Antibiotics – Page 7 – Emergency Medicine Literature of Note

Let’s Make MRSA Stronger

Yesterday, the NEJM published two new trials regarding new lipoglycopeptide antibiotics targeting MRSA. And, it remains to be seen whether their use represents the beginning of the end.

Oritavancin and dalbavancin differ from vancomycin – and this is their primary advertised advantage – in terms of substantially lengthened terminal half-life. This means oritavancin may be used as a one-time dose, and dalbavancin as a two-dose regimen a week apart. Both trials involved severe soft-tissue infection, and were non-inferiority trials comparing each against either intravenous vancomycin alone or intravenous vancomycin transitioning to oral linezolid. Exclusion criteria were extensive for each, but the ultimate non-inferiority results for treatment failure are reasonably generalizable. Adverse events, as well, were similar between study populations. At face validity – if you trust trials that are designed, conducted, and analyzed by pharmaceutical companies – these treatments are safe and effective.

The accompanying editorial enthusiastically supports these new options, saving patients unnecessary costs and risks associated with hospitalization or indwelling intravenous catheters. This is likely true, although it remains to be see whether single-dose infusion pricing will ultimately prove less expensive than a transition to oral linezolid. Then, single-dose antibiotic strategies may have a horrible downside: induced resistance. With terminal half-lives up to two weeks in the case of oritavancin, the active metabolite will be present in the body for a prolonged period of time below the minimum inhibitory concentration. As we’ve seen with azithromycin, another antibiotic with a long half-life, increased use was associated with a rapid rise in macrolide resistant streptococcus. It’s hardly a stretch to project similar effects here.

Widespread use of these “convenient” antibiotics may eventually result in significant unintended harms, and possibly the loss of an entire class of effective treatment for MRSA.

“Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection”
http://www.nejm.org/doi/full/10.1056/NEJMoa1310480

“Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections”
http://www.nejm.org/doi/full/10.1056/NEJMoa1310422

More of the Same Inappropriate Antibiotic Prescribing

There is no debate regarding the correct treatment of acute bronchitis in patients without underlying immunodeficiency or pulmonary structural disease. The correct antibiotic treatment is: none. This is not a controversial subject. Indeed, as this research letter in JAMA notes, since 2005 the National Committee of Quality Assurance has published a measure in the Healthcare Effectiveness Data and Information Set stating the correct rate of antibiotic prescribing in acute bronchitis is: zero.

If you’re hoping this next part is where I excitedly share a successful reduction in inappropriate antibiotic use, you’ll be more than a little disappointed.

Using The National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, these authors found, unfortunately, that 71% of patients with acute bronchitis are receiving a prescription for antibiotics in outpatient settings. There was essentially no difference in prescribing rates over any of the NAMCS samples – we were just as irresponsible in the 2008-2010 survey period as we were in the 1996-1998 period. There was no difference in rate between Emergency Department and primary care settings, nor in race, age, insurance status, nor care location. 41% of patients received an extended macrolide – azithromycin – followed most commonly by fluroquinolones, aminopenicillins, and cephalosporins.

Yes, Virginia, a self-limited condition for which antibiotics confer no benefit frequently receives fluoroquinolone therapy.

Words fail me. I will simply quote the authors’ conclusion:

“Avoidance of antibiotic overuse for acute bronchitis should be a cornerstone of quality health care. Antibiotic overuse for acute bronchitis is straightforward to measure. Physicians, health systems, payers, and patients should collaborate to create more accountability and decrease antibiotic overuse.”

“Antibiotic Prescribing for Adults With Acute Bronchitis in the United States, 1996-2010”
http://jama.jamanetwork.com/article.aspx?articleid=1872806

VUR, Renal Scarring and other Fictitious Maladies

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

As Emergency Physicians, one of the more vexing tasks asked of us is to identify the otherwise well appearing patient who has an occult illness that, if not identified, will lead to poor outcomes. With this in mind, we now turn our attention to the well appearing febrile infant and our unfounded obsession with urine. The fear that these children are quietly infarcting their nephrons is one of the more far fetched tales in emergency medicine.

  In a recent NEJM article published by the RIVUR Trial Investigators, the authors examined whether prophylactic antibiotics for children with voiding cystourethrogram (VCUG) confirmed vesicoureteral reflux(VUR) were effective in preventing recurrent infections and more importantly, decreasing the extent of renal scarring (as per DMSA scan). Patients were randomized to either daily trimethoprim-sulfamethoxazole (TMP-SMX) suspension or placebo for one year. Authors found that children treated with prophylactic antibiotics had an absolute decrease in the recurrence of urinary tract infections by 12%. Meaning, you would have to treat 8 children for 12 months to prevent one case of recurrent UTI. More importantly the rate of renal scaring at follow up was identical.   Among the children who experienced their first recurrent UTI, the rates of E. coli resistance to to TMP-SMX was 63% in the active group vs 19% in the controls.

