Catching-up with the Red Queen: Vancomycin MIC and clinical outcomes in severe MRSA infections

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Catching-up with the Red Queen Vancomycin MIC
and clinical outcomes in severe MRSA infections

• Carlos A. DiazGranados, MD, MS
• Assistant Professor of Medicine
• Emory University School of Medicine
• April 2, 2009

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Through the Looking-Glass, by Lewis Carroll
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The Red QueenThrough the Looking-Glass, by
Lewis CarrollChapter 2

• "Well, in our country," said Alice, still panting
  a little, "you'd generally get to somewhere else
  -- if you ran very fast for a long time, as we've
  been doing."
• "A slow sort of country!" said the Queen. "Now,
  here, you see, it takes all the running you can
  do, to keep in the same place..."

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The Red Queen Evolutionary Hypothesis

• "For an evolutionary system, continuing
  development is needed just in order to maintain
  its fitness relative to the systems it is
  co-evolving with.
• Leigh Van Valen, 1973

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Bugs vs. Humans?
2 Methicillin- resistant
Methicillin
35 Methicillin- resistant
Penicillin discovered
Penicillin clinical use
1996
1950
1928
1944
1956
1960
2003
Methicillin Resistance
1925
1950
1975
2000
50 SA Penicillin resistant
Vancomycin
Vancomycin- resistance
Intermediate Resistance to Vancomycin
Staphylococcus aureus
Sir Alexander Fleming
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one aspect of our current race with MRSA

• Possible poor clinical outcomes of patients with
  severe MRSA infections treated with Vancomycin
  when the MIC is close to the upper limit of the
  SUSCEPTIBLE range

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Clinical perception
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IDSA / ICAAC - 2008
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Studies exploring association of Vancomycin MIC
within the susceptible range and clinical
outcomes

• Different overall results (many positive, but
  some negative)
• Different effect sizes (some show large
  differences in outcomes, others minimal or null).
• Different outcomes (some mortality, others
  failure).
• Different patient populations (some mixed
  infections, others BSI only).
• Different laboratory methods (some Etest, some
  broth microdilution).

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High Vancomycin MIC and clinical outcomes in
Patients with Staphylococcus aureus infections

• Systematic Review with Meta-analysis

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Objectives

• To explore the association of high vancomycin MIC
  within the susceptible range with poor clinical
  outcomes (failure and mortality) in patients with
  MRSA infections.

Exposure
Outcomes
Population
High MIC
Failure
Patients with MRSA infections
Low MIC
Mortality
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Methods
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Definitions

• High MIC
• MIC 1 mg/L by broth microdilution (BMD)
• MIC 1.5 mg/L by Etest.
• Low MIC
• MIC lt 1 mg/L by BMD.
• MIC lt 1.5 mg/L by Etest.
• Failure
• Failureas defined by authors.
• If Failurenot defined or reported, then failure
  mortality.
• Mortality
• 30-day, 28-day, in-hospital.

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Study eligibility criteria Inclusion criteria

• Evaluating outcomes (failure or/and mortality) of
  patients with MRSA infections
• MIC testing methods for MRSA isolates BMD or
  Etest.
• Estimates of failure or mortality provided by
  authors according to high and low MICs
• (if estimates not provided in original
  paper/abstract/poster, authors were contacted in
  an effort to obtain missing data).

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Study eligibility criteria Exclusion criteria

• Studies that used Vitek or Microscan for
  categorization of high vs. low MIC.
• Studies that categorized isolates and patients at
  extreme ranges (less or equal than 0.5 vs. 2 or
  more).

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Search Strategy

• Sources
• Databases
• Medline
• Cochrane database of systematic reviews
• References of identified manuscripts.
• Grayliterature Abstracts IDSA meeting 2007 and
  Joint IDSA-ICAAC meeting 2008.
• Search terms - Methicillin resistance -
  Staphylococcal infections - Microbial
  sensitivity tests
• Conectors AND
• Limits HUMANS, ALL ADULTS and years 2000-2008.
• No language restrictions.

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Data Extraction and Analysis

• Two independent reviewers (CAD, JTJ).
• Differences between reviewers resolved by
  consensus.
• Publication bias assessed using Funnel Plot
• Heterogeneity assessed using heterogeneity test
  and I2 calculation.
• Individual study quality assessed by exploration
  of possible selection and misclassification bias.
  
• Sensitivity analysis performed.

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Sensitivity analysis

• Studies that reported failure in patients with
  MRSA BSI.
• Studies that reported mortality in patients with
  MRSA BSI.
• Studies that used Etest for MIC classification
  and reported mortality of patients with MRSA BSI.
  

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Statistics

• Revman software 4.2 (Cochrane collaboration)
• Fix-effect models and random-effects models
  (DerSimonian and Laird) were performed.

