@xrayspex
Out of all of the macrolide antibiotics, azithromycin is likely the safest, although some studies have linked it to QT prolongation and arrhythmia.
One of the major concerns is a type of arrhythmia called tdp or torsades de pointes, which can be fatal. Interestingly, azithromycin seems unique in that it does not have the same tendency to induce TDP as other macrolide antibiotics. Functionally, it induces a different pattern in the monophasic action potential of the cardiomyocyte, even with similar QT prolongation to other macrolides.
While the evidence does suggest azithromycin is safer, I wouldn't say it's risk free - or that any macrolides (or drugs for that matter) are. There are definitely some case reports of azithromycin causing arrhythmia, often in individuals with unusual susceptibility - not not necessarily always. Remember that azithromycin is one of the most prescribed antibiotics out there right now, so there may be more case reports just because the drug is more widely used in the US now.
Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes.
http://www.ncbi.nlm.nih.gov/pubmed/12235254
Azithromycin Can Prolong QT Interval and Suppress Ventricular Contraction, but Will Not Induce Torsade de Pointes.
http://www.ncbi.nlm.nih.gov/pubmed/25367413
Also interestingly, there was an article published about the effects of azithromycin on chronic fatigue syndrome.
http://www.translational-medicine.com/content/4/1/34
This study showed a beneficial response to azithromycin in about 60% of patients, with some returning to 80% of premorbid capacity. It was a second line drug when response to acetyl-carnitine was deemed insufficient.
This was a retrospective study and not blinded, but still interesting. The macrolide antibiotics are known to have potent immunomodulatory effects. This paper suggests that it functions by altering il-1beta in the brain, in particular with regard to glia. This is not shown - it is only a theory - and I have not seen any follow up research confirming the results.
Azithromycin does have a number of potent immunomodulatory effects. If you take a quick look at pubmed you will find a lot of articles on it. These effects may be beneficial. However, in this case I suspect that any cardiac side effects are related to its action at the hERG potassium channels in the heart (hERG is actually a gene coding for a subunit of a delayed rapid inward rectifying potassium channel present in the heart that plays a key role in the repolarization of the cardiomyocyte after contraction - hERG stands for the "human ether a go go" gene). hERG channels are the most widely studied potassium channels when it comes to drug induced QT prolongation.
Personally, I noticed a nearly instant and marked reduction in arrhythmia when I took azithromycin for a time. The mechanism may be immunomodulatory or it may have to do with it's effect on the cardiac action potential.
This paper shows that not only do very high levels of azithromycin NOT induce tdp, but levels of erythromycin that do induce tdp, when combined with azithromycin, no longer induce tdp. i.e. Azithromycin actually prevents tdp.
http://austinpublishinggroup.com/vascular-medicine/fulltext/ajvm-v1-id1006.php
Again, this appears to be because azithromycin prolongs the resting portion of the cardiac action potential, creating a rectangulated potential as compared to the triangulated potential of other macrolide antibiotics.
Azithromycin may have antiarrhythmic activity in some cases - and I believe in my case that it did. However, there are case reports of cardiac risks with azithromycin (roughly comparable to ciprofloxacin, but 2.x fold greater than amoxicillin, which has no known effect on the heart), so caution is still warranted, especially in a patient with known QTc prolongation or with polypharmacy.
This is one of those things you need to talk to your doctor about before trying for ME - which is obvious since it's a prescription drug anyways!