Misunderstood Antimicrobials — The Tigecycline Edition

Tigecycline is a somewhat controversial antimicrobial. I’m considering starting a collection of articles discussing “misunderstood antimicrobials” - chloramphenicol would of course be the series finale. Since tigecycline is an often discussed antimicrobial in infection circles, I thought I would detail out my position.

History

As always, we must start with some history and context. Tigecycline emerged in the beginning of the new millenium, and was approved by the FDA in 2005. It was of a novel class - a glycylcycline. Even two decades later, we still do not know how it should be pronounced. We think of it as similar to tetracyclines. The timing of its introduction is important. It came at a time when the new antimicrobial pipeline was considered “dry”. It also came with much promise - on paper (or in vitro) it demonstrated a very broad spectrum of activity against all sorts of bacteria. It appears to have some sort of sentience and awareness of bacterial taxononomic names, since it is has poor efficacy against bacteria that start with P, such as the pseudomonads. Otherwise, one could say that it gave hope that novel class broad-spectrum agents could still be developed.

Where are we now

Tigecycline has had a mixed couple of decades. On the one hand, it has a well established niche in the management of intra-abdominal infections, and has a bit part role in prominent guidelines for the treatment of such infections. It also enjoys licences for skin and soft tissue infection and community-acquired pneumonia.

The flip side is a lot more ominious. Despite multiple studies showing non-inferiority to comparatory antimicrobials in the pre-approval stage, a later meta-analysis of trial data showed an increased all-cause mortality in the tigecycline group. This led to a black box warning, and understandably, reluctance to use in severe infections. However, as is often the case when heterogenous data is re-analysed, a later meta-analysis did not show a statistically significant increased mortality risk when tigeycyline is used for its approved indications.

The reported increased mortality, alongside the fact that serum levels of tigecycline during therapy are low, and its bacteriostatic mode of action, have led to an almost universal reluctance to use tigecycline monotherapy for pretty much any sort of infection. This is particularly so for patients who have concominant bacteraemia. Most infection specialists would always combine tigecycline with another agent (or use another agent altogether) in bacteraemic patients, regardless of source. It is assumed that tigecycline is an ineffective choice in bacteraemia - although evidence may suggest otherwise. I am not sure it is fair to assume that low serum levels will lead to treatment failure in patients with bacteraemia. Most patients have “secondary” bacteraemia, caused by some focal source. In a way, the bacteraemia is merely a symptom of the true problem, albeit one that we can easily measure. Particularly for intra-abdominal infections, the high tissue concentrations of tigecycline means that it is treating infection at its source. The killing of bacteria while they are circulating in blood seems a secondary concern to me. Indeed distant site dissemination with such infections is almost unheard of.

Closing thoughts

One can’t help but feel that tigecycline has had a rough time, and I am not sure it fully deserves it’s now ubiquitous reputation as a second class antibiotic. It’s reputation has been clouded by arbitrary non-inferiority thresholds and post-hoc analyses - with what appears to be a bias to overstate negative results and ignore positive ones. It’s relatively (in antimicrobial timelines) recent introduction into clinical use means that it has been subject to strict analysis and critical appraisal - and rightly so. There are many older antibiotics in routine use that have never been subjected to such investigation. One wonders what results we would find if those hypothetical trials were done. We sometimes go through such acrobatics to come up with complex regimes (particularly in the presence of penicillin allergy), often with toxic agents, just to avoid using agents such as tigecycline.

Therefore, I designate Tigecycline a Misunderstood Antibiotic, it’s use limited by collective practice and opinion. The evidence behind such beliefs now fades into legend. We must all now combine tigecycline with another agent, regardless of the situation in which it is used.

Note: this article is an opinion piece and has not been peer-reviewed. Any opinions are my own