Extended-Spectrum ?-lactamases: Current situation, Diagnosis

1
Extended-Spectrum ?-lactamases Current
situation, Diagnosis Management

• Siriluck Anunnatsiri, MD
• Infectious Diseases Tropical Medicine
• Faculty of Medicine
• Khon Kaen University

2
Extended-spectrum ?-lactamases

• Mutant, plasmid-mediated ?-lactamases enzymes
  derived from amino acid substitutions in native
  ?-lactamases, particularly TEM-1, TEM-2, and
  SHV-1
• Their ability permit hydrolyze all penicillins,
  cephalosporins (except cephamycins), and
  monobactams
• Typically associated with multidrug resistance
  (fluoroquinolones, co-trimoxazole,
  aminoglycosides)

3
Extended-spectrum ?-lactamases

• Most commonly produced by Klebsiella spp.,
  Escherichia coli but can occur in other GNB,
  including Enterobacter, Salmonella, Proteus, and
  Citrobacter spp., Morganella morganii, Serratia
  marcescens, Shigella dysenteriae, Pseudomonas
  aeruginosa, and Burkholderia cepacia

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Major groups of ?-lactamases
Functional group Major subgroup Molecular class Functional group Inhibition by clavulanate
1 C Cephalosporinases, often chromosomal enzymes in GNB but may be plasmid-encoded, confer resistance to all classes of ?-lactams, except carbapenems (unless combine with porin change) -
2 2a A Penicillinases, confer resistance to all penicillins, primarily from Staphylococcus and enterococci
2 2b A Broad-spectrum ?-lactamases (penicillinases/cephalosporinases) , primarily from GNB.
2 2be A ESBLs, confer resistance to oxyimino-cephalosporins and monobactams.
2 2br A Inhibitor-resistant TEM (IRT) ?-lactamases - ( for tazobactam)
2 2c A Carbenicillin-hydrolyzing enzymes
Shah AA, et al. Research in Microbiology 2004
155 409-421.
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Major groups of ?-lactamases
Functional group Major subgroup Molecular class Functional group Inhibition by clavulanate
2 2d D Cloxacillin- (oxacillin)- hydrolyzing enzymes /-
2 2e A Cephalosporinases, confer resistance to monobactams
2 2f A Carbapenem-hydrolyzing enzymes with active site serine (serine based carbapenemases)
3 3a, 3b, 3c B Metallo-?-lactamases (zinc based carbapenemases), confer resistance to carbapenems and all ?-lactam classes, except monobactams. -
4 Miscellaneous unsequenced enzymes that do not fit into other groups -
Functional group classified by Bush-Jacoby-Medeiros. Molecular group classified by Ambler. Functional group classified by Bush-Jacoby-Medeiros. Molecular group classified by Ambler. Functional group classified by Bush-Jacoby-Medeiros. Molecular group classified by Ambler. Functional group classified by Bush-Jacoby-Medeiros. Molecular group classified by Ambler. Functional group classified by Bush-Jacoby-Medeiros. Molecular group classified by Ambler.
Shah AA, et al. Research in Microbiology 2004
155 409-421.
6
Selected ?-lactamases of gram-negative bacteria
?-lactamase Examples Substrates Inhibition by clavulanate Amblers class / Bushs class
Broad-spectrum TEM-1, TEM-2, SHV-1 Penicillin G, aminopenicillins, carboxypenicillins, piperacillin, narrow-spectrum cephalosporins A / 2b
Broad-spectrum OXA family Broad-spectrum group plus cloxacillin, methicillin, and oxacillin D / 2d
Extended-spectrum TEM family, SHV family Broad-spectrum group plus oxyimino-cephalosporins, and monobactam (aztreonam) A / 2be
Extended-spectrum CTX-M family Expanded-spectrum group plus, for some enzymes, cefepime A
Extended-spectrum OXA family Same as for CTX-M family D / 2d
Extended-spectrum Others (PER-1, PER-2, BES-1, GES/IBC family, SFO-1, TLA-1, VEB-1, VEB2) Same as for TEM family and SHV family A
, , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition.
Peterson DL. Am J Med 2006 119 (6 Suppl 1)S20-8.
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Selected ?-lactamases of gram-negative bacteria
?-lactamase Examples Substrates Inhibition by clavulanate Amblers class/ Bushs class
AmpC ACC-1, ACT-1, CFE-1, CMY family, DHA-2, FOX family, LAT family, MIR-1, MOX-1, MOX-2 Expanded-spectrum group plus cephamycins 0 C / 1
Carbapenemase IMP family, VIM family, GIM-1, SPM-1 (metallo-enzymes) Expanded-spectrum group plus cephamycins and carbapenems 0 B / 3
Carbapenemase KPC-1, KPC-2, KPC-3 Same as for IMP family, VIM family, GIM-1, and SPM-1 A / 2f
Carbapenemase OXA-23, OXA-24, OXA-25, OXA-26, OXA-27, OXA-40, OXA-48 Same as for IMP family, VIM family, GIM-1, and SPM-1 D / 2d
, , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition. , , and denote relative sensitivity to inhibition.
Peterson DL. Am J Med 2006 119 (6 Suppl 1)S20-8.
8
Major sources of extended-spectrum ?-lactamases
Type Major sources
TEM, SHV E. coli, K. pneumoniae
Cefotaxime hydrolyzing (CTX-M) S. Typhimurium, E. coli, K. pneumoniae
Oxacillin hydrolyzing (OXA) P. aeruginosa
PER-1 PER-2 P. aeruginosa, A. baumanii, S. Typhimurium S. Typhimurium
VEB-1 E. coli, P. aeruginosa
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Prevalence of ESBL-producing isolates in Europe
(1997-2004) and USA (1999-2004)
Europe
USA
Goossens H, Grabein B. Diagn Microbiol Infect Dis
2005 53 257-64.
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Distribution of ESBL in E. coli SMART, 2003,
IAI, Asia-Pacific Countries

