Category: Antibiotics

Predicting Cellulitis Treatment Failure

To (mostly) no one’s surprise, in descending order:

  • Tachypnea at triage
  • Chronic skin ulcers
  • History of MRSA
  • Recurrent cellulitis
  • Chronic kidney disease
  • Diabetes mellitus

Adjusted ORs for failure topped out at ~6.3, and descend into statistical noise from there.

However, reliably unpacking and generalizing these data is far more challenging, considering the variety of permutations for treatment and treatment failure. Of the initial 500 consecutive non-purulent skin-and-soft-tissue infections enrolled, patients were managed with all manner of combinations of inpatient and outpatient oral and intravenous antibiotics (including 6 patients with both). Treatment failure in the 288 managed primarily as outpatient, as evaluated from 48 hours to 14 days after the initial ED visit, could result in a change of oral agent, change to outpatient intravenous antibiotics, or hospitalization. While the validity of the predictive features of treatment failure is probably not affected by the specifics of their clinical setting, the rate of failure of oral antibiotics – almost 30% – is likely unique to their population and practice pathway.

At least, in contrast to my last cellulitis article, only 3 patients were subsequently judged by an infectious disease specialist to have a misdiagnosis of cellulitis.

“Predictors of Oral Antibiotic Treatment Failure for Non-Purulent Skin and Soft Tissue Infections in the Emergency Department”
https://www.ncbi.nlm.nih.gov/pubmed/29869364

Anti-Calcitonin

The use of procalcitonin to guide antibiotic therapy has been gradually increasing over the past several years – driven, in no small part, by increased recognition of the harms of antibiotic overuse. However, what evidence we have regarding its utility is primarily derived from manufacturer-sponsored trials – including virtual carpet-bombing of the literature by their sponsored representatives.

So, what happens when the manufacturer isn’t part of the trial?

No benefit.

This is the ProACT trial, an individual-randomized comparison between a procalcitonin-guided arm and “usual care” in patients with suspected lower respiratory tract infection for whom the indication for antibiotics is unclear. Physicians caring for patients randomized to the procalcitonin arm were provided results tied to antibiotic use recommendations – “strongly discouraged”, “discouraged”, “encouraged”, “strongly encouraged” – on initial presentation in the Emergency Department, and then in serial fashion for those admitted to the hospital. In those in the “usual care” arm, procalcitonin results were obtained, but not provided to the treating clinicians.

Then: Across 14 hospitals and 1,656 patients, there were no statistically significant differences between antibiotic-free days or adverse outcomes between the two arms. Done? Done.

Except, as skeptical as I might be regarding procalcitonin-guided therapy, there are big holes in these data as the definitive word on its disutility. Unlike other trials, these centers provided only passive guidance to clinicians regarding the procalcitonin algorithm. This resulted in only 72.9% of physicians adhering to protocol, with the greatest numbers of violations being antibiotic use in patients for whom it were discouraged, including 30% of those for whom antibiotic use was “strongly discouraged”:

Even though the “per-guideline” analysis also shows no difference, this is mostly because the bulk of the procalcitonin “per-guideline” population were those who appropriately received antibiotics – effectively eliminating the possibility of showing a difference in antibiotic use.

There are a few signals within these data reflecting the potential advantages of a procalcitonin-guided algorithm, should the protocol actually be followed. There were small differences in prescribing favoring the procalcitonin arm for almost every final clinical diagnosis – excepting about 15% absolute advantages for “acute bronchitis” and for those with non-specific diagnoses. It is likely these represented the cases for which the appropriateness of antibiotics was lowest, and probably also represent the majority of protocol violations. That said, one could easily make the argument this advantage only exists as a result of culturally-ingrained poor antibiotic prescribing habits for these sorts of borderline cases.

In short, these data clearly show there is no advantage to introducing procalcitonin into practice specifically in the fashion demonstrated here – but these cannot be generalized to say a different implementation or application of procalcitonin has no value.  On the flip side, however, places that have implemented procalcitonin-driven stewardship programs also struggle with inappropriate and high-volume test ordering.  There is work yet to be done for both proponents and skeptics of its value.

“Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection”
https://www.nejm.org/doi/full/10.1056/NEJMoa1802670

Whoa! Fosfomycin in Prime Time!

For many years, I’ve tossed out the idea of using fosfomycin for uncomplicated urinary tract infections to various trainees – the vast majority of whom looked at me as though I had three heads. Even now, it’s easy to find folks who’ve never heard of fosfomycin, despite its mention in the most recent guidelines for UTIs. In the United States, the land of low-value health care, fosfomycin is preposterously expensive for a single dose – and rarely used.

