WEBVTT 00:00:00.000 --> 00:00:02.399 Welcome to the deep dive. Today, we're going 00:00:02.399 --> 00:00:05.639 to get into cipofloxacin. It's a really powerful 00:00:05.639 --> 00:00:09.640 antibiotic, hugely influential in modern medicine. 00:00:10.179 --> 00:00:11.820 Absolutely. I mean, think about it. Back in 2010, 00:00:12.359 --> 00:00:15.019 it was, what, the fifth most prescribed antibacterial 00:00:15.019 --> 00:00:18.699 in the US? Over 20 million prescriptions. That's 00:00:18.699 --> 00:00:21.780 huge. It really is. And for this deep dive, we've 00:00:21.780 --> 00:00:24.179 looked at a whole range of sources, scientific 00:00:24.179 --> 00:00:27.059 papers, regulatory docs, maybe even some personal 00:00:27.059 --> 00:00:29.300 accounts you might have come across online. Right. 00:00:29.399 --> 00:00:32.119 And the mission here is to really unpack the 00:00:32.119 --> 00:00:35.399 story of Cipro, its history, how it's used, the 00:00:35.399 --> 00:00:37.799 risks we've learned about, and its wider impact. 00:00:38.060 --> 00:00:40.740 Exactly. We want you, our listener, to join us 00:00:40.740 --> 00:00:43.079 as we figure out not just what it does, but why 00:00:43.079 --> 00:00:45.740 it got so big, the downsides, and what its whole 00:00:45.740 --> 00:00:47.899 journey tells us about, well, fighting infections 00:00:47.899 --> 00:00:51.719 today. OK, so let's rewind. Before Ciprofloxacin, 00:00:51.740 --> 00:00:53.280 what did things look like? What were doctors 00:00:53.280 --> 00:00:56.340 using? Well, you had the early quinolones, nullidicic 00:00:56.340 --> 00:00:58.840 acid is an example. They worked, but they weren't 00:00:58.840 --> 00:01:01.299 super potent, mostly just for UTIs, really, because 00:01:01.299 --> 00:01:03.820 they concentrated in the urine. OK, so limited 00:01:03.820 --> 00:01:06.439 use. Pretty limited, yeah. But then came a big 00:01:06.439 --> 00:01:11.120 moment. 1979, Kyurin Sayaku in Japan discovers 00:01:11.120 --> 00:01:14.340 norefloxacin. And the key insight was adding 00:01:14.340 --> 00:01:18.290 a fluorine atom. Just one atom. Just one fluorine 00:01:18.290 --> 00:01:20.370 atom. It dramatically increased the antibacterial 00:01:20.370 --> 00:01:22.109 strength. That was the breakthrough, really. 00:01:22.150 --> 00:01:24.849 It turned those early quinolones into fluoroquinolones. 00:01:24.969 --> 00:01:27.549 Wow. OK. So that set off more research. Oh, absolutely. 00:01:27.629 --> 00:01:30.430 The whole wave of research into these new fluoroquinolones. 00:01:30.730 --> 00:01:32.909 And that's where ciprofloxacin comes in. Bayer 00:01:32.909 --> 00:01:36.530 developed it. The code name was B -A -Y -O -9 00:01:36.530 --> 00:01:40.590 -8 -6 -7 and launched it in 1987. 1987. And it 00:01:40.590 --> 00:01:43.170 really took off. Big time. Because of its broad 00:01:43.170 --> 00:01:45.250 spectrum, it hit a lot of different bacteria. 00:01:45.319 --> 00:01:47.519 and its potency, people started calling it one 00:01:47.519 --> 00:01:50.140 of the great medicines of the 20th century. Hi, 00:01:50.159 --> 00:01:52.480 praise. So what specific infections was this 00:01:52.480 --> 00:01:54.340 great medicine approved for? What was its main 00:01:54.340 --> 00:01:56.540 job description? Well, the FDA gave it the green 00:01:56.540 --> 00:01:59.319 light for a very wide range of bacterial infections, 00:01:59.739 --> 00:02:03.200 UTIs, of course, various STIs, gonorrhea, chancroid, 00:02:03.840 --> 00:02:07.120 skin infections, bone and joint infections, prostatitis, 00:02:07.359 --> 00:02:11.900 typhoid fever, GI infections, lower respiratory 00:02:11.900 --> 00:02:14.419 tract infections, even really serious things 00:02:14.419 --> 00:02:17.460 like anthrax and plague. Anthrax and plague, 00:02:17.599 --> 00:02:20.280 wow. Yeah. So its broad usefulness really made 00:02:20.280 --> 00:02:22.759 it a first choice for doctors dealing with all 00:02:22.759 --> 00:02:25.120 sorts of bacterial issues. You can see why it 00:02:25.120 --> 00:02:27.400 was seen as so valuable early on. It sounds like 00:02:27.400 --> 00:02:30.039 the go -to drug for almost any bacterial problem 00:02:30.039 --> 00:02:32.240 back then. It was certainly viewed that way for 00:02:32.240 --> 00:02:35.139 a while, especially good against gram -negative 00:02:35.139 --> 00:02:37.840 bacteria and also useful when you had mixed infections 00:02:37.840 --> 00:02:39.919 with multiple bacteria involved. And it wasn't 00:02:39.919 --> 00:02:41.840 just pills, right? Were there other forms? Right. 