lt48 hours
?48 hours
Paterson DL et al. J Antimicrob Chemother
200555965-73.
11
Distribution of ESBL in Klebsiella spp. SMART,
2003, IAI, Asia-Pacific Countries

lt48 hours
?48 hours
Paterson DL et al. J Antimicrob Chemother
200555965-73.
12
Prevalence of ESBL producing organisms 346
isolates of GNB, Siriraj Hospital, 2003
Chayakulkeeree M, et al. Southeast Asian J Trop
Med Public Health 2005 36 1503-9.
13
Prevalence of ESBL-producing organisms 2974
isolates of GNB, Srinagarind Hospital, 2005

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Risk factors associated with infection or
colonization with ESBL-producing pathogens

• Critically ill patients / Severely debilitated
  residents
• Prolonged hospital or ICU unit stay
• Invasive procedures
• indwelling catheter, central venous
  catheter, gastrostomy, tracheostomy,
  endotracheal or nasogastric tube
• Residency in long-term care facility
• Decubitus ulcer
• Total dependence on health care workers
• Prior antibiotic use in last 3 months
• Exposure to 2nd-3rd cephalosporins, aztreonam,
  penicillins, and quinolones
• Delayed appropriate therapy

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CLSI screening criteria for ESBLs in K.
pneumoniae, K. oxytoca, and E.coli
Antimicrobial agents Disk diffusion zone (mm) MIC (?/g/ml)
Cefpodoxime lt17 gt8
Ceftazidime lt22 gt2
Aztreonam lt27 gt2
Cefotaxime lt27 gt2
Ceftriaxone lt25 gt2
Stürenburg E, Mark D. J Infect 2003 47 273-95.
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Laboratory tests for ESBLs detection
Tests Method Presence of ESBLs if..
Double disk approximation or double disk synergy Disk of 3rd cephalosporin placed 30 mm from amoxicillin-clavulanic acid Enhanced inhibition
Combination disk Uses 2 disks of 3rd cephalosporin alone and combined with clavulanic acid An increase of gt5 mm in zone inhibition with use of the combination disk
Microdilution A broth containing 1 ?g/mL 3rd cephalosporin Presence of growth
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Laboratory tests for ESBLs detection
Tests Method Presence of ESBLs if..
MIC broth dilution MIC of 3rd cephalosporin alone and combined with clavulanic acid A decrease in the MIC of the combination of gt3 log2 dilutions
E-test (MIC ESBL strips) Two-sided strip containing ceftazidime on one side and ceftazidime-clavulanic acid on the other MIC ceftazidime gt 8 MIC combination Phantom zone
Automated instruments (e.g., Vitek) Measures MICs and compares the growth of bacteria in presence of ceftazidime vs. ceftazidime-clavulanic acid
Molecular (DNA probes, PCR, RFLP) Targets specific nucleotide sequences to detect different variants of TEM and SHV genes Targets specific nucleotide sequences to detect different variants of TEM and SHV genes
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Confirmatory tests for ESBL detection
Stürenburg E, Mark D. J Infect 2003 47 273-95.
20
Multi-drug resistance in ESBL-producing organisms
Chayakulkeeree M, et al. Southeast Asian J Trop
Med Public Health 2005 36 1503-9.
21
Resistance of ESBL-Producing E. coli and K.
pneumoniae 1,182 Isolates, Srinagarind Hospital,
Khon Kaen 2005

