1 00:00:00,000 --> 00:00:12,680 Thanks for joining us again at the Canadian Breakpoint, a Canadian infectious diseases 2 00:00:12,680 --> 00:00:16,660 podcast by Canadian infectious diseases physicians. 3 00:00:16,660 --> 00:00:22,000 I'm Summer Stewart, back again with Dr. Rupeena Purewal, pediatric infectious diseases physician 4 00:00:22,000 --> 00:00:24,040 from Saskatoon. 5 00:00:24,040 --> 00:00:29,740 In this episode, we welcome back Dr. George Zhanel, medical microbiologist in Winnipeg 6 00:00:29,740 --> 00:00:35,280 and research director for CARA to expand on the clear registry and spotlight clear results 7 00:00:35,280 --> 00:00:36,600 for IV fosfomycin. 8 00:00:36,600 --> 00:00:37,600 Dr. Purewal. 9 00:00:37,600 --> 00:00:38,600 Hi everyone. 10 00:00:38,600 --> 00:00:44,520 Welcome to another episode of our podcast, the Canadian Breakpoint. 11 00:00:44,520 --> 00:00:49,680 Today we are joined by Dr. George Zannell, as a microbiologist and pharmacologist who 12 00:00:49,680 --> 00:00:54,680 received his PhD in the Department of Medical Microbiology and Infectious Diseases at the 13 00:00:54,680 --> 00:01:00,720 Faculty of Medicine, University of Manitoba and a doctor of clinical pharmacy at the University 14 00:01:00,720 --> 00:01:01,720 of Minnesota. 15 00:01:01,720 --> 00:01:06,280 He is presently professor and associate head in the Department of Medical Microbiology and 16 00:01:06,280 --> 00:01:11,840 Infectious Diseases, Max Reidy College of Medicine and research director of the Canadian 17 00:01:11,840 --> 00:01:14,080 Antimicrobial Resistance Alliance. 18 00:01:14,080 --> 00:01:20,320 Dr. Zannell is the founding and chief editor of the Canadian Antimicrobial Resistance Alliance 19 00:01:20,320 --> 00:01:25,080 website www.can-r.com. 20 00:01:25,080 --> 00:01:30,360 Dr. Zannell has published over 1200 papers, chapters and abstracts in the area of treatment 21 00:01:30,360 --> 00:01:32,320 and prevention of infectious diseases. 22 00:01:32,320 --> 00:01:38,760 He has presented over 1300 lectures as an invited speaker at international, national 23 00:01:38,760 --> 00:01:43,400 and local meetings, speaking on the topics of antimicrobial resistance infections, as 24 00:01:43,400 --> 00:01:48,120 well as treatment and prevention of infectious diseases in Canada, United States, Central 25 00:01:48,120 --> 00:01:53,800 and Southern America, Western and Eastern Europe including Russia, Australia, Southern 26 00:01:53,800 --> 00:01:56,840 and Northern Africa, the Middle East and Asia. 27 00:01:56,840 --> 00:02:01,960 He has been extensively involved in the treatment guidelines for a variety of infections in 28 00:02:01,960 --> 00:02:04,160 Canada, the US and internationally. 29 00:02:04,160 --> 00:02:09,440 Dr. Zannell has received or been nominated for more than 100 teaching awards including 30 00:02:09,440 --> 00:02:14,800 the Canadian Association for Medical Education Merit Teaching Award in 2020. 31 00:02:14,800 --> 00:02:16,360 Congratulations Dr. Zannell. 32 00:02:16,360 --> 00:02:21,240 Dr. Zannell is a member of the Who's Who in Medical Sciences Education. 33 00:02:21,240 --> 00:02:27,540 In 2022, he was elected as a fellow of the Canadian Academy of Health Sciences in recognition 34 00:02:27,540 --> 00:02:32,160 of sustained excellence in research and teaching within the health sciences. 35 00:02:32,160 --> 00:02:38,760 In 2023, Web of Science identified Dr. Zannell as one of the world's most influential researchers 36 00:02:38,760 --> 00:02:44,920 selected among an elite group recognized for exceptional research influence demonstrated 37 00:02:44,920 --> 00:02:51,140 by the production of multiple highly cited papers that rank in the top 1% by citations 38 00:02:51,140 --> 00:02:53,160 for field and year. 39 00:02:53,160 --> 00:03:00,080 Also in 2022, Dr. Zannell received the Dr. Fred Ioki Career Achievement Award in recognition 40 00:03:00,080 --> 00:03:05,040 of a career of dedication and excellence in multiple domains of medical microbiology and 41 00:03:05,040 --> 00:03:10,920 infectious diseases including research, education, clinical practice, service and administration. 