Treatment Failure, or is Treatment the Failure?

Acute respiratory tract infections – otitis media, streptococcal pharyngitis, and sinusitis – comprise virtually a laundry list for antibiotic overuse in self-limited conditions. Certainly, a subset of each of these conditions are true bacterial infections and, again, a subset of these have their resolution hastened by antibiotics – and, finally, a subset of those would have clinically important worsening if antibiotics were not used. Conversely, the harms of antibiotics are generally well-recognized,though not necessarily routinely appreciated in clinical practice.

This patient-centered outcomes study, with both retrospective and prospective portions, enrolled children diagnosed with the aforementioned “acute respiratory tract infections” and evaluated outcomes differences between those receiving “narrow-spectrum” antibiotics and those receiving “broad-spectrum antibiotics”. Before even delving into their results, let’s go straight to this quote from the limitations:

Because children were identified based on clinician diagnosis plus an antibiotic prescription to identify bacterial acute respiratory tract infections, some children likely had viral infections.

“Some children likely had viral infections” is a strong contender for understatement of the year.

So, with untold numbers of viral infections included, it should be no surprise these authors found no difference in “treatment failure” between narrow-spectrum and broad-spectrum antibiotics. Nor, in their prospective portion, did they identify any statistically difference in surrogates for wellness, such as missed school, symptom resolution, or pediatric quality of life. However, adverse events were higher (35.6% vs. 25.1%, p < 0.001) in the broad-spectrum antibiotic cohort, and this accompanied smaller, but consistent, differences favoring narrow-spectrum antibiotics on those wellness measures.

So, the takeaway: broad-spectrum antibiotics conferred no advantage, only harms. If you’re using antibiotics (unnecessarily), use the cheapest, most benign ones possible.

“Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections”

The Best Antibiotic Stewardship Money Can Buy

Believe it, or not:

Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.

So, should we all be jumping on the procalcitonin bandwagon? Chances are, you probably already have – check with your critical care team, and I expect you’ll find some implementation of a procalcitonin-based protocol supporting antibiotic stewardship. The underlying concept is hardly unreasonable – when sensitive markers of bacterial infection are low, antibiotics can be discontinued.

However, the evidence base – as helpfully pooled in this individual-patient meta-analysis – is nothing more than a carefully orchestrated disinformation campaign by the manufacturers of these assays. Roche, Thermo-Fisher and bioMérieux have an obvious vested business interest in publishing favorable research findings in support of procalcitonin-based treatment algorithms, and it should come as no surprise the authors have a couple items to declare:

PS, MC-C, and BM have received support from Thermo-Fisher and bioMérieux to attend meetings and fulfilled speaking engagements. BM has served as a consultant for and received research support from Thermo-Fisher. HCB and MB have received research support from Thermo-Fisher for a previous meta-analysis regarding procalcitonin. DWdL’s hospital received financial support for the randomisation tool by ThermoFisher. DS, OB, and MT have received research support from Thermo-Fisher. TW and SS have received lecture fees and research support from Thermo-Fisher. CEL has received lecture fees from Brahms and Merck Sharp & Dohme-Chibret. JC has received consulting and lecture fees from P zer, Brahms, Wyeth, Johnson & Johnson, Nektar-Bayer, and Arpida. MW has received consulting and lectures fees from Merck Sharp & Dohme-Chibret, Janssen Cilag, Gilead, Astellas, Sano , and Thermo-Fisher. FT’s institution received funds from Brahms. CC has received an unrestricted grant of €2000 from Thermo-Fisher Scientific, and non-fiancial support from bioMérieux for the ProToCOLD study. YS has received unrestricted research grants from Thermo-Fisher, bioMérieux, Orion Pharma, and Pfizer. ARF has served on advisory boards for Novavax, Hologic, Gilead, and MedImmune; and has received research funding from AstraZeneca, Sanofi Pasteur, GlaxoSmithKline, and ADMA Biologics. J-USJ declares that he was invited to the European Respiratory Society meeting 2016 by Roche Pharmaceuticals.

And, it’s clearly no coincidence most of the 26 trials included in this systematic review are authored by those same financially-supported authors above – so, it’s turtles all the way down for this meta-analysis.