Though this trial fails to address the futility of our quixotic attempts to diagnose and treat every UTI, clearly the utility of searching for and diagnosing VUR in febrile children in the hopes of preventing future renal scarring is a flawed concept. Furthermore it is unclear whether the surrogate endpoint of renal scarring, as seen on DMSA, is clinically relevant. Not only are we most likely treating a fictitious disease process, but as the RIVUR authors demonstrated we are doing so ineffectively.

“Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux.” http://www.ncbi.nlm.nih.gov/pubmed/24795142

The End of Appendectomies?

We’ve seen dogma challenged regarding diverticulitis and the necessity of antibiotics. This isn’t the first post regarding a change in initial strategy for appendicitis, however, it’s certainly reasonable to revisit again as the evidence accumulates.

This study is simply a prospective, observational case series of 159 patients with acute, uncomplicated appendicitis. In 2010, this institution in Italy made surgical appendectomy the exception, rather than the rule. Patients without serious illness or complicated appendicitis were admitted for short term observation and started on amoxicillin-clavulanate. Patients who failed to improve or worsened went to the OR. Others were discharged and re-examined at 5-7 days as an outpatient, and, again, those without significant improvement went to the OR. Over a 2 year follow-up period patients were assessed by phone.

Within 7 days, there were 19 (12%) treatment failures; 17 of 19 were acute appendicitis, 2 were tubo-ovarian abscess with secondary appendiceal inflammation. Over the 2 year follow-up, 22 (13.8%) patients had recurrent appendicitis – 14 of which were managed with antibiotics without complication. 8 went to the OR, 6 of which were confirmed as acute appendicitis.

I don’t think we’d have the same issue with misdiagnosed TOAs in our population – 73% of their diagnoses were by ultrasound, and only 17% underwent CT. 12% short-term treatment failure is also nothing to scoff at – and this number is consistent with other studies. Routine surgery, however, is much costlier, resource-intensive, and carries with it a similar or greater risk of major complications. It seems to me this is absolutely a viable strategy.

Is it time surgery added “Consider a trial of antibiotic therapy prior to surgery for acute, uncomplicated appendicitis” to their Choosing Wisely list?

“The NOTA Study (Non Operative Treatment for Acute Appendicitis)”
http://www.ncbi.nlm.nih.gov/pubmed/24646528

Azithromycin, the World’s Most Effective Antiviral

The only thing better than providing one mostly useless treatment for influenza: providing two.

Sponsored by Pfizer and overseen by authors with Pfizer COI, this study randomizes patients between oseltamivir (Tamiflu) monotherapy and oseltamivir + azithromycin dual-therapy for influenza. The theory behind the madness is azithromycin modulates anti-inflammatory processes and decreases the susceptibility to secondary bacterial pneumonia. Thus, the primary endpoint of the study was … well, there wasn’t one. “The primary endpoint was defined as variations in the levels of inflammatory markers” – 20-odd co-primary endpoints – while patient-oriented, symptom-oriented endpoints were secondary.

Of the 107 patients enrolled, baseline characteristics were similar – although the dual-therapy arm had significantly more cough. And, as far as could be possibly conceived as relevant, all the outcomes were identical – although the dual-therapy arm had 16.1% incidence of possible drug-related adverse events, compared with 7.8% in the monotherapy arm. As far as the “primary endpoint”, the authors data-dredged ten different inflammatory cytokines and serum markers for changes in levels between day 2 and day 5 – and also could not find any clinically significant positive findings.

Sadly, the authors were undeterred in their desire to support their initial hypothesis – and thus conclude in their abstract “combination therapy showed an early resolution of some symptoms.” Specifically, on day 2 of therapy, there was a statistically significant difference in improvement in sore throat symptoms that evaporated by day 5 – and, using ANOVA, they found “sensation of heat” was decreased in the azithromycin group. Considering this was an open-label study and the authors performed at least 60 different statistical comparisons, it’s simply tragic science they bothered to make any substantial note of these outcomes.

This is simply junk. The pre-study likelihood of finding a difference must be considered low, so even the “trends” they observe in secondary endpoints should not encourage anyone to adopt this treatment strategy. Please, please – don’t use either of these treatments for influenza in the absence of any sort of reliable evidence for benefit. We have enough waste and harm in the world from these medications already.

“Efficacy of Combination Therapy with Oseltamivir Phosphate and Azithromycin for Influenza: A Multicenter, Open-Label, Randomized Study”
http://www.ncbi.nlm.nih.gov/pubmed/24632748

Can We Escape Antibiotics in Sore Throat?