00:02:41.960 --> 00:02:44.460 Beyond the usual tablets and IV drips, Cypro 00:02:44.460 --> 00:02:46.960 also comes with eye drops for things like corneal 00:02:46.960 --> 00:02:50.139 ulcers, conjunctivitis, and ear drops, too, for 00:02:50.139 --> 00:02:53.219 swimmer's ear, basically acute otitis externa. 00:02:53.419 --> 00:02:56.500 There's even a specific gel suspension, OTP RIO, 00:02:56.599 --> 00:02:58.439 for kids with certain types of ear infections 00:02:58.439 --> 00:03:01.199 involving fluid buildup. Interesting. Did doctors 00:03:01.199 --> 00:03:03.180 ever use it in ways that weren't officially approved, 00:03:03.699 --> 00:03:06.960 off -label uses? Oh yes, definitely. Often in 00:03:06.960 --> 00:03:10.580 really critical situations, like for newborns 00:03:10.580 --> 00:03:13.319 with really bad sepsis, infections resistant 00:03:13.319 --> 00:03:16.539 to lots of other drugs. Cipro has been used as 00:03:16.539 --> 00:03:19.159 a kind of salvage therapy, a last resort. A last 00:03:19.159 --> 00:03:21.699 resort, okay. And perhaps more surprisingly, 00:03:21.960 --> 00:03:24.199 there's been research into its potential against 00:03:24.199 --> 00:03:27.650 cancer cells. Lab studies, mind you, very early 00:03:27.650 --> 00:03:30.289 stage. Cancer, how? Yeah, looking at cell lines 00:03:30.289 --> 00:03:33.870 for things like bladder cancer, carcinoma, osteosarcoma, 00:03:34.050 --> 00:03:36.289 leukemia. Some studies suggest it might have 00:03:36.289 --> 00:03:39.159 effects that could, perhaps. kill cancer cells 00:03:39.159 --> 00:03:41.939 or slow them down. But again, lots more research 00:03:41.939 --> 00:03:43.979 needed there. It's not a cancer treatment. Got 00:03:43.979 --> 00:03:46.500 it. Early days on that front. Definitely. But 00:03:46.500 --> 00:03:48.539 it was crucial, as we mentioned, for prevention 00:03:48.539 --> 00:03:51.659 after anthrax exposure, like in 2001, and for 00:03:51.659 --> 00:03:54.360 treating plague outbreaks. So important in those 00:03:54.360 --> 00:03:56.699 specific public health scenarios, too. OK, so 00:03:56.699 --> 00:03:58.819 it hits a lot of targets. How does it actually 00:03:58.819 --> 00:04:00.939 work on the bacteria? What's the mechanism? Right, 00:04:01.000 --> 00:04:03.379 the nitty gritty. So ciprofloxacin goes after 00:04:03.379 --> 00:04:05.759 two really essential enzymes inside bacteria. 00:04:05.800 --> 00:04:08.870 They're called DNA gyrase. and DNA to poismaris 00:04:08.870 --> 00:04:11.289 afi. OK, fancy names. What do they do? Think 00:04:11.289 --> 00:04:13.849 of the bacteria's DNA like a super tangled up 00:04:13.849 --> 00:04:16.769 phone cord or yarn. These enzymes are like the 00:04:16.769 --> 00:04:19.350 little hands that unwind it, cut it, pass strands 00:04:19.350 --> 00:04:21.509 through, and stick it back together so the bacteria 00:04:21.509 --> 00:04:24.629 can copy its DNA, read its genes, repair damage, 00:04:25.389 --> 00:04:28.069 basically live and multiply. So essential machinery. 00:04:28.319 --> 00:04:31.240 Absolutely essential. Cipron messes that up. 00:04:31.399 --> 00:04:33.579 It binds to these enzymes while they're attached 00:04:33.579 --> 00:04:36.379 to the DNA, kind of freezing them in place. This 00:04:36.379 --> 00:04:39.379 traps them and leads to breaks in the DNA strands. 00:04:39.519 --> 00:04:41.620 Double strand breaks. And that stops the bacteria? 00:04:41.939 --> 00:04:44.180 Usually, yes. It stops them from reproducing. 00:04:44.279 --> 00:04:46.040 That's what we call a bacteriostatic effect. 