WEBVTT 00:00:00.000 --> 00:00:02.160 Welcome to the Deep Dive. You're here because 00:00:02.160 --> 00:00:06.360 you want to get smart fast. And today, we're 00:00:06.360 --> 00:00:09.000 doing just that, focusing on azithromycin. That's 00:00:09.000 --> 00:00:11.439 right, a really common antibiotic one many people 00:00:11.439 --> 00:00:13.880 have probably encountered. Exactly. So we've 00:00:13.880 --> 00:00:16.359 gone through a ton of material, scientific reviews, 00:00:16.660 --> 00:00:19.120 market reports, clinical trial data, even patents. 00:00:19.300 --> 00:00:21.980 All the good stuff. Our mission today, to really 00:00:21.980 --> 00:00:25.579 unpack azithromycin, its history, how it works, 00:00:25.960 --> 00:00:28.750 what it's used for, and its wider impact. Think 00:00:28.750 --> 00:00:30.789 of it as the essential guide. We'll cover the 00:00:30.789 --> 00:00:33.990 science, the story, and, well, some of the controversies, 00:00:34.130 --> 00:00:36.590 too. OK, let's jump right in. The history. Where 00:00:36.590 --> 00:00:38.950 did this drug actually come from? It wasn't like 00:00:38.950 --> 00:00:41.149 an ancient discovery, right? No, no, not at all. 00:00:41.189 --> 00:00:43.149 It's actually relatively modern, discovered in 00:00:43.149 --> 00:00:46.270 the late 1970s. Oh, OK. Yeah, by a Croatian pharmaceutical 00:00:46.270 --> 00:00:49.329 company called Pliva. But the interesting part 00:00:49.329 --> 00:00:52.109 is, it wasn't built from scratch. How so? It's 00:00:52.109 --> 00:00:54.789 what we call a semisynthetic derivative. It's 00:00:54.789 --> 00:00:57.969 based on an older antibiotic, erythromycin A, 00:00:58.390 --> 00:01:02.289 which had been around since the early 1950s. 00:01:02.369 --> 00:01:04.230 Ah, so they were trying to improve on something 00:01:04.230 --> 00:01:07.370 that already existed. Precisely. Erythromycin 00:01:07.370 --> 00:01:10.640 worked, but it had some drawbacks. One big one 00:01:10.640 --> 00:01:14.180 was instability in stomach acid, meaning it could 00:01:14.180 --> 00:01:16.579 get broken down before your body fully absorbed 00:01:16.579 --> 00:01:18.540 it. Right, less effective then. And it wasn't 00:01:18.540 --> 00:01:20.480 quite as good against certain types of bacteria, 00:01:21.000 --> 00:01:23.920 particularly some gram negatives. So pliva scientists 00:01:23.920 --> 00:01:26.439 were looking for ways to tweak the erythromycin 00:01:26.439 --> 00:01:29.480 molecule to overcome these limitations. Clever. 00:01:29.689 --> 00:01:31.989 And they succeeded, obviously. They did. And 00:01:31.989 --> 00:01:34.170 they were smart about it, too. They secured pretty 00:01:34.170 --> 00:01:36.530 broad patent protection for their new compound, 00:01:36.930 --> 00:01:39.409 azithromycin. Which turned out to be a very valuable 00:01:39.409 --> 00:01:42.370 move, I imagine. Hugely valuable. Because in 00:01:42.370 --> 00:01:45.329 1986, they struck a licensing deal with Pfizer. 00:01:45.810 --> 00:01:49.329 Ah, Pfizer. That explains the global reach. Exactly. 00:01:49.469 --> 00:01:52.269 Pfizer marketed it as Zikromax pretty much everywhere 00:01:52.269 --> 00:01:54.709 except Central and Eastern Europe, where Pliva 00:01:54.709 --> 00:01:57.849 kept the rights. That partnership really transformed 00:01:57.849 --> 00:02:01.609 azithromycin from a promising discovery into 00:02:01.609 --> 00:02:04.969 a, well, a blockbuster drug. It's a classic story 00:02:04.969 --> 00:02:07.049 of innovation meeting market power. It really 00:02:07.049 --> 00:02:09.550 is. Shows how both discovery and strategic business 00:02:09.550 --> 00:02:11.509 decisions are needed to get important medicines 00:02:11.509 --> 00:02:14.310 out there. Okay, so we know when and who. Let's 00:02:14.310 --> 00:02:17.949 get into the how. How does azithromycin actually 00:02:17.949 --> 00:02:21.150 fight off bacteria? What's the mechanism? Right. 00:02:21.469 --> 00:02:24.169 So azithromycin is classified as a macrolide 00:02:24.169 --> 00:02:27.340 antibiotic. Its main job is to stop bacteria 00:02:27.340 --> 00:02:29.560 from making proteins. Proteins are essential 00:02:29.560 --> 00:02:31.939 for bacteria, right? For growth and everything 00:02:31.939 --> 00:02:34.719 else. Absolutely essential. Think of a bacterium 00:02:34.719 --> 00:02:37.300 having a little factory inside it to build proteins. 00:02:38.460 --> 00:02:41.439 Azithromycin jams up a key piece of that factory's 00:02:41.439 --> 00:02:43.439 machinery. Which piece is that? It specifically 00:02:43.439 --> 00:02:46.699 binds to something called the 50S ribosomal subunit. 00:02:47.020 --> 00:02:49.620 By sticking there, it basically prevents the 00:02:49.620 --> 00:02:51.740 factor from assembling proteins correctly. No 00:02:51.740 --> 00:02:54.840 proteins, no growth, no multiplication. throwing 00:02:54.840 --> 00:02:57.340 a wrench in the works. Exactly like that. It 00:02:57.340 --> 00:02:59.979 doesn't usually kill the bacteria outright. It 00:02:59.979 --> 00:03:02.199 mostly stops them from growing bacteriostatic, 00:03:02.219 --> 00:03:04.680 we call it. Okay. Now, the sources mention cross 00:03:04.680 --> 00:03:06.719 -resistance with erythromycin. What does that 00:03:06.719 --> 00:03:08.479 mean for us? That's a really important point, 00:03:08.560 --> 00:03:10.780 especially now. It means if bacteria figure out 00:03:10.780 --> 00:03:13.180 a way to resist erythromycin, that same trick 00:03:13.180 --> 00:03:15.500 often works against azithromycin too. Why is 00:03:15.500 --> 00:03:17.919 that? Because they're so similar chemically, 00:03:18.180 --> 00:03:20.460 and they target basically the same spot on that 00:03:20.460 --> 00:03:23.699 ribosome. So a change the bacteria makes to protect 00:03:23.699 --> 00:03:25.680 itself from one often protects it from the other. 00:03:25.759 --> 00:03:27.539 It's a major issue with antibiotic resistance. 00:03:27.800 --> 00:03:30.300 Got it. Something else that stood out was its 00:03:30.300 --> 00:03:33.080 pharmacology, how it gets taken up by our own 00:03:33.080 --> 00:03:36.719 cells, like white blood cells. Yes. This is one 00:03:36.719 --> 00:03:39.759 of azithromycin's quite unique features. Its 00:03:39.759 --> 00:03:41.960 chemical structure, this dual -based thing it 00:03:41.960 --> 00:03:44.659 has, allows it to be actively transported into 00:03:44.659 --> 00:03:48.250 certain human cells. fibroblasts, white blood 00:03:48.250 --> 00:03:50.409 cells like phagocytes. And why is that useful? 00:03:51.069 --> 00:03:54.030 Well, think about where infections happen. White 00:03:54.030 --> 00:03:56.330 blood cells naturally travel to those sites to 00:03:56.330 --> 00:03:59.610 fight the bacteria. So if the azithromycin hitches 00:03:59.610 --> 00:04:02.349 a ride inside these white blood cells, it gets 00:04:02.349 --> 00:04:04.830 delivered in high concentrations right to the 00:04:04.830 --> 00:04:07.129 battlefield, so to speak, directly to where the 00:04:07.129 --> 00:04:09.060 bacteria are causing problems. That's pretty 00:04:09.060 --> 00:04:11.560 smart drug design or maybe a beneficial property 00:04:11.560 --> 00:04:13.819 they discovered. It's certainly a key part of 00:04:13.819 --> 00:04:16.160 its effectiveness and it's not just about killing 00:04:16.160 --> 00:04:19.660 bacteria directly. What else does it do? There's 00:04:19.660 --> 00:04:23.480 growing evidence for immunomodulatory effects. 00:04:23.709 --> 00:04:26.730 It seems to be able to influence our immune system's 00:04:26.730 --> 00:04:29.970 response. Like calming down inflammation. Exactly. 00:04:30.310 --> 00:04:32.850 It can reduce the production of certain pro -inflammatory 00:04:32.850 --> 00:04:35.189 signals, cytokines. This can be really helpful 00:04:35.189 --> 00:04:37.629 in conditions like, say, lung infections where 00:04:37.629 --> 00:04:39.850 excessive inflammation can actually cause more 00:04:39.850 --> 00:04:42.389 damage. So it fights the bugs and helps manage 00:04:42.389 --> 00:04:44.730 the body's reaction. A double whammy almost. 00:04:45.269 --> 00:04:48.120 Sort of, yeah. It adds another layer to its therapeutic 00:04:48.120 --> 00:04:50.540 benefit, especially in respiratory diseases. 