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.