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Resistance of ESBL-Producing E. coli and K.
pneumoniae 1,182 Isolates, Srinagarind Hospital,
Khon Kaen 2005

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Inadequate antimicrobial treatment of infections
a risk factor for hospital mortality among
critically ill patients
Independent risk factors for hospital mortality
Risks Adjusted OR 95CI
Inadequate antimicrobial therapy 4.26 3.355.44
Acquired organ system derangements (1-organ increment) 3.25 2.98-3.54
Use of vasopressors 2.20 1.81-2.66
Underlying malignancy 1.81 1.44-2.27
APACHE II score 1.05 1.04-1.07
Increasing age (1-year increment) 1.02 1.01-1.03
Surgical patient 0.40 0.33-0.49
Kollef MH et al. Chest 1999 115 462-74.
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• Retrospective study, 32/187 (17) patients died
• Inadequate initial antimicrobial therapy (IIAT)
  was a risk factor for mortality
• OR 10.04, 95 CI (1.90-52.96)

• Risk factors for IIAT
• Infection with multidrug-resistant ESBLs (14.58
  1.91-111.36)
• Health care-acquired ESBLs infection (4.32
  1.49-12.54)

Arch Intern Med 20051651375-80.
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Outcome of cephalosporin treatment for serious
infections due to apparently susceptible
organisms producing ESBL
MIC (?g/mL) Patients, (n) Patients, (n)
MIC (?g/mL) Experienced failure of cephalosporin therapy Died of bacteremia within 14 Days
8 100 (6/6) 33 (2/6)
4 67 (2/3) 0 (0/3)
2 33 (1/3) 0 (0/3)
lt1 27 (3/11) 18 (2/11)
Total 54 (15/28)
MIC minimum inhibitory concentration Includes 5 patients with isolates for which MICs were recorded simply as 0.5 to 4 mg/L. MIC minimum inhibitory concentration Includes 5 patients with isolates for which MICs were recorded simply as 0.5 to 4 mg/L. MIC minimum inhibitory concentration Includes 5 patients with isolates for which MICs were recorded simply as 0.5 to 4 mg/L.
Peterson et al. J Clin Microbiol 2001 39
2206-12.
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Clinical implications of ESBL-producing
Klebsiella species and Escherichia coli on
cefepime effectiveness

• A retrospective, casecontrolled study
• None-urine source (80 from lung) of 10
  ESBL-cases 20 controls (non-ESBL) treated with
  cefepime (2 grams/day, adjusted for GFR)

Risk estimates for the effect of ESBL presence on cefepime outcomes Risk estimates for the effect of ESBL presence on cefepime outcomes
Variables OR (95CI)
Unsuccessful clinical response 9.7 (1.4-68.8)
Unsuccessful microbiological response 28.5 (2.6-306.6)
All-cause mortality 2.0 (0.396-10.1)
Infection-related mortality 4.7 (0.38-60.1)
Kotapati S, et al. J Infect 2005 51 211-7.
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High-dose cefepime as an alternative treatment
for infections caused by TEM-24 ESBL-producing
Enterobacter aerogenes in severely-ill patients

• Retrospective study
• Seriously-ill patients infected with
  ESBL-producing Enterobacter aerogenes, mostly
  TEM-24
• 21 treated with cefepime (6 grams/day) / 23
  treated with carbapenems (in combination with
  ciprofloxacin or amikacin)
• Cefepime Carbapenems P-value
• Clinical improvement 62 70 0.59
• Bacteriological eradication 14 22 0.76
• 30-day mortality rate 33 26 0.44
• Nevertheless, a statistically significant
  increase in failure to eradicate ESBL-producing
  E. aerogenes was observed as the MICs of cefepime
  rose (p0.017).

