Abscess Management in the Era of MRSA

Every so often, it’s good to circle back from the esoteric to the basics, and remind ourselves how to provide the best, evidence-based treatment for some of the most common diseases – in this case, abscesses.

This review in the New England Journal is a reasonable, concise overview of the evidence behind management of cutaneous abscesses, updated for the increasing prevalence of methicillin-resistant Staphylococcus aureus.  And, quite simply, there’s no evidence for any reason yet to panic.  The authors of this article summarize the literature thusly:

  • Incision & drainage is definitive treatment.  Non-complicated disease does not require additional antibiotic treatment, and the incremental benefit – if any – would be single-digit differences in clinical failure.
  • Packing of abscesses is a matter of tradition, and evidence is neither sufficient to conclusively confirm nor refute this practice.
  • Primary closure of abscesses after I&D is reasonable, particularly for larger, exposed, and cosmetically important areas.
  • Antibiotic coverage for primarily cellulitic soft-tissue infections ideally includes both MRSA and streptococcal coverage, but recent evidence showed no advantage to double-coverage.  Clinical trials regarding antibiotic use are ongoing:  NCT00729937 NCT00730028  NCT00729937
  • Wound cultures are not necessary.

One could argue covering such basics in infection and wound management is a sundry affair for a blog frequently covering the cutting edge.  However, current management of such a common condition is so highly variable and frequently low-value, ACEP even made a point to include abscess management in their Choosing Wisely campaign list.

Now, go and do as little harm as possible.

“Management of Skin Abscesses in the Era of Methicillin-Resistant Staphylococcus aureus”
http://www.ncbi.nlm.nih.gov/pubmed/24620867

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

Infections & Transfusions

We love our transfusions down in the Emergency Department.  We especially love them in our trauma patients – and, if anything, the move is to provide earlier, more aggressive volume replacement, and to use more FFP, cryoprecipitate, and platelet product to maintain optimal coagulation parameters.

The downside?  Besides cost, over-utilization of a limited resource, and the various adverse reactions that may occur – there’s a bit of an infection risk.

This JAMA meta-analysis pools together the results of 18 trials comparing “restrictive” vs. “liberal” transfusion strategies for PRBCs.  These trials ranged across medicine from cardiovascular settings, the critically ill, sickle cell disease, and other surgical settings.  In most trials, the restrictive transfusion setting ranged from a Hgb of 7 to 9 g/dL, while the liberal strategies were typically goals above 10 g/dL.  These authors simply looked at the pooled incidence of “serious infection”, which was typically reported as wound infection, bacteremia, pneumonia, or a broad definition of sepsis.

In the “restrictive” transfusion group, there was an overall pooled risk of infectious complication of 11.8% (95% CI, 7.0%-16.7%), compared with an infectious complication rate of 16.9% (95% CI, 8.9%-25.4%) in the “liberal” transfusion group.  The authors estimated a “number needed to harm” between 20 and 38, depending on the restrictive transfusion threshold.

This study does not, by itself, indicate transfusions ought to be withheld when indicated.  Rather, these authors primarily suggest, in order to fully describe the risks and benefits of any transfusion strategy, that infectious complications be included in data collection during trials.  This ought to be of even greater importance in the new surveillance of massive transfusion protocols – as PRBC products aren’t typically even the highest-risk for subsequent infectious complications.

“Health Care–Associated Infection After Red Blood Cell Transfusion”
http://www.ncbi.nlm.nih.gov/pubmed/24691607

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

Tamiflu, the Bell Tolls for Thee

Have you read the revised Cochrane Review regarding neuraminidase inhibitors for preventing and treating influenza?  If you have, I’m impressed; it’s 559 pages long.   There are almost 250 pages of outcomes and treatment comparisons.  It is serious business.

And, it needs to be – because these folks from the Cochrane Collaboration are going up against Roche and a spin machine supporting of billions of dollars in revenue and pandemic flu strategic stockpiling.  The question:  do oseltamivir and zanamivir provide symptomatic relief and prevent serious complications from influenza infection with a reasonable safety margin?

Covering 20 oseltamivir (9,623 participants) and 26 zanamivir (14,628 participants) trials under a new data-sharing agreement, these authors ultimately conclude any faith in neuraminidase inhibitors is unwarranted.  Each treatment provided an advantage of less than a day with regard to symptom resolution – reducing the average duration of symptoms from nearly 7 days to slightly over 6 days.  Neither treatment had any effect on hospitalizations.  Pneumonia definitions were not standardized across trials; a 1% relative risk reduction was seen in investigator-reported pneumonia, but no reduction was seen in studies with radiologic objective measures of pneumonia.  Importantly, both neuraminidase inhibitors – osletamivir especially – were associated with adverse effects.  Nausea & vomiting were the most prominent symptoms, but neuropsychiatric disturbances were increased in a dose-dependent fashion.