42 00:03:10,920 --> 00:03:12,640 Hi Dr. Zannell. 43 00:03:12,640 --> 00:03:14,600 Thank you so much for joining us again. 44 00:03:14,600 --> 00:03:18,280 We really appreciate you being here today and offering your advice. 45 00:03:18,280 --> 00:03:24,120 So we had, you had actually initially come on the podcast this season for episode 6. 46 00:03:24,120 --> 00:03:28,120 So some of our listeners are probably familiar with what we talked about then, which was 47 00:03:28,120 --> 00:03:29,120 the CLEAR registry. 48 00:03:29,120 --> 00:03:31,560 We introduced the CLEAR registry. 49 00:03:31,560 --> 00:03:36,080 And so for our listeners, just so they recall, that's the Canadian Leadership on Antimicrobial 50 00:03:36,080 --> 00:03:38,880 Real Life Usage Registry. 51 00:03:38,880 --> 00:03:44,400 And basically during that episode, we gave a lot of information, a lot of resources, 52 00:03:44,400 --> 00:03:49,040 but today we're actually going to dive in deeper and talk about some of the data on 53 00:03:49,040 --> 00:03:50,440 the registry. 54 00:03:50,440 --> 00:03:56,800 And so we're going to talk about IV Fosamycin or IV Vosso and we'll go into that in a second 55 00:03:56,800 --> 00:03:57,800 here. 56 00:03:57,800 --> 00:04:00,960 So Dr. Zannell, if you want to just remind some of our listeners a little bit about the 57 00:04:00,960 --> 00:04:01,960 CLEAR registry. 58 00:04:01,960 --> 00:04:06,460 Has there been any updates and really what does it encompass and what's the ultimate 59 00:04:06,460 --> 00:04:07,760 purpose of this registry? 60 00:04:07,760 --> 00:04:10,280 Well, Dr. Uppina, thanks for inviting me again. 61 00:04:10,280 --> 00:04:15,480 You know, we had so much fun last time talking about CLEAR, I thought, well, let's just go 62 00:04:15,480 --> 00:04:16,520 more clear. 63 00:04:16,520 --> 00:04:25,600 As a reminder to all your listeners, CLEAR is a national Canadian voluntary registry that 64 00:04:25,600 --> 00:04:33,240 captures data and then shares information with all clinicians across Canada about how 65 00:04:33,240 --> 00:04:38,800 new intravenous antimicrobials are being used across Canada. 66 00:04:38,800 --> 00:04:47,240 And the whole purpose of this is to inform Canadians how clinically these new IV antimicrobials 67 00:04:47,240 --> 00:04:49,340 are being used in Canada. 68 00:04:49,340 --> 00:04:51,680 Why are clinicians using them? 69 00:04:51,680 --> 00:04:53,540 How are they using them? 70 00:04:53,540 --> 00:04:55,400 Are they working clinically? 71 00:04:55,400 --> 00:04:57,100 Are there adverse effects? 72 00:04:57,100 --> 00:05:01,760 So in the clinical context, how are we using them across Canada? 73 00:05:01,760 --> 00:05:04,080 And it's been very exciting to be part of it. 74 00:05:04,080 --> 00:05:05,080 Yeah. 75 00:05:05,080 --> 00:05:10,400 So like you just said, it's about the IV antibiotics, some of the newer antimicrobials that we have 76 00:05:10,400 --> 00:05:11,400 on the market. 77 00:05:11,400 --> 00:05:18,040 And so I became familiar with IVOS a few years back when we started thinking about what are 78 00:05:18,040 --> 00:05:23,680 we going to use for some of the antimicrobial resistance organisms that we are facing now 79 00:05:23,680 --> 00:05:26,260 and the patterns that we're facing here in Canada. 80 00:05:26,260 --> 00:05:30,880 So why don't we talk a little bit about, because I know our listeners are excited to probably 81 00:05:30,880 --> 00:05:35,760 hear about the data that you've collected in the registry about IVOS. 82 00:05:35,760 --> 00:05:41,080 So what is some of the shared experiences by providers for this drug across Canada? 83 00:05:41,080 --> 00:05:47,480 So just as a quick reminder, the CLEAR registry captures data on intravenous phosphomycin, 84 00:05:47,480 --> 00:05:49,200 and that's our focus today. 