The results, then, for what they’re worth, despite all the concerted effort to spin them, are rather bland. The mortality differences are zero in the outpatient settings, and small enough in the intensive care unit side to potentially be skewed by design. The only signal I might ascribe reliable in these data is: procalcitonin does reduce antibiotic exposures. This manifests in practice in two different fashions, depending on the setting. In the outpatient setting, where virtually all the antibiotics are unnecessary (one of these trials enrolled patients with “bronchitis”!), it gives the clinicians a crutch to fall back upon to prevent them from practicing bad medicine.  In the intensive care unit, it helps titrate the use of broad-spectrum intravenous antibiotics, which is likely to reduce a number of important downstream effects.  I don’t object to the latter application, but my recommendation for the former: just don’t practice bad medicine in the first place (easier said than done, sadly).

So, the takeaway I’d like to promote in the context of this article – and its simultaneously published Cochrane Review by the same, COI-infested authors – is skepticism regarding the effect sizes for procalcitonin-guided therapy. These data do not exclude its clinical utility for the stated purposes, but its use ought be considered in the narrowest of clinical situations, and probably in those at the highest-risk for harms from otherwise clinically confounded antibiotic exposures.

“Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis”

Also, if you’re persistent enough to scroll to page 126 in the Cochrane Review full text, you glean this lovely pearl:
Philipp Schuetz received support (paid to his employer) from Thermo Fisher, Roche Diagnostics, Abbott and bioMerieux to attend meetings and fulfil speaking engagements. These conflicts breach Cochrane’s Commercial Sponsorship Policy (Clause 3), therefore Philipp Schuetz will step down as lead author at the next update of the review. Dr Schuetz’s declared conflicts were referred to the Funding Arbiter Panel and Cochrane’s Deputy Editor-in-Chief who have agreed this course of action but as an exception which does not set a precedent for similar situations in the future.

Alas, Abscesses [heart] Antibiotics

“Fake news!” All you need for effective treatment for abscesses is an incision and drainage procedure – adjunctive antibiotics are just unnecessary exposures with only marginal benefit, at best.

Then, unfortunately, two trials have been published in the New England Journal of Medicine showing benefit for antibiotics – either trimethoprim-sulfamethoxazole or clindamycin – improve the rate of clinical cure. The magnitude of benefit was somewhere in the range of a number needed to treat between 7 and 14, with infrequent harms, suggesting the balance of benefit may favor antibiotics. However, the abscesses included in these study tended to be large, suggesting perhaps these results weren’t easily generalizable.

This is a subgroup analysis of one of these two studies, trying to dredge out a specific population for whom antibiotics weren’t actually of value. And, unfortunately, for the purists among us, the results are bleak. Accounting for the diminishing statistical power and reliability of such an analysis, there are few useful signals within these data. Neither the size of the abscess nor the area of surrounding erythema reliably predicted diminishing returns from adjunctive antibiotics, nor did presence of fever or comorbid illness. The only probably reliable signal in these data, consistent with results in the era prior to MRSA, shows antibiotics are probably unnecessary for those who are not infected with staphylococci. Unfortunately, until that point where the causative agent can be easily ascertained at the time of I&D procedure, these data aren’t terribly useful in a practical sense.

So, the benefit is not universal, but it’s nothing at which to scoff. Perhaps a delayed antibiotic strategy could be considered, but, it seems most patients ought be offered antibiotics following drainage of a clinically significant abscess.

“Subgroup Analysis of Antibiotic Treatment for Skin Abscesses”

Azithromycin Ruins Everything

For some reason – and by “some reason”, I mean extensive evaluation of immunomodulatory properties – there is an obsession with azithromycin use for more than simply its anti-bacterial indications. It has been hypothesized to diminish inflammation and have antiviral properties, and, of course, functions as a floor wax and dessert topping.

This is a randomized, controlled trial of azithromycin versus placebo in pre-school children with acute wheezing as a primary diagnosis. The primary outcome was time to resolution of respiratory symptoms, and secondary outcomes included any use of short-acting beta-agonists, adverse events, and time to any repeat exacerbation of wheezing.  These authors enrolled 300 before funding ran out, and were able to follow-up 222 with completed symptom diaries. Patients were generally similar between the two groups, and over 80% of each cohort had prior episodes of wheezing, and a similar percentage used or was prescribed a beta-agonist at discharge from the Emergency Department.

