CameronForbes.org

MedPage Today Roundup

2017-05-12T00:00:00+00:00

Trying out a new post type. I keep track of a few days of interesting links from MedPage Today emails (they have great summaries!) in a draft post and jot down a few notes for each. Then, when there’s a reasonable number of links, I’ll publish the post.

FDA Okays Antioxidant Drug for ALS

edaravone (Radicava) approved in the US, works to relieve oxidative stress caused by ALS
- reduces blood vessel and neuron injury
- leads to reduced decline of daily functioning
- may only work for mildly symptomatic patients
has been approved (for brain damage prevention post stroke) since 2002 in Japan
IV infusion only, risk for allergic reaction, complicated dosing schedule.

Most Docs Make Wrong Choices in Stopping PPIs

Simulation-based survey found that docs would continue PPIs in low risk (bleed) patients but discontinue in high risk patients
We should be discontinuing PPIs in more low risk patients given that they are not nearly as innocuous as we once thought
This makes sense to what I’ve seen in practice - trying to stop PPIs in patients at risk of c diff recurrence. The hardest part is figuring out why they were on the PPI in the first place!

AACE: Iron Indices Tied to HbA1c in Poorly Controlled T2D

Not much data yet. Elevated iron indicies (e.g., serum iron & ferritin) are associated to poorly controlled type two diabetes.

AACE: GLP-1 Receptor Agonist Successful Tx for T1D

Liraglutide reduced HbA1c by 0.29% vs placebo in type 1 diabetes patients, based on a systemic review and meta-analysis
Also found reduction in insulin dose requirements
Surpringly fast effect (within 3 months)

“The group suggested these findings may be attributed to the reduction in post-prandial glucagon surge following appetite suppression induced by liraglutide, due to the lack of functioning beta cells in those with type 1 diabetes.”

Eating Raw Meat Tied to Toxoplasmosis in Japan

Found that raw meat had a much higher association with toxo in pregnancy than did scooping cat litter
- Unfortunately for guys with cats and pregnant wives, the guy should still definitely be scooping the cat litter. But the risk is probably far less than what most people think
People in the region studies routinely eat raw horse meat and raw chicken meat. UGH

One in Three Newly Approved Drugs Has Safety Issues

Looked at drugs approved between 2001 and 2010, and found 32% had post-market safety issues
Lead to 3 market removals and 61 black box warnings
Only so much you can do with the number of participants in clinical trials
Very important to fill out those Health Canada Vigilance Reports!

Quinine for Leg Cramps Tied to Increased Death Risk

Quinine for muscle cramps or restless legs can lead to 3-fold increase in risk of death… in patients under age 50
- less risk in older adults
- higher doses increased risk
Not that effective to begin with
Were unable to factor out unmeasured confounders, so it might not be because of the quinine
They are also worried about daily consumption of Gin and Tonic. Thankfully no evidence against it though. (one would imagine the alcohol would be the more concerning part!)

Antibiotics in Palliative Care

2017-05-12T00:00:00+00:00

The issue comes up a lot lately on Stewardship rounds regarding antibiotics in palliative/”comfort-only” care. Often we see orders like “discontinue all medications, except IV antibiotics”. This is often a difficult and controversial topic with very little evidence behind it. There main arguments in favour of keeping antibiotics are for non life-threatining infections, where the infection will not shorten lifespan, but treating will help as a symptom management. This argument is backed, for example, by this paper: Antibiotic Treatment in End-of-Life Cancer Patients—A Retrospective Observational Study at a Palliative Care Center in Sweden (cancers, 2016). Here they found that antibiotics helped symptoms in 37% of patients, and had minimal adverse events. The discussion section of the paper also has an excellent literature review showing many papers that agree and ones that disagree.

This paper is a bit older, and looks more at longer term palliation. Survival and Comfort After Treatment of Pneumonia in Advanced Dementia (JAMA, 2010). In this patient population, when treating pneumonia, comfort scores decreased as intensity of therapy increased (i.e., no therapy -> PO antibiotics -> Parenteral Antibiotics). The reasons behind the decrease in comfort could not be validated (dementia patients), but were thought to be due to ADRs and the invaseness of injectable formulations.

Overall, nothing conclusive enough to sway the decision in either direction. Unfortunately, the papers in favour of palliative Abx do not look at the situation from a Stewardship mindset; yes, the individual patients did not experience many adverse events, but there may be overall impact on hospital antibiogram and resistance patterns for other patients. In practice, the biggest factor we find in decision making tends to be the patient’s family looking for one last shred of hope… meaning that most of the pros and cons discussed in these papers tend to be irrelevant anyway.

