The Achilles Heel of Antibiotics
On the sometimes fatal promise of Fluoroquinolones
Cipro, the common name for an antibiotic once commonly prescribed, is not a safe drug. Cipro is short for Ciprofloxacin, and it is the most familiar antibiotic in a class called Fluoroquinolones.
Cipro is one of very few drugs that I always had with me when traveling and doing research in Latin America and in Madagascar in the 1990’s, when I was in my 20s. I took it more often than I like to remember. Cipro acts fast on many problems, including intestinal bugs. If you find yourself needing to board a bus for an uncertain duration while suffering GI distress, Cipro can solve the immediate problem. It seems to be your friend and ally.
I have no doubt that Cipro has saved some lives. I also have no doubt that Cipro has damaged many people beyond what should be considered acceptable, and that many of those damaged had insufficient information with which to make choices about their own health.
We deserve to have informed consent.
We do not have informed consent.
Ten years ago this month, while playing ultimate frisbee barefoot on an Oregon beach with my students, I fully ruptured my left Achilles tendon. In the moment, I heard a sound so intense and shattering that I thought it was gunfire. Nobody around me heard any sound at all. I also thought that someone had hurled a large rock at my heel. Of course no one had. My brain was searching frantically for an explanation for the experience that my body was having, and it was coming up with nonsense.
I leapt for the disk—the frisbee—and then heard gunfire, felt the hurled rock. I fell, sprawled in the sand.
I knew immediately that this was not a sprain.
Just before it had happened, I had been jumping in place to stay warm before the next point began, joyful to be playing one of my favorite games in the world, in a beautiful place, with a group of young people who were inquisitive and open. There had been just one thing that nagged at my consciousness—my Achilles tendons hurt just a bit. I had never before given my Achilles tendons a second thought.
Achilles was half mortal, half god, and his mother, the sea nymph Thetis, felt betrayed by the fact that her son could die. So she took her precious baby down to the river Styx, that provider of immortal life, and dipped him in it, providing him protection against the slings and arrows of mortality. But she held him by his heel, and so it was his heel, only, that remained at risk. Years later, while heroically giving battle in the Trojan War, Achilles would be felled by an arrow to his heel. His heel, his one vulnerability, was his downfall. He was killed.
Humans became bipeds well over a million years ago, evolving away from our chimp cousins and standing tall. For all the virtues of walking on two feet, this innovation came at considerable cost to other systems.
Women must have hips wide enough to bear viable big-brained babies, but the wider our hips, the less stable our stance. Widen our hips sufficiently that we do not suffer while giving birth, and we can’t walk well. We fall down.
The lower back pain that is common to many humans can also be chalked up to our bipedal stance.
And of course the fact that, because we only have two legs on which to stand, rather than four, the single giant tendon that connects our calf muscles to our heel bone in each of our legs, our Achilles tendon, has no back-up. We are utterly dependent on it functioning.
But some of us have been taking drugs that do our Achilles tendons no favors at all.
After the gunshot that wasn’t a gunshot, and the hurling of a rock at my heel that never happened, after I fell, I was helped to the edge of the field. I could not walk. Unlike with a sprain, which provides ample evidence of injury but does allow some pressure to be applied, I had no control at all. If I tried to bear weight, I crumpled.
A few hours later we went to a small town emergency room, and I was seen by an excellent orthopedic surgeon whose occasional gig was helping out in the ER. He did a simple test, the Thompson test, which involved me lying on my stomach while he squeezed my calf muscle.
Because an intact Achilles tendon connects the calf muscles to the heel bone, when the calf muscle is squeezed in an intact leg, the heel moves.
When the good doctor squeezed my calf muscle, my heel did not move.
He assured me that my Achilles tendon was fully ruptured. He told me that I would require surgery. In fact, he said, he could do it, sometime in the next few days. But we didn’t live there, on the Oregon coast, and we had a class full of students to attend to, so I held off until we returned home. This gave me several days in which to brood and dwell and feel a bit sorry for myself and also to do some research on what I should do now, and on why my Achilles tendon had given out.
This would turn out to be quite the pharmaceutical rabbit hole.
