011 Jan;27(1):163-205• Dhillon R, Clark J, “ESBLs: A Clear and Present Danger?”, Crit Care Res Pract. 2012;2012:625170. Epub 2011 Jun 6.• Jacoby, Munoz-Price, “The new beta-lactamase”, N Engl J Med. 2005 Jan 27;352(4):380-91• Calgary Laboratory Services, “Antibiograms 2008-2010”• Peirano G, “Molecular epidemiology of extended-spectrum-b-lactamase-producing Klebsiella pneumoniae over a 10 year period in Calgary, Canada”, J

Antimicrob Chemother, Advanced Access published Feb 14th 2012• Zhanel et al., “Prevalence of Antimicrobial-Resistant Pathogens in Canadian Hospitals: Results of the Canadian Ward Surveillance Study (CANWARD 2008) ”,

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2010, p. 4684–4693• Peirano et al, “Molecular Epidemiology over an 11-Year Period (2000 to 2010) of Extended-Spectrum -Lactamase-Producing Escherichia coli Causing

Bacteremia in a Centralized Canadian Region``, J. Clin. Microbiol. 2012, 50(2):294.• Pitout et al, “Molecular Characteristics of Extended-Spectrum--Lactamase- Producing Escherichia coli Isolates Causing Bacteremia in the Calgary Health

Region from 2000 to 2007: Emergence of Clone ST131 as a Cause of Community-Acquired Infections“, Antimicrob. Agents Chemother. 2009, 53(7):2846.• Bertrand et al, “Antimicrobial Susceptibility Among Gram-Negative Isolates Collected From Intensive Care Units in North America, Europe, the Asia-Pacific

Rim, Latin America, the Middle East, and Africa Between 2004 and 2009 as Part of the Tigecycline Evaluation and Surveillance Trial“, Clinical Therapeutics, /Volume 34, Number 1, 2012

• Baquero et al, “In Vitro Susceptibilities of Aerobic and Facultatively Anaerobic Gram-Negative Bacilli Isolated from Patients with Intra-Abdominal Infections Worldwide: 2005 Results from Study for Monitoring Antimicrobial Resistance Trends (SMART) “, SURGICAL INFECTIONS, Volume 10, Number 2, 2009

• Polsfuss et al., “Comparison of European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI screening parameters for the detection of extended-spectrum β-lactamase production in clinical Enterobacteriaceae isolates “, J Antimicrob Chemother. 2012 Jan;67(1):159-66. Epub 2011 Oct 3.

• Rodriguez-Bano et al., “Impact of changes in CLSI and EUCAST breakpoints for susceptibility in bloodstream infections due to extended-spectrum β-lactamase-producing Escherichia coli.“, Clin Microbiol Infect. 2011 Sep 13. doi: 10.1111/j.1469-0691.2011.03673

• Matsumara et al., “Cefotaxime for the detection of extended-spectrum β-lactamase or plasmid-mediated AmpC β-lactamase and clinical characteristics of cefotaxime-non-susceptible Escherichia coli and Klebsiella pneumoniae bacteraemia.“, Eur J Clin Microbiol Infect Dis. 2011 Dec 31. [Epub ahead of print]

Bibliography (2/4)• Rodriguez-Bano et al., “Community-Onset Bacteremia Due to Extended-Spectrum b-Lactamase–Producing Escherichia coli: Risk Factors and Prognosis

“, Clin Infect Dis. 2010 Jan 1;50(1):40-8.• Rodriguez-Bano et al., “Epidemiology and clinical features of community-acquired, healthcare-associated and nosocomial bloodstream infections in

tertiary-care and community hospitals.”, Clin Microbiol Infect. 2010 Sep;16(9):1408-13.• Sang-Oh et al., “Reduced Use of Third Generation Cephalosporins Decreases the Acquisition of Extended‐ ‐Spectrum Beta Lactamase–Producing ‐

Klebsiella pneumoniae”, Control and Hospital Epidemiology, Vol. 25, No. 10 (October 2004), pp. 832-837• Huang et al., “Risk factors of nosocomial infection with extended-spectrum beta-lactamase-producing bacteria in a neonatal intensive care unit in

China.”, Infection. 2007 Oct;35(5):339-45. Epub 2007 Aug 25.• Otéo et al., “Extended-spectrum b-lactamase producing Escherichia coli: changing epidemiology and clinical impact”, Infection. 2007 Oct;35(5):339-45.

Epub 2007 Aug 25.• Harris et al., “Risk factors for colonization with extended-spectrum beta-lactamase-producing bacteria and intensive care unit admission.”, Emerg

Infect Dis. 2007 Aug;13(8):1144-9.• Kuster et al., “Risks factors for infections with extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae at a tertiary

care university hospital in Switzerland.”, Infection. 2010 Feb;38(1):33-40. Epub 2010 Jan 27.• Tangdén et al., “Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases: a

prospective study with Swedish volunteers.”, Antimicrob Agents Chemother. 2010 Sep;54(9):3564-8. Epub 2010 Jun 14.• Leung et al., “Prevalence and predictors of MRSA, ESBL, and VRE colonization in the ambulatory IBD population.”, J Crohns Colitis. 2012 Jan 9. [Epub

ahead of print] • Paterson et al., “International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production

in nosocomial Infections.”, Ann Intern Med. 2004 Jan 6;140(1):26-32• Pena et al., ” Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended-spectrum beta-lactamases.”,

Antimicrob Agents Chemother. 1998 Jan;42(1):53-8.• Lucet et al., “Outbreak of multiply resistant enterobacteriaceae in an intensive care unit: epidemiology and risk factors for acquisition.”, Clin Infect Dis.

