Notes for IDWeek 2016 Day 1

These notes will be disorganized and may be riddled with typos…. typing in real time during talks on my wife’s iPAD. I will hit the upload button periodically as I go so this page will change as the day goes on.

Vancomycin Concentration Monitoring

• meta analysis shows know mortality difference between high and low troughs (except microbiologic)
• possibly not a great surrogate marker
• “We can’t get there from here” 2011 only MIC of 0.5 really showed actual hit of the AUC/MIC ratio, not for MIC >1
• You can hit MIC of 1 with 15-20 but not as soon as the MIC is over
• insane variability of AUC with the same trough
• trough is not serving as a good surrogate marker
• Should we instead monitor for AUC?
  • two meta analysis showed it does relate to failure
  • Etest vs BMD, variability in finding AUC
  • Estimatino of AUC from Dose/Clearance of vanco, formula is not that great
• IDSA guidlines don’t care about MIC < 2 anyway, change based on pt response
• Chasing troughs is a slow way to get things therapeutic
• one paper looked at aiming higher AUC/MIC for “high risk” based on the source of bacteremia
• new studies shows the ratio you amin for is based on initial bacerial load (For SA)
• troughs important for predicting nephrotoxicity (similar for any trough < 20, around or less than 15%)
  • reversible
• can probably push through and continue with vanco despite new nephrotoxicty (shown by a paper in 2012) to avoid new expensive agents
• AUC/MIC is best if AUC <= 1.5, ranges based on MIC test differences
  • min tox by trough < 20 and AUC<800
• current weight/RF based dose nomograms are not ideal
• Bayesian EStimation of AUC0-24 - uses computer, it works… lots of papers
  • Can simplify with equation based models

Key points

• 24 hr AUC/MIC of 400 do not correlate to troughs of 15-20
• can use troughs for nephrotoxicity but AUC may still be better
• two vanco concentrations drawn in the first 24-48 hrs (before steady state) used with Bayesian may be a better dosing method for vancomycin
• This data is strictly representing bacteremia

Daptomycin Dose Selection; PK/PD Considerations

• Manufacturer dosing is 4 or 6mg/kg but IDSA recommends 8-10 depending on indication
  • Case studies and cohort studies that long term high dose is well tolerated
  • Concerns about risk of CPK elevation
• I haven’t grown up much since finishing pharmacy school because I still find “C-Min” funny when said out loud
• Interesting studies looking at PK/PD data as a predictor of various outcomes with high dosing
• Simulated data showed up to 10% improvement in clinical reponse with higher dose, esp with more severe infections
  • Also predict higher probabilities of CPK elevation but need to consider clinical context (high risk infection vs reversable CPK elevation)
• Pts likely to benefit: loner durations, complex infections with multiple risk factors, higher baseline MIc values
• Thoughts that going with higher dose may reduce resistance longterm
• Obesity: Cmax and AUC are 60% higher in morbidly obese patients, but looking at data, clearance doesn’t change too much
  • Still not enough data. Manufacturer recommends actual body weight

Under Dosing of Antibiotics in the ICU - A PK/PD Approach

• Very few dose validation studies for critically ill patients
• keyboard battery might be needing of a charge, so these notes could go downhill very quickly if I have to use the onscreen keyboard
• many factors in critical illness (organ dysfunction, fluid balance etc) that can affect dosing and lead to suboptimal therapy
• major factor for altered PK is CrCl - ICU patients have higher CrCl (like 200?) aka “Augmented Renal Clearance”
• often critically ill patients are subject to bugs with decreased susc eg German study showing ICU vs ward (meropenem 8x MIC!). Very important when you factor in that all abx efficacy are measured compared to MIC
• Speaker suggests TDM for all abx, if it were possible
  • No RCT has shown a mortality benefit from TDM, unfort
  • Emerging data (RCTs in preparation) looking at TDM for beta-lactams
  • in absence of TDM, dosing nomogram more specific to ICU pts will still be better than standardized dosing
• Continuous infusion beta-lactams can eliminate the PK differences

Under and Overdosing in Obesity

• Obesity isn’t just a problem in America. More obese than underweight humans in the world right now
• 1/3 individuals in the US
  • based on BMI, currently obesity is defined as >30 globally
• In pharmacy we rely instead on IBW (20-30% above). Originally based on insurance tables (?). Based on height
• Adipose tissue concentrations may or may not reflect other organs
• Organs change size with obesity but can this correlate to clearance effect changes?
• This talk is making me feel pretty chubby
• We have data on how drugs distribute but not where
• CYP 2E1 is the only pathway shown to change consistently in obesity. Unfort not many drugs actually clear via this
• Abx have wide range of estimates Vd
  • may not increase proportionally with body size but we often assume that it does
• if Volume increases but clearance doesn’t, Initial concentrations are lower but t1/2 increases so you may need a loading dose but not higher maintenance dose
• Clearance does not increase proportionately, a 2x size person may have 1.5 x clearance
  • if clearance increased but volume dose not, lower AUC -> would need higher dose
• Higher chance of OD with weight based, higher chance of underdose with fixed dose
• Original body surface area equations came by locking dogs in boxes and starving them and measuring the heat their body gave off as they shrank
• We use some cutoff of 0.65 to decide which drugs are fixed and which are weight based but I didn’t understand what this number meant
• Polymixin B
  • still not really sure
  • a well designed study is underway (due 2020)
  • high doses (>250mg) don’t make sense because you don’t expense clearance to incrase. - many other drugs with this profile would just use a fixed dose rather than weight based
  • paradoxical relationship between exposure and resistance (^ exposure = ^ resistance)
• Dapto
  • Vd did not change much with obesity, neither was clearance so might be questionable as to why we’re dosing it based on body weight…
• Does the paradoxical relationship thing apply to other drugs too? (wasn’t clear)
• Clearance of levaquin correlates very strongly with creatinine clearance
  • ONe studies showed that with very CrCl, should be using super high levaquin doses (like 1500mg)
• TBW may be useful for loading dose in obesity but not for maintenance dose

Opening Plenary - Looking Back, Moving Forwards

Combating Antimicrobial Resistance

presented by the head of the CDC

• 23000 deaths in US from ressistant bacteria (>2 mill illnesses) + 15000 from c diff
• Need to work together with other health care facilities, huge interconnected network
• CDC really wants ASPs, you guys
• Insanely cool data tracking for stewardship in the US
• Lifetime achievement award for Dr Baker who invented GBS screening in pregnant women! super cool.