00:04:50.879 --> 00:04:53.339 Okay, that makes sense. So, with all that in 00:04:53.339 --> 00:04:55.759 mind, what are the main things azithromycin... 00:04:55.899 --> 00:04:58.100 actually prescribed for it. The list seems pretty 00:04:58.100 --> 00:05:00.540 long. It is quite broad -spectrum. It's definitely 00:05:00.540 --> 00:05:02.480 a go -to for a community -acquired pneumonia 00:05:02.480 --> 00:05:06.259 CAP. Both oral and IV forms are used there. Okay. 00:05:06.560 --> 00:05:09.540 Also, acute bacterial sinusitis is really nasty 00:05:09.540 --> 00:05:13.079 sinus infections. Pharyngitis or tonsillitis 00:05:13.079 --> 00:05:14.959 like strep throat, especially if someone can't 00:05:14.959 --> 00:05:17.300 use penicillin or the other first -line options. 00:05:17.360 --> 00:05:20.589 Right, as an alternative. Yes. and uncomplicated 00:05:20.589 --> 00:05:23.050 skin infections. Then there's a whole range of 00:05:23.050 --> 00:05:25.509 sexually transmitted infections. Ah, yes. That 00:05:25.509 --> 00:05:28.569 comes up a lot. Definitely. For non -gonococcal 00:05:28.569 --> 00:05:31.610 urethritis and cervicitis, often caused by chlamydia, 00:05:32.069 --> 00:05:35.230 it's famous for that single one -gram dose. Super 00:05:35.230 --> 00:05:37.709 convenient. One dose and done. For that specific 00:05:37.709 --> 00:05:40.490 indication, yes. Makes adherence much easier. 00:05:40.649 --> 00:05:43.110 For gonorrhea, it's a bit different now due to 00:05:43.110 --> 00:05:45.550 resistance. It usually requires a higher single 00:05:45.550 --> 00:05:48.110 dose, two grams, and it's almost always given 00:05:48.110 --> 00:05:51.110 with another antibiotic, like ceftriaxone. Because 00:05:51.110 --> 00:05:53.430 resistance is a big problem with gonorrhea. A 00:05:53.430 --> 00:05:55.829 huge problem. Using two drugs helps combat that. 00:05:56.329 --> 00:05:58.509 It's also used as a single dose for chandroid, 00:05:58.750 --> 00:06:00.709 another type of genital ulcer disease. And I 00:06:00.709 --> 00:06:02.990 saw something about mycobacterium avian complex, 00:06:03.170 --> 00:06:05.470 MAC. Yes, that's important, especially for people 00:06:05.470 --> 00:06:07.850 with compromised immune systems, like advanced 00:06:07.850 --> 00:06:10.649 HIV. Azithromycin is used both for preventing 00:06:10.649 --> 00:06:12.930 M .A .C. infection, usually a 1200 -milligram 00:06:12.930 --> 00:06:15.550 dose once a week, and for treating active M .E 00:06:15.550 --> 00:06:17.970 .C. infection, typically 600 -milligram daily, 00:06:18.329 --> 00:06:20.990 as part of a multi -drug regimen. Wow. And even 00:06:20.990 --> 00:06:23.310 eye drops. Yep, for bacterial conjunctivitis. 00:06:23.829 --> 00:06:26.209 Azazite is a common brand name for the ophthalmic 00:06:26.209 --> 00:06:28.129 solution. It really does cover a lot of ground. 00:06:28.389 --> 00:06:31.470 It certainly does. Now, during the COVID -19 00:06:31.470 --> 00:06:33.850 pandemic, azithromycin got a lot of attention, 00:06:33.990 --> 00:06:36.040 didn't it? often mentioned with hydroxychloroquine. 00:06:36.259 --> 00:06:39.519 It absolutely did. There were some early small 00:06:39.519 --> 00:06:42.220 studies, often in vitro or observational, that 00:06:42.220 --> 00:06:44.620 suggested it might have some antiviral activity 00:06:44.620 --> 00:06:47.860 or could potentially help maybe synergistically 00:06:47.860 --> 00:06:50.120 with hydroxychloroquine. But that didn't really 00:06:50.120 --> 00:06:53.920 pan out in larger trials. Largely no. Subsequent, 00:06:54.079 --> 00:06:56.300 much larger, well -controlled clinical trials 00:06:56.300 --> 00:06:59.220 like the recovery trial in the UK or the action 00:06:59.220 --> 00:07:02.379 trial for outpatients generally found no significant 00:07:02.379 --> 00:07:05.040 clinical benefit for azithromycin in treating 00:07:05.040 --> 00:07:07.839 COVID -19 patients, especially those who weren't 00:07:07.839 --> 00:07:10.600 severely ill. So the initial hype didn't match 00:07:10.600 --> 00:07:12.839 the rigorous