1996 Mar;22(3):430-6.• Apisarthanarak et al., “Duration of Stool Colonization in Patients Infected with Extended-Spectrum b-Lactamase–Producing Escherichia coli and

Klebsiella pneumoniae “ , Clinical Infectious Diseases 2008; 46:1322–3 • Tham et al., “Duration of colonization with extended-spectrum beta-lactamaseproducing• Escherichia coli in patients with travellers ’ diarrhoea”, Scandinavian Journal of Infectious Diseases, 2012; Early Online, 1–5• Alsterlund et al., “Long-term carriage of extended-spectrum beta-lactamase-producing Escherichia coli”, Scandinavian Journal of Infectious Diseases,

2012; 44: 51–54 • Freeman et al., “Bloodstream infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae at a tertiary care hospital in New

Zealand: risk factors and outcomes.”, Int J Infect Dis. 2012 Mar 6. [Epub ahead of print]

Bibliography (3/4)• Ben-Avi et al., “Influx of extended-spectrum beta-lactamase-producing enterobacteriaceae into the hospital.”, Clin Infect Dis. 2006 Apr

1;42(7):925-34. Epub 2006 Feb 27.• Martins et al., “Endemic extended-spectrum beta-lactamase-producing Klebsiella pneumoniae at an intensive care unit: risk factors for

colonization and infection.”, Microb Drug Resist. 2006 Spring;12(1):50-8.• Skrlin et al., “Impact of ceftriaxone de-restriction on the occurrence of ESBL-positive bacterial strains and antibiotic consumption.”, J Chemother.

2011 Dec;23(6):341-4.• Tumbarello et al., “Costs of bloodstream infections caused by Escherichia coli and influence of extended-spectrum-beta-lactamase production and

inadequate initial antibiotic therapy.”, Antimicrob Agents Chemother. 2010 Oct;54(10):4085-91. Epub 2010 Jul 26.• Marchaim et al., “National multicenter study of predictors and outcomes of bacteremia upon hospital admission caused by Enterobacteriaceae

producing extended-spectrum beta-lactamases.”, Antimicrob Agents Chemother. 2010 Dec;54(12):5099-104. Epub 2010 Sep 13.• Tumbarello et al., “Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing

Enterobacteriaceae: importance of inadequate initial antimicrobial treatment.”, Antimicrob Agents Chemother. 2007 Jun;51(6):1987-94. Epub 2007 Mar 26.

• Wouter et al., “Effects of confounders and intermediates on the association of bacteraemia caused by extended-spectrum b-lactamase-producing Enterobacteriaceae and patient outcome: a meta-analysis”, J Antimicrob Chemother. 2012 Mar 5. [Epub ahead of print]

• Schwaber et al., “Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis.”, J Antimicrob Chemother. 2007 Nov;60(5):913-20. Epub 2007 Sep 11.

• Rottier et al., “Effects of confounders and intermediates on the association of bacteraemia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae and patient outcome: a meta-analysis.”, J Antimicrob Chemother. 2012 Mar 5. [Epub ahead of print]

• Park et al., “Clinical and Microbiologic Characteristics of Cephalosporin-Resistant Escherichia coli in Three Centers in the United States.”, Antimicrob Agents Chemother. 2012 Apr;56(4):1870-6. Epub 2012 Jan 30.

• Kanj et al., “Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, andMultidrug-Resistant Pseudomonas aeruginosa”, Mayo Clin Proc. 2011 Mar;86(3):250-9.

• Garau J, “Other antimicrobials of interest in the era of extended-spectrum b-lactamases: fosfomycin, nitrofurantoin and tigecycline``, Clin Microbiol Infect. 2008 Jan;14 Suppl 1:198-202.

• Meier et al., “Extended-spectrum b-lactamase-producing Gram-negative pathogens in community-acquired urinary tract infections:an increasing challenge for antimicrobial therapy”, Infection. 2011 Aug;39(4):333-40. Epub 2011 Jun 25.

Bibliography (4/4)• Éveillard et al., “Diffusion des entérobactéries productrices de β-lactamase à spectre élargi et évolution de leur incidence sur une

période de 16 mois dans un centre hospitalier universitaire”, Pathol Biol (Paris). 2001 Sep;49(7):515-21.• Lowe et al., “Disparity in infection control practices for multidrug-resistant Enterobacteriaceae.”, Am J Infect Control. 2012 Feb 21.

[Epub ahead of print]• Ofner-Agostini, “Infection control and antimicrobial restriction practices for antimicrobial-resistant organisms in Canadian tertiary care

hospitals.• Ofner-Agostini M, Varia M, Johnston L, Green K, Simor A, Amihod B, Bryce E, Henderson E, Stegenga J, Bergeron F; Canadian

Nosocomial Infection Surveillance Program, Gravel D.”, Am J Infect Control. 2007 Nov;35(9):563-8.• Thomas et al., “Radical reduction of cephalosporin use at a tertiary hospital• after educational antibiotic intervention during an outbreak of extended-spectrum b-lactamase-producing Klebsiella pneumoniae”, J

Antimicrob Chemother. 2011 May;66(5):1161-7. Epub 2011 Mar 4.• Matasaje et al., “Carbapenem-resistant Gram-negative bacilli in Canada 2009–10: results from the Canadian Nosocomial Infection

Surveillance Program (CNISP)”, J Antimicrob Chemother. 2012 Mar 7. [Epub ahead of print]• Baldwin et al., “Carbapenem resistance in Canada”, • Cordova er al., “[Clinical and epidemiological study of an outbreak of KPC-producing Klebsiella pneumoniae infection in Buenos Aires,

Argentina.]”, Enferm Infecc Microbiol Clin. 2012 Feb 15. [Epub ahead of print]