The History of Penicillin and a new QT Interaction

2017-05-09T00:00:00+00:00

Just been catching up with Dr. Mark Crislip’s Puscast. Checked out a few of the references he linked to in the most recent one. Not really a reference I suppose, but there is a really interesting read about the history of Penicillin and other antibiotics. Many details you don’t usually hear about. I especially liked their conclusion, basically “look how much work goes into making an antibiotic… now stop wasting them!” The full article is available online here.

Another reference he mentioned is Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation from the Journal of the American College of Cardiology. I recognize one of the authors (Dr. Woosley) as the president of AZCERT, basically the best reference for QT prolongation information, so I’m pretty confident it’s a legit paper. It’s actually a really interesting read - essentially, the authors used advanced data mining techniques to scour databases looking for yet unrecognized drug-drug interactions leading to QT prolongation. They do this using methods like flagging ADR reporting of ADRs that often present alongside QT prolongation. From this data mining, the found the combination of Ceftriaxone and Lansoprazole lead to some pretty serious QT prolonging - especially interesting considering neither drug alone is known to have this effect! They compared against Cefuroxime and Lansoprazole combination and found it had no issues… so presumably it isn’t a class effect. They then validated the results in the lab using patch-clamp electrophysiology, and had results mirroring their data-mining findings.

This interaction could be significant in hospital given that lansprazole is our PPI of choice in tube-feed or crushed med patients, and ceftriaxone is our antibiotic of choice in… well, pretty much anything. That said, most of the patients who will be receiving this combination will be ICU patients, who are the most closely monitored and would be the easiest to spot a QT prolongation on.

Antibiotic Use in Pregnancy - Update

2017-05-01T00:00:00+00:00

Use of antibiotics during pregnancy and risk of spontaneous abortion - CMAJ

Interesting outcomes - we already don’t use tetracyclines and quinolones in pregnancy, so the miscarriage risk is not too relevant for those. I was surprised about macrolides being higher risk. Nitrofurantoin is fine, which I did not find surprising given its does not have good distribution anywhere but bladder.

Septra also has a higher risk, and it is recommended a second line tx for UTI in pregnancy, so that may need reassessed. However, the guidelines also stipulate avoiding use in first trimester due to the potential for fetal abnormalities (not miscarriage, but as with tetracyclines/quinolones, you are already avoiding its use). Given the study focused on 20 weeks and earlier, it looks like not much needs changing in current practice, except maybe the use of macrolides.

Good Medscape Summary Here

Easter Article Catchup

2017-04-14T00:00:00+00:00

Been far too long since a post - here are some brief summaries of articles or posts that I found interesting.

FDA Okays First Tardive Dyskinesia Drug

VMAT2 inhibitor (vesicular monoamine 2 transporter - a dopamine regulating pathway)
valbenazine (Ingrezza)
another QT prolonging agent for people already taking QT prolonging agents… awesome!
improves severity of involuntary movements
another VMAT2 approved recently: deutetrabenazine, but for Huntington’s chorea. Would be suprised if they also didn’t try for a TD indication too though. (Also… TEVA makes novel drugs?)

Canadians with cystic fibrosis have a significant survival advantage over American patients

Public healthcare can have its disadvantages, but I would take it over the US’s model any day.

While adjusting for all other risk factors did not change the differences observed in patient outcome between countries, differences in survival did vary depending on U.S. patients’ private insurance status.

‘Virtual’ Management Improves In-Hospital Glucose Control

Took a few searches to figure out what a virtual glucose management service is, but essentially it looks like an algorithm built into the EMR that detects uncontrolled blood glucose
Helped prevent consecutive high glucose readings; basically physicians can lock things down sooner
Looks like it’ll need far more research to determine if it’s really cost effective but it’s a cool idea nonetheless

Extended rivaroxaban superior to aspirin in lowering risk of recurrent venous thromboembolism: The EINSTEIN CHOICE trial

Compared xarelto 10mg daily, 20mg daily, and ASA 100mg for VTE prophylaxis in patients with previous clot
10mg did have efficacy with a small bleed risk, but the trial is sponsored by a drug company
- Compared against ASA, which IS recommended in long term prophylaxis once anticoagulation is stopped… still not sure it’s a fair comparitor. Anticoagulants SHOULD be more effective than ASA. I guess they’re trying to get the guidelines changed to low dose NOAC instead.

Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection

Very relevant paper for my practice, as we review every active C. difficile case in the hospital
It is (anecdotally) difficult to corroborate PPI with risk of first C. diff incidence, as so many patients are already on PPI; but we are never sure if it is worth tapering PPI to lower recurrence risk
This meta-analysis looked at CDI recurrence 15-90 days post initial episode, and did find an elevated risk of recurrence in the patients receiving PPIs (60.7% of patients looked at were on PPI)
- Interesting: only 47.1% of the patients on PPI had an evidence-based indication
Often, the hardest part about stopping a PPI (esp in elderly patients) is that you have no idea why they were on it to begin with and what will happen if you stop it
- As well, they will be experiencing GI symptoms with the C. diff and it may be hard to tell if stopping the PPI is also having a negative effect.

Limiting Fluoroquinolone Use Linked to Less C Diff

2017-01-25T00:00:00+00:00

Curbing Antibiotics Tied to Britain’s Drop in C. Diff

This looked at the impact of fluoroquinolone prescribing restriction in Britain and found a reduction in C. Diff occurrance as well as fluoroquinolone resistant organisms. Generally antibiotic rotation is not recommended as a stewardship intervention but there seem to be ever more reasons to move away from prescribing FQs first line in general.

Thankfully we don’t have a high rate of nosocomial c diff at my institution but anecdotally I have not noticed a particular increased incidence secondary to any particular antibiotic or antibiotic class. Interestingly if you delve into the full paper, it mentions:

Hospital cephalosporin and fluoroquinolone prescribing were also positively associated with incidence of C difficile infection (CC=0·73, 0·15 to 0·86, and 0·62, −0·09 to 0·81; appendix), but associations were estimated much less precisely given the much smaller population (approximately 1% of England). Positive associations were also observed between C difficile infection decline and decline in extended spectrum penicillins (0·84, 0·24 to 0·90) and beta-lactamase-resistant penicillins (0·67, −0·04 to 0·81; appendix).

The paper was only fully powered it seems for fluoroquinolones because their prescribing was actually restricted. The interesting part is they correlated with FQ-sensitive and FQ-resistant strains of c-diff, and once they reduced FQ prescribing, the only c-diff infections were with FQ-sensitive c. diff strains. This is a bit confusing to me as we never used a FQ to treat c-diff; I had no idea any of the c. diff strains were sensitive.

Conclusion? I’m still not sure which abx are the worst for causing c diff (surely you would even need to specific specific cephalosporins rather than the whole class??) so I’ll stick to my current principle, which is try to use less of all antibiotics in the first place.

Notes from Canadian Pharmacists Letter - Jan 2017

2017-01-16T00:00:00+00:00

new study suggesting all NSAIDs have equal risk when used in pts with CV disease
- only looked at celebrex 200mg total daily dose
- traditionally naproxen is supposed to be the safest in CV disease, up to 500mg BID
- celebrex still preferred if GI risk factors (even in concurrent CV disease)
pts on chronic suboxone, if also have pain issues (and non-opioid adjuncts not helping), you can divide the suboxone dose out to q6-8h to improve its analgesic effects
new Canadian guidelines for prevnar/pneumovax in >65 y/o… give both, prevnar first is better.
- See guidelines for timelines depending on when/what is given first, etc
- Prevnar not covered unless immunocompromise, may change
give Tdap to pregnant moms after week 26. This is being done in the US but not in Canada yet
- transfers immunity to the fetus.
- many cases of pertussi (whooping cough) in newborns, but they don’t get tdap until week 8
calcium supps + CV risk may be overblown; stay less than recommended daily max
- 1g a day for women <=50, men <=70, 1200mg otherwise
- max 2500 < 50y/o, 2000mg <50
- ca supps likely don’t cause dementia
quinolones in kids: no joint damage or tendon rupture actually observed. (original data was in beagels)
- may still cause joint or muscle pain
beta-blockers & PPIs should be tapered to stop safely (eg in palliation)
biologics can have “biosimilars” - not a generic version, but should work the same
- infliximab already has one (Inflectra)
- now etanercept has one (Brenzys) -> $200 less /month but doesn’t have all the indications
  - no washout needed to switch and dosing is the same

New Evidence Regarding Zika and Microcephaly

2016-12-19T00:00:00+00:00

Zika Virus RNA Replication and Persistence in Brain and Placental Tissue

Not something that will affect my practice but I did find it interesting. I was (incorrectly) under the impression that we only had a corrollary link with Zika and microcephaly, but we did have a causal link with Zika, microcephaly, and pregnancy loss. This study looked at presence of Zika in microcephalic infants and pregnant women and had some scary results (like mean 163 days between maternal symptom onset and detection in fetal brain!)

