Category: Antibiotics

JAMA, Integrity, Accessibility, and Social vs. Scientific Peer Review

Yesterday, I posted regarding a JAMA Clinical Evidence series article involving procalcitonin measurement to guide antibiotics stewardship.  This is an article I read, raised concerns regarding other negative trials in the same spectrum, and depressingly noted conflict-of-interest with each of the three authors.


Graham Walker, M del Castillo-Hegyi, Javier Benitez and Chris Nickson picked up the blog post, spread it through social media and Twitter, and suggested I write a formal response to JAMA for peer-reviewed publication.  My response – I could put time into such a response, but what would JAMA’s motivation be to publish an admission of embarrassing failure of peer-review?  And, whatever response they published would be sequestered behind a paywall – while BRAHMS/ThermoFisher continued to happily reprint away their evidence review from JAMA.  Therefore, I will write a response – but I will publish it openly here, on the Internet, and the social peer review of my physician colleagues will determine the scope of its dissemination based on its merits.


Again, this JAMA article concerns procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections.  This is written by Drs. Schuetz, Briel, and Mueller.  They each receive funding from  BRAHMS/ThermoFisher for work related to procalcitonin assays (www.procalcitonin.com).  The evidence they present is derived from a 2012 Cochrane Review – authored by Schuetz, Mueller, Christ-Crain, et al.  The Cochrane Review was funded in part by BRAHMS/ThermoFisher, and eight authors of the review declare financial support from BRAHMS/ThermoFisher.


The Cochrane Review includes fourteen publications examining the utility of procalcitonin-based algorithms to initiate or discontinue antibiotics.  Briefly, in alphabetical order, these articles are:

  • Boudama 2010 – Authors declare COI with BRAHMS.  This is a generally negative study with regards to the utility of procalcitonin.  Antibiotic use was reduced, but mortality trends favored standard therapy and the study was underpowered for this difference to reach statistical significance (24% mortality in controls, 30% mortality in procalcitonin-guided at 60 days).
  • Briel 2008 – Authors declare COI with BRAHMS.  This study is a farce.  These ambulatory patients were treated with antibiotics for such “bacterial” conditions as the “common cold”, sinusitis, pharyngitis/tonsilitis, otitis media, and bronchitis.  
  • Burkhardt 2010 – Authors declare COI with BRAHMS.  Yet another ambulatory study randomizing patients with clearly non-bacterial infections.
  • Christ-Crain 2004 – Authors declare COI with BRAHMS.  Again, most patients received antibiotics unnecessarily via poor clinical judgement, for bronchitis, asthma, and “other”.
  • Christ-Crain 2006 – Authors declare COI with BRAHMS.  This is a reasonably enrolled study of community-acquired pneumonia patients.
  • Hochreiter 2009 – Authors declare COI with BRAHMS.  This is an ICU setting enrolling non-respiratory infections along with respiratory infections.  These authors pulled out the 47 patients with respiratory infections.
  • Kristofferson 2009 – No COI declared.  Odd study.  The same percentage received antibiotics in each group, and in 42/103 cases randomized to the procalcitonin group, physicians disregarded the procalcitonin-algorithm treatment guidelines.  A small reduction in antibiotic duration was observed in the procalcitonin group.
  • Long 2009 – No COI declared.  Unable to obtain this study from Chinese-language journal.
  • Long 2011 – No COI declared.  Most patients were afebrile.  97% of the control group received antibiotics for a symptomatic new infiltrate on CXR compared with 84% of the procalcitonin group.  85% of the procalcitonin group had treatment success, compared with 89% of the control group.  Again, underpowered to detect a difference with only 81 patients in each group.
  • Nobre 2008 – Authors declare COI with BRAHMS.  This is, again, an ICU sepsis study – with 30% of the patients included having non-respiratory illness.  Only 52 patients enrolled.
  • Schroeder 2009 – Authors declare COI with BRAHMS.  Another ICU sepsis study with only 27 patients, of which these authors pulled only 8!
  • Schuetz 2009 – Authors declare COI with BRAHMS.  70% of patients had CAP, most of which was severe.  Criticisms of this study include critique of “usual care” for poor compliance with evidence supporting short-course antibiotic prescriptions, and poor external validity when applied to ambulatory care.
  • Stolz 2007 – Authors declare COI with BRAHMS.  208 patients with COPD exacerbations only.
  • Stolz 2009 – Authors declare COI with BRAHMS.  ICU study of 101 patient with ventilator-associated pneumonia.