The winner: nothing and no one. Azithromycin did not improve any outcomes versus placebo, and should not be used for suspected viral wheezing in the hopes of anti-inflammatory symptom improvement until better evidence of benefit emerges.

“Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial”

Steroids, Not Universally Useful For Wheezing

In asthma, steroids are fantastic. The earlier, the better. In bronchiolitis, another wheezing-spectrum illness, mostly probably not. How about the general, ambulatory, viral lower respiratory tract infections with wheezing?

This randomized, controlled trial enrolled patients at family practice clinics in Britain with non-asthmatic wheezing relating to a suspected “chest infection”. Patients received either 40mg of oral prednisolone for five days or matching placebo. The primary outcome was duration of moderately bad or worse cough, as recorded by a patient-reported symptom diary, with secondary outcomes of subsequent antibiotic use, cumulative symptom scores, and quality of life scores, and other resource utilization measures.

These authors enrolled 401 patients, 398 of whom received the study intervention. There were no important differences between enrolled groups at baseline – and, there were no reliable, important differences in measured outcomes, either the primary symptom-related outcome, or any of the secondary outcomes.

The strength of this evidence is not such that it eliminates the possibility of a clinically important benefit for a subgroup of patients, but I consider it practice-changing because there was such little reliable evidence at baseline. I have certainly felt it was reasonable to discharge patients with suspected viral LRTI, wheezing, and bronchospasm on an oral steroid based on a low risk profile and at least a hoped-for, physiologically-justified, benefit. Now, the onus is on a subsequent trial to demonstrate said benefit before resuming such practice.

“Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection”

The Impermanence of Non-Operative Appendicitis Management

Novelty is no guarantee of superiority. In the olden days, appendicitis meant: out, damned vestigial worm! In modern times, it gives rise to any number of potential antibiotics-first strategies, under observation or as an outpatient.

But, following resolution of the initial appendicitis symptoms, the appendix persists. And, left to its own devices, the risk of recurrence remains. In the few trials and observational series to date, the risk seems to be on the order of 20-30% at one year.

This study suggests the practical rate outside of controlled trial settings may be even higher. This retrospective review of administrative data from 45 pediatric hospitals examines management and resource utilization relating to appendicitis diagnoses. Over the six year study period, approximately 6% of cases of non-perforated appendicitis were managed non-operatively, a rate that increased 20% over the course of the study period – with most of the increase occurring in the final two years. Compared with those managed operatively, those managed non-operatively had higher rates of advanced imaging (8.9%), Emergency Department visits (11.2%), hospitalizations (43.7%) – and, finally, 46% of those managed non-operatively underwent subsequent appendectomy.

Interestingly, the median time elapsed before subsequent appendectomy was only one day – a result these authors found skewed relating to those who were discharged from the Emergency Department rather than after hospitalization for multiple doses of intravenous antibiotics. These authors also found 14% of those with recurrent appendicitis suffered perforation, a much higher proportion than the ~3% found in previous trials.

It certainly sounds appealing, from a superficial standpoint, to avoid surgery in anyone – least of all children. It is reasonable, however, to suggest the rush to transform practice to elevate non-operative management is unwarranted without better long-term data. Patients may be offered a non-operative management strategy, but only in the context of substantial uncertainty regarding ultimate outcomes, and the non-trivial risk of re-hospitalization for subsequent appendectomy.

“Outcomes of non-operative management of uncomplicated appendicitis”


Predicting Treatment Failure in AOM

Like most infectious diseases, acute otitis media generally breaks down into three cohorts. There are viral infections, for which early antimicrobial therapy is virtually, by definition, unhelpful. Then, there are true bacterial infections – many of which resolve without substantial morbidity regardless of antimicrobial treatment, and those which require antimicrobial therapy to prevent such. The trick, and where modern medicine typically fails miserably, is rapidly predicting into which of these cohorts a patient may fall – a conundrum leading to the epidemic of antibiotic overuse.