The summary I read was here. Scary stuff.

Notes for IDWeek 2016 Day 4

2016-10-29T00:00:00+00:00

7am on a Saturday in New Orleans. #hardcore

Antibiotic Dosing in Special Populations

Critically Ill

abx dosing more difficult because you’re not just trying to exert pharmadynamic effects on the patient, you are actually targetting the pathogen
- more difficult to monitor than, say, blood pressure
plasma concentrations are surrogates, and not always a great representation of tissue
Vanco was rushed through clinical development, 2gm/day was considered “effective and minimally toxic” (1958)
cefotaxime breakpoints was originally decided based on peaks except it’s not a concentration dependent drug
polymixin B - CrCl dependent dosing but it’s not elminated renally
hydrophilic abx: lower Vd, mostly renally cleared, low intracellular penetration
lipophilic: higher Vd, mostly hepatically cleared, good intracellular penetration
- see slide for some examples
changes in critically ill:
- imparied absorpation -> decreased AUc
- capillary leak -> increased Vd,. decreased plasma concentration, delyayed distribution
- end-organ damage -> decreasee clearance, increased AUC
  - pharmacists good at lowering dose of drug, but generally less good at bumping doses when appropriate.
- hypoalbuminemia: increased free fraction, variable effects
  - only imporant for protein-bound drugs
- augmented clearance -> decreased AUC and drug exposure
Roberts JA. Clin Pharmacokinet 2006;; Udy AA clin pharmacokinet 2010; Uildemolis M; CHEST 2011
- see slide in the lecture; shows common changes for different critically ill states
Augmented renal clearance
- GFR >150, 160 (different definitions)
- caused by a variety of fators in multiple states (eg sepsis, trauma) has increased cardiac output; we add fluid and pressors, things get pushed through quickly
- no renal dosing guidelines for things like CrCl 150
- Current formulas available for CrCl are terrible at calculating augmented. Baptista JP Critical Care 2011
  - Cockcroft gault was actually the best, but all were a severe underestimate
Roberts JA et al In J Antimicrob Agents 2010:
- 30 bed ICu over 11 months, adjuted abxx based on twice weekly stead state troughs
- had to increase doses 50% of the time from the initial doses physicians were ordering
- 72% did not achieve target endpoints
DALI study: defining antibiotic levels in intensive care patients
- Roberts JA et al Clin Infect Dis 2014
- large study doing similar to the last one but with multicenter and way more patients
- up to 500 fold difference in unbound concentrations of abx at both sampling points
- 16% did not achieve target and this was associated with clinical failure
summary: Roberts JA, Lipman J. Clin Pharmacokinet 2006 (table in slides)
should probably be loading patients when they have an increased Vd

Obesity

increased failures: low relative dosing or effects of obesity itself?
antibiotic use in early age is associated with obesity due to changes in the microbiome
absorption - not significantly modified
distribution: hydrophilic drugs should not be reatly incluenced as only 5% of cardiac output is blood flow into fat (maxes out)
Vd increases generally occurs
Metabolism: changes not well defined in obesity
Elimination: higher glommerular planar surface area
Pk effects of obesity are hard to predict in infected, ill patients
- sometimes decreases likelyhood of target attainment but sometimes increases it too (depends on drug)