So, we have an industry-funded collation of 14 studies – 11 of which involve relevant industry COI.  Most studies compare procalcitonin-guided judgement with standard care – and, truly, many of these studies are straw-man comparisons against sub-standard care in which antibiotics are being prescribed inappropriately for indications in which antibiotics have no proven efficacy.  We also have three ICU sepsis studies included that discard the diagnoses other than “acute respiratory infection” – resulting in absurdly low sample sizes.  As noted yesterday, larger studies in ICU settings including 1,200 patients and 509 patients suggested harms, no substantial benefits, and poor discriminatory function of procalcitonin assays for active infection.  

Whether the science eventually favors procalcitonin, improved clinical judgement, or another biological marker, it is a failure of the editors of JAMA to publish such deeply conflicted literature.  Furthermore, the traditional publishing system is configured in such a fashion that critiques are muted compared with the original article – to the point where I expect this skeptical essay to reach a far greater audience and have a greater effect on practice patterns via #FOAMed than through the traditional route.

Diverticulitis – The Sinusitis of the Colon?

Antibiotics are wonderful things.  They treat and provide life-saving amelioration of symptoms from the common cold, the flu, bronchitis, sinusitis, and otitis – or, more accurately, they don’t.  Rather than generalize the treatment with antibiotics for all these illness, it is rather the avoidance of antibiotics that should be generalized, with specific exceptions made as necessary.

The next “-itis” to go under the microscope is diverticulitis.  These authors from Iceland and Sweden deserve, at the minimum, kudos for innovation in swimming against the tide.  The treatment of acute diverticulitis – a febrile illness with an elevated WBC and left-lower quadrant pain – is generally gram-negative and anaerobic coverage as an inpatient or outpatient, depending on comorbidities.  These authors propose that diverticulitis is most frequently a self-limited process, rather than one that requires antibiotics.

This a non-blinded trial of antibiotics vs. non-treatment for CT-demonstrated acute, uncomplicated diverticulitis.  Over 600 patients were admitted, with half receiving simple observation and symptomatic treatment vs. half with the same plus antibiotics.  1% of patients in the antibiotic group suffered treatment failure – progression to abscess or perforation – compared with 2% of patients in the placebo group.

Unfortunately, we’re not quite done with antibiotics based on just this study.  It is unblinded with variable enrollment between centers, leading to several sources of potential bias.  Then, ten patients in the no-antibiotics group crossed over to receive antibiotics for clinical worsening during hospitalization.  However, this is still below the 6.5% complication rate the authors thought might be an acceptable failure rate for conservative therapy.

Many more questions to be answered regarding external validity, so hopefully this inspires other investigators to further explore which subset patients will derive benefit from antibiotics in diverticulitis.

“Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis”
www.ncbi.nlm.nih.gov/pubmed/22290281

Viral Testing in Children With Fever

This study attempts to address the question we’ve been asking ourselves since the dawn of antibiotics – does this child with a fever have a viral infection, or a bacterial infection?  Of course, in reality, we should be asking a more complicated question – does this child have a viral infection, or a bacterial infection for which the increased likelihood of positive outcome with antibiotics outweighs the harms of the antibiotics?  But, I digress.

One hypothesis that is bandied about in literature and practice is, if rapid viral testing were available in the Emergency Department, perhaps a positive viral test result would reduce the likelihood of antibiotic usage.  These folks from Washington University performed viral PCR for a host of common viruses on 75 children with fever without a source, 15 children with probable bacterial infections, and 115 afebrile children presenting for outpatient surgery.  The authors note the patients with bacterial infections were less likely to test positive for a virus – and suggest prospective trials might describe a strategy in which viral testing decreased antibiotic use.

In their cohort, 55% of children aged 2 to 12 months and 39% of those aged 13 to 24 months with no obvious source for fever received antibiotics.  This is irresponsible lunacy.  However, a much faster, cheaper way to decrease antibiotic use is:  to simply return from the abyss of antibiotic overuse to a land of rational practice.  

After all, 40% of the bacterial infections and 35% of the outpatient surgical patients tested positive for a virus – clearly indicating the presence of a virus has limited association with acute viral illness or absence of an acute bacterial infection.  More tests are not the answer – at least, certainly not this battery of PCR tests.

“Detection of Viruses in Young Children With Fever Without an Apparent Source”
http://www.ncbi.nlm.nih.gov/pubmed/23129086

Azithromycin – Not Guilty of Murder

The FDA has announced it is reviewing the safety of azithromycin in lieu of a recent NEJM article documenting an association between azithromycin and cardiovascular death.  In theory, azithromycin has been implicated in QT-prolongation and pro-arrhythmic effects, leading to torsades de pointes and polymorphic ventricular tachycardia.  The authors of this study therefore hypothesized an association between azithromycin use and cardiovascular death.