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Results
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Study selection process
Additionally, 8 studies presented At IDSA/ICAAC
were included.
13 studies included in meta-analysis
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Summary of included studies
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Overall findings

• N
• Failure assessment 1696
• Mortality assessment 1309
• n1 (High MIC group)
• Failure 1129
• Mortality 987
• n2 (Low MIC group)
• Failure 567
• Mortality 322

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Overall findings

• Failure rates
• High MIC 380/1129 33.7
• Low MIC 117/567 20.6
• Mortality rates
• High MIC 270/987 27.4
• Low MIC 49/322 15.2

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Heterogeneity tests

• p-value gt 0.1 for all analyses.
• I2 lt 50 for all analyses.
• Conclusion no significant heterogeneity.

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Assessment of Publication bias - Funnel plot
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Failure analysis OverallAll infections, all
methods
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Mortality analysis OverallAll infections, all
methods
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Sensitivity analysis for Failure BSI only
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Sensitivity analysis for Mortality BSI only
(all studies used Etest for classification)
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Conclusions

• In patients with MRSA infections, those with high
  Vancomycin MIC have a risk of failure and death
  1.7 times higher than those with lower Vancomycin
  MIC.
• Absolute risk of failure increases by about 13.
• Absolute risk of death increases by about 12.

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Limitations

• Quality of original studies
• Some had very small sample
• Most were retrospective
• Some risk for selection bias and
  misclassification of outcome

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So...what?
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Implications

• Therapy monitoring, dose, agent.
• Laboratory (antimicrobial susceptibility
  testing) cut-offs, methods.
• Research / Academia we need to look for answers.
  

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Therapy implications

• Monitoring and Dosing
• Agent Selection

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Monitoring and Dosing
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Monitoring recommendations IDSA/ASHP/SIDP 2009
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Monitoring recommendations IDSA/ASHP/SIDP 2009
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Dosing Recommendations IDSA/ASHP/SIDP 2009
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Agent Selection
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Agent Recommendations IDSA/ASHP/SIDP 2009
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Agent Recommendations IDSA/ASHP/SIDP 2009
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Implications for the laboratory (antimicrobial
susceptibility testing)

• How do different tests agree?
• Which test to use for clinical decisions?

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Sader et al. ICAAC/IDSA 2008, abstract D-2209.
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The one dilution dilemma...
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Clinically useful performance characteristics of
tests

• Sensitivity
• Specificity
• Kappa statistic

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Performance characteristics of automated
antimicrobial susceptibility methods to detect
isolates with Etest MIC 1.5 or more
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Inter-observer agreement for E-test MIC
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Implications for Research

• We need answers!

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Utopia MRSA therapy study

• Multicenter RCT in patients with suspected MRSA
  bacteremia.
• Strata Pneumonia, No Pneumonia
• Groups
• First Stratum Linezolid, Vanc1, Vanc2, Bactrim
• Second Stratum Daptomycin, Linezolid, Vanc1,
  Vanc2.
• Outcomes 30-day mortality, length of stay, need
  for ICU stay.

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Utopia MRSA therapy study

• Safety analysis include all enrolled patients.
• Efficacy analysis include all patients with MRSA
  bacteremia, and perform a subgroup analysis of
  patients with MRSA bacteremia and MIC of 1.5 or
  more.
• Problem sample size (approx. 270 per group,
  close to 1000 pts for efficacy analysis, possibly
  1200 pts with MRSA bacteremia and 10000-20000
  patients to be enrolled and included in safety
  analysis).

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Needed study MRSA MIC agreement

• Patients with MRSA BSI.
• MIC of isolates evaluated by different methods
  Etest (R1), Etest (R2), Microscan, Vitek,
  Phoenix.
• Large sample to improve precision.
• Ideally accompanied by outcome assessment.
• Sensitivity, specificity and kappa of non-Etest
  methods.

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Conclusions

• Patients with MRSA infections and high Vancomycin
  MIC by Etest or BMD seem to have worse clinical
  outcomes (clinical failure and mortality).
• Awaiting further studies, it is reasonable to use
  more aggressive Vancomycin dosing and therapeutic
  monitoring when treating serious MRSA infections.
  
• Use clinical judgment (persistence of clinical
  syndrome and positive cultures) and microbiology
  data (Etest MIC ?) to decide which patients may
  be candidates for alternative antimicrobial
  agents.
• Antimicrobial susceptibility testing has to
  evolve to assist clinicians in this difficult
  Red Queen race.
• We may need new automated panels that include
  multiple Vancomycin concentrations between 0.5
  and 2.
• We need studies exploring the utility of those
  panels in predicting Vancomycin therapy success
  or failure.

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Acknowledgements

• MIC agreement
• Angie Caliendo
• Eileen Burd
• Cindy McCloskey
• Henry M. Blumberg
• Susan Ray
• Carlos del Rio
• Wayne Wang
• Mark Shapiro
• Tamayo Barnes
• Anushay Ishtiaq
• Bianca Humphrey
• Xanthia Berry

• Meta-analysis
• Jesse Jacob (second reviewer)

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Presence of agr II polymorphisms?
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agr group II may be a different measure of the
same thing

• (Risk of decreased susceptibility to
  glycopeptides)