K. Goethaert et al. Clin Microbiol Infect 2006
12 56-62.
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Cefepime versus Imipenem-Cilastatin for Treatment
of Nosocomial Pneumonia in Intensive Care Unit
Patients a Multicenter, Evaluator-Blind,
Prospective, Randomized Study

• A randomized, evaluator-blind, multicenter tria
• Compared cefepime (6 g/day) vs.
  imipenem-cilastatin (2 g/day) for the treatment
  of nosocomial pneumonia in 281 intensive care
  unit patients.
• In subgroup analysis, therapy of pneumonia caused
  by an organism producing an extended
  spectrum-lactamase failed in 4 of 13 patients
  (31) in the cefepime group but in none of 10
  patients in the imipenem group.

Zanetti G, et al. Antimicrobe Agents Chemother
2003 47 3442-7.
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Bacteremia due to Klebsiella pneumoniae isolates
producing the TEM-52 extended-spectrum
?-lactamase treatment outcome of patients
receiving imipenem or ciprofloxacin

• Retrospective study
• ESBL (TEM-52) K. pneumoniae bacteremia,
  non-fatal disease
• 10 treated with imipenem / 7 treated with
  ciprofloxacin
• Ciprofloxacin Imipenem P-value
• Treatment failure 5/7 2/10 0.03
• 2/7 partial response
• Because the isolates had MICs of ciprofloxacin
  close to the susceptibility breakpoint, treatment
  failure could be ascribed to the inability of the
  drug to reach therapeutic concentrations at
  infected sites.

Endimiani et al. Clin Infect Dis 2004 38 243-51.
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• A prospective, observational study
• 12 centers, 455 episodes
• 18.7 with ESBL-K. pneumoniae

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Pharmacodynamics of intermittent infusion
piperacillin/tazobactam and cefepime against
ESBL-producing organisms

• ? Cefepime 1 gram q 12 hrs ? Pip/tazo 4.5
  grams q 8 hrs
• ? Cefepime 1 gram q 8 hrs ? Pip/tazo 3.375
  grams q 6 hrs
• ? Cefepime 2 gram q 12 hrs ? Pip/tazo 3.375
  grams q 4 hrs

Reese AM, et al. Int J Antimicrobe Agents 2005
26 114-9.
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Pharmacodynamics of continuous infusion
piperacillin/tazobactam and cefepime against
ESBL-producing organisms

• ? Cefepime 3 grams ? Pip/tazo 6.75 grams
• ? Cefepime 4 grams ? Pip/tazo 13.5 grams

Reese AM, et al. Int J Antimicrobe Agents 2005
26 114-9.
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Pharmacodynamics of levofloxacin, gatifloxacin,
and ciprofloxacin against ESBL-, and non-ESBL
producing organisms
Regimen Probability () of achieving a free AUC/MIC gt 125 Probability () of achieving a free AUC/MIC gt 125
Regimen Non-ESBL producers (n45) ESBL producers (n39)
Levofloxacin 500 mg q 24 hr 88 11
Levofloxacin 750 mg q 24 hr 91 13
Gatifloxacin 400 mg q 24 hr 85 8
Ciprofloxacin 400 mg q 12 hr 88 2
Moczygemba LR, et al. Clin Ther 2004 26 1800-7.
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Summary of 3rd-generation cephalosporins on
treatment of ESBL-producing organisms

• Clinical significance of inoculum effect
• Poor clinical outcomes are observed when
  3rd-generation cephalosporins are used for
  treatment
• Higher fatal outcome
• Higher rate of clinical failure
• 3rd-generation cephalosporins should not be used
  to treat serious infections with ESBL-producing
  organisms, even in the presence of apparent
  susceptibility.