The story, however, is a little different outside the U.S. Thus, the question – which is a better options, fosfomycin or nitrofurantoin? The answer: in Israel, Switzerland, and Poland, nitrofurantoin, probably.

This is an open-label trial with 513 patients randomized either to five days of nitrofurantoin or a single 3g dose of fosfomycin. Outcomes included clinical and microbiologic cure, and both favored nitrofurantoin by an absolute margin of ~10%. Oddly enough, their primary outcome was a 28-day clinical cure – which starts to stretch the measurement window into the range of subsequent, unrelated infection, rather than response to the initial therapy. This is apparent when looking at the 14-day and 28-day microbiologic response, in which bacterial counts were clearly creeping back up after an initial nadir.

Regardless, both agents are options – and fine options, depending on local resistance patterns, suspected pathogens, and other contextual clinical features. That said, in the U.S., most of the current appropriate prescribing is for trimethoprim-sulfamethoxazole – so, a similar trial comparing this with these alternative agents would need to be performed to better inform practice here.

“Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women”
https://jamanetwork.com/journals/jama/article-abstract/2679131

The Penicillin Allergy Lie

This is a short follow-up study that touches upon a ubiquitous subject of which we’re mostly familiar – most patients with a stated allergy to penicillin do not actually have a true, IgE-mediated reaction. In the original study, these authors performed a standard 3-tier allergy testing on 100 patients with “low-risk” reported allergy symptoms, all of whom tested negative and ultimately passed a 500mg amoxicillin challenge dose.  Now, in this study, these authors re-contacted the patients and the primary care physicians to determine the downstream communication, effects of the allergy testing notification, and any adverse events related to prescribing after removal of the allergy from the patient’s chart.

Without going into much detail, there was a huge disconnect – most parents reported relaying the information, most physicians reported no information was relayed, and about half the patients had the allergy still listed in their chart. Regardless, 26 patients filled at least one prescription for a pencillin-derivative medication within the year, and one child developed a rash attributed to the amoxicillin.

The authors use this narrow experience to estimate cost savings attributed to using penicillin derivatives versus cephalosporins or clindamycin, and determine their allergy testing resulted in $1,368.13 in savings. Across the 6,700 reported penicillin allergies annually in their ED, they estimate accurate allergy information and delabeling could save nearly $200k each year.

This hardly represents all the benefits of delabeling, as the antibiotics avoided are also typically broader-spectrum, with greater contributions to antibiotic resistance. Clearly, a simpler, accepted pathway to expedite penicillin allergy delabeling would be of great value.

“Antibiotic Use After Removal of Penicillin Allergy Label”

http://pediatrics.aappublications.org/content/early/2018/04/18/peds.2017-3466

Less is More, Cellulitis Edition

Generally speaking, the diagnosis of cellulitis is a fairly straightforward clinical evaluation – even in the Emergency Department. This article, however, says “we’re doing it wrong!” to the tune of $225M of waste on the inpatient side.

These authors retrospectively reviewed 183 patients admitted through their hospital system for a diagnosis of cellulitis, with a focus on imaging and blood cultures obtained. Of these, 83 (45%) underwent at least one form of imaging, with a handful a greater number, with 8 identifying an important additional or alternative diagnosis. Then, 60 (33%) received blood cultures, one of whom had conclusive culture growth – although the authors do not characterize whether it changed or narrowed antibiotic therapy. They ultimately conclude, in these otherwise non-toxic patients, these tests are of low value and ought be severely curtailed.

As much as I generally agree with the various Less is More-themed articles in this vein, I’m not sure this one entirely hits the mark. These 183 patients are inpatient hospitalizations, with progressive disease or significant comorbid disease – a far cry from the uncomplicated cellulitis representing the majority of our throughput. While these statistics may look grim, and they absolutely reflect generally low-value practice, this is a heterogenous cohort of patients in whom some of these tests were reasonable based on clinical examination and a reasonable pretest likelihood of a clinical important alternative entity. There is prudence and value to be found in reflecting on the assessment of cellulitis – but $225M might be a little bit of hyperbole.

“Clinical Usefulness of Imaging and Blood Cultures in Cellulitis Evaluation”

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2676998

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”

https://jamanetwork.com/journals/jama/article-abstract/2666503

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”
https://www.ncbi.nlm.nih.gov/pubmed/29037960

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”
http://www.annemergmed.com/article/S0196-0644(17)31383-5/abstract

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”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182411

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”
http://jamanetwork.com/journals/jama/article-abstract/2649201