evidence later on. That's a fair 00:07:12.839 --> 00:07:15.839 summary. It highlights how science works. Initial 00:07:15.839 --> 00:07:18.350 observations need to be tested robustly. There 00:07:18.350 --> 00:07:20.649 was also some real -world data, like a study 00:07:20.649 --> 00:07:23.110 from India mentioned, suggesting it helped with 00:07:23.110 --> 00:07:25.750 upper respiratory symptoms over five days. But 00:07:25.750 --> 00:07:27.389 that's different from proving in effect against 00:07:27.389 --> 00:07:30.089 the virus itself. Right. And I see notes about 00:07:30.089 --> 00:07:32.589 potential synergy with other antibiotics against 00:07:32.589 --> 00:07:35.209 biofilms. That sounds interesting. Yeah, biofilms 00:07:35.209 --> 00:07:38.569 are these slimy layers, bacteria form, making 00:07:38.569 --> 00:07:41.189 them harder to treat. There's some research looking 00:07:41.189 --> 00:07:44.569 if combining azizromycin with drugs like tiging 00:07:44.569 --> 00:07:46.829 cyclane could be more effective against these 00:07:46.829 --> 00:07:49.069 resistant structures. Still early days for some 00:07:49.069 --> 00:07:52.230 of that, though. And off -label use in pediatric 00:07:52.230 --> 00:07:55.389 ICUs, any major concerns there? Well, off -label 00:07:55.389 --> 00:07:57.939 use always requires careful consideration. But 00:07:57.939 --> 00:08:00.519 one study we saw indicated that in that specific 00:08:00.519 --> 00:08:02.839 setting, it didn't seem to increase the risk 00:08:02.839 --> 00:08:05.259 of serious adverse events compared to its approved 00:08:05.259 --> 00:08:08.019 uses, but again, requires careful judgment by 00:08:08.019 --> 00:08:10.199 the clinicians. OK, let's shift to how the body 00:08:10.199 --> 00:08:12.540 handles it. Pharmacokinetics, pharmacodynamics. 00:08:12.939 --> 00:08:14.839 You mentioned the long half life earlier. Right. 00:08:14.860 --> 00:08:17.319 That's a key pharmacokinetic feature. Its half 00:08:17.319 --> 00:08:19.720 life is quite long, which allows for that once 00:08:19.720 --> 00:08:22.300 daily dosing and often shorter treatment courses, 00:08:22.519 --> 00:08:24.860 like the famous three day or five day Z -pack. 00:08:24.939 --> 00:08:26.579 Makes it easier for people to take all their 00:08:26.579 --> 00:08:29.339 medicine. Definitely a plus for adherence. Another 00:08:29.339 --> 00:08:32.159 key point is its distribution. Even though oral 00:08:32.159 --> 00:08:34.220 bioavailability, the amount that actually gets 00:08:34.220 --> 00:08:36.460 into your bloodstream when you take a pill, is 00:08:36.460 --> 00:08:39.019 only around 38 % compared to IV. Which sounds 00:08:39.019 --> 00:08:41.980 low. It is relatively low compared to some drugs. 00:08:42.740 --> 00:08:45.299 But azithromycin has this fantastic ability to 00:08:45.299 --> 00:08:48.909 penetrate tissues extensively. Concentrations 00:08:48.909 --> 00:08:51.429 in tissues like lung tissue or those white blood 00:08:51.429 --> 00:08:53.570 cells we talked about can be much, much higher 00:08:53.570 --> 00:08:55.570 than the concentration just floating around in 00:08:55.570 --> 00:08:57.330 your blood plasma. So it gets where it needs 00:08:57.330 --> 00:08:59.570 to go, even if not all of it gets into the blood 00:08:59.570 --> 00:09:02.330 initially. Exactly. That tissue concentration 00:09:02.330 --> 00:09:04.610 is crucial for fighting infections located in 00:09:04.610 --> 00:09:07.970 those tissues. As for getting rid of it, it's 00:09:07.970 --> 00:09:10.470 primarily metabolized or processed by the liver 00:09:10.470 --> 00:09:13.049 and then eliminated mainly through bile. into 00:09:13.049 --> 00:09:15.590 the feces. Okay, so how do they actually make 00:09:15.590 --> 00:09:17.950 this stuff? It's not like baking cookies, I assume. 00:09:18.690 --> 00:09:20.529 Definitely not. Pharmaceutical manufacturing 00:09:20.529 --> 00:09:23.769 is pretty complex. For drugs like erythromycin, 00:09:23.990 --> 00:09:26.470 it's typically done using batch production. Batch 00:09:26.470 --> 00:09:28.830 production, meaning they make it in large separate 00:09:28.830 --> 00:09:32.009 loads. Precisely. It involves multiple chemical 00:09:32.009 --> 00:09:35.110 reaction steps, starting usually from that erythromycin 00:09:35.110 --> 00:09:38.009 A precursor. Then there are critical stages like 00:09:38.009 --> 00:09:40.870 crystallization, where the drug forms into solid 00:09:40.870 --> 00:09:43.970 crystals, and purification, often involving filtration 00:09:43.970 --> 00:09:46.730 and washing, to get rid of impurities and isolate 00:09:46.730 --> 00:09:49.129 the pure azithromycin. And the sources mentioned 00:09:49.129 --> 00:09:51.450 that the chemical transformation from erythromycin 00:09:51.450 --> 00:09:54.210 to azithromycin requires strong reaction conditions. 00:09:54.409 --> 00:09:56.129 Yes, some of the chemical steps involved can 00:09:56.129 --> 00:09:59.289 be quite harsh, maybe requiring specific temperatures, 00:09:59.750 --> 00:10:02.279 pressures. or reactive chemicals. Controlling 00:10:02.279 --> 00:10:04.820 these conditions precisely is vital for safety 00:10:04.820 --> 00:10:07.220 and also for ensuring you get a good yield of 00:10:07.220 --> 00:10:09.379 the desired product without too many unwanted 00:10:09.379 --> 00:10:11.639 side products. Sounds like scaling that up from 00:10:11.639 --> 00:10:14.259 a lab bench to giant factory vats would be a 00:10:14.259 --> 00:10:16.980 challenge. It absolutely is. That's process chemistry 00:10:16.980 --> 00:10:19.620 and chemical engineering. You need large, specialized 00:10:19.620 --> 00:10:22.059 reactors, often stirred tanks. Some might need 00:10:22.059 --> 00:10:25.399 vacuum systems. Then specific equipment for crystallization 00:10:25.399 --> 00:10:27.639 to control the crystal size and shape, which 00:10:27.639 --> 00:10:30.169 can affect how the drug dissolves later. and 00:10:30.169 --> 00:10:32.750 robust filters like filter presses to separate 00:10:32.750 --> 00:10:35.070 the solid drug from liquids. And they're always 00:10:35.070 --> 00:10:37.250 trying to make the process faster and more efficient, 00:10:37.269 --> 00:10:40.029 right? Constantly. Optimizing reaction times, 00:10:40.490 --> 00:10:43.610 improving yields, minimizing waste, ensuring 00:10:43.610 --> 00:10:45.549 consistent purity. That's the name of the game 00:10:45.549 --> 00:10:48.070 in pharmaceutical manufacturing. It's a highly 00:10:48.070 --> 00:10:50.309 regulated and controlled environment. Speaking 00:10:50.309 --> 00:10:53.029 of regulated, let's talk about the regulatory 00:10:53.029 --> 00:10:55.110 side and maybe some of the bumps in the road. 00:10:55.409 --> 00:10:59.139 It got FDA approval for Lots of uses. Yes, it 00:10:59.139 --> 00:11:01.480 went through the standard FDA approval process 00:11:01.480 --> 00:11:04.580 for its various indications and dosage forms, 00:11:05.100 --> 00:11:07.820 tablets, suspensions, IV injections. But then 00:11:07.820 --> 00:11:10.100 generics came along. How did that change things? 00:11:10.440 --> 00:11:13.279 Massively. Once Pliva's and Pfizer's patents 00:11:13.279 --> 00:11:15.820 expired, other companies could get approval to 00:11:15.820 --> 00:11:18.940 make generic azithromycin. To do that, they have 00:11:18.940 --> 00:11:21.080 to demonstrate bioequivalence. Meaning they're 00:11:21.080 --> 00:11:23.399 version X the same in the body as zithromax. 00:11:23.580 --> 00:11:26.350 Essentially, yes. Same rate and extent of absorption. 00:11:26.850 --> 00:11:28.629 They also have to show their inactive ingredients 00:11:28.629 --> 00:11:31.850 are safe. The result was a dramatic drop in price 00:11:31.850 --> 00:11:35.070 and a huge increase in access. Generics dominate 00:11:35.070 --> 00:11:37.090 the market volume now. But it hasn't all been 00:11:37.090 --> 00:11:39.070 smooth sailing. There have been safety concerns 00:11:39.070 --> 00:11:42.179 raised, particularly about the heart. Yes, that's 00:11:42.179 --> 00:11:44.620 been a significant point of discussion and ongoing 00:11:44.620 --> 00:11:47.820 surveillance. Several large observational studies 00:11:47.820 --> 00:11:50.519 and meta -analyses have suggested a potential 00:11:50.519 --> 00:11:53.080 link between macrolide antibiotics, including 00:11:53.080 --> 00:11:56.019 azithromycin, and a slightly increased risk of 00:11:56.019 --> 00:11:58.500 cardiovascular events. Like what kind of events? 