Category: Antibiotics

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 

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 

Down-Titrating Antibiotics for HCAP

The 2005 IDSA guidelines for healthcare-associated pneumonia are a little bit broad.  If you, a family member, or a pet has e-mailed or read about someone in the hospital, the recommendations are for a full-court press with coverage for multi-drug resistant pathogens.

However, this is clearly inappropriate.  The HCAP population is profoundly heterogenous, where patients receiving home wound care are grouped with patients with recent hospitalization and receipt of IV antibiotics.  It is clear, then, patients will suffer adverse effects and costs from overly-broad spectrum antibiotic coverage.

This group in Japan developed a decision instrument to guide antibiotic therapy, and prospectively evaluated it in 124 CAP and 321 HCAP patients over a two-year period.  Their HCAP stratification is very reasonable: mild disease with 1 additional risk factor for MDR or severe disease with zero risk factors for MDR were treated as CAP.  Everyone else received full HCAP coverage, with MRSA and anti-pseudomonal coverage.

A presumptive causative organism was diagnosed in about 50% of CAP and 60% of HCAP.  Of the 93 patients an organism isolated in the “low-risk” HCAP category, none had MRSA, and 3 had pseudomonas.  In the higher-risk HCAP groups, the low-severity group had 18 of 63 with an MDR pathogen, and the high-severity group had 28 of 56.

It is difficult to conclusively describe the safety of the treating-HCAP-as-CAP strategy, given the lack of a control group and the differences between baseline disease severity.  However, on first glance, it seems unlikely this conservative strategy impacts initial treatment failure and mortality rates in a clinical significant fashion.  This is an approach I’ve advocated for in the past, and plan to continue based on this addition to the body of evidence for individualized antibiotic selection for HCAP.

“A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter Cohort Study Using Risk Factors for Multidrug- Resistant Pathogens to Select Initial Empiric Therapy”
http://www.ncbi.nlm.nih.gov/pubmed/23999080

Yet More Unnecessary Antibiotics

One would think educational efforts regarding the inefficacy of antibiotics for viruses would at some point take root.  I’m pretty sure it’s explicitly covered in our medical school curriculum that antibiotics are indicated specifically to treat infection caused by bacteria.  Despite this, however, the overwhelming evidence is that clinicians have somehow forgotten these basic fundamentals of medicine.
This is a research letter reviewing the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (NAMCS,NHAMCS) databases for visits to primary care or Emergency Departments for code 1455: “sore throat”.  Considering the prevalence of group A strep infection is about 10%, and a small number of additional cases are pathogenic bacterial infections requiring acute treatment, I suppose you would expect the rate of antibiotic prescribing to be quite low?
Is 60% the number you had in mind?
U.S. physicians have been prescribing antibiotics at a mostly steady rate of 60% of visits for sore throat for over a decade.  Not only are they prescribing antibiotics, almost half of prescriptions are for non-ß-lactam antibiotics – including a huge proportion of azithromycin, as if there weren’t enough macrolide-resistant streptococci out there.  Beyond that, a full 15% were not even close to options on the recommended list for acute sore throat, such as fluoroquinolones.
When smart folks like David Newman are calling for the end of routine treatment of strep throat, certainly we are way off base with a 60% rate of treatment.  Forget about OP-15 – we should have a quality measure based on rates of antibiotic prescription for sore throat and ear pain.
“Antibiotic Prescribing to Adults With Sore Throat in the United States, 1997-2010”