By: Valic
I noticed something in the clinic this week with two patients that prompted me to do some digging. The first woman came in complaining of shoulder pain. She started telling the doc her history by leading with the fact that she had a urinary tract infection a month ago that was treated with ciprofloxacin. Why was this relevant? She was convinced that Cipro caused a tendon in her rotator cuff to tear.
Wtf? Yeah. I was trying my hardest not to roll my eyes as I typed all of this nonsense. She continued by saying that in the middle of her course of antibiotics she decided to read the warning that comes with Cipro that specifically mentions “fluoroquinolones are associated with an increased risk of tendonitis and tendon rupture.” Funny how she all of the sudden noticed that her shoulder was hurting after she read this warning. This is reminiscent of the nocebo effect.
I wrote that lady off as insane and quickly forgot about her. However, the following clinic day we had another woman complaining of the SAME thing, but this time with moxifloxacin, another antibiotic that is in the same class of drugs as ciprofloxacin, the so called “fluoroquinolones.” Maybe I was feeling in a more compassionate mood, or maybe this woman sold me a better story, but in any case I decided to look into validity of the issue.
So I first hit the blogs of my favorite ID docs. I immediately was overwhelmed by anecdotes written in the comments section of the blogs by a lot of people who sounded exactly like the two patients I heard earlier. At this point, I am still not sold on the issue, mainly because everybody appears to be making the classic logical fallacy of finding correlations and labeling them as causations.
I will admit, anecdotally, that every doctor I have ever shadowed or scribed for has handed out quinolones like they were candy. Infection prophylaxis? Here’s some Levaquin. You THINK you have an infection? Here’s some Cipro.
There is a notion in society that I have become increasingly aware of in regards to antibiotics. That is the fact that people forget that antibiotics are drugs with active ingredients that come with risks. There are no free lunches. As my favorite ID doc REPEATEDLY says “No good deed goes unpunished.”
So what’s the deal with antibiotics? The overwhelming majority of antibiotics inhibits microbes from replicating and then let the immune system handle the rest. This is the case with the quinolone class of antibiotics. Most antibiotics have a relatively good safety profile and the reason, of course, is evolutionary. Let me remind you that all life on earth is descended from a single common ancestor. Bacteria are ancient organisms that figured out an effective way of living very early in life’s history. They are the so called prokaryotes with very different cellular features and mechanisms. Humans are composed of eukaryotic cells. Eukaryotes and prokaryotes are not ancestral to each other, but instead share a common ancestor. However, that common ancestor is so old that prokaryotes and eukaryotes are DISTINCTLY different morphologically and metabolically. In medicine, we exploit these differences when designing drugs. The safest medicines are the ones that target cell features that are unique to prokaryotes. For example, many anti-fungal medicines are considered harmful because fungi are eukaryotes, their cellular machinery is similar to our own so there is less unique targets for drugs to seek.
Quinolones are a class of antibiotics that inhibit DNA replication in bacteria. Remember mitosis? That seemingly meaningless bullshit you had to learn and re-learn in every god damn biology class you have ever taken, EVER. Well, now it’s time to dust it off and get some use out of it. Early on in mitosis before any of the actual fun stuff happens there is a “subphase” within interphase called S-phase which stands for “synthesis phase.” In the S-phase the cell is replicating its entire genome to pass onto the daughter cell. Prior to that, the DNA needs to be unpacked. Much like Christmas lights, when DNA isn’t used it’s wound up real tight and stored until it’s needed. To increase the efficiency of its packing, it is wound REAL TIGHT around balls of proteins called histones. To unwind this DNA from the histone proteins requires two enzymes. The first enzyme is DNA gyrase. DNA gyrase helps relax the tightness of the DNA around the histone proteins, and then the 2nd enzyme DNA helicase does the unwinding. DNA gyrase is not present in humans, so it makes for a great target for antibiotics. And that is exactly what quinolones do. Quinolones bind to DNAgyrase in bacteria and prevent replication.
Quinolones are considered bactericidal, because they bind irreversibly to their target. Antibiotics like tetracyclines are considered bacteriostatic because they bind reversibly with their target (side note: they are considered bactericidal at high concentrations). However, both do their killing in similar ways, by jamming up their metabolism and turning them into sitting ducks for the immune system. Quinolones completely inhibit bacteria from accessing their DNA to replicate or to manufacture proteins. Tetracyclines, on the other hand only inhibit protein synthesis because they bind to bacterial ribosomes. Moreover, tetracyclines ALSO inhibit DNA replication because the bacteria can’t even accumulate the proteins required for G1 phase of mitosis.
Beta-lactams are another beast altogether (and are my favorite). The beta-lactam penicillin is considered bactericidal because it binds irreversibly to the enzyme responsible for bacterial cell membrane synthesis. Bacteria are constantly re-structuring their outer membrane to accommodate for their growth and changes in environment. Penicillin throws a wrench into this process and disrupts cell membrane synthesis. A bacterium with no cell membrane will make it very sensitive to osmotic pressure and it’ll either explode, or be very susceptible to phagocytosis.
Ok so we’ve established that quinolones target an enzyme that is unique to bacteria (gyrase), so why in 2008 did the FDA issue a boxed warning that quinolones could cause tendon damage? EVOLUTION BRO.