00:11:59.220 --> 00:12:02.080 Primarily ventricular arrhythmias, irregular 00:12:02.080 --> 00:12:03.960 heartbeats originating in the lower chambers 00:12:03.960 --> 00:12:07.059 of the heart, and, in some studies, a small increased 00:12:07.059 --> 00:12:10.620 risk of sudden cardiac death. or overall cardiovascular 00:12:10.620 --> 00:12:13.940 death, particularly when compared to no antibiotic 00:12:13.940 --> 00:12:17.269 or perhaps penicillin derivatives. Some data 00:12:17.269 --> 00:12:19.429 also hinted at a slight increase in heart attack 00:12:19.429 --> 00:12:21.629 risk. That sounds serious. Did regulators act 00:12:21.629 --> 00:12:24.470 on this? Yes. The FDA, for example, issued a 00:12:24.470 --> 00:12:27.389 drug safety communication back in 2013. They 00:12:27.389 --> 00:12:29.429 highlighted a specific study published in the 00:12:29.429 --> 00:12:31.529 New England Journal of Medicine that suggested 00:12:31.529 --> 00:12:34.009 a higher risk of cardiovascular death in patients 00:12:34.009 --> 00:12:37.169 taking a five -day course of azithromycin compared 00:12:37.169 --> 00:12:39.789 to amoxicillin or no antibiotic. But they also 00:12:39.789 --> 00:12:42.320 noted limitations with that study. They did. 00:12:42.500 --> 00:12:45.000 It was an observational study, not a randomized 00:12:45.000 --> 00:12:47.919 control trial, which means it can show associations 00:12:47.919 --> 00:12:50.480 but can't definitively prove cause and effect. 00:12:51.100 --> 00:12:53.820 It relied on death certificate data, which can 00:12:53.820 --> 00:12:56.500 sometimes be inaccurate, and it focused on an 00:12:56.500 --> 00:12:59.220 outpatient population. So there was context. 00:12:59.480 --> 00:13:02.080 And this relates to the QT prolongation issue. 00:13:02.399 --> 00:13:05.279 Exactly. Zithromycin, like other macrolides, 00:13:05.419 --> 00:13:07.379 is known to have the potential to prolong the 00:13:07.379 --> 00:13:10.200 QT interval on an electrocardiogram. Which is 00:13:10.200 --> 00:13:12.059 a measure of the heart's electrical recharging 00:13:12.059 --> 00:13:14.159 time. Correct. If that interval gets too long, 00:13:14.580 --> 00:13:16.799 it can increase the risk of a dangerous arrhythmia 00:13:16.799 --> 00:13:19.519 called torsitis de pointe. This risk is higher 00:13:19.519 --> 00:13:22.240 in people who already have QT prolongation, low 00:13:22.240 --> 00:13:24.980 potassium or magnesium levels, a slow heart rate, 00:13:25.179 --> 00:13:27.440 or who are taking other drugs that also prolong 00:13:27.440 --> 00:13:29.960 the QT interval. So doctors need to be aware 00:13:29.960 --> 00:13:33.080 of patient risk factors. Absolutely. It's a known 00:13:33.080 --> 00:13:35.299 risk that needs to be managed. There have also 00:13:35.299 --> 00:13:38.080 been reports of other potential issues, like 00:13:38.080 --> 00:13:40.519 hepatotoxicity, liver injury, though that seems 00:13:40.519 --> 00:13:43.840 rare, and reports of infantile hypertrophic pyloric 00:13:43.840 --> 00:13:47.460 stenosis, a stomach muscle thickening in newborns 00:13:47.460 --> 00:13:50.799 treated very early in life, also possible worsening 00:13:50.799 --> 00:13:54.279 of myasthenia gravis. And inevitably, antibiotic 00:13:54.279 --> 00:13:57.409 resistance. The big one. Because azithromycin 00:13:57.409 --> 00:14:00.129 has been used so widely, often very conveniently, 00:14:00.549 --> 00:14:02.769 it has unfortunately driven the development of 00:14:02.769 --> 00:14:05.190 resistance in many bacteria. We mentioned gonorrhea 00:14:05.190 --> 00:14:07.789 earlier. Where else is resistance a concern? 00:14:07.889 --> 00:14:10.070 It's a growing problem in streptococcus pneumonia, 00:14:10.309 --> 00:14:12.230 a common cause in pneumonia and ear infections. 