This is a secondary analysis of a pediatric AOM trial, first published in the New England Journal of Medicine, looking at which patients were more likely to potentially fail conservative treatment. The intervention arm received amoxicillin/clavulanate, and treatment failure occured in 31.7% of children – vastly favoring the antibiotic arm – 44.9% vs. 18.6%. In theory, this exaggerated treatment effect might help better illuminate any small predictors – but, unfortunately, with only 319 patients, meaningful statistical significance on this data dredge is hard to come by. Worse still, the best predictor of treatment failure (or, really, lack thereof)? A peaked tympanogram (A and C curves) – you know, because we’re all routinely measuring tympanometry. Grossly bulging tympanic membranes were predictive of treatment failure, which has some face validity, at least – but, again, this is as compared between severe, moderate, and mild, which requires pneumatic otoscopy to differentiate.

The question here primarily concerns: can you take away good conclusions from bad data? The magnitude of the treatment effect seen in this trial far exceeded the treatment effect expected from antibiotics in other trials. And, consistent with that questionable generalizability, their findings reflect the stringent criteria determining their diagnosis of AOM. Then, they are relying upon their misguided definition for treatment failure, which relies on otoscopic signs, the same ones that will be colinear with worsened disease on initial examination. Unfortunately, the net result of all of this meandering is essentially no clinically useful insight. Considering the limitations the examination of the screaming ill toddler, more pragmatic approaches are necessary.

“Prognostic Factors for Treatment Failure in Acute Otitis Media”

Now It’s Fluids that Matter in Sepsis?

A few weeks ago, there was an article in the New England Journal of Medicine that dredged a retrospective data set to generate an association between timeliness different elements of a sepsis bundle and outcomes. In their analysis, antibiotics, but not fluid administration, was associated with a mortality increase. This has, at least, face validity – although, the association between timely blood cultures and serum lactate a little less so.

Now, conversely, we have another sepsis registry review attempting to tie time to fluid administration to mortality. This quality improvement registry prospectively identified patients with sepsis – and retrospectively abstracted their clinical data – between 2014 and 2016, resulting in a database of 11,182. In their analysis, mortality for patients receiving their first crystalloid within 30 minutes or within 30-120 minutes was ~18%, while mortality for patients whose fluids were initiated beyond the 120 minute limit was 24.5%.

Again, however, because these are comparisons performed on observational data, it is still subject to the slings and arrows of unmeasured confounders. Most patients whose fluid administration was started early had their care initiated in the Emergency Department – and, in clearly co-linear processes, had major elements of their care completed appropriately. This included repeat lactate measurements, antibiotics within 180 minutes of time zero, and, not only IVF within 120 minutes, but frankly, any IVF at at all. Nearly 60% of patients analyzed for their >120 minute cohort received <5 mL/kg or zero IVF in their first six hours from measurement time zero.

This is, probably, another study just cherry picking out one single feature of an entire process predicated on timely identification and treatment of sepsis. These patients did not simply have a mortality advantage because of the timeliness of IVF – it ties in to all aspects of care and attention given sepsis patients properly identified. The effect size here is probably less associated with delays just in IVF, but a comprehensive delay in diagnosis – and all its associated therapeutic misadventures.

“Patterns and Outcomes Associated With Timeliness of Initial Crystalloid Resuscitation in a Prospective Sepsis and Septic Shock Cohort”

Conjunctivitis: No Antibiotics, Please!

It’s the sad state of modern medicine – choose a common ambulatory condition, and you can find widespread avoidable overuse and waste. There is a spectrum of acceptability to this practice variation, of course, depending on the severity of consequences for missed or delayed diagnoses – but, for the most part, we’re just setting our professional respectability aflame.

This is a simple retrospective review of prescriptions associated with diagnoses of acute conjunctivitis. These authors reviewed records from a large managed care network and identified 340,372 patients with a clinical visit coded for acute conjunctivitis. Within 14 days of this visit, 58% of patients filled prescriptions for topical ophthalmologic medications. Considering most conjunctivitis encountered in the clinical setting is viral or allergic, obviously, the vast majority of these are wholly unnecessary. Then, frankly, while topical antibiotics mildly hasten the improvement of bacterial conjunctivitis, it is still a generally self-limited condition.