00:04:46.620 --> 00:04:48.579 But there's also evidence it might sometimes 00:04:48.579 --> 00:04:51.420 outright kill the bacteria, a bactericidal effect, 00:04:51.660 --> 00:04:54.519 possibly by increasing damaging molecules called 00:04:54.519 --> 00:04:57.540 reactive oxygen species inside the cell. So it 00:04:57.540 --> 00:04:59.899 kind of jams their internal works. That's a good 00:04:59.899 --> 00:05:02.139 way to put it. It cripples their DNA management 00:05:02.139 --> 00:05:04.360 system. Now, related to that is how the drug 00:05:04.360 --> 00:05:07.259 actually moves through our bodies, pharmacokinetics 00:05:07.259 --> 00:05:10.100 and pharmacodynamics. Right, PKPD. How we absorb 00:05:10.100 --> 00:05:13.120 it, use it, get rid of it. Exactly. Generally, 00:05:13.360 --> 00:05:15.279 Cipro is absorbed pretty well when you take it 00:05:15.279 --> 00:05:18.480 by mouth. One interesting point, older people, 00:05:18.740 --> 00:05:22.000 say over 65 or 70, might have slightly higher 00:05:22.000 --> 00:05:24.319 levels in their blood. Why is that? Their kidneys 00:05:24.319 --> 00:05:27.300 might just clear it a bit more slowly. Usually, 00:05:27.459 --> 00:05:29.279 though, these differences aren't big enough to 00:05:29.279 --> 00:05:32.319 need a different dose automatically. But if someone 00:05:32.319 --> 00:05:35.279 has significant kidney problems, then yes, the 00:05:35.279 --> 00:05:37.720 dose often needs to be adjusted downwards. And 00:05:37.720 --> 00:05:40.180 liver problems. Liver issues generally don't 00:05:40.180 --> 00:05:42.420 seem to impact cipro levels too much, interestingly. 00:05:42.920 --> 00:05:45.000 Kidney function is the main one to watch. What 00:05:45.000 --> 00:05:48.069 about taking it with food? Or other medicines? 00:05:48.550 --> 00:05:50.569 Any conflicts there? Oh, definitely. This is 00:05:50.569 --> 00:05:52.889 important. You can take Cipro with or without 00:05:52.889 --> 00:05:55.350 food, that part's flexible, but you need to avoid 00:05:55.350 --> 00:05:57.389 taking it at the same time as certain things. 00:05:57.709 --> 00:06:00.209 Like what? Magnesium or aluminum -containing 00:06:00.209 --> 00:06:04.029 antacids, think malox, mylanta. Also, some drugs 00:06:04.029 --> 00:06:06.449 called phosphate binders, used in kidney disease. 00:06:06.990 --> 00:06:10.189 Sucralpate, for ulcers. And even some forms of 00:06:10.189 --> 00:06:12.949 didanosine, an older HIV drug. Basically, things 00:06:12.949 --> 00:06:15.589 that can bind to the Cipro. Okay, so they interfere 00:06:15.589 --> 00:06:18.319 with absorption. Exactly, and that includes supplements 00:06:18.319 --> 00:06:21.420 or foods with a lot of calcium, iron, or zinc. 00:06:21.860 --> 00:06:24.180 So multivitamins with minerals, iron tablets, 00:06:24.319 --> 00:06:27.399 things like that. The usual advice is to separate 00:06:27.399 --> 00:06:30.620 them. Take Cipro either two hours before or six 00:06:30.620 --> 00:06:32.920 hours after those products. Six hours after? 00:06:32.920 --> 00:06:35.579 That's a long time. It is. It really highlights 00:06:35.579 --> 00:06:38.540 how significant the interaction can be. Now, 00:06:38.560 --> 00:06:41.160 dairy products or calcium -fortified juices are 00:06:41.160 --> 00:06:43.720 a bit different. You shouldn't take Cipro just 00:06:43.720 --> 00:06:45.899 with a glass of milk or fortified juice on its 00:06:45.899 --> 00:06:49.220 own, as that can also lower absorption. But okay 00:06:49.220 --> 00:06:51.300 with a meal? Generally, yes. If you have them 00:06:51.300 --> 00:06:53.279 as part of a larger meal, the effect on absorption 00:06:53.279 --> 00:06:55.870 seems to be much less significant. So having 00:06:55.870 --> 00:06:58.069 milk on your cereal with Cipro is usually fine. 00:06:58.129 --> 00:07:00.490 That's a lot to keep track of. What about typical 00:07:00.490 --> 00:07:02.889 doses for adults? Does it vary a lot? It really 00:07:02.889 --> 00:07:04.730 does. Depends entirely on the infection, what 00:07:04.730 --> 00:07:07.889 kind it is, how severe it is. A simple UTI might 00:07:07.889 --> 00:07:10.569 just need a couple days at a lower dose. But 00:07:10.569 --> 00:07:13.889 a serious bone infection, osteomyelitis, might 00:07:13.889 --> 00:07:16.389 need high doses for six weeks or even longer. 