Even more damning, there was universal risk of bias across trials – particularly for osletamivir.  The quality of the outcome follow-up for post-treatment complications was poor, allocation was not always blinded, and there was evidence of selective reporting of results.  That any government or guideline organization would base massive public health expenditures on a pharmaceutical corporation’s incomplete reporting of low-quality trials is simply indefensible.

So, there is a small, debatably unimportant effect on symptom duration.  There is zero evidence supporting the routine use of these agents to reduce subsequent infection.  This evidence does not exclude an important effect in a selected sub-population, but the authors of this review feel the underlying mechanism of action does not support such use until an effect is verified.  Furthermore, with regard to follow-up trials, the overall incidence of bacterial complications from influenza is low enough a sample size of over 20,000 patients would be required to detect a clinically meaningful difference.

It must be said – there is likewise potential bias on the side of these authors, who have long been vilifying Roche in this battle over open drug data.  The next step, we hope, will be opening the data to all to review and verify their findings.  We can hope, through repeated battles such as this, the open data day will come where we are able to properly protect patients from inadequate trial evidence.

In the meantime – let us purge ourselves of mandates and patient expectations for Tamiflu before the next influenza season rears its ugly head.

“Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children”
http://www.bmj.com/content/348/bmj.g2545

Procalcitonin in Serious Bacterial Infection: Spoiler Alert – It Doesn’t Help Here Either

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the years, numerous studies have been published attempting to show the benefit for serum markers in diagnosing sepsis or other infections. These markers include ESR, CRP and more recently, procalcitonin (PCT). Despite the reams of literature published, no study has shown a true patient centered outcome benefit to using these markers. Instead of doing an in depth review here of the literature on PCT, I recommend reading Rory Spiegel’s post here.

This recent article from Academic Emergency Medicine attempts to use PCT as an indicator of serious bacterial infection (SBI) in children under 3 years of age. They basically compared PCT with WBC, absolute neutrophil count (ANC) and absolute band count. PCT had the largest area under the curve (0.80 vs. 0.76 for WBC, 0.73 for ANC and 0.67 for absolute band count). Overall, the study found that all of these tests suffered from poor sensitivities but that specificity for PCT (92.7% at a cutoff of 0.6 ng/ml) coupled with its sensitivity (51.6% at the same cutoff) yielded the best positive likelihood ratio of any of these tests (+LR = 7.04). Based on this finding, the investigators conclude that PCT is a “more accurate marker than white blood count, absolute neutrophil count or absolute band count in identifying young febrile infants and children with serious bacterial infections.”
But, are we asking the right question? This study, as with many of the others, tries to use PCT to identify patients that we would otherwise miss as having a serious infection. However, they don’t compare PCT to physician clinical judgment. Or, more importantly, they do not investigate if PCT adds to clinical judgment. Instead, they compare it to markers we know are seriously lacking in their ability to predict (WBC, ANC and absolute band count).
Additionally, the investigators focus on the positive likelihood ratio and the high specificity. But we aren’t concerned about overworkup in febrile kids. As with all bad diseases, we want high sensitivity to make sure we miss as few SBIs as possible and a low negative likelihood ratio to aid in risk stratification. With a strong negative likelihood ratio (-LR < 0.10) we could use a PCT < 0.5 ng/ml to risk stratify patients to a low or very low risk of SBI and potentially send them home with follow up. Here, a PCT < 0.5 ng/ml had a – LR = 0.52. In this study, 13.3% (30/226) patients ultimately had an SBI. If you started with a pretest probability of 13.3% and apply a – LR of 0.52 using the Fagan Nomogram (below) you’d get a post-test probability of around 10%. This is nowhere near low enough for us to stop our workup.
Where does this leave us? Biomarkers will continue to be pushed since there are strong industry interests. Additionally, we want something concrete, objective and tangible to help us with our clinical decision-making. Future studies, though should focus on the additional benefit of markers to the clinician’s assessment and gestalt instead of looking at the biomarker in a vacuum. Show us this and we’ll all sit up and take notice. Until then, procalcitonin is simply another test without a clear indication.

Special thanks to Rory Spiegel (@CaptainBasilEM) and Mike Mojica for the help with this post.

