Azithromycin & Cardiovascular Risk, Belabored

Last year, I noted a study concerning a report of excess deaths associated with azithromycin use.  This study, a retrospective, observational cohort from Tennessee Medicaid data suggested a death rate double that of other antibiotics.  This led to the FDA issuing a warning regarding azithromycin use.


I thought all this fuss was absurd – the data quality was one step above junk and the absolute magnitude of the proposed harms was trivial.


Now, we have the counterpoint – a retrospective, observational cohort from Denmark, using their national health system database to compare prescriptions for azithromycin to penicillin V over the last 13 years.  In their cohort, there’s an obvious increase in risk of death from cardiovascular causes simply from being prescribed any antibiotics – but no difference between azithromycin and penicillin V.  This seems to indicate either the systemic infectious process contributes to excess cardiovascular risk, or that respiratory symptoms are being misdiagnosed as infectious rather than cardiovascular.  The absolute effect in their propensity matched cohorts is also tiny – a handful of patients or fewer spread across a million prescription events.


The accompanying opinion seems to attempt to justify the FDA review based on the wide confidence intervals in the Danish study – the OR for death from cardiovascular causes vs. penicillin V is 1.06 (0.54 – 2.10) and doesn’t statistically contradict the Tennessee study.  However, yet again, I would point to the reason behind the wide confidence intervals – the nearly trivial absolute magnitude of the harms, which amount to fractions of a patient per 1000 patient-years.

Again, plenty of reasons to responsibly reduce azithromycin prescriptions – but this cardiovascular hullabaloo probably isn’t one of them.


“Use of Azithromycin and Death from Cardiovascular Causes”
http://www.nejm.org/doi/full/10.1056/NEJMoa1300799

Levamisole-Induced Vasculitis

Let the good times roll – unless, of course, those good times are cut with levamisole.

This short case report from my good friends across the street at Baylor showcases a couple lovely pictures of the purpuric and necrotizing skin lesions associated with the anti-helminth levamisole – which, for some reason, is an increasingly popular additive to cocaine.  They are quite distressing and usually present following several courses of failed outpatient antibiotics.

I don’t think I specifically ever saw the exact patient these authors report upon, but it’s not a unique presentation in our county healthcare system.  This article is open-access for all to view without an institutional subscription.

“Levamisole-adulterated Cocaine Induced Vasculitis with Skin Ulcerations”
http://www.escholarship.org/uc/item/4rd630zt



Bonus link nomination for best article title ever:

Mixed “Cost-Conscious” Ordering Results

It’s a little bit of a messy study, sadly, because it’s probably a lovely idea.

These authors performed a before-and-after interventional trial in which they measured laboratory test ordering rates.  After a six-month baseline phase, the intervention phase consisted of displaying the 2008 Medicare allowable charge for a subset of frequent lab tests.  The theory, of course, is that displaying price information in the context of test ordering will alter physician behavior.

Most of the orders were placed on internal medicine services – and yes, there was a decrease in the number of orders with cost information displayed.  At the same time, however, the tests without cost information increased.  The net result, overall, was a decrease in total testing.  Interestingly, the impact seemed to mostly include a reduction by replacing CMP orders by BMPs.  $3.79 per patient-day costs were reduced during the intervention period.

So, the impact was mixed – slightly expensive tests were replaced by slightly less expensive tests.  More evaluation is necessary to determine whether these reductions have unanticipated impact on patient outcomes.

“Impact of Providing Fee Data on Laboratory Test Ordering”
www.ncbi.nlm.nih.gov/pubmed/23588900

New South Wales Dislikes Cerner

The grass is clearly greener on the other side for these folks at Nepean Hospital in New South Wales, AUS.  This study details the before-and-after Emergency Department core measures as they transitioned from the EDIS system to Cerner’s FirstNet.  As they state in their introduction, “Despite limited literature indicating that FirstNet has decreased performance” and “reports of problems with Cerner programs overseas”, FirstNet was foisted upon them – so it’s clear they have an agenda with this publication.


And, a retrospective, observational study is the perfect vehicle for an agenda.  You pick the criteria you want to measure, the most favorable time period, and voilà!  These authors picked a six month pre-intervention period and a six-month post-intervention period.  Triage categories were similar for that six month period.  And then…they present data on a three-month subset.  Indeed, all their descriptive statistics are of only a three-month subset excepting ambulance offload waiting time – for which they have full six month data.  Why choose a study period fraught with missing data?