CRRT

a lot of dosing literature is out of date due to improvments in CRRT machines etc; we underdose a lot of drugs
Hemofiltration -> Convection
- activvel removal of solutes and drugs by pump-drive pressure gradient
- higher propensity to remove larger drugs
- independent of concentration gradients or molecular drugs
- Sieving coefficeint can be helpful if you have it
Hemodialysis -> diffusion
- Passive moment of substances down concentration gradients across semipermiable membrane
CVVH = convection, CVVHD mostly diffiusion (little convection), CVVHDF = lots of both => more drug removed than expected
Dose of CRRT -> factors effluent flow and duration of CRRt; most important variable
Blood flow rate and surface area of the filter have low impact on drug concentration
Filter material: where sieving coeffecient comes into play
Protein binding -> only unbound drug removed by CRRt
increase in Vd in CRRT: larger loading dose needed, but decreased efficacy of CRRT removal
Heintz BH. Pharmacotherapy 2009: amazing reference paper
Beumier M, Crit care 2014: looked at non renal dose adjusted abx in CRRT patients
- only 10% proportion of inadequate concentrations
- trade off, 53% had very high levels
- how do we know what an actual toxic level is for a beta lactam? they tend to be relatively safe agents in terms of dose related toxicity so aiming for efficacy targets may be more appropriate
most CRRT dose studies assume 1-2L/hr and minimal residual function; check on your patients, often it’s running more like 2-3 L/hr and pt may have some residual renal function
consider loading doses! esp in drugs we know will be cleared well (like low protein bound etc) and possibly more aggressive maintenance doses
moving target: CRRT is constantly changing (like while a patient is on it), need to constantly reassessing the dose adjustments

Strategies

Individualized dosing, determined by physiological characteristics that may affect PK
Scaglione F et al Eur Respir J 2009: Pk/PD optimization on the patient level in HAP
- real time TDR for several abx, made dose adjustments in ~40% of the patients in the study (pts were underdosed)
- pts who got the adjustments had better clinical and microbiological outcomes
Roberts JA lancet infect Dis 2014: Bayesian calculations
Presenters do not recommend dose capping for vanco; will use 2-2.5 g loading doses (sometimes divided LD strategies) and one has gone up to 6g daily for vanco
Also do not dose cap for daptomycin (use TBW)
recommended max is 600 q8h for ceftaroline but have used 900 for 450lb pt

Use of New Antibiotics: FDA Indications and Beyond

www.pewtrusts.org -> great overview of current abx pipeline
37 abx in development bt only 11 in phase 1
6 in phase 3 for gram neg infections

**Gram Positives **

Oritavancin
- SOLO-2 trial. ABSSSI, gram positive only; possible warfarin DI due to cyp interaction but recent study shows no issue as long as you wait 12 hours after oritavancin dose
- several trials ongoing
Dalbavancin
- some enterococcal activity; two doses 1 week apart, or one single 1500mg dose (new single dose study)
- may have utility in OPAT
- case reports in bacteremia but no real studies
- being studied for CAP
Tedizolid
- ongoing study for HAP/VAP; 50% enrolled. once a day for 7 days vs linezolid standard dose x 10 days
Solithromycin
- Fluroketolide with boroad spectrum
- IV/PO
- strep pneumo; atypicals; MSSA/MRSA; h influ, n gonorrhea
- SOLITAIRE-ORAL study: PO vs moxifloxacin for CABP. Lancet 2016
  - 800mg day 1, 400mg day 2-5, placebo day 6-7
  - managed to isolate a baseline lung pathogen in 50% of the patients; surprisingly high percentage found atypical pathogens
    - serologic testing may overestimate atypical prevalence
- SOLITAIRE-IV : same drugs and study type. sicker patients
  - File et al CID 2016
  - Saw more infusion related adverse events, but few led to discontinuation
  - LFT abnormalities found too
  - was hard to gauge QTc differences but seemed better than Moxifloxacin
- studies still undergoing including for gonorrhea
- concern giving history with telithromycin (was pulled post-marketing for hepatotoxicity)
Fusidic Acid
- Craft et al CID 2011
- orally bioavailable, currently in phase 2 ABSSSI vs linezolid
- open label study underway for prosthetic joint infection
- concern about resistance and need for combination therapy
Iclaprim
- TMP like dihydrofolate reductase inhibitor
- was around in the early 2000s
- new IDweek poster showing in vitro activtiy vs clinical HAP
- phase 2 HCAP study vs vancomycin
- REVIVE studies - for ABSSSI
Lefamulin
- Pleuromutilin Antibacterial
- Concentration depent
- novel MOA - protein synthesis inhibitor
- Phase 2 for ABSSI vs vancomycin
- LEAP trials; phase 3 underway vs moxi for CAP
- exploring HAP, prosthetic joint, gonorrhea
Delfloxacin (Melinta)
- broad spec quinolone with MRSA activity
- oral biovailbility, broad spec, efficacy in obese patients
- no QTc prolongation observed, less side effects - no LFT, glucose changes, etc
- Studied 300mg IV BID vs vanco/aztreoname phase 3 ABSSSI
- new study for this IDWeek: delafloxacin IV then 450mg PO BID vs vanco/aztreoname phase 3 ABSSSI
- NDA filed for ABSSSI (phase 3 complete); CAP study slated to start this winter
Omadacycline
- minocycline derivate, active against tetracycline resistant pathogens
- potentially active against MRSA
- ABSSSI:100mg IV / 300mg PO vs linezolid, comparable
- infusion-related extravasation found, otherwise just nausea
- recruting for CAP vs moxifloxacin
still need better data for VRE
- McKinnell and Arias, CID 2015: evidence gap for current GP abx

