Mortality and Delay in effective therapy associated with Extended-Spectrum

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Mortality and Delay in effective therapy
associated with Extended-Spectrum ß-Lactamase
production in Enterobacteriaceae bacteraemia a
systematic review and meta-analysis

• Mitchell J. Schwaber and Yehuda Carmeli
• Journal of Antimicrobial Chemotherapy (2007) 60,
  913920
• Presented by Dr. Toh Han Siong
• Supervised by Dr. Wen-Liang Yu
• 21 January 2008

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IntroductionESBL-producing Enterobacteriaceae

• 1990s ESBL-E. coli K. pneumoniae ? 7 of
  infections in hospital
• 2003 20 of pathogenic K. pneumoniae in US ICU
  resistant to third-generation cephalosporins
• Associated with high proportions of resistance to
  non-b-lactam classes of antibiotics as well
• Impact of antimicrobial resistance on patient
  outcomes ?
• Schwaber et al, Antimicrob Agents Chemother 2006
• Outcomes of ESBL- vs non-ESBL- Enterobacteriaceae
  bacteraemia
• ESBL production independent predictor of
  mortality, length of stay, delay in institution
  of appropriate therapy cost

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IntroductionDetection / Treatment / Control

• Confirmation of ESBL presence by the clinical
  microbiology laboratory remains expensive and
  labour-intensive and is no longer mandatory per
  European Committee on Antimicrobial
  Susceptibility Testing (EUCAST) guidelines
• Treatment options for ESBL-associated infection
  are limited and often withheld from empirical
  use.
• Extensive infection control resources are
  required to contain ESBL spread, which is
  generally plasmid-mediated.
• Published literature on outcomes of ESBL
  infections is sparse, and without consistent
  conclusions.
• SYSTEMIC REVIEW META-ANALYSIS
• Association of ESBL production, delay in
  effective therapy mortality

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Methods

• Literature search PubMed database through to 30
  April 2006
• bacteremia or bloodstream ESBL or
  extended-spectrum beta-lactamase
• Mortality of ESBL-associated Enterobacteriaceae
  bloodstream infection
• Only published articles were included
• Comparing mortality of ESBL- non-ESBL
  Enterobacteriaceae bacteraemia
• Statistical analyses MORTALITY DELAY IN
  EFFECTIVE THERAPY
• Stata software, version 7 (Stata Corporation,
  College Station, TX, USA)
• Relative risk (RR) 95 CI for mortality using
  crude numbers reported
• Subgroup meta-analyses Asian vs non-Asian
  studies pediatrics studies
• Q statistic heterogeneity among study result
• P lt 0.1 significant heterogeneity
• DerSimonian Laird random effects model pooled
  estimate of RR 95 CI
• Bias was assessed via funnel plot and Beggs test

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Data Collected

• Location and years of the study
• Age range of the population studied
• Number of ESBL bacteraemia included Number who
  died
• Number of non-ESBL bacteraemia included Number
  who died
• Adjusted OR 95 CIs for mortality associated
  with ESBL
• Percentage of patients for whom there was a delay
  of effective therapy

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16 of 111 studies met inclusion criteria ?
META-ANALYSIS 19962003, 11 countries, large
acute care hospitals 4 studies included
paediatric patients exclusively
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Only 1 reported an OR for mortality after
adjustment by multivariable analysis. Meta-analysi
s therefore assessed only the pooled unadjusted
RR for mortality
Significantly increased mortality in
ESBL-associated bacteraemia (Pooled RR 1.85, 95
CI 1.392.47, P lt 0.001)
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Results

• Organisms K. pneumoniae E. coli
• 2 included Proteus spp.
• 1 included salmonellae
• 1 included a number of species of
  Enterobacteriaceae
• Significant heterogeneity among study results (P
  0.001)
• Publication bias was not found (P 0.45)
• Comparison of pooled crude RR similar results
• 6 Asian vs 10 non-Asian 1.61 vs 2.00
• 4 pediatrics vs 12 adult or mixed populations
  2.19 vs 1.74

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10 included studies provided comparative data on
delay in effective therapy Significant
association between ESBL production and
delay (pooled crude RR 5.56, 95 CI 2.9410.51, P
lt 0.001) Significant heterogeneity was present (P
lt 0.001)
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Discussion

• ESBL production is responsible for adverse
  outcomes in invasive infection
• Half of studies did not yield a significantly
  increased RR for mortality
• Almost all existing studies do not provide
  adjusted results
• Our study
• 2-fold increase in mortality associated with ESBL
  production
• gt 5-fold increase in the proportion of patients
  with delayed institution of effective therapy in
  the ESBL group
• We could not prove that this increased mortality
  is directly attributable to ESBL production
• Lack of consensus regarding effect of ESBLs on
  mortality
• SMALL sample sizes ? lack of sufficient
  statistical power

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Discussion Enterobacteriaceae bacteraemia

• Even with susceptible pathogens, is not benign
• Pooled crude mortality of 20 among the non-ESBL
  patients
• Pooled crude mortality of 34 among the ESBL
  patients
• Sample size required to detect a significant
  association 342
• 171 ESBL patients 171 non-ESBL patients
• 80 power, an a level of 5 a ratio of 11
  between groups
• Many of the included studies had much smaller
  sample sizes
• Not surprising that while only about half of the
  studies showed a significant association between
  ESBL presence and mortality

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Discussion

• Plausible explanations for increased mortality in
  ESBL bacteraemia
• Delay in institution of effective therapy
• Strong association between ESBL production and
  such a delay
• Risk factor for mortality in serious infections
• Not all apparently appropriate therapies are
  equally effective
• Variability in outcomes has been noted even
  according to the class of agent used, with
  carbapenems the most reliable class for treatment
  of ESBL infections
• Enhanced virulence among ESBL-producing pathogens
  
• One virulence mechanism shown to be present
  preferentially in ESBL producers is serum
  resistance
• Other not-yet-elucidated virulence factors

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Limitation

• LACK of adjusted outcomes analyses
• ONLY on crude mortality not on attributable
  mortality, or causality
• Available literature does not permit a
  meta-analysis of adjusted mortality
• Other adverse outcomes NOT explored in our
  analysis
• Increased length of hospital stay increased
  costs
• Additional published studies regarding these
  outcomes, as well as further multivariable
  analyses of mortality delayed effective
  therapy, will permit future meta-analyses to
  provide a more complete picture regarding the
  extent of the effect of ESBLs on patient
  outcomes.
• Additional studies will be required in order to
  distinguish differences in outcome generated by
  heterogeneity in such factors as study
  population, type of infection, ICU stay,
  treatment regimens, and species and type of ESBL
  causing infection.

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Increased risk of death of delay in effective
therapy associated with ESBL bacteraemia
As we await further studies to expand our
knowledge in this area, we would be well advised
to invest the resources necessary to control and
reduce the burden of ESBLs in the hospital
setting, as well as to develop diagnostic
therapeutic strategies to ensure timely and
effective treatment for infections caused by
ESBL-producing pathogens