Then, yes, by every measure they are less efficient at seeing patients with the Cerner product.  The FirstNet system had been in place for six months by the time they report data – but, it’s still not unreasonable to suggest they’re somewhat suffering the growing pains of inexperience.  Then, they also understaff the ED by 3.2 resident shifts and 3.5 attending shifts per week.  An under-staffed ED for a relatively new implementation of a product with low physician acceptance?  

As little love I have for Cerner FirstNet, I’m not sure this study gives it a fair shot.


“Effect of an electronic medical record information system on emergency department performance”
www.ncbi.nlm.nih.gov/pubmed/23451963

How Marriage Works in Medicine

…extremely well, in the majority of cases, according to this survey.  55.4% of physician spouses (73.2% female, 27.1% male) responded by saying they were “extremely satisfied” with their relationship, while another 31.4% were “somewhat satisfied”.  Only a tiny 2.1% of spouses said they were “extremely dissatisfied” – and these numbers, as best can be reasonably compared, are very similar to the general population.

Of course, this is a survey of a subset of the Physician Masterfile that even provided an e-mail address for their spouse – so it has all sort of potential for response biases.  Regardless, it’s an interesting glimpse into a few elements that seem to make for healthy relationships:

  • The spouses that saw their partner less than 20 minutes a day were far less likely to be satisfied.
  • Increasing hourly workweeks and nights on-call were negative influences.
  • Spouses employed less than full-time seemed to be less satisfied than unemployed or full-time employed.
  • Fatigue and time commitment were the greatest reported family stressors.

According to these authors, no differences were found between practice type or physician specialty (“data not shown”).  Perhaps they were simply lacking statistical power, because previously published data indicated significant variability in likelihood of divorce between specialties – with psychiatry (50%) and surgery (33%) leading the pack over the base rate of general medical specialties (22-24%).

“The Medical Marriage: A National Survey of the Spouses/Partners of US Physicians”
http://www.mayoclinicproceedings.org/article/S0025-6196(12)01187-1/fulltext

“Healthcare-Associated” Pneumonia Update

While trying to summarize an evidence-based approach to pneumonia for our residency, I discovered an aimless morass that’s far less helpful than originally envisioned.

“Healthcare-associated” pneumonia is a clinical entity introduced by the 2005 Infectious Disease Society of America pneumonia guidelines.  The problem with these guidelines is immediately apparent in the title – “Hospital-acquired”, “Ventilator-acquired”, and “Healthcare-associated” are clearly distinct in their infectious epidemiology – but this guideline lumps them all together into a single empiric treatment strategy.  They recommend triple antibiotic therapy, including double coverage for multi-drug resistant gram-negatives (pseudomonas, among others) and MRSA coverage.  This is a fine recommendation for a critically ill ventilated patient with a new lower respiratory tract infection, but preposterous overkill for an otherwise healthy patient with a short hospital stay a couple months ago.  The harms include increasing antibiotic resistance and incidence of iatrogenic end-organ damage secondary to antibiotic adverse effects.

Several articles have detailed the fallacies in this guideline and its validity in the Emergency Department setting.  Furthermore, meta-analysis of studies evaluating guideline-concordant and guideline non-concordant therapy have shown no survival advantage – as most non-concordant therapy covered the community-acquired organisms that occur with far greater regularity than the multi-drug resistant organisms in the “Healthcare-associated” cohort.

With consultation from Brian Hayes and Haney Mallemat, along with my brief literature review, this is my ad hoc approach:

1) Assess risks for MDR pathogens: recent antibiotics, recent hospitalization, poor functional status, immunosuppression.

2a) Non-severe illness and community-acquired organisms likely (low MDR risk), consider antipseudomonal fluoroquinolone monotherapy (covers some pseudomonas and atypical CAP organisms) and outpatient management.