00:14:12.809 --> 00:14:15.990 Also in mycoplasma genitalium, another STI, and 00:14:15.990 --> 00:14:18.389 even in common bacteria causing respiratory infections. 00:14:18.730 --> 00:14:20.990 It limits the drug's usefulness over time. The 00:14:20.990 --> 00:14:23.169 COVID situation probably didn't help with lots 00:14:23.169 --> 00:14:27.049 of potentially inappropriate use. Our sources 00:14:27.049 --> 00:14:29.990 mention concerns from Italy, for instance, where 00:14:29.990 --> 00:14:32.490 widespread azithromycin use during the pandemic, 00:14:33.029 --> 00:14:35.850 often for a viral illness, might have accelerated 00:14:35.850 --> 00:14:38.809 resistance development. It really emphasizes 00:14:38.809 --> 00:14:41.210 the need for antibiotic stewardship using these 00:14:41.210 --> 00:14:43.570 drugs only when necessary. And there are even 00:14:43.570 --> 00:14:46.169 restrictions on using it in animals we eat. Yes, 00:14:46.409 --> 00:14:48.570 off -label use in food -producing animals is 00:14:48.570 --> 00:14:51.389 restricted in many places due to concerns about 00:14:51.389 --> 00:14:53.909 drug residues getting into the food supply and 00:14:53.909 --> 00:14:56.129 potentially contributing to resistance in bacteria 00:14:56.129 --> 00:14:58.149 that could affect humans. Okay, let's look at 00:14:58.149 --> 00:15:01.090 the money side. Zithromax was a monster hit for 00:15:01.090 --> 00:15:03.750 Pfizer. Oh, absolutely. A true blockbuster. Peak 00:15:03.750 --> 00:15:05.750 annual sales were somewhere around $2 billion 00:15:05.750 --> 00:15:09.429 back in 2005. Huge numbers. But generics changed 00:15:09.429 --> 00:15:12.309 that picture dramatically. Completely. Once generics 00:15:12.309 --> 00:15:15.370 enter the market, branded Zithromax sales plummeted. 00:15:15.470 --> 00:15:18.149 That's the typical life cycle. But the overall 00:15:18.149 --> 00:15:20.889 market for Zithromycin remained huge, just shifted 00:15:20.889 --> 00:15:23.750 to lower priced generics. So more accessible, 00:15:24.009 --> 00:15:26.370 less profitable for the original maker. Pretty 00:15:26.370 --> 00:15:30.440 much. Key players now include Pfizer still, but 00:15:30.440 --> 00:15:32.960 also major generic companies like Teva Mylon, 00:15:33.100 --> 00:15:36.039 now Viatris, Indian companies like Zytus, Cadilla, 00:15:36.379 --> 00:15:39.139 Lupin, Chinese manufacturers. It's a global market. 00:15:39.440 --> 00:15:41.779 Rising awareness of infections keeps the demand 00:15:41.779 --> 00:15:44.539 strong. How does it stack up in terms of cost 00:15:44.539 --> 00:15:46.899 effectiveness? It depends heavily on what you're 00:15:46.899 --> 00:15:49.350 treating and what you're comparing it to. That 00:15:49.350 --> 00:15:51.889 single dose regimen for chlamydia was often considered 00:15:51.889 --> 00:15:54.629 very cost effective, mainly because you could 00:15:54.629 --> 00:15:56.809 be pretty sure the patient took the full treatment 00:15:56.809 --> 00:15:59.529 course, potentially avoiding complications and 00:15:59.529 --> 00:16:02.450 further spread. For other infections, the comparisons 00:16:02.450 --> 00:16:05.009 get more complex. And its impact goes beyond 00:16:05.009 --> 00:16:07.509 just treating individual infections into public 00:16:07.509 --> 00:16:09.350 health. Definitely. This is a really important 00:16:09.350 --> 00:16:12.250 aspect. Azithromycin has been absolutely crucial 00:16:12.250 --> 00:16:14.970 for global efforts against neglected tropical 00:16:14.970 --> 00:16:18.230 diseases. Like trachoma. Yes, trachoma especially. 00:16:18.750 --> 00:16:20.990 It's a leading cause of preventable blindness. 