Ok the shit I’m about to type is super cool and just took me like 2 hours of reading and re-reading to understand so bear with me.
Quinolones have been found to increase reactive oxygen species (ROS) intracellularly. That is a bad thing. Reactive oxygen species are… reactive. They have an unpaired valence electron and get hungry to react with things that should not be reacted with. They’re BAD because they LOVE fucking up DNA.
How does this happen? Well, quinolones are great for treating intracellular infections because it can easily get inside of eukaryotic cells via porins. Now… since we’ve established earlier that quinolones bind specifically to a protein unique to bacteria. What are inside of eukaryotic cells that are even remotely similar to bacteria….? I’ll give you some hints; it has its own genome and makes a shitload of energy for the cell. Oh yeah, and it’s also theorized that it has bacterial ancestry. The powerhouse of the cell—the mitochondrion.
Ok. Now think back to cell biology and recall the electron transport chain. A quick, dirty, and SIMPLE recap is in order: The electron transport chain is at the inner membrane of the mitochondrion and is composed of 4 complexes. These 4 complexes work as proton pumps to create an electrochemical gradient to ultimately generate chemical energy in the form of ATP. These pumps are fueled by electrons being passed from one complex to the next, then ultimately to oxygen. An important molecule is ubiquinone (also known as coenzyme Q10) that ferries electrons from complex 1 to 2 and from 2 to 3. Then a small protein called cytochrome C ferries a single electron from complex 3 to 4, after four electron carrying cytochrome C proteins reach complex 4 their electrons are directed to oxygen forming 2 water molecules and fueling 4 H+ protons through to the intermembrane space.
Ok, remember reactive oxygen species? How are those formed? Every once in a great while, the electron transport chain fucks up and tries to skip steps. It is very important that the electrons get shuttled in the same way every time from complex 1 to 2 to 3 to 4 then to elemental oxygen. If the electrons ever skip straight to the end before going through the assembly line it will prematurely and incompletely reduce oxygen to a REACTIVE OXYGEN SPECIES. Naturally, this is rare and happens to about .1-2% of electrons passing through the chain.
However, our dear friend the quinolone has been implicated in increasing the production of ROS. How? Well, scientists in 2010 did some studies with plants. Plants have a nifty system with chloroplasts that is VERY similar to how mitochondria work. What these researchers found was that fluoroquinolones INHIBIT quinone (the plant version of ubiquinone) binding sites on complexes 1 and 2. Quinone in plants is structurally and functionally IDENTICAL to ubiquinone in mitochondria. Remember that ubiquinone ferries electrons from complexes 1-2-3. So when ubiquinone can no longer hand off electrons between complexes because of quinolone inhibition they prematurely get passed to oxygen, forming reactive oxygen species.
Once ROS are formed, shit starts hitting the fan. Once quinolones bind to these complexes the mitochondrion starts making A LOT of ROS. But, thankfully the mitochondrion is equipped to handle this sort of situation. All of our cells are equipped with a real badass protein called glutathione. Glutathione is an antioxidant; it literally hangs out and throws electrons at asshole oxygens who decide to get all reactive. Once it gives up its own electrons it becomes reactive itself, but it readily reacts with another nearby reactive glutathione to form glutathione disulfide. However, when quinolones are bound in the electron transport chain, ROS overwhelm the glutathione stores and start mashing mitochondrial DNA and proteins.
Ah, but guess what? The mitochondrion is equipped to handle this situation too. On the outer membrane of the mitochondrion are layered proteins that detect damage going on inside and activate a class of proteins called Bax. Bax proteins then punch holes in the mitochondrial membrane causing cytochrome C to leak out (the protein that shuttles electrons from complex 3 to 4 in the last step of electron transport) of the membrane into the cell’s cytoplasm. Once cytochrome C is in the cytoplasm it binds a free-floating protein called apoptotic protease activating factor-1 (Apaf-1). Once cytochrome C and Apaf-1 complex they bind an enzyme called pro-caspase, upon binding they activate the caspase cascade which eventually leads to whole cell destruction (apoptosis). When this happens inside of tenocytes (the cells that make tendons), you get ruptured tendons.
Why tendons? Well, muscles compose 50% of body weight and serve as a large volume organ for drug distribution. It’s postulated that older patients are at a higher risk of tendon rupture because they have lower metabolic rates, and insufficient vascularization. In addition decreased renal clearance in old folks may increase serum drug concentrations and add gas to the already burning fire of toxicity.
So what would be a good solution? How about supplementing with antioxidants to control ROS? There is a bunch of studies out there that have tested this and had great success. Antioxidants do a great job attenuating the toxic effects of quinolones on tendon cells. I have also failed to mention that fluoroquinolones can be photoactivated. That is, solar and artificial radiation will photo-activate the quinolone and greatly potentiate this whole ROS production business. Multiple studies recommend that if you’re on a quinolone, stay out of sunlight, take a break from exercising, and hit the antioxidants.
God damn, I guess those 2 patients weren’t crazy.
(I used like 14 sources for this. If you want one of them, let me know.)
The Tumescence Monitor 