00:07:17.029 --> 00:07:20.069 So big range. And do doctors ever check the drug 00:07:20.069 --> 00:07:23.189 levels in the blood? Sometimes, yes. It's called 00:07:23.189 --> 00:07:26.399 therapeutic drug monitoring, or TDM. They might 00:07:26.399 --> 00:07:29.480 consider it in specific cases. Patients with 00:07:29.480 --> 00:07:32.740 kidney or liver problems, maybe someone at an 00:07:32.740 --> 00:07:36.040 extreme weight, very elderly patients say, over 00:07:36.040 --> 00:07:38.779 80. Why then? Just to make sure the levels are 00:07:38.779 --> 00:07:41.139 right, not too high, causing side effects, not 00:07:41.139 --> 00:07:44.660 too low to be ineffective. Also, if they suspect 00:07:44.660 --> 00:07:47.379 the person isn't absorbing the oral drug well, 00:07:47.379 --> 00:07:50.740 or if it's really tough to treat infection, the 00:07:50.740 --> 00:07:52.980 goal is usually to keep the drug concentration 00:07:52.980 --> 00:07:55.399 above a certain level needed to kill the bacteria. 00:07:55.240 --> 00:07:57.540 for the whole time between doses. Makes sense, 00:07:57.660 --> 00:08:00.220 it's quite tailored. Now, how is Cipro actually 00:08:00.220 --> 00:08:02.279 made? What forms does it come in? Well, the most 00:08:02.279 --> 00:08:05.000 common are the oral tablets. Then there's an 00:08:05.000 --> 00:08:06.800 oral suspension that's a powder you mix with 00:08:06.800 --> 00:08:08.939 water, often used for kids or people who can't 00:08:08.939 --> 00:08:11.220 swallow pills. Right. Then you have the IV solution 00:08:11.220 --> 00:08:13.180 for hospital use and the eye drops and ear drops 00:08:13.180 --> 00:08:15.720 we mentioned earlier. The oral suspension actually 00:08:15.720 --> 00:08:17.939 involves mixing tiny microcapsules of the drug 00:08:17.939 --> 00:08:21.699 with the liquid dilatant. Okay. Is manufacturing 00:08:21.699 --> 00:08:24.040 changing at all? Any new approaches? There's 00:08:24.040 --> 00:08:26.279 some really interesting research happening, yeah. 00:08:26.519 --> 00:08:29.160 Looking at highly efficient ways to synthesize 00:08:29.160 --> 00:08:32.139 drugs like Cipro using continuous manufacturing. 00:08:32.659 --> 00:08:35.659 The idea is maybe having small portable plug 00:08:35.659 --> 00:08:37.379 -and -play factories. Preservable factories. 00:08:37.580 --> 00:08:39.740 Yeah, that could potentially make the drug on 00:08:39.740 --> 00:08:41.879 demand right where it's needed. It could be huge 00:08:41.879 --> 00:08:45.139 for, say, remote areas or emergency situations. 00:08:45.460 --> 00:08:47.879 Still in development, but very forward thinking. 00:08:48.159 --> 00:08:49.799 That does sound like science fiction almost. 00:08:50.519 --> 00:08:52.799 Okay, let's shift gears a bit. The regulatory 00:08:52.799 --> 00:08:55.519 side. Cipro wasn't always seen with the level 00:08:55.519 --> 00:08:58.279 of caution it is today, right? Its reputation 00:08:58.279 --> 00:09:00.659 changed. That's a really crucial part of the 00:09:00.659 --> 00:09:02.860 story, absolutely. When it first came out, it 00:09:02.860 --> 00:09:06.120 was embraced, widely used, even for simple UTIs, 00:09:06.120 --> 00:09:08.779 it became very common. But then reports of side 00:09:08.779 --> 00:09:10.519 effects started accumulating. A serious one. 00:09:10.580 --> 00:09:12.960 Yes, serious enough that regulatory agencies, 00:09:13.200 --> 00:09:15.460 especially the FDA and the US, had to take action. 00:09:15.799 --> 00:09:18.100 It's a stark reminder that we need to keep watching 00:09:18.100 --> 00:09:21.320 drugs long after they hit the market. Post -market 00:09:21.320 --> 00:09:23.840 surveillance is critical. So what were the big 00:09:23.840 --> 00:09:25.620 regulatory milestones? When did the warnings 00:09:25.620 --> 00:09:27.879 start appearing? The first really major one was 00:09:27.879 --> 00:09:31.240 2008. The FDA added a black box warning. That's 00:09:31.240 --> 00:09:33.039 their strongest type of warning about the risk 00:09:33.039 --> 00:09:36.480 of tendinitis, and more severely, tendon rupture. 