2b) If high risk for MDR or severe illness, recommend admission with anti-pseudomonal and MRSA coverage:
 • Cephalosporin (e.g. cefepime) OR carbapenem (e.g. imipenem) OR ß-lactam/ß-lactamase inhibitor (e.g., piperacillin-tazobactam)
If severe illness, recent mechanical ventilation, or prior documented pseudomonas infection, add:
 • Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) OR aminoglycoside (e.g. amikacin)
MRSA coverage:
 • Linezolid or vancomycin

Note these recommendations should be guided by your local antibiogram as well – at my institution, cefepime is ~90% efficatious against pseudomonas, which makes it a fine option for monotherapy.  However, our fluoroquinolones are ~70%, which makes them a less desirable choice for the monotherapy option when admitting patients.

Patients clearly do better when their causative organism is effectively covered – but we also have to be responsible stewards of our strongest antibiotics.  Given the heterogeneity of the patient cohort described in the 2005 IDSA guidelines, it’s reasonable to take a stepwise approach to therapy.

“Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia”
http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/HAP.pdf

“Guideline-Concordant Antimicrobial Therapy for Healthcare- Associated Pneumonia: A Systematic Review and Meta-analysis”
www.ncbi.nlm.nih.gov/pubmed/23572322

“Guidelines for hospital-acquired pneumonia and health-care-associated pneumonia: a vulnerability, a pitfall, and a fatal flaw.”
http://www.ncbi.nlm.nih.gov/pubmed/21371658/

“Healthcare-associated pneumonia is a heterogeneous disease, and all patients do not need the same broad-spectrum antibiotic therapy as complex nosocomial pneumonia.”
http://www.ncbi.nlm.nih.gov/pubmed/19352176/

“Low incidence of multidrug-resistant organisms in patients with healthcare-associated pneumonia requiring hospitalization.”
http://www.ncbi.nlm.nih.gov/pubmed/21463391/

How To Evaluate Decision Instruments

This lovely editorial by Steven Green from Loma Linda succinctly summarizes the limitations of clinical decision instruments.  Decision instruments, referred to in this article as decision “rules”, are potentially valuable distillations of data from large research cohorts meant to concisely address vital clinical concerns.  These include such well-known instruments as NEXUS, PERC, Centor, Alvarado, Wells, and Geneva.

He describes a need for rigorous derivation, external validation, and ease of application as important criteria.  However, the most important topics he addresses are the related issues of “1-way” versus “2-way” application and whether the rule improves upon pre-existing clinical practice.  A “1-way” decision instrument informs clinicians only when its criteria are all met – such as the PERC rule.  A patient who fails the PERC rule does not necessarily need any additional testing due to its low specificity.  The NEXUS criteria, on the other hand, is a 2-way decision rule – where its use in appropriately selected patients typically leads to radiography if its criteria are not met.

The danger, however, is the natural propensity to using a “1-way” rule like a “2-way” rule.  His example for this error is the PECARN blunt abdominal trauma article for which I previously expressed concerns.  In the PECARN blunt trauma instrument, the specificity of the derivation was actually lower than the performance of the clinical gestalt of the physicians involved.  This means the authors recommend its use only as a “1-way” rule, based on sensitivity.  However, if the cognitive error is made to apply it as a “2-way” rule, CT scanning will increase by 13%.  Then, unfortunately, if used as a “1-way” rule, the PECARN instrument only has 97% sensitivity compared with the clinician gestalt of 99% sensitivity.  This means that, if implemented as routine practice, the PECARN instrument may have a non-trivial number of misses while potentially increasing scanning.  This illustrates his point as a “poorly-designed” decision rule, despite the statistical power of the cohort evaluated.

Overall, a lovely read regarding how to properly evaluate and apply decision instruments.

“When Do Clinical Decision Rules Improve Patient Care?”
www.ncbi.nlm.nih.gov/pubmed/23548403

Neurosurgery’s Takedown of Steroids in SCI

A brave new day dawns – clinicians who otherwise lived in fear of medicolegal reprisal from failing to administer steroids in acute spinal cord trauma may now safely withhold them.