00:16:21.950 --> 00:16:25.090 Mass drug administration programs, often involving 00:16:25.090 --> 00:16:28.190 donations of azithromycin, like through the International 00:16:28.190 --> 00:16:30.210 Trachoma Initiative, supported by Pfizer for 00:16:30.210 --> 00:16:33.490 many years, using single dose therapy, have made 00:16:33.490 --> 00:16:35.730 incredible progress towards eliminating trachoma 00:16:35.730 --> 00:16:38.039 in many parts of the world. It's also used for 00:16:38.039 --> 00:16:40.639 Yaw's eradication efforts. So its single dose 00:16:40.639 --> 00:16:43.080 efficacy and availability have had a massive 00:16:43.080 --> 00:16:46.019 global health impact. Unquestionably. It's also 00:16:46.019 --> 00:16:48.399 been studied quite extensively actually for reducing 00:16:48.399 --> 00:16:51.320 overall child mortality in high mortality settings 00:16:51.320 --> 00:16:54.019 in Africa and Asia, given periodically to young 00:16:54.019 --> 00:16:56.950 children. Some trials showed significant reductions 00:16:56.950 --> 00:17:00.269 in death rates. Wow. That's huge. Shifting slightly, 00:17:00.309 --> 00:17:02.549 what about its cultural impact? The Z -Pak is 00:17:02.549 --> 00:17:05.150 almost a brand in itself. It really is. That 00:17:05.150 --> 00:17:07.390 term became synonymous with a short, convenient 00:17:07.390 --> 00:17:09.849 course of antibiotics. It represented ease of 00:17:09.849 --> 00:17:12.029 use. But maybe too convenient. Did it contribute 00:17:12.029 --> 00:17:15.009 to overuse? That's the concern many people raise. 00:17:15.970 --> 00:17:18.390 The sheer convenience and widespread availability 00:17:18.390 --> 00:17:20.769 might have lowered the threshold for prescribing 00:17:20.769 --> 00:17:23.859 or requesting antibiotics. potentially for conditions 00:17:23.859 --> 00:17:25.819 like colds or bronchitis where they wouldn't 00:17:25.819 --> 00:17:28.259 help because those are usually viral. Leading 00:17:28.259 --> 00:17:30.920 to that resistance problem we discuss. It's all 00:17:30.920 --> 00:17:33.279 interconnected. Increased awareness of antibiotic 00:17:33.279 --> 00:17:36.339 resistance is in part a consequence of the era 00:17:36.339 --> 00:17:39.660 of widely used convenient antibiotics like azithromycin. 00:17:39.980 --> 00:17:42.240 And when supplies run short, like the recent 00:17:42.240 --> 00:17:44.720 issues in Germany affecting SDI treatment. Right, 00:17:44.720 --> 00:17:47.359 I saw that. It really underscores how reliant 00:17:47.359 --> 00:17:50.140 public health systems have become on having these 00:17:50.140 --> 00:17:52.920 key antibiotics readily available. shortages 00:17:52.920 --> 00:17:56.200 can have immediate serious consequences. So wrapping 00:17:56.200 --> 00:17:59.059 this all up, it's been quite a journey for azithromycin. 00:17:59.380 --> 00:18:01.200 Absolutely, from an innovative improvement on 00:18:01.200 --> 00:18:04.140 an older drug, becoming this incredibly widely 00:18:04.140 --> 00:18:06.480 used tool for everything from common infections 00:18:06.480 --> 00:18:09.960 to major global health campaigns. But also facing 00:18:09.960 --> 00:18:12.440 significant challenges, the heart risks, the 00:18:12.440 --> 00:18:14.940 ever -growing threat of resistance. It truly 00:18:14.940 --> 00:18:17.660 exemplifies the double -edged sword of powerful 00:18:17.660 --> 00:18:21.319 antibiotics, an amazing tool. but one whose effectiveness 00:18:21.319 --> 00:18:24.019 we constantly risk losing if we're not careful. 00:18:24.380 --> 00:18:26.980 Its story really forces us to think about how 00:18:26.980 --> 00:18:29.440 we develop, use, and protect these vital medicines. 00:18:29.680 --> 00:18:31.980 It does. The benefits have been immense, but 00:18:31.980 --> 00:18:34.359 the challenges are real and demand ongoing attention. 00:18:34.519 --> 00:18:36.880 Which leads us to a final thought for you, our 00:18:36.880 --> 00:18:39.099 listeners. Considering this rise of resistance, 00:18:39.279 --> 00:18:41.299 not just for azithromycin, but across the board, 00:18:41.519 --> 00:18:44.599 how do we strike that critical balance? How do 00:18:44.599 --> 00:18:46.839 we ensure access to life -saving antibiotics 00:18:46.839 --> 00:18:49.700 while simultaneously preserving their power for 00:18:49.700 --> 00:18:52.019 the future? It's not just a question for scientists 00:18:52.019 --> 00:18:54.220 or doctors, but for all of us, something to really 00:18:54.220 --> 00:18:56.259 mull over. Thanks for joining us on this deep 00:18:56.259 --> 00:18:56.519 dive.