00:09:36.639 --> 00:09:38.759 Tendon rupture, like Achilles tendon. Exactly. 00:09:38.899 --> 00:09:41.200 Achilles is the most common one reported. The 00:09:41.200 --> 00:09:43.440 warning noted the risk was higher in people over 00:09:43.440 --> 00:09:46.840 60, anyone taking corticosteroid drugs, like 00:09:46.840 --> 00:09:50.120 prednisone, and also organ transplant recipients. 00:09:50.600 --> 00:09:53.460 And other risk factors too, like heavy exercise, 00:09:53.740 --> 00:09:56.080 kidney failure, or if someone had tendon problems 00:09:56.080 --> 00:09:58.159 before. And that was just the start. It was. 00:09:58.480 --> 00:10:00.860 In 2011, the warning was brought in to include 00:10:00.860 --> 00:10:03.340 worsening of myasthenia gravis, which is a muscle 00:10:03.340 --> 00:10:06.759 weakness disorder. Then, 2013, another update, 00:10:07.039 --> 00:10:08.799 this time highlighting the risk of peripheral 00:10:08.799 --> 00:10:11.019 neuropathy nerve damage, which could potentially 00:10:11.019 --> 00:10:14.240 be permanent. Nerve damage too. Wow. And it didn't 00:10:14.240 --> 00:10:17.340 stop there. No. 2016 was another huge step. The 00:10:17.340 --> 00:10:20.320 FDA updated the black box warning again. This 00:10:20.320 --> 00:10:23.100 time, they really emphasized that fluoroquinolones 00:10:23.100 --> 00:10:25.720 could cause multiple disabling and potentially 00:10:25.720 --> 00:10:28.639 irreversible serious side effects. Multiple side 00:10:28.639 --> 00:10:31.159 effects. Like what specifically? Affecting tendons, 00:10:31.419 --> 00:10:34.059 muscles, joints, nerves, the peripheral neuropathy 00:10:34.059 --> 00:10:36.460 we mentioned, and also the central nervous system. 00:10:36.720 --> 00:10:39.799 Things like confusion, hallucinations, anxiety. 00:10:39.960 --> 00:10:42.220 To a whole constellation of potential issues. 00:10:42.600 --> 00:10:45.120 Exactly. And importantly, the FDA recommended 00:10:45.120 --> 00:10:47.840 limiting their use. They said for common things 00:10:47.840 --> 00:10:51.320 like acute sinusitis, acute bronchitis flare 00:10:51.320 --> 00:10:54.620 -ups, and uncomplicated UTIs, fluoroquinolones 00:10:54.620 --> 00:10:57.139 like Cipra should only be used if there are no 00:10:57.139 --> 00:10:59.789 other TREX options available. So reserve them 00:10:59.789 --> 00:11:01.769 for when they're really needed. Precisely. A 00:11:01.769 --> 00:11:03.929 major shift from being a first -line drug for 00:11:03.929 --> 00:11:07.669 those conditions. Then, in 2018, even more warnings 00:11:07.669 --> 00:11:10.850 were added. Increased risk of aortic aneurysm 00:11:10.850 --> 00:11:12.850 and dissection tears in the main artery from 00:11:12.850 --> 00:11:14.929 the heart, especially in the elderly. Oh, wow. 00:11:15.190 --> 00:11:17.289 And also warnings about blood sugar disturbances, 00:11:17.429 --> 00:11:19.230 both high and low, and more detailed warnings 00:11:19.230 --> 00:11:21.669 about psychiatric side effects. And other countries' 00:11:21.929 --> 00:11:24.649 regulators, like the MHRA in the UK, issued similar 00:11:24.649 --> 00:11:26.610 restrictions and warnings. With all these serious 00:11:26.610 --> 00:11:28.990 warnings piling up, I imagine that led to legal 00:11:28.990 --> 00:11:33.460 challenges. Oh, inevitably, yes. Thousands of 00:11:33.460 --> 00:11:35.440 lawsuits have been filed against the manufacturers, 00:11:35.759 --> 00:11:39.460 Bayer for Cipro, J &J for Lavakian, Merck, too. 00:11:40.100 --> 00:11:42.379 The core allegation is usually that the companies 00:11:42.379 --> 00:11:44.940 didn't adequately warn doctors and patients about 00:11:44.940 --> 00:11:46.919 these severe risks. Like the tendon ruptures 00:11:46.919 --> 00:11:49.740 and nerve damage. Exactly. Tendon rupture, peripheral 00:11:49.740 --> 00:11:52.299 neuropathy, and more recently, the aortic injuries. 