In the 1990s, when I was doing a lot of tropical field work, I made myself into a walking pharmacy on my field expeditions so that I could treat most ailments that were likely to come up. I carried a few courses of Cipro on each trip, along with Zithromax and Doxycycline (also antibiotics), a small amount of opioids, plus anti-malarials1. I also carried over-the-counter treatments including topical antibiotics, anti-fungals, and steroid creams; Tylenol, NSAIDs and Benadryl. Benadryl is the only other drug that I took with some regularity then, and I now regret that as well. At the end of those extended trips I had often used some of the Cipro, Benadryl, and topical anti-fungal; what I hadn’t used I donated to a local doctor.
I thought that I was being both responsible and appropriately skeptical. I did not take painkillers when I had a headache or other pain—I drank water and monitored my activity and considered dietary and environmental exposures. I did not presume that my body needed chemical intervention to stay healthy or, for the most part, to return to health when exposed to pathogens. But I was willing to use antibiotics, mostly Cipro, to treat the occasional bug that was going to make it impossible to do what I thought I needed to do, like take a bus ride. My bad.
It turns out—I learned while unable to walk and before I had been surgically repaired and was beginning the arduous return to mobility—that Cipro had already long since been recognized as putting tendons at risk. The most recognized risk was acute and short term: people who are actually on Cipro should avoid stressing their tendons. But it also turns out that exposure accumulates, and that taking a lot of Cipro even decades earlier could have bad effects on tendons later on. Especially that most famous tendon of all, the Achilles tendon.
Fluoroquinolones, including Cipro, have been widely prescribed in part because they are broad spectrum antibiotics. Being “broad spectrum” means that the drug kills off a wide swath of bacteria. This is useful if it’s not clear what pathogen is making you sick: a broad spectrum antibiotic is more likely to help you in such a situation than is a narrow spectrum antibiotic, one that is targeted to particular bacteria. The flip side of being a broad spectrum antibiotic, however, is that it kills off your “good” bacteria as well. We all have a lot of “good” bacteria, and we depend on them for our health. We do, it turns out, contain multitudes.
The toxicity of Fluoroquinolones is not inherently related to their being broad spectrum, however, as other broad spectrum antibiotics2 are not (yet?) understood to produce such a wide range of medical problems as do the Fluoroquinolones.
From the abstract of a 2003 paper3 that I cannot access the full text of, we find the following list of “long-term toxicities” that Fluoroquinolones were already understood to cause:
cardiotoxicity, aortic aneurysm, tendon rupture, nephrotoxicity, hepatotoxicity, peripheral neuropathy, vagus nervous dysfunction, reactive oxygen species (ROS), phototoxicity, glucose hemostasis, and central nervous system (CNS) toxicity.
So, in addition to being associated with tendon rupture, Fluoroquinolones are implicated in heart, kidney, liver, nervous system, and eye damage. And that’s not all.
In 2008, the FDA announced “black box” warnings on Fluoroquinolones, with concerns about tendon ruptures. In 2013, the FDA would add its third warning in 5 years to the packaging, this one advising of the “potential for irreversible peripheral neuropathy”—serious, permanent nerve damage. Meanwhile, there was growing evidence that many broad-spectrum antibiotics damage mitochondria—and that Fluoroquinolones do so most of all4.
Fluoroquinolones have also been known to cause such severe locomotory problems that people have lost the ability to walk. Thousands of people have died. This may be a considerable underestimate.
The toxicity that some people get from Fluoroquinolones is colloquially referred to as having been floxed. On-line communities of people who have been floxed are abundant.
By 2016, the FDA had seen enough evidence of the risks of these drugs that it was advising that they should be reserved for use only in patients who had “no alternative treatment options.” Two years later the FDA put out yet another update, warning of risks to mental health and “blood sugar disturbances.”
By 2018, the scientific journal Nature was finally reporting on the disabling side-effects of Fluoroquinolones. Therein, Nature acknowledges that one of the reasons that the toxicity of these drugs has taken so long to be made public is that drug companies are known to take “adverse action against people who expose drug and chemical harms.” Thus, the research has mostly not been done. From a career vantage point, scientists can’t afford the exposure.