This is a retrospective study of computerized data generated from the Tennessee Medicaid program between 1992 and 2006, linking deaths to any concurrent antibiotic prescriptions.  The authors data-mined for a cohort aged 30 to 74 years of age, had no “life threatening non-cardiovascular illness”, did not abuse drugs, and did not reside in a nursing home.  They compared azithromycin prescriptions to non-prescription controls, as well as amoxicillin, ciprofloxacin, and levofloxacin cohorts.  And, after a little statistical maneuvering, they report a death rate of 85.2 per 1,000,000 courses of antibiotics with azithromycin, which compares to a death rate of 29.8 with no antibiotic and 31.5 with amoxicillin.

So, for every ~20,000 prescriptions of azithromycin written, there is one additional death from cardiovascular causes.  This is another one of those cases where the severity of the absolute difference doesn’t quite match the relative difference – it is likely any efficacy difference between a macrolide and a second-line agent results in greater morbidity than the magnitude of effect found in this study.

Then, azithromycin is frequently prescribed for upper and lower respiratory tract infections – conditions that, in the absence of other specific signs, might be non-infectious cardiovascular disease misdiagnosed as having an infectious etiology.  In their non-propensity matched cohorts, 50% more azithromycin prescriptions were written for respiratory symptoms than amoxicillin.  The propensity matching in their statistical analysis attempts to account for this, but 30% of their azithromycin prescriptions had no documented indication – which I think means there’s likely a hidden statistical difference in underlying pathophysiology secondary to unknown indications.

Finally, this runs contrary to a 2005 article “Azithromycin for the Secondary Prevention of Coronary Events” published in NEJM – at one point, it was theorized that azithromycin would be protective for coronary events.  For 4,000 patients who took azithromycin weekly for a year, there was no difference in cardiovascular outcomes as compared to placebo (CI -13% to +13% relative risk reduction).

There are lots of reasons not to prescribe azithromycin, but this study isn’t the one that should change your practice.

“Azithromycin and the Risk of Cardiovascular Death”
http://www.nejm.org/doi/full/10.1056/NEJMoa1003833

Over-Prescribing of Antibiotics Happens Everywhere

On Twitter a couple weeks back, in response to my plea to reduce empiric macrolide use for benign clinical syndromes, there was an allusion suggesting Pediatricians were the culprits of a poor antibiotic stewardship.

Of course, that’s clearly not the case.  And, while we all envision Urgent Cares and customer-service medicine contributing to the over-prescription of antibiotics, it’s happening in our academic medical centers, as this article indicates.  This is a retrospective chart review from San Diego that evaluated 836 patients receiving a diagnosis of “acute bronchitis”, a typically self-limited disease that evolves into pneumonia only in a minority of cases in elderly patients or patients with significant pulmonary comorbidities.

The average age was 46, 10% had comorbid COPD noted, 17% asthma, 8% diabetes, and 4% HIV/AIDS.  All told, 74% were prescribed antibiotics – 50% received a macrolide, 15% a tetracycline, 6% a fluoroquinolone, along with a few others.

Unfortunate.

And certainly not just the Pediatricians.

“Antibiotic and bronchodilator prescribing for acute bronchitis in the Emergency Department.”
http://www.ncbi.nlm.nih.gov/pubmed/22341759

The Tiniest Three Year Sinusitis Trial

Yet again, another article that saturated the lay press due to its publication in JAMA – this time regarding amoxicillin for acute sinusitis.

The problem is, I agree with the fundamental point the authors are making – according to the introduction, antibiotics for sinusitis account for 1 in 5 antibiotic prescriptions in the United States and they’re typically unnecessary, especially in an era where better antibiotic stewardship is needed.  However, I cannot imagine how a multicenter study of ten community clinics in St. Louis over three years only managed to enroll 166 adults into this study over the course of three years.  Their recruitment diagram states only 244 patients were assessed for eligibility – which seems like it ought to be a a couple months worth of URI presentations in an outpatient setting.

If you read the newspaper, you already know the main results – “no difference between 10 days of amoxicillin and placebo.”  But 11 of 85 intervention group patients discontinued treatment, as well of 12 of 81 placebo patients.  Due to lost data, 4 of 85 intervention patients were excluded from analysis, as well as 7 of 81 placebo patients.  Then, 32% of patients in the intervention group were non-compliant with the intervention – so, while this is valid in a real-world effectiveness sense, they’re increasingly no longer relevant to the actual efficacy of the intervention.  These are big holes in a small study.

And, bizarrely, the baseline characteristics they use to describe the two groups include more social characteristics than clinical characteristics – healthcare insurance, family income, etc.  Children living in the home, children in day care, etc., is an interesting demographic criteria, suggesting unique infectious exposure – 9% more intervention group patients had children at home, but this isn’t statistically significant because the sample sizes are so tiny.  Then, the clinical characteristics they chose only seem to partially reflect issues relevant to antibiotic efficacy – “usual health excellent or good” isn’t a very useful descriptor of whether they have impaired baseline immune function that places them at increased risk of significant bacterial superinfection.  For what it’s worth, the control group was significantly “healthier”, but also had significantly more smoking history.