Peterson et al. J Clin Microbiol 2001 39
2206-12. Ariffin H et al. Int J Infect Dis 2000
4 21-5. Wong-Beringer et al. Clin Infect Dis
2002 34 135-46.
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Summary of 4th-generation cephalosporins on
treatment of ESBL-producing organisms

• More stable than 3rd-generation cephalosporins
  againt some ESBLs and very stable against
  AmpC-type ?-lactamases
• Inoculum effect, susceptible to SHV-type
• Need high dosage (gt 4 grams/day) of cefepime for
  achieving the TgtMIC target, preferably in
  combination with aminoglycoside for synergistic
  effect
• Cefepime should not be used to treat serious
  infections with ESBL-producing organisms.

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Summary of ?-lactam/?-lactamase inhibitor on
treatment of ESBL-producing organisms

• Limited clinical information
• Class A ESBLs are susceptible to clavulanate and
  tazobactam in vitro, nevertheless many producers
  are resistant to ?-lactamase inhibitor due to
• Hyperproduction of the ESBLs ? overwhelm
  inhibitor
• Co-production of inhibitor-resistant
  penicillinases (e.g. OXA-1) or AmpC enzyme
• Relative impermeability of the host strain
• ?-lactam/?-lactamase inhibitor should not be used
  to treat serious infections with ESBL-producing
  organisms.

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Summary of cephamycins on treatment of
ESBL-producing organisms

• Limited clinical data
• Generally effective against Enterobacteriaceae
  producing TEM-, SHV-, and CTX-M-derived ESBLs
• Cefotetan gt cefoxitin lower MICs
• Reports of cephamycins resistance development
  during prolonged therapy
• Loss of outer membrane porin (porin deficient
  mutant)
• Acquisition of plasmid-mediated AmpC ?-lactamase
  (ACT-1)