Yes. And no.

It is well-established complications of acute sore throat are incredibly rare. The likelihood of a patient developing the most concerning of suppurative complications – a peritonsillar abscess or “quinsy” – is less than a fraction of a percent. Rheumatic fever is virtually eliminated in the United States. Yet, as we see from this British cohort, over half of patients visiting primary care received a prescription for antibiotics.

This is study reports on a combination of several, prospectively gathered cohorts presenting with acute sore throat to British primary care practices. Comprising 14,610 adults, only 5,243 escaped the physicians office without an antibiotic prescription, while the remainder received immediate or delayed antibiotics. Suppurative complications across all cohorts – peritonsillar abscess, sinusitis, otitis media, and cellulitis – ranged from 0.1% to 0.6%.

Unfortunately, this is not a randomized trial – the patients who were given antibiotics by their physician had much more severe initial clinical presentations. This means, unfortunately, there is no information in this data set describing the actual protective effect of antibiotics without making statistical contortions. The main value, however, is in describing the futility of clinical judgement for selecting patients for antibiotics. Of all the various clinical features recorded prospectively for each patient, only severe ear pain and severely inflamed tonsils were significant predictors of suppurative complications – with ORs of 3.02 and 1.92, respectively. However, these still constituted hundreds of patients with symptoms who otherwise did not progress. High scores on the Centor and FeverPAIN criteria were similarly, minimally predictive.

In the end, it is ultimately apparent antibiotics confer some protective effect. The absolute benefit, however, will represent just a handful of patients out of thousands. The authors sum it up just as nicely as I might:

“Since a policy of liberal antibiotic prescription for sore throat to prevent complications is highly unlikely to be cost effective, and clinicians cannot rely on clinical targeting to predict most complications, clinicians will need to rely on strategies such as safety netting or delayed prescription in managing the low risk of suppurative complications.”

“Predictors of suppurative complications for acute sore throat in primary care: prospective clinical cohort study”
http://www.bmj.com/content/347/bmj.f6867 (open access)

Stop Using the Antibiotic Sledgehammer

There’s an interesting cultural phenomenon regarding inpatient treatment of respiratory illnesses – a sense that monitoring and close evaluation for treatment failure isn’t enough, and we must immediately deploy the nuclear option when the admission decision is made. This includes nonsense use of intravenous administration when oral is equivalent and unnecessary use of broad-spectrum agents.

This comparative-effectiveness study evaluated the necessity of broad-spectrum agents versus narrow-spectrum antibiotics for the treatment of pediatric community-acquired pneumonia. 492 CAP admissions from four children’s hospitals in 2010 were retrospectively reviewed for outcomes, stratified by antibiotic choice. Narrow-spectrum antibiotic choices were penicillin-like agents +/- macrolide, while broad-spectrum included cephalosporins or fluoroquinolones.

In their propensity-matched cohort, with the acknowledged limitations of unmeasured baseline characteristics, there were no useful differences in outcomes. Most trends favored narrow-spectrum antibiotics, but these are at best statistical noise, and at worst reflect underlying unmatched treatment-episode confounders.

Current consensus-based recommendations are for initial treatment with narrow-spectrum agents – follow them. I’d also note 51% of the population received blood cultures – 2.8% of which were positive. I’m sure these were also entirely a waste of money.

“Comparative Effectiveness of Empiric Antibiotics for Community-Acquired Pneumonia”
http://www.ncbi.nlm.nih.gov/pubmed/24324001

Sepsis, NHAMCS, and Non-Truths

“… our results provide a worrisome view of the quality of care of septic patients in U.S. EDs.”

Crikey.

This is serious business. Tell me more.

“Our data suggest that many emergency department patients (31%) with sepsis do not receive antibiotics until they arrive on the inpatient unit.”

This is somewhat concerning data. Of course, some patients can have sepsis from viremia, and would not warrant antibiotics – but, I think most admitted patients with SIRS and a suspected infectious source ought to receive treatment.

But, unfortunately, for this study, the question is less the quality of ED care, and more the quality of the data source. The National Hospital Ambulatory Medical Care Survey is a lovely data set, whose quality is only increasing as coding and structured data become more prevalent – but a retrospective analysis of these data is not appropriate substrate to make sweeping generalizations regarding the care in the Emergency Department.

From the ~400 Emergency Departments providing yearly data to NHAMCS, 0.32% of patients met their definition of sepsis. That meant these data reflect a sample of 1,141 patients, and the admitted limitation of “studies relying on NHAMCS data are vulnerable to errors of omission in data collection.” These authors lack information regarding previously administered antibiotics from transferred patients, and admit some patients – those spending <1 hour in the ED – may simply have left the ED before antibiotic administration could be completed.