Gram Negatives

new beta-lactamase inhibitor combos hit key serine beta-lactamases inc class A(esbl, KPC) class C(ampcC)
none hit Class B metallo beta-lactamases(NDM-1)
ceftolozane/tazobactam
- activity against pseudomonas, much better breakpoints than ceftaz or piptaz
- about 50% of mero/ceftaz resistant orgs will be resistant to zerbexa
- MDR Kleb : sucks compared to mero
- ESBL: better than piptazo or ceftaz but not as great as mero
ceftaz/avibactam:
- pseudo activity is dependent on low efflux versions of the bug
- govers KPC, enterobacteriscia
- approved for cUTIs on phase. date, phase 3 is completed and under FDA review
- phase 3 trial for cIAIAs (cid 2016), nosocomial pneumonia completed but not published
- compared against other drugs in Lancet 2016 but didn’t look at CRE
- Dosed as a prolonged infusion (2g q8h over 2 hrs each)
Meropenem-Vaborbactam
- ESBL, CRE -> activity similar to plain mero against non CRE
- well matched PK properties of mero and vaborbactam
- MIC vs pseduo,acinetbacter same as mero but may work better as high dose/prolonged infusion
Plazomicin
- Aminoglycoside designd not to be affected by major aminoglycoside modifying enzymes
- Better activity than amikacin against MDR, ecloi but not improved for pseudomonas
- Active vs CRE but not in NDM versions
- Some posters here regarding TDM- similar toxicity etc to other aminoglycosides
Eravacycline
- Fluorotetracycline
- Similar to tigecycline
- Potent gram +ve and -ve coverage; 2-4 fold more potent than tige
- Covers kleb, acintobacter; anaerobes
- Orally bioavailable
- trials in cIAI (vs erta), planned vs mero; cUTI
See slide: statistically powered NI trials for New Gram Negative Agents provide Important Data
- Levo R at baseline for UTI in the ceftolozane study
- Decreased CTOl.TAZZO efficacy in pts with crcl 30-50 in the cIAI study vs mero
  - same with the ceftaz-avi study
  - may have been renal dosed but then renal function rapidly recovered and dose wasn’t bumped up
  - renal dose guidelines from manufacturer are based on simulations
- Eravacyclin vs Levo in cUTI -> missed endpoint, study showed that the patients who were stepped down to the PO eravacycline had clinical failure. Company working on a new PO formulation to try again
there are ongoing trials for treatment of CRE; can be difficult because you have really sick patients and you really need to widen your inclusion criteria
- TANGO 2, CARe, RESTORE-IMI-1 (mero-vabor, plazomicin, imi/cilastatin/relebactam)

Antifungal Agents

Posaconazole and Isavuconazole
broad spectrum; cover mucorales (historically only have amphoB)
Posaconazole: - originally PO posa required high fat meals and stuff for absorption. 2013-2014 came out with a adelayed release that gives once daily dosing and better bioavailability
- tablets better than the oral suspension for blood levels
- approved for oropharyngeal candidiasis, prophylaxis of aspergillus and candida
- non FDA indications: aspergillosis, mucormycosis, scedosporium and fusarium
  - voriconazole is first line for aspergillosis but toxicitys can limit its use (like photopsia, hallucinations, photosensitivity, skin carcinogensis, fluorosis)
Isavuconazole:
- IV and PO, water soluble but does not require cyclodextrin for solubilization so don’t need to adjust for renal failure
- QTc Interval shortening - WHA!? - not yet sure of clinical impact
- FDA for invasive aspergillosis