Despite even the FDA having gotten worked up over Fluoroquinolones well before I busted my Achilles tendon, a year or so later I had some infection that a doctor wanted to prescribe antibiotics for. She suggested Cipro.
“I don’t want Cipro,” I said, expecting a fight. “I suspect that having been on Cipro a fair bit in my 20s contributed to me rupturing my Achilles last year.”
“That sounds right,” she said, nodding. “Probably a good idea that you not be on Cipro anymore.” She stood down easily, but had I not objected, I would have been put on Cipro once again, for no good reason.
Perhaps Cipro had nothing to do with my Achilles tendon rupture. Perhaps it did, but some people are particularly prone to suffering that particular side effect, and I am just among those unlucky few. Or perhaps Cipro had something to do with my Achilles tendon rupture, and that was wholly predictable, and those who do drug safety testing should have known, and those in the medical field who prescribed all that Cipro to me should therefore also have known, and they should have provided me sufficient information that I could in turn provide informed consent.
Ultimately, it’s my decisions that contributed to me going down on that cold beach ten years ago, and that sent me to surgery, the effects of which are still tangible in and on my body. I am responsible for the choices that I make—what to eat and take and do, when to reject the advice of “experts” and when to accept it, eyes wide open.
Even I, skeptical as I always have been of quick pharmaceutical solutions, made some bad decisions. On the question of Fluoroquinolones: we now know enough to be extremely cautious about their use.
The next time you are told that you need to take X in order to treat Y (especially if you are told that you should also take Z to treat the side-effects of X), ask every question that you can think of. And know that the answers that come back may not be accurate. There is risk in every decision. Do not let fear drive yours.
The on-going saga of how to prevent malaria in the field is itself a pharmaceutical minefield, but not one for today.
There are risks with all antibiotics, especially broad spectrum ones, but doxycycline, for instance, which is an effective anti-malarial and can also be used to treat plague (but causes considerable photosensitivity), is not understood to cause the damage that Fluoroquinolones cause.
Hussen et al 2023. Long-term toxicity of Fluoroquinolones: a comprehensive review. Drug and Chemical Toxicology 47(5): 795–806.
Kalghatgi et al 2013. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in mammalian cells. Science Translational Medicine 5(192): 192ra85.
Dr. Heying,
I cannot tell you how much I appreciate your work. This MD uses Cipro and its first cousin Levaquin only on very rare occasions because of exactly what you are saying. Usually with severe infections of the urine with multi-drug resistant organisms and this is the only choice. However, the patients are very carefully talked to about all the problems. I see it being handed out like Halloween Candy by the NPs and the PAs in our urgent care system around here, however.
It is important to alert your readers to the circus that has become modern medicine.
I am old enough to remember when all of these flouroquinolones were introduced.
One that is hardly mentioned today was the Pfizer product known as Trovan. It came out in the late 90s or so. Such was the push among the housestaff to get them to prescribe this that a weekly celebration of pizza party became known as "Trovan Tuesday". Thousands and thousands of dollars at a time were spent on this indoctrination. Interestingly, the tendon and orthopedic toxicity of this agent, as well as the kidney problems, were so intense they were not able to be hidden - and this drug was not black-boxed, it was pulled off the market in short order.
Levaquin also had a very similar Pharma push - just all kinds of drug reps, parties, cool restaurant invitations and such. It is hard to describe that 10 years - levaquin was THE antibiotic of choice for that 10 years. It was incredible. The entire profession had been trained not to abuse wide-spectrum antibiotics in this way - but it was the frontline drug of that entire era. Shame on us all.
I have given up long ago trying to make any difference in these issues. There is an animal spirit in medicine, and I am not sure what it will take to put it down.
I had antibiotics only twice in my growing up years and four times after, I am 60. My husband had the constantly and more times later as he is more inclined to take drugs he is prescribed. He gets sick in Latin America, once with amoebic dysentery for which he was hospitalized. I was fine and fought everything off naturally. Everything he ate as a child was scrubbed and boiled. I ate carrots out of the garden only wiping them off my on my jeans first. I believe my unsanitary childhood made me sturdier and my mother's innate distrust of medicines.