Quite simply, it’s (mostly) garbage in and (mostly) garbage out.

The authors also attempt an assessment of antibiotic appropriateness from this retrospective chart abstraction. It is so egregiously flawed it doesn’t even warrant comment.

“Sepsis Visits and Antibiotic Utilization in U.S. Emergency Departments”
http://www.ncbi.nlm.nih.gov/pubmed/24201179

Another Appeal for Prudent Antibiotics

Bronchitis, deadly scourge of man – at least, considering the quantity of antibiotics prescribed, it must be, right?

Or, the cure is worse than the disease, as these authors seem to demonstrate. This is a parallel, single-blinded, placebo-controlled trial in 9 primary care centers in Catalonia, Spain, enrolling patients with acute bronchitis. Non-immunosuppressed patients with a productive cough of less than a week’s duration were randomized to amoxicillin-clavulanic acid, ibuprofen, or placebo for a 10 day course. The primary outcome was time to cure, with treatment failure and safety outcomes as secondary outcomes.

With approximately 140 patients in each group, the only clinically meaningful significant difference between groups was the incidence of adverse events in the amoxicillin-clavulanic acid group. These were mostly gastrointestinal events, occurring in 12% of the antibiotic group, compared with 5% of the ibuprofen group and 3% of the placebo group. Days with cough, treatment failure, and time to overall symptom resolution showed no significant differences between groups. There was some suggestion of a trend towards benefit from the ibuprofen arm, but this would have to be confirmed in a larger trial.

The main limitation of this article is failure to include a macrolide antibiotic as a comparator, considering the expected bacterial epidemiology of ambulatory respiratory infections. Regardless, this adds to the body of evidence demonstrating the futility of antibiotics in healthy patients with bronchitis – and I’d expect similar findings even if azithromycin were included.

“Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial”
www.ncbi.nlm.nih.gov/pubmed/24097128

A Plea For Strep Throat Simplicity

A recent article published in the BMJ delightfully demonstrates that regardless of how we choose to overcomplicate the treatment of acute pharyngitis, our patients will all do just fine. The authors do have to be commended for their ambition as they attempt to supplant the mighty Centor’s claim as the clinical tool to guide antibiotic use. Not as self-aggrandizing as Centor, they named their rule FeverPAIN, an acronym for its five components. Their ambition is even more noteworthy as they endeavored to describe this rule’s derivation, validation, revision, bootstrap validation and clinical implementation all in one paper.

Despite the authors’ attempts to woo us with promises of bootstrapping and stepwise logistic regression, this study was essentially a pragmatic trial examining the effectiveness of three treatment strategies to guide antibiotic utilization in patients with acute pharyngitis. Patients (3 years or older) were randomized into one of three groups, either delayed antibiotics, antibiotics as determined by the FeverPAIN score, or antibiotics as determined FeverPAIN score and a positive rapid antigen test.

Overall all three groups did well. The average duration of symptoms was 4 days. Both the clinical score group and clinical score + antigen test group had on average one day fewer symptoms than the delayed antibiotic group, all while receiving 10% fewer courses of antibiotics. Initially this finding seems counterintuitive. If more antibiotics were given in the delayed antibiotic group, how then did their symptoms last longer than those in the clinical score groups? Unless of course antibiotics played no role in this difference.

Its important to keep in mind that although this was a randomized trial, it was not blinded. Patients in both the clinical score group and the clinical score + antigen group had an experience in which the doctors spent time medically evaluating them and in some cases even running a “test”. Whereas in the delayed antibiotic group the patients had a less fulfilling experience, instructed to go home and a prescription for antibiotics would be waiting for them if they did not improve. Seemingly the prior two groups had a far stronger meaningful response than those in the delayed antibiotic group, demonstrating it is not antibiotics but rather talking to your patients and explaining the expected course of the disease that makes a difference on symptom burden. Interestingly the rapid antigen test added very little to reduction in antibiotic use and had no effect of length of symptoms.

This trial suffers from what is known as the Pollyanna Effect. If everyone will do well regardless of the intervention they receive, then it is almost impossible to show a clinically relevant superiority of one treatment strategy over another. More importantly with the incidence of rheumatic fever being so low it is considered clinically irrelevant. The question is not which of these strategies is most effective for the treatment of acute pharyngitis but rather is any treatment necessary at all?

“Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomized controlled trial of PRISM (primary care streptococcal management)”. www.ncbi.nlm.nih.gov/pubmed/24114306

Nihilsm, Emergency Medicine and the art of doing nothing at emnerd.com