The steroids in spinal cord debate, a one-man crusade lead by Michael Bracken, distorted by performing Cochrane Reviews of his own articles, has hopefully been definitively settled.  These authors, as part of a comprehensive update on the diagnosis and management of acute spinal cord injury, definitively summarize the flawed literature supporting methylprednisolone administration.  Their recommendation:

Administration of methylprednisolone (MP) for the treatment of acute spinal cord injury (SCI) is not recommended. Clinicians considering MP therapy should bear in mind that the drug is not Food and Drug Administration (FDA) approved for this application. There is no Class I or Class II medical evidence supporting the clinical benefit of MP in the treatment of acute SCI. Scattered reports of Class III evidence claim inconsistent effects likely related to random chance or selection bias. However, Class I, II, and III evidence exists that high-dose steroids are associated with harmful side effects including death. 

We’ve come a long way since the NIH faxed a letter to every Emergency Department in the country instructing physicians to give steroids.  Another amazing saga demonstrating the danger of inadequately reviewed medical evidence.

“Pharmacological Therapy for Acute Spinal Cord Injury”
http://www.ncbi.nlm.nih.gov/pubmed/23417182

How I (Hardly Ever) Scan For Pulmonary Embolism

There’s probably no diagnosis in the Emergency Department that confounds residents more than the practice variation between attendings regarding the evaluation for pulmonary embolism.  Some folks send d-Dimers with reckless abandon on patients with near-zero pretest probability, others make emotional decisions to “take PE off the table” when faced with no other explanation, and then there’s a group that only very rarely pursues the diagnosis.

I rarely pursue the diagnosis – mostly because the epidemiological evidence suggests we’re only harming folks by making additional diagnoses of pulmonary embolism.  Therefore, in a patient who is otherwise physiologically intact, a diagnosis of pulmonary embolism is more likely to result in iatrogenic bleeding risk rather than treatment benefit.  And, then, there’s the backwards fashion in which I use d-Dimer: I order it at the same time as the CTA in an otherwise intermediate- or high-risk patient, and then cancel the CTA if the d-Dimer is normal.

I use this strategy based on this prospectively collected data from the Kaiser system, published obscurely in The Permanente Journal several years back.  These authors evaluated 744 patients over 16 months who underwent CTA for rule-out PE, 347 of which had latex agglutination d-Dimer levels less than 1.0 µg/mL.  In this cohort of 347, there were seven positive scans – six of which were ultimately found to be false positives.  A handful of patients were lost, but the remainder had zero events in the three-month follow-up period.

So – d-Dimer negative, cancel the CTA, regardless of the pretest probability.  So far, so good!

“Computed Tomography Angiography in Patients Evaluated for Acute Pulmonary Embolism with Low Serum D-dimer Levels: A Prospective Study”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911823/

“Neuroimaging Negative” Strokes Are A Lie

Back in 2011, there was an article in Annals of Emergency Medicine discussing what a fantastic job we were doing in diagnosing stroke and avoiding administering tPA to “stroke mimics”.  They reported a rate of 1.4% administration to stroke mimics – none of whom had bleeds.  The problem I pointed out, both on my blog and in a response letter to Annals, was that the authors invented a new category called “neuroimaging negative” acute stroke – which was probably actually all stroke mimics.  This would have changed the rate of tPA administration to stroke mimics from 1.4% to 29.3%.  The authors, having financial conflict of interest with the manufacturers of tPA, disagreed.

This study, part of the “Lesion Evolution in Stroke and Ischemia On Neuroimaging” project, evaluated the progression of lesions on MRI following tPA administration.  These authors found 231 patients with acute stroke who were initially screened by MRI prior to tPA administration and had evidence of infarction on diffusion weighted imaging.  They found that, following tPA administration, only 2 patients had resolution of an MRI DWI lesion.  They therefore conclude that “Patients with a stroke are unlikely to have complete DWI lesion reversal within 24 hours after IV tPA treatment,” and patients with no DWI lesion following tPA administration should be considered to have a diagnosis other than acute stroke.

Thus, this confirms my conclusion that the 27.9% of patients from the prior study with “neuroimaging negative” acute stroke ought to universally be considered to have had a diagnosis other than acute stroke.  The reality is that we are likely treating an ever-greater number of acute ischemic strokes – and further efforts to push Emergency Physicians to treat additional patients more quickly are certainly going to expose additional patients to avoidable harms.

“Negative Diffusion-Weighted Imaging After Intravenous Tissue-Type Plasminogen Activator Is Rare and Unlikely to Indicate Averted Infarction”
http://www.ncbi.nlm.nih.gov/pubmed/23572476