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

Kids with Tubes and Otitis Media Get Drops not Pills

A guest post by Anand Swaminathan (@EMSwami) of EM Lyceum and Essentials of EM fame.

Over the last decade, researchers have sought to determine the usefulness, or lack there of, for systemic antibiotics in a number of infectious etiologies previously thought to require antibiotics for resolution. This includes strep throat, sinusitis, bronchitis and, more recently, diverticulitis. Acute otitis media (AOM) has long been a target for such studies and recently, the guidelines have changed. The American Academy of Pediatrics now endorses a “wait and see” approach for many children with AOM while also recommending a more stringent definition of the disease.

What about for patients with tympanostomy tubes who present with signs of AOM? These patients typically present with otorrhea (pus from the tympanostomy tube). Is the presence of drainage adequate to treat or should these patients be placed on oral or topical antibiotics? Small trials have shown good efficacy of topical antibiotics but Pediatricians and Emergency Physicians continue to prescribe oral antibiotics in the face of inadequate evidence.

The researchers here attempt to answer this question. They performed a fairly large study of 230 children who were randomized to either observation, oral antibiotics or topical antibiotic-glucocortocoid drops in an open-label fashion. The primary endpoint was resolution of otorrhea at 2 weeks. The results are surprising. Resolution was seen in 95% in the group given drops, 56% in the oral antibiotic group and 45% in the observation group. These numbers yield a miniscule NNT = 3 for resolution of otorrhea with topical antibiotics-glucocortocoids vs. oral antibiotics.

A couple of notes are important. All of the patients had otorrhea for up to 7 days prior to entering the study and the presence of a fever excluded them from the study. Additionally, tubes couldn’t be recently placed (< 2 weeks) there couldn’t be recent antibiotic use (< 2 weeks) or otorrhea (< 4 weeks).

As evidence mounts to the harms of inappropriate and unnecessary systemic antibiotic use, it’s important to tailor therapy based on the available literature. Many patients with tympanostomy tubes that develop otorrhea will resolve with simple observation. However, treatment with topical antibiotic-glucocortocoid drops should be the first line treatment as they are superior to oral antibiotics with fewer side effects.

“A trial of treatment for acute otorrhea in children with tympanostomy tubes.” 

Warning: Jolt At Your Own Risk…

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

Jolt accentuation is a means of perturbing the meninges of a patient presenting with a headache, in the hopes of delineating those who have meningitis from those with a more benign cause. Similar to the “rock the gurney” test in appendicitis or the Dix-Hallpike in BPPV, we are exacerbating the patient’s symptoms in the hopes of better understanding their illness. It has been claimed that the jolt accentuation test is the most sensitive physical exam finding available to rule out meningitis. A recent article published in American Journal of Emergency Medicine suggests otherwise.

This elegantly constructed prospectively gathered cohort was performed at two inner city hospitals over a 4-year period. Authors enrolled all neurologically intact patients older than 18 years old presenting with symptoms suspicious for meningitis. Physicians were asked to answer a questionnaire of physical examination findings before receiving CSF results.  Cunningly the authors surreptitiously placed the LP trays at the research staff’s station to ensure capture of eligible candidates.

47 patients (20%) out of 230 total enrolled were found to have CSF pleocytosis (defined as > 5 WBC ). The jolt accentuation test performed poorly at identifying these patients, with a sensitivity of 21% and a specificity of 82%. Kerning sign, Brudzinski sign, and nuchal rigidity performed no better with sensitivities and specificities of 2%, 2%, 13% and 97%, 98%, 80% respectively. Dishearteningly, the Emergency Physicians overall gestalt performed just as poorly with a sensitivity of 44% and a specificity of 40%.

Unfortunately the authors do not tell us how the jolt accentuation test performed in patients diagnosed with bacterial or fungal meningitis.  In this cohort only 3 of the 230 patients had culture positive meningitis, with only 2 from bacterial or fungal sources (one Cryptococcal and one Meningococcal ). The Emergency Physician identified both of these cases as high-risk upon initial evaluation. The authors failed to mention whether the jolt accentuation was positive in either of these patients. To truly examine jolt accentuation’s diagnostic performance, further studies using culture positive bacterial meningitis rather than pleocytosis as our diagnostic criteria are needed. This would require a much larger cohort, including a significantly larger quantity of cases of bacterial meningitis. But until then perturb with caution…

“Jolt accentuation of headache and other clinical signs: poor predictors of meningitis in adults” www.ncbi.nlm.nih.gov/pubmed/24139448