85 00:05:49,200 --> 00:05:56,720 But we also capture data on intravenous cephtovipral, intravenous ceftozanthazobactam, and intravenous 86 00:05:56,720 --> 00:06:04,000 dalbovansin, and I've committed to Canadian clinicians that for every new IV antimicrobial 87 00:06:04,000 --> 00:06:09,280 that comes onto the market, we will get it into CLEAR and we will share the data. 88 00:06:09,280 --> 00:06:16,520 But today in terms of IV phosphomycin, top line summary, and we'll go into this deeper, 89 00:06:16,520 --> 00:06:24,400 this drug is used in Canada to treat a variety of infections, both on label, Health Canada 90 00:06:24,400 --> 00:06:27,760 indication approved, and also off label. 91 00:06:27,760 --> 00:06:33,880 It is used to treat a variety of multi-drug resistant gram negative infections, but also 92 00:06:33,880 --> 00:06:36,520 some gram positive infections. 93 00:06:36,520 --> 00:06:44,240 It is almost always used in combination treatment with other agents, and we'll talk about that. 94 00:06:44,240 --> 00:06:50,160 Surprisingly, even though it's frequently used late in the game due to resistance, due 95 00:06:50,160 --> 00:06:57,000 to clinical failure of other agents, we have relatively high microbiological efficacy and 96 00:06:57,000 --> 00:07:01,840 clinical efficacy rates, and it's turning out to be a pretty safe drug. 97 00:07:01,840 --> 00:07:06,560 We'll talk about hypocholemia, which is important to know about. 98 00:07:06,560 --> 00:07:11,200 All in all, quite a success story for IV phosphomycin in Canada. 99 00:07:11,200 --> 00:07:12,400 It's fantastic. 100 00:07:12,400 --> 00:07:16,440 And so what are some of the indications when you've collected this data and prescribers 101 00:07:16,440 --> 00:07:17,560 are using nationally? 102 00:07:17,560 --> 00:07:21,960 So what are colleagues using it for, like you mentioned, overall multi-drug resistant 103 00:07:21,960 --> 00:07:23,280 organisms? 104 00:07:23,280 --> 00:07:28,800 Are there certain clinical conditions where IV phosphomycin has done superior? 105 00:07:28,800 --> 00:07:34,280 So let me first talk about what are the Health Canada approved indications, and then we'll 106 00:07:34,280 --> 00:07:38,080 talk about what clinicians are actually using it for in Canada. 107 00:07:38,080 --> 00:07:44,560 So according to Health Canada, intravenous phosphomycin can be used in adults and children, 108 00:07:44,560 --> 00:07:45,560 including neonates. 109 00:07:45,560 --> 00:07:51,640 And this is because there's so much data internationally that's been available on the drug, but it's 110 00:07:51,640 --> 00:07:59,520 indicated in Canada for bacterial meningitis, bone and joint infections, complicated intraabdominal 111 00:07:59,520 --> 00:08:06,600 infections, complicated skin soft tissue, complicated urinary tract infections, hospital 112 00:08:06,600 --> 00:08:13,200 acquired pneumonia, including ventilatory associated pneumonia, infective endocarditis, 113 00:08:13,200 --> 00:08:20,040 and also bacteremia that occurs in association with or suspected to be a part of any of those 114 00:08:20,040 --> 00:08:21,040 infections. 115 00:08:21,040 --> 00:08:23,680 Those are the Health Canada indications. 116 00:08:23,680 --> 00:08:27,400 What are Canadian clinicians actually using it for? 117 00:08:27,400 --> 00:08:32,160 All of those, believe it or not, except skin soft tissue. 118 00:08:32,160 --> 00:08:37,240 We have yet to see anyone use it for skin soft tissue, but clinicians using it for every 119 00:08:37,240 --> 00:08:39,680 one of the indications I talked about. 120 00:08:39,680 --> 00:08:45,520 And in addition, they've also used it to treat community acquired bacterial pneumonia. 121 00:08:45,520 --> 00:08:51,320 So a real wide variety of infections that are being treated with intravenous phosphomycin 122 00:08:51,320 --> 00:08:53,080 by Canadian clinicians. 123 00:08:53,080 --> 00:08:54,080 Okay. 124 00:08:54,080 --> 00:08:58,440 And so in terms of what dose are they using this at? 125 00:08:58,440 --> 00:09:02,920 And then you mentioned that this is frequently used in combination therapy. 126 00:09:02,920 --> 00:09:07,440 And so do you want to discuss maybe a little bit about what real life usage looks like 127 00:09:07,440 --> 00:09:09,600 in terms of combination therapy? 128 00:09:09,600 --> 00:09:12,320 Which other antibiotics are we combining it with? 129 00:09:12,320 --> 00:09:13,320 Yeah. 130 00:09:13,320 --> 00:09:15,920 So number one, why are they using it? 131