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Summary of treatment recommendations for
infections with ESBL producers
No treatment
Colonization with ESBL producers
Imipenem or meropenem
Bloodstream infection Ventilator-associated pneumonia Any producers that appear to have reduced susceptibility to ertapenem
Ertapenem
Complicated urinary tract infections Intra-abdominal infections Diabetic food infections
Quinolones
Infections in patients with risk for allergy to carbapenems, if isolates are susceptible
Nitrofurantoin or fosfomycin
Uncomplicated lower urinary tract infection
Tigecycline, colistin, or polymyxin B
Isolates resistant to all other antibiotic options Patients allergic to ?-lactams
Livermore DM, Peterson DL. ESBLs in resistance
2006.
39
Carbapenem classification
GROUP 1 Carbapenems (community acquired infections) GROUP 2 Carbapenems (hospital acquired infections pseudomonas activity) GROUP 3 Carbapenems (hospital acquired infections Pseudomonas and MRSA activity)
Ertapenem Imipenem Meropenem Doripenem Panipenem CS-023
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Dosage and Cost of Treatment in Patients with
ESBL-producing bacteria Infections
Dose / Day Cost / Unit (Baht) Cost / Day (Baht)
Ertapenem 1 gm OD 1,735.00 1,735.00
Imipenem/Cilastatin 0.5 gm q 6 hr 750.00 3,000.00
Meropenem 1 gm q 8 hr 1,390.00 4,170.00
Choice of Ertapenem can save cost of treatment
about 1,265-2,435 Baht in patients with
ESBL-producing bacteria infections.
?????????????????????????? ? ?????? 21 ????????
?.?. 2549
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Control of a Prolonged Outbreak of ESBL-Producing
Enterobacteriaceae in a University Hospital
Imported ESBL-cases ? Acquired ESBL-cases
Lucet JC, et al. Clin Infect Dis 1999
29 1411-8.
42
Class restriction of cephalosporin use to control
total cephalosporin resistance in nosocomial
Klebsiella
Kg drug/month 1995 1996
Total cephalosporins 3rd-generation cephalosporins Cefuroxime Cefotetan Cephazolin Imipenem No. cephalosporin-resistant Klebsiella No. imipenem-resistant Pseudomonas 5.6 0.78 2.2 1.5 1.4 0.2 150 67 1.1 0.39 0.19 0.06 0.44 0.47 84 113
P lt 0.01
Rahal JJ, et al. JAMA 1998 280 1233-7.
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OASIS I Bowel Colonization with resistant GNB
after antimicrobial therapy of IAI
Organism recovered from assessable patients a Ertapenem gr. Ertapenem gr. Ertapenem gr. Piperacillin/Tazobactam gr. Piperacillin/Tazobactam gr. Piperacillin/Tazobactam gr.
Organism recovered from assessable patients a Baseline (n 162) End of therapy (n 155) 2 weeks post- therapy (n 133) Baseline (n 160) End of therapy (n 156) 2 weeks post- therapy (n 133)
Piperacillin/Tazo-resistant Enterobacteriaceae, n () 1 (0.6) 2 (1.3) 3 (2.3) 1 (0.6) 19 (12.2) 6 (4.5)
Ertapenem-resistant Enterobacteriaceae, n () 0 (0) 1 (0.6) 0 (0) 0 (0) 3 (1.9) 0 (0.8)
ESBL-producing Enterobacteriaceae, n () 1 (0.6) 0 (0) 1 (0.8) 1 (0.6) 4 (2.6) 1 (0.8)
Imipenem-resistant P. aeruginosa, n () 0 (0) 0 (0) 0 (0) 2 (1.3) 2 (1.3) 0 (0)
Piperacillin/Tazo-resistant P. aeruginosa, n () 1 (0.6) 3 (1.9) 0 (0) 0 (0) 1 (0.6) 0 (0)
DiNubile MJ et al. Eur J Clin Microbiol Infect
Dis 2005 24 443-9.
44
OASIS II Bowel Colonization with resistant GNB
after antimicrobial therapy of IAI
Organism recovered from assessable patients a Ertapenem Ertapenem Ertapenem Ceftriaxone/Metronidazole Ceftriaxone/Metronidazole Ceftriaxone/Metronidazole
Organism recovered from assessable patients a Baseline (n 201) End of therapy (n 196) 2 weeks post- therapy (n 182) Baseline (n 195) End of therapy (n 193) 2 weeks post- therapy (n 174)
Ceftriaxone-resistant Enterobacteriaceae, n () 9 (4.5) 3 (1.5) 5 (2.7) 5 (2.6) 33 (17.1) 39 (22.4)
Ertapenem-resistant Enterobacteriaceae, n () 1 (0.5) 1 (0.5) 0 (0) 0 (0) 1 (0.5) 0 (0)
ESBL-producing Enterobacteriaceae, n () 8 (4.0) 0 (0) 4 (2.2) 4 (2.1) 18 (9.3) 30 (17.2)
Imipenem-resistant P. aeruginosa, n () 0 (0) 2 (1.0) 1 (0.5) 0 (0) 0 (0) 0 (0)
DiNubile MJ et al. Eur J Clin Microbiol Infect
Dis 2005 24 443-9.
45
OASIS I-II Bowel Colonization with resistant
GNB after antimicrobial therapy of IAI
ESBL-producing Enterobacteriaceae
DiNubile MJ et al. Eur J Clin Microbiol Infect
Dis 2005 24 443-9.
46
OASIS I-II Bowel Colonization with resistant
GNB after antimicrobial therapy of IAI
P. aeruginosa resistance
DiNubile MJ et al. Eur J Clin Microbiol Infect
Dis 2005 24 443-9.
47
Summary of interventions that could be used to
prevent problem with ESBL-producing bacteria in
hospitalized patients
Individual patient level
Avoid use of 3rd-generation cephalosporins, aztreonam, or cefuroxime Avoid unnecessary use of invasive devices Ensure good hand hygiene before and after patient-care activities
Institutional level
Restrict use of 3rd-generation cephalosporins Introduce contact isolation precautions for patients documented to have carriage or infection with ESBL-producing organisms Investigate envirinmental contamination if increased rates of ESBL-producing organisms occur
Livermore DM, Peterson DL. ESBLs in resistance
2006.
48
Take Home Messages

• ESBL-producing bacterial infection is an emerging
  problem worldwide.
• These organisms are associated with multi-drug
  resistance causing high rate of mortality and
  treatment failure.
• The significant risk factors for ESBL-producing
  bacterial infection are prior use of antibiotics,
  especially 3rd generation cephalosporins, and
  critically ill or debilitated patients.
• Need the ESBL-laboratory testing for establish
  the problem.
• Carbapenems is the drug of choice for serious
  ESBL-producing bacterial infection.
• Avoiding overuse or misuse of 3rd generation
  cephalosporins and implementing isolation and
  contact precaution to prevent and control the
  ESBL outbreak.

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Thank You for your attention