00:11:52.759 --> 00:11:55.100 To manage all these cases, the court set up multi 00:11:55.100 --> 00:11:58.139 -district litigations, MDLs. These consolidate 00:11:58.139 --> 00:12:00.919 similar federal lawsuits into one court to streamline 00:12:00.919 --> 00:12:03.809 the process. OK. There was an MDL specifically 00:12:03.809 --> 00:12:06.590 for levokane tendon ruptures years ago. More 00:12:06.590 --> 00:12:08.649 recently, there's been one covering peripheral 00:12:08.649 --> 00:12:11.029 neuropathy linked to several fluoroquinolones, 00:12:11.330 --> 00:12:13.470 Cipro included. And what happened with those 00:12:13.470 --> 00:12:16.129 lawsuits? It's been mixed, really. Some cases 00:12:16.129 --> 00:12:18.009 have resulted in settlements where the companies 00:12:18.009 --> 00:12:20.409 pay out to resolve the claims. Some have gone 00:12:20.409 --> 00:12:22.470 to trial with verdicts for the plaintiffs, the 00:12:22.470 --> 00:12:25.330 injured people. Others have resulted in verdicts 00:12:25.330 --> 00:12:28.269 for the defendants, the drug companies. The peripheral 00:12:28.269 --> 00:12:31.309 neuropathy MDL seems to be winding down now with 00:12:31.309 --> 00:12:33.549 reports that many of those cases have been settled. 00:12:33.789 --> 00:12:36.450 It's quite a fall from grace, from wonder drug 00:12:36.450 --> 00:12:40.090 to basing all these warnings and lawsuits. What 00:12:40.090 --> 00:12:42.870 about the money side, the economics? Well, Cypro 00:12:42.870 --> 00:12:45.789 was a true blockbuster for Bayer initially. While 00:12:45.789 --> 00:12:48.450 they had the patent, it generated enormous revenue. 00:12:48.909 --> 00:12:51.809 Patent exclusivity was key to that market dominance. 00:12:52.070 --> 00:12:54.450 When did the patent run out? In the U .S., the 00:12:54.450 --> 00:12:56.629 main patent for the twice -a -day tablet expired 00:12:56.629 --> 00:13:00.490 around 2003 -2004. That naturally opened the 00:13:00.490 --> 00:13:02.789 floodgates for generic versions. So the price 00:13:02.789 --> 00:13:05.970 came down. Significantly. Lots of generic manufacturers 00:13:05.970 --> 00:13:08.889 jumped in, like Cipla and others, globally. But 00:13:08.889 --> 00:13:11.730 even with generic competition, the global market 00:13:11.730 --> 00:13:14.230 for Ciprofloxan is still pretty significant. 00:13:14.690 --> 00:13:17.950 You mentioned the 2024 estimate, around $155 00:13:17.950 --> 00:13:20.870 million. Lower respiratory infections are still 00:13:20.870 --> 00:13:23.470 a big driver of its use. And did they try to 00:13:23.470 --> 00:13:25.950 extend the brand life, like with different versions? 00:13:26.230 --> 00:13:28.750 Yes. They developed extended release formulations 00:13:28.750 --> 00:13:31.750 like Ciprex R, which offered once a day dosing. 00:13:32.110 --> 00:13:34.029 Those sometimes had their own patents, extending 00:13:34.029 --> 00:13:36.879 the brand's presence for a bit longer. Interesting. 00:13:37.279 --> 00:13:38.860 Beyond the medicine cabinets and courtrooms, 00:13:39.039 --> 00:13:41.960 did CIPRA make any waves in, like, popular culture 00:13:41.960 --> 00:13:44.580 or public awareness? It did, in a couple of really 00:13:44.580 --> 00:13:48.419 distinct ways. Firstly, and... Perhaps most memorably 00:13:48.419 --> 00:13:52.059 for many, was its role during the 2001 anthrax 00:13:52.059 --> 00:13:54.460 attacks in the US. Oh, right. I remember that. 00:13:54.779 --> 00:13:56.840 Cipro suddenly became a household name because 00:13:56.840 --> 00:13:59.759 it was the main drug recommended for post -exposure 00:13:59.759 --> 00:14:02.340 prophylaxis, taking it to prevent illness if 00:14:02.340 --> 00:14:04.500 you thought you'd been exposed to anthrax spores. 00:14:04.960 --> 00:14:07.419 It really highlighted its role in biodefense 00:14:07.419 --> 00:14:10.480 and public health emergencies. A very specific 00:14:10.480 --> 00:14:13.299 kind of fame. Indeed. And then there's the other 00:14:13.299 --> 00:14:15.960 side. The experiences of patients who believe 00:14:15.960 --> 00:14:19.200 they've suffered severe, long -lasting side effects. 