Getting back to the main results – yes, the average SNOT-16 scores were equal at day 0, 3 and 10, but favored the intervention at day 7 – leading to their final conclusion that amoxicillin was of no benefit.  But, at the individual patient level, the control group patients were impaired from their usual activities almost 50% longer – 1.67 days vs. 1.15 days, and there was a 12% absolute difference in satisfaction with treatment favoring the intervention – 53% vs. 41 %.  But, due to the tiny sample size, none of these differences reached statistical significance.

In the end, it’s a fair real-world trial and addition to the literature, but it’s far too small and flawed a trial to stand on to as evidence.

Oddly, one of the authors receives royalties for the SNOT-16 scale.

“Amoxicillin for Acute Rhinosinusitis: A Randomized Controlled Trial”
http://jama.ama-assn.org/content/307/7/685

Dog Bites and Antibiotics

Nicholas Genes of…well, multiple sites of fame, including recurring columns in several EM publications, SAEM leadership, and the long-standing medical blog “blogborygmi” beat me to this ACEP News item from today:

MedPage Today (12/9, Walsh) reports that a study presented in a poster session at the midyear clinical meeting of the American Society of Health-System Pharmacists (ASHP) found that only 64% of the patients presenting to the emergency department with animal bites “were discharged on the appropriate antibiotic.”


I won’t attempt to replicate his scathing criticism of ACEP News for publicizing a poster from an interim pharmacy conference, just read it for yourself:
http://blogborygmi.tumblr.com/post/13967004314/among-98-patients-seen-with-bites-over-the-course

Ceftaroline – The New Wonder Drug

Don’t use it.

If you’re like me, every journal you pick up nowadays has a three page glossy fold-out of some confident-looking fake doctor showing off the new broad-spectrum magic medicine, ceftaroline fosamil (Teflaro).  600mg IV q12, ask your doctor if you should be receiving Teflaro.

So, finally, when I got a booklet mailed to my house, I gave in and looked at the literature.  And, I was almost legitimately defeated by the literature because most of the recent, relevant published literature regarding outcomes in the phase III trials…is written by employees of Forest Laboratories and published in a special “clinical supplement” to an infectious disease journal.  There isn’t much data out there that isn’t just advertising.

However, my survey of the animal studies, and presuming the human studies aren’t blatantly made up, seems to indicate this is a great antibiotic.  It doesn’t work against VRE, pseudomonas, ESBL e. coli, ESBL klebsiella, or acinetobacter, but it’s active against many strains of MRSA, DNS MRSA, and VISA, along with the other strep and staph we worry about.

Which is exactly why we shouldn’t use this antibiotic – it’s so good it should be on every hospital’s formulary, but locked in a vault with the same key system a nuclear launch requires.  Keep it as third- or fourth-line to prevent additional resistances.  But, don’t use it.

Sadly, the article I have for you is just a review of all the manufacturer-supported data – but at least it’s not written by them.

“Ceftaroline: a comprehensive update.”
http://www.ncbi.nlm.nih.gov/pubmed/21420284

Move Over MRSA – It’s VISA and VRSA Time

Is it too late to buy stock in the company that makes linezolid?

This group up in Detroit reviewed 320 patients with MRSA bacteremia and found that 52.5% experienced Vancomycin failure.  Their conclusion states several significant OR for failure, but review of the between-group differences doesn’t show a lot of significant differences.  Nursing homes, for example, were the only p < 0.05, and predicted vancomycin success with a p of 0.02.

What is more important than their clinical predictors, however, is their review of the bactericidal activity of vancomycin – and that higher MICs and higher troughs are needed to effectively treat patients.  I’ve seen our pharmacists recognize this at my hospital as well – the 1g IV Vancomycin standard initial load is transitioning to a weight-based dose.

But, more importantly, what we’re probably really observing is the initial stages of the end of vancomycin’s utility for MRSA.  And, I hate to see what happens when TMP/SMX stops working, too….

http://www.ncbi.nlm.nih.gov/pubmed/21460309

Pediatric Septic Shock Protocol

Another sort of goal-directed sepsis study, this time in Pediatrics at Primary Children’s.  They implemented a protocolized triage system in their ED designed explicitly identify more cases of sepsis – which led to increased percentages getting early fluid resuscitation, early lactate level measurements, and more frequently antibiotics in the first three hours.

But the net effect of all these interventions…the only detectable difference in their 345 patient cohort was improved length-of-stay for survivors, from IQR 103-328 hours pre-intervention to IQR 86-214 post-intervention.  Total hospital costs were not significantly different.  No change in mortality – which was already low at 7%.
So, yet again – adherence to “quality measures” has debatable clinical significance.