Ophthalmologists and optometrist visits were the least likely to have an antibiotic prescription associated with a visit for acute conjunctivitis, but 36% and 44%, respectively. Urgent Care Physicians and “Other Provider” – probably inclusive of Emergency Medicine – were at 68% and 64%, respectively. Fluoroquinolones accounted for 33% of antibiotic prescriptions – which is fabulous, because they are typically the most costly, and result in both increased risk for antimicrobial resistance and S. aureus endophthalmitis. Then, one in five prescriptions were for combination corticosteroid-antibiotic combination products – which are contraindicated, as they can prolong viral infections or worsen an underlying herpes simplex infection.

The American Academy of Ophthalmology contribution to Choosing Wisely recommends avoiding antibiotic prescriptions for viral conjunctivitis, and deferring immediate antibiotic therapy when the cause of conjunctivitis is unknown. Stop the madness! Everyone!

“Antibiotic Prescription Fills for Acute Conjunctivitis among Enrollees in a Large United States Managed Care Network”

I&D Alone or With Antibiotics for the Little Guys

Most physicians provide adjunctive antibiotic therapy for large abscesses following incision and drainage – the sorts where you need a bucket and a hose. Less clear has been the small abscess – but, in the age of MRSA, the fear factor has led many to cover these, regardless. Recent evidence suggests there is a small absolute benefit to antibiotic use and clinical cure, with an NNT around 14, along with other apparent benefits regarding re-infection and spread to household contacts. These trials, however, still enrolled patients with abscesses much larger than typically encountered in routine practice.

This trial is specifically designed to break the glass on “smaller skin abscesses” – just like in the title! What does small mean to these authors? It means a suppurative cavity of 5cm in diameter, or, up to the size of a cupcake:
abscess cakeSo, before we even start, we can see we may end up with issues regarding generalizability to many of the abscesses we encounter in the Emergency Department.

This trial is comprised of three arms – clindamycin, trimethoprim-sulfamethoxazole, and placebo – and enrolled 786 patients in an attempt to detect a 10% difference between arms while accounting for 20% attrition rate. The primary outcome was test of cure at 10 days after therapy, with a variety of secondary outcomes, including new infections at one month and treatment-related adverse events.

The winner, if one can be crowned, was not placebo. At the test of cure visit in the intention-to-treat population – and likewise, the population that could be evaluated – placebo lagged behind both clindamycin and TMP-SMX by approximately a 12% absolute magnitude of difference. Recurrent infections at the same site, or another site, were lowest in the clindamycin group at 6.8% – and similar between TMP-SMX and placebo, at 13.5% and 12.4%, respectively. However, clindamycin was implicated in the highest rate of adverse events, at 21.9%, compared with TMP-SMX and placebo, at 11.1% and 12.5%, respectively. Most of the difference in adverse events can be attributed to diarrhea illness, although clostridium difficile was not isolated in any cases. There was one case of systemic hypersensitivity reaction thought to be related to TMP-SMX.

There were two main drivers for the difference in test of cure between the placebo cohort and the two antibiotic cohorts, and these were use of rescue antibiotics during the follow-up period and new infections at another site. The use of rescue antibiotics is not necessarily a reliable measure of treatment failure, but it is still reasonable to suggest this difference would not arise by chance alone, despite the small sample. Regarding generalizability to practice, the minority of abscesses were cupcake-sized, but these were still fairly substantial infections. The median size of the abscess was about 2.2cm in diameter, with surrounding erythema of 5.9cm in greatest dimension.

The takeaway, then, hinges on the generalizability of their population to your individual patient. If these are “smaller” skin abscesses, then I wager the bulk of my abscess encounters are for “tinier” abscesses. I doubt this changes much current practice with regard to antibiotics, or antibiotic selection, for those treating abscesses in the 2+cm range, but I expect the differences in cure rates shrink for smaller lesions. It falls within the realm of acceptable practice variation to weigh the harms of antibiotic use with the chance of recurrence or new infection for those lesions.

“A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses”