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Designs to determine the impact of Ab resistance

Designs to determine the impact of Ab resistance. How do we correctly measure the outcomes of antibiotic resistance?. Measuring impact of resistance -methodological issues :. Which study designs are appropriate? Case control vs. Cohort studies. what is the right control?

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Designs to determine the impact of Ab resistance

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  1. Designs to determine the impact of Ab resistance How do we correctly measure the outcomes of antibiotic resistance?

  2. Measuring impact of resistance -methodological issues : • Which study designs are appropriate? • Case control vs. Cohort studies. • what is the right control? • What are we measuring? • Confounders. What do we have to adjust for? • Defining the outcomes?

  3. Study designs used to define the impact of Ab resistance: • Descriptive studies • Case-control studies • Cohort studies • Meta-analysis • Mathematical models

  4. Descriptive studiesEmergence of MDR19A pneumococcal strain…Pichichero JAMA 2007 • What type of a study is this? • Prospective cohort study. • Cohort study: • A cohort – a group of people who share a common experience / condition • Compare exposure of interest and follow to measure outcomes in exposed vs. non-exposed.

  5. Emergence of MDR19A / Pichichero JAMA 2007 Trend in time: • More non-VT • More non-VT resistance • More total Sp resistance • More 19A among non-VT 211 tympanocentesis 9 19A strain 1816 AOM 375 AOM included 59 S. pneumonia

  6. Emergence of MDR19A / Pichichero JAMA 2007 • What are the bad outcomes of the resistant strain? • Can we determine that the bad outcome is a result of the resistance?

  7. 19A MDR S. pneumoniae; an emerging pathogen • Resistant to all FDA approved antibiotics (for AOM). • Susceptible only to FQ. • Caused bad outcomes (compared to what?) • But this is just a case series… • Can we conclude that the bad outcomes are related to it being resistant? • Can we conclude that due to the emergence of this MDR clone we will observe worse outcomes? • Yet, it is an important descriptive study.

  8. CA-MRSA with no identified predisposing risk / Herold et al. JAMA 1998 • Design: Retrospective review of medical records • Objective: To determine whether community-acquired MRSA infections in children with no identified predisposing risks are increasing and to define the spectrum of disease associated with MRSA isolation. • Case series and descriptive studies may be of great importance. • Controlled studies should follow.

  9. Study designs used to define the impact of Ab resistance: • Descriptive studies • Case-control studies • Cohort studies • Meta-analysis • Mathematical models

  10. Exposure Outcome Exposure Outcome Case-control / Cohort studiesconfusing terms Risk factors: Ward Time Time in hospital comorbidities Ab rx IC measures Resistance Health / economical outcomes Vs. Who?

  11. Resistant bacteria compared to what???what is the counterfactual? • The control group • Patients infected by resistant strains (cases)vs. susceptible strains (controls) • Assesses the independent impact of the acquisition of a resistance determinant. • Patients infected by resistant strains (cases)vs. patients w/o resistant strains (controls) • Assesses the burden of having resistant infection Two different questions! 70 MRSA MSSA 60 50 40 30 20 10 0 1a 2a 1b 2b

  12. Exposure Outcome Confounders Risk factors: Ward Time LOS Comorbidities Ab rx IC measures Resistance Health / economical outcomes

  13. VRE Mortality Very sick (comorbidities) Confounders: direction of bias they induce LOS / comorbidities • Bias towards worse outcome (away from the null) Time • Bias in either direction

  14. Which outcomes?Defining the outcomes • Mortality • Distinguish all cause mortality from disease-specific mortality • In-hospital vs. post-discharge mortality • Morbidity - more difficult to define • Clinical failure • Length of stay in hospital • Need for surgery • Economic outcomes (hospital costs vs. charges vs. resource used)

  15. Health & Economic outcomes of VRE / Carmeli Arch Inter Med 2002 • Design: Retrospective Matched cohort study • 233 cases of VRE infections • 647 controls matched by (randomly picked from the cohort): • Place (Hospital ward) • Time (calendar day) • Duration of hospital stay till infection

  16. Health & Economic outcomes of VRE / Carmeli Arch Inter Med 2002 • Outcomes • Mortality - ICU admission • LOS - Surgery • Hospital Costs - discharge to institution • To control for confounding: • Propensity score (RF for being VRE) • CVD, ID, DM, transplantation, MRSA, C. difficile, Ab Rx: 3rd cephalosporins

  17. Health & Economic outcomes of VRE / Carmeli Arch Inter Med 2002

  18. But they did not compare to VSE • What is the right control? • What does this tell us? • What would be the counterfactual of not having VRE?

  19. Study designs used to define the impact of Ab resistance: • Descriptive studies • Case-control studies • Cohort studies • Meta-analysis • Mathematical models

  20. Meta-analysis“an objective review of the literature” • A statistical method for combining information from independent studies to derive an overall estimate (a summary estimate). • Great appeal: response to treatments may vary among individuals and different studies • Main problems: • Publication bias • Varying quality of the studies • Are we not adding apples and oranges? Did all studies measure the outcome similarly? Did they adjust for the same confounders?

  21. Comparison of mortality associated with MRSA vs. MSSA / Cosgrove et al. CID 2002 • Included studies that did not exclude CA-MRSA. • Most studies did not adjust for LOS. • Subset of 11 studies with adjustment to LOS - no different results.

  22. Meta-analysis VRE vs. VSE /DiazGranados et al. CID 2005 • Limitations: • Most studies retrospective (leading to inaccurate/incomplete data) • Most studies in pre-linezolid, dalfopristin-quinupristin (Synercid) era (no appropriate treatment for VRE): external validity for the current environment? • Did not adjust for LOS, but only for comorbidities

  23. Meta-analysis PNSSP vs. PSSP CID 2006 Tleyjeh et al • Raised a lot of controversy. • In contrast to “conventional wisdom” • Same criticism: not all studies adjusted for confounding factors. • How was quality of the studies assessed? • Resistance & virulence not linked in PRSP

  24. Resistance & virulence not linked in PRSP • Concordant vs. non-concordant Rx. analysis resulted in same RR.

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