Several antibiotic classes are associated with QTc prolongation: macrolides, quinolones, the antimalarials that share the quinine structure, and many azole antifungals. FDA warned about the proarrhythmic effects of azithromycin in 2013 [i] but it is a recent publication by Rao which brings the message home again with some very disquieting quantitative figures [ii].
Analyzing a very large sample size (approx. 1.6 mio courses of antibiotics in a VA population) the authors found that – compared to amoxicillin – mortality was increased by 47% and 149% with azithromycin (Zithromax®) and levofloxacin (Levoquin®), respectively, during the first 5 days of drug administration.
Didn’t they teach us in medical school that erythromycin was one of the safest antibiotics? Well, it can prolong the QT interval by >40 msec. I very much doubt that it would be approved today.
Much of our understanding about QTc prolongation and its impact is based on the moxifloxacin (Avelox®) program. Moxifloxacin has a linear dose-related QT effect. Fortunately, 400 mg is an effective dose resulting in minimal (5-7 msec) QT prolongation. It certainly helped that Bayer studied the issue upfront and in great detail. An unintended byproduct of this effort: Moxifloxacin became the de-facto positive control for all future Thorough QT studies.
Several antibiotics failed because of QT prolongation. Remember sparfloxacin (Zagam®) and grepafloxacin (Raxar®)? Both were eventually taken off the market.
However, levofloxacin and azithromycin have been on the market for a long time now, and both have accumulated an impressive safety record. In contrast to most other fluoroquinolones, levofloxacin has a very small effect on QT prolongation, and azithromycin is clearly safer than erythromycin.
Are the reported results by an aberration, a population-specific finding only, restricted to a predominantly male, elderly VA population with significant comorbidities and subject to all kinds of drug interactions? I don’t think so. There are other studies that confirm these findings [iii]. The Rao study suggests that even a small effect is not benign. Nonetheless, we need to put this into perspective.
First, we value antibiotics for their benefits over, well, not having antibiotics. There is no need to study millions when comparing mortality ratios of antibiotic vs placebo treatment: it does not take more than a small cohort to demonstrate their value.
Secondly, there are considerable differences among the classes of antibiotics which make them individually useful. For example, in upper respiratory tract infections, macrolides provide coverage for atypical bacteria, legionella, and even pseudomonas. The entire class also has an anti-inflammatory component. Quinolones improve on this profile by excellent tissue penetration, bactericidal MoA and even broader coverage. Ampicillin is good for S. pneumoniae and H. influenzae only, not much else.
As mentioned before, both azithromycin and levofloxacin are safe drugs. Their QT-related risks are small compared to the overall benefit they provide. And yes, they carry a small cardiovascular risk.
Rao’s study reminds us to use these drugs less liberally. Recent data show that physicians are heeding the call to avoid antibiotics for trivial infections like the common cold, sinusitis or otitis that are most likely viral in nature. Nonetheless, over half of all practitioners still prescribe antibiotics in order to cover the mere possibility of a bacterial infection, even if unlikely.
I guess what we really need are better diagnostics to distinguish viral from bacterial infections. Talking about “appropriate” vs “inappropriate” use is a judgement call that does not solve much.
Last, we need to relearn the chapter on erythromycin, that great old antibiotic, recognizing that it isn’t quite so safe after all.
[ii] Rao. Ann Fam Med. 2014 Mar-Apr;12(2):121-7
[iii] Owens. Clin Infect Dis. 43: 1603, 2006