Notes for IDWeek 2016 Day 3

2016-10-28T00:00:00+00:00

IDSA/SHEA Guidelines: Implementing an Antibiotic Stewardship Program

learning “how the sausage was made”
newer IDSA guidelines use the “GRADE” system to rank suggestions, factors in more than just evidence quality (old system)
new guidelines no longer prefer prospective audit and feedback over preauthorization
- restrictive prescribing worked better and faster but strategies become equivalent at 12 mo
- switching preauth to PAF showed inreased DOT and length of stay
- PAF only has an impact if implemented in an existing ASP
- comparison table available in the guidelines
- TL;DR: implement one or both and keep doing it consistently
syndrome -specific: new guidelines emphasize the benefit of this approach (eg SSTI, CAP, asymptomatic bacteruria)
rapid testing in micro lab has no ASP benefit unless the ASP team is directly involved in real time
- results will just sit there without ASP intervening
limited study for procalcitonin; may not even do that much
DDDs are less good than DOTs but way easier to calculate
- DOT are not consistent in q2d dosing
antibiotic costs ideally measured based on rx or actual administrations rather than by purchasing data and normalized by patient census
cost savings wane as asp continues so measure what costs would be if you didn’t have a stewardshiop program
- apparently there are metrics and guidelines available to calculate what costs would be without a stewardship program. F/U!!

Impact of Clinical Practice Guidelines on Antimicrobial Stewardship

Value = (Quality + Service) / Cost
- service relates to patient perspective
HICPAC: ASP workshop, july 2016 - guidelines are helpful for defining abx use but have not routinely incorporated stewardship principles
Guidelines don’t factor in cost effectiveness
wholesale prices of abx in the states are crazy (dapto like $500/day?)
issues with restricted drugs being cheaper than non-restricted (like linezolid vs vanco)
Wachter et al. public reporting of antibiotic timing in patients with pneumonial ann intern med 2008
- focus on patients interests above all else
1 hour rule in sepsis has become the 3 hour rule as of 2015
HAP/VAP guidelines 2016: only include MRSA drug in pts with risk factor for MRSA infection or at high risk for mortality
- only in pts with an increased likelyhood of pseudomonas/resistant GNR do you need an antipseudomonal
- a good stewardship-based guideline

Impact of Core Measures on Antimicrobial Stewardship Programs

measures come from NQF (National Quality Forum), non profit organization
SCIP - surgical care improvement project
- retired now due to great compliance… except for the 24 hrs stop recommendation
the CAP measures have a very confusing pseudomonas section, taken out of guidelines but should not be included as a core measure
- beta-lactam + FQ for ICU CAP is probably excessive and unnecessary
sepsis: recent meta analysis did not find an association with antibiotic timing and increased mortality in severe sepsis and septic shock
- all retrospective studies
- Kumar study 2006 (study where most of our guidelines come from) is actually an outlier in the meta-analysis
- CMS has put out new release notes commenting on pts with sepsis with known pathogen or with c diff
  - jointcommission.org
  - also have de-escalation release notes that came out a few days ago

Who Really Needs Antimicrobials? Rapid Diagnostics & BioMarkers

pathogen specific tests: hard to tell colonizers, test site inaccessible/unknown, etc
biomarkers: no info on etiology, can tell if infection is present, can’t generalize to special populations
current rapid tests: GAS, influenza
- quicker resp panels
- limited biomarkers: procalcitonin, urinalysis
- more robust biomarker panels in the works
point of care pathogen tests: molecular tests coming with excellent sensitive and specificity (even compared to PCR)
currently available CLIA-waived molecular tests:
- Alere i inflenza A&B, Roche Cobas Liat influenza A/B
- 15-20 min, roche 99.2% sensitive and 100% specific vs Simplexa PCR
- will people still rx Abx “just in case”
POC tests have risks of contamination, huge user manual with checklist to mitigate risk. Will be a challenge
New direct from blood pathogen test T2
- works like a tiny MRI for bacteria, works on magnetic fields
- Covers top 6 bacteria; SA, E faecium, ecoli, kleb, pseudo, acintobacter; still missing a lot
- No info on susc so may not be super useful for ASP
Forthcoming tests:
- DNAe: similar to T2 but will give some sus data
- Qvella FAST ID BSI panel: 15 species/genus pathogens in blood, 96% sens and 99% spec. 45 minutes from blood draw
Biomarkers - what’s available today
- c reactive protein, ESR, lactate, urinalysis, procalcitonin (show host response)
- some others exist for showing presence of microorganisms
- procalcitonin: secretion starts 4 hrs post stimulus, peaks at 32 hrs. produced by tissues during infection
  - nonspecific and can be affected by other conditions
  - may help with differentiating bacterial vs viral and duration of abx

The Third Leg of the Antimicrobial Stewardship Stool - Laboratory Diagnostics and Antimicrobial Stewardship

(huh?)