00:14:19.879 --> 00:14:21.620 This community often refers to themselves as 00:14:21.620 --> 00:14:25.019 being floxed. Floxed. Yeah, short for fluoroquinolone 00:14:25.019 --> 00:14:28.059 toxicity. They've formed extensive online support 00:14:28.059 --> 00:14:31.059 groups, advocacy organizations, sharing stories, 00:14:31.179 --> 00:14:33.259 raising awareness about the potential dangers, 00:14:33.620 --> 00:14:35.779 pushing regulators for stronger warnings, demanding 00:14:35.779 --> 00:14:37.700 more research, and just supporting each other 00:14:37.700 --> 00:14:39.580 through some really difficult health challenges. 00:14:39.779 --> 00:14:42.480 So it created its own patient advocacy movement, 00:14:42.480 --> 00:14:44.759 essentially. It really did. And the whole Cipro 00:14:44.759 --> 00:14:46.919 controversy, you could call it, really throws 00:14:46.919 --> 00:14:49.879 into sharp relief the complexities of antibiotic 00:14:49.879 --> 00:14:52.360 use. You know, balancing the incredible power 00:14:52.360 --> 00:14:54.759 these drugs have against the potential for serious 00:14:54.759 --> 00:14:57.980 harm. It underscores why informed consent and 00:14:57.980 --> 00:15:00.460 really robust post -market safety monitoring 00:15:00.460 --> 00:15:03.379 are just so crucial. Absolutely. And that brings 00:15:03.379 --> 00:15:05.840 us to maybe the biggest challenge facing Cipro 00:15:05.840 --> 00:15:08.840 and all antibiotics today. The elephant in the 00:15:08.840 --> 00:15:11.720 room, yes. Antibiotic resistance is a massive 00:15:11.720 --> 00:15:14.740 growing global threat and ciprofloxacin resistance 00:15:14.740 --> 00:15:17.919 is a major part of that problem. How do bacteria 00:15:17.919 --> 00:15:20.580 become resistant to Cipro specifically? They 00:15:20.580 --> 00:15:23.100 have a few tricks up their sleeves. One main 00:15:23.100 --> 00:15:25.960 way is through small changes, mutations, in the 00:15:25.960 --> 00:15:28.360 bacterial genes that code for those target enzymes, 00:15:28.600 --> 00:15:31.080 DNA gyrase, and topoisomerase, the fee. It's 00:15:31.080 --> 00:15:33.139 like the bacteria changing the shape of the lock 00:15:33.139 --> 00:15:35.320 just enough so the sipper key doesn't fit as 00:15:35.320 --> 00:15:38.019 well. And the more mutations accumulate, the 00:15:38.019 --> 00:15:41.539 more resistant the bacteria can become. Another 00:15:41.539 --> 00:15:44.539 strategy is pumping the drug out. Bacteria can 00:15:44.539 --> 00:15:47.639 develop or ramp up efflux pumps, little molecular 00:15:47.639 --> 00:15:50.659 pumps in their cell walls that actively spit 00:15:50.659 --> 00:15:53.139 the ciprofloxacin back out before it can do its 00:15:53.139 --> 00:15:55.940 job. While they pump it out. Yeah. Or they can 00:15:55.940 --> 00:15:57.720 change their outer membranes, making it harder 00:15:57.720 --> 00:16:00.220 for cipro to get inside in the first place, especially 00:16:00.220 --> 00:16:02.580 in gram -negative bacteria with their complex 00:16:02.580 --> 00:16:05.399 cell walls. And can this resistance spread easily? 00:16:05.549 --> 00:16:08.309 That's the really scary part, yes. Resistance 00:16:08.309 --> 00:16:10.409 doesn't just happen through random mutation. 00:16:10.909 --> 00:16:12.850 Bacteria can share resistance genes with each 00:16:12.850 --> 00:16:16.090 other on small, mobile pieces of DNA called plasmids. 00:16:16.230 --> 00:16:18.830 Plasmids, right. So one resistant bacterium can 00:16:18.830 --> 00:16:21.190 pass that resistance trait directly to others, 00:16:21.350 --> 00:16:23.509 including bacteria of different species. This 00:16:23.509 --> 00:16:25.809 allows resistance to spread much more rapidly 00:16:25.809 --> 00:16:29.190 through bacterial populations. We call this plasmid 00:16:29.190 --> 00:16:32.490 -mediated quinolone resistance, or PMQR. And 00:16:32.490 --> 00:16:34.529 we're seeing this in practice. Oh, absolutely. 