Category: Antibiotics

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.

Procalcitonin Misleads Antibiotic Therapy In Sepsis

An important negative study of an inflammatory biomarker that’s been getting a fair amount of push.

It is absolutely true that procalcitonin levels may be elevated in an inflammatory states such as sepsis.  This group tried to make a clinically relevant protocol for procalcitonin trends by saying, if the procalcitonin level is not decreasing with current therapy, then antibiotic coverage should be expanded and aggressive testing should be undertaken to evaluate for missed source control.

Unfortunately, in the treatment arm where procalcitonin was used in clinical decision making, there was extensively greater broad-spectrum and multiple-antibiotic utilization without any demonstrated mortality benefit.  In addition, LOS and ventilator-depended days were longer in the procalcitonin arm.

There were very minor differences between the two groups, probably favoring the control, but not nearly enough to suggest that procalcitonin has any value in assessing failure of current therapy.

http://www.ncbi.nlm.nih.gov/pubmed/21572328

Early Antibiotics Show No Benefit in Sepsis

Interesting analysis of the EMSHOCKNET cohort, looking to see if there was any association between time to antibiotic administration and survival benefit in septic shock.

And, no.  Earlier antibiotic administration, as measured by arrival time in the the ED, showed no significant impact.

They do another secondary analysis where they try to say, well, if the patient received antibiotics before they met criteria for septic shock – then they had a 2.59 (1.17 – 5.74) OR for survival.  I’m not sure how to interpret this finding – perhaps because they looked at 10 different cut-off points for antibiotic administration, they found one that favored antibiotics by chance.

Or, perhaps antibiotics really aren’t the lynchpin in treating sepsis – if you can give antibiotics ahead of SIRS, perhaps you have a milder case – but once you have end-organ dysfunction, the interventions that target improving the physiologic changes of sepsis are more important.

http://www.ncbi.nlm.nih.gov/pubmed/21572327

Augmentin Is Non-Inferior to Appendectomy

A lovely study out of The Lancet that tells us what we already know…is not as right as we thought it was.  We’ve all seen the pediatric patient, usually female, that went to their pediatrician’s office with abdominal pain, had evidence of cystitis on a UA, and was prescribed amoxicillin or cephalexin.  They got a little better, but they’re still having some nausea, some pain, and some loose stools.  In your ED, the ultrasound is positive for free-fluid without visualization of the appendix, and a CT scan subsequently shows evidence for appendiceal rupture.  But – as we’ll see here – most cases probably resolved before you saw them.

This is a prospective study randomizing patients to antibiotics versus early surgery, and the antibiotic group here actually had a lot more success than we imagine – since all we see/remember are those patients where we discovered the “latent” appendicitis, partially treated and festering after that initial course of antibiotics.  Only 12% of their CT-proven uncomplicated appendicitis went on to have a appendectomy in the first 30 days, and 30% within a year.  So, you could almost argue that with an 88% short-term cure rate with antibiotics and a 70% medium-term cure rate, antibiotics should be first-line therapy with observation for clinical worsening.

Definitive therapy has its advantages – you could almost equate the appendix to the gallbladder, and say that the 30% recurrence is almost certain to rise in subsequent years.  But, is there an advantage to waiting to do an appendectomy on an elective basis?  Are the adhesions that might develop more or less of an issue that the risks associated with emergent surgery?  And, of course, in the female pelvis, any undertreated appendicitis represents a significant fertility risk.  This study raises great questions about whether we should change our practice regarding our approach to appendicitis, and it might just be we find a role for being less aggressive with surgery.

“Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial.”
http://www.ncbi.nlm.nih.gov/pubmed/21550483