Randomized Trial of Rapid Multiplex PCR - based Blood Culture Indetification and Suceptibility Testing
- 2015 Clin Infect Dis (Banerjee R et al)
- Proescptive RCT; grp 1 (Control) = standard BC processing; grp 2 = rapid multiplex PCR with templated comments; grp 3 = grp 1 + grp 2 process + stewardship intervention
  - ID physician or pharmacist paged with the result 24/7
  - 3 groups were similar, about 200 people each
  - stewardship group had the best results in terms of deescalation - seemed to be an independent effect with ASP
Langford BJ et al J clin microbiol toronto 2016
- suppressed cipro reporting on enterobacterecia when other things were sensitive
- showed a steep decline in cipro use over time (statistically significant)
- non statistically significant possible rise in cirpo Sus for ecoli and pseudo
epstein et al infect control hosp epidemiol 2016
Sarg et al infect control hosp episdemiol 2016
- studies looking to try and reduce unnecessary uine cultures in ICU
- screening proceudre to precede urine culturing will reduce lab testing

Studies that will Impact your Practice

Antimicrobial Agent Shortages and Concerns for Adverse Patient Outcomes are Now Part of Everyday Practice: 2016 Follow-up Survey of Infectious Diseases Physicians

Obtained opinions regarding shortages from ID docs in 2011 and follow up in 2016
not much change from 2011 to 2016.
US had shortages of piptazo, mero, doyxycycline tabs…
lots of places developed guidelines relating to shortages
“we are lucky to have great antimicrobial stewardship pharmacists” :)

Budgetary Impact of Compliance with STI screening Guidelines in Persons Living with HIV

It’s a pretty darn big impact.

Location, Location, Location: A Change in Urine Testing Order Sets on Culturing Practices At and Academic Emergency Department

one study found 8% of admitted medicine patients had asymptomatic bacteruria
CPOE based set modification (from “frequent orders” area) to see if that would reduce unnecessary cultures (unlinking the culture from the UA on the frequent sets)
46% decrease
didn’t track abx ordering changes

The Successful Use of Telemedicine with Virtual Face to Face Evaluation for Inpatient Infectious Diseases Consulation

Telemedicine is a thing that you can do. Saves a 30 minute drive.

The Impact of Infectious Disease Consultation On Clinical Management and Outcome of Patients with Bacteremia in China: A retrospective cohort study

Chinese hospitals can be very crowded

Clindamycin vs Trimethoprim-Sulfamethoxazole vs Placebo for Uncomplicated Skin and Soft Tissue Abscesses

The >5 cm arm of the study did not use placebo. already published in NEJM
got I&D, then wound check at 48hrs, then fu at dat 12, 20, and 40
excluded patients with significant comorbities
cultures were obtained in 99% of patients
abx were the same outcome; both were better than placebo
clinda was bad at SA
non SA bugs: abx were no better than placebo
resistance for clinda wasn’t too bad for pus in the ER compared to other infection sites (10-15%) apparently

Healthcare Epidemiology and Antimicrobial Stewardship in Community Hospitals: Musings about the Present and Future

US has 800-1000 teaching hospitals
Data collecting for ASP is very lacking in community hospitals
2009 study: empicircal antimicorbail therapy for bloodstream infections due to MRSA - >50% pts received inappropriate empiric abx
many community hospitals do not have good hand hygiene programs
community hospitals in the US do not have real time active interventions
new focus on training physicians in ASP formally

Stewardship in Community Hospitals - Optimizing Outcomes and Resources (SCORE)

5000 hosps in US, 72% have less than 200 beds
38% have ASPs
new US mandate that all hospitals have ASPs by Jan 2017
looked at 3 different stewardship program types in 15 small hospitals over 15 months
basic stewardship education, infectious diseases hotline (ID) => program 1
program 2 = program 1 + advanced AS education, “light” prospective AF, local restrictions (controlled by local pharmacy staff)
program 3 = program 1+2 + ID resriction, FULL PAF, ID review of designated cultures
sorted 5 categories of antibiotics (cat 5 = broadest or most expensive/fancy)
program 3 crushed it compared to program 1; program 1 and 2 were similar