00:16:34.830 --> 00:16:37.450 We're seeing worrying levels of ciprofloxacin 00:16:37.450 --> 00:16:40.330 -resistant E. coli. For instance, a super common 00:16:40.330 --> 00:16:44.049 cause of UTIs and other infections in people, 00:16:44.529 --> 00:16:47.370 in livestock, in the environment. It's a classic 00:16:47.370 --> 00:16:49.970 one health problem, meaning the health of humans, 00:16:50.370 --> 00:16:52.929 animals, and the environment are all interconnected 00:16:52.929 --> 00:16:56.750 here. So the resistance is widespread. How has 00:16:56.750 --> 00:16:58.960 that changed treatment recommendations? It's 00:16:58.960 --> 00:17:00.899 had a big impact, as we mentioned with the FDA 00:17:00.899 --> 00:17:03.279 warnings, but also in treatment guidelines generally, 00:17:03.620 --> 00:17:05.779 because of resistance concerns and also what's 00:17:05.779 --> 00:17:07.579 called collateral damage. No enderal damage. 00:17:07.680 --> 00:17:09.700 Yeah, meaning the unintended consequences of 00:17:09.700 --> 00:17:12.599 antibiotic use, like wiping out beneficial gut 00:17:12.599 --> 00:17:14.859 bacteria, which can allow harmful ones like seed 00:17:14.859 --> 00:17:17.980 difficult to take over, or selecting for resistance 00:17:17.980 --> 00:17:21.410 and other bacteria. Because of all that, guidelines 00:17:21.410 --> 00:17:24.029 now strongly advise against using Floryfin alone 00:17:24.029 --> 00:17:26.970 like Cipro as the first choice for uncomplicated 00:17:26.970 --> 00:17:29.170 UTIs. So trying to save them for when they're 00:17:29.170 --> 00:17:32.349 really necessary. Exactly. Stewardship. trying 00:17:32.349 --> 00:17:35.730 to preserve their effectiveness. Meanwhile, researchers 00:17:35.730 --> 00:17:38.250 are working hard on ways to overcome resistance, 00:17:38.789 --> 00:17:40.809 looking at combination therapies using Cipro 00:17:40.809 --> 00:17:42.930 with another drug that might help it work better, 00:17:43.390 --> 00:17:45.990 trying to develop F -flux pump inhibitors, drugs 00:17:45.990 --> 00:17:48.329 that would block those pumps, spitting Cipro 00:17:48.329 --> 00:17:51.390 out, blocking the pumps, right? Or finding new 00:17:51.390 --> 00:17:53.589 ways to deliver the drug to the bacteria more 00:17:53.589 --> 00:17:57.170 effectively. And ethically, it's complex to balancing 00:17:57.170 --> 00:17:59.869 the need for access to these drugs in low income 00:17:59.869 --> 00:18:02.529 countries versus the need for careful stewardship 00:18:02.529 --> 00:18:05.269 everywhere to slow resistance development, it's 00:18:05.269 --> 00:18:08.650 a global challenge. It really is. Semper Floxacin's 00:18:08.650 --> 00:18:11.029 story, from being hailed as revolutionary to 00:18:11.029 --> 00:18:13.250 facing all these safety issues and the huge problem 00:18:13.250 --> 00:18:16.069 of resistance, it's a powerful lesson in how 00:18:16.069 --> 00:18:18.170 medicine evolves. It truly is. It shows that 00:18:18.170 --> 00:18:20.690 our understanding is never static. This deep 00:18:20.690 --> 00:18:22.910 dive, I hope, has really highlighted for you, 00:18:22.930 --> 00:18:25.450 the listener, why it's so important to look beyond 00:18:25.450 --> 00:18:28.170 just the immediate effectiveness of a drug. We 00:18:28.170 --> 00:18:30.210 have to constantly weigh the benefits against 00:18:30.210 --> 00:18:32.359 the potential potential risks, both for the individual 00:18:32.359 --> 00:18:35.220 and for public health down the line. So as you 00:18:35.220 --> 00:18:37.259 think about everything we've talked through today, 00:18:38.380 --> 00:18:41.680 the journey of Cipro, maybe consider that balance, 00:18:42.119 --> 00:18:44.440 the incredible power of broad spectrum antibiotics 00:18:44.440 --> 00:18:47.619 versus the potential for long term harm, the 00:18:47.619 --> 00:18:50.720 development of resistance. What other questions 00:18:50.720 --> 00:18:52.519 does this raise for you about how we approach 00:18:52.519 --> 00:18:55.319 antibiotics, how we regulate them, and the choices 00:18:55.319 --> 00:18:57.420 we make in health care? A lot to think about. 00:18:57.559 --> 00:18:59.440 Definitely. Thanks for joining us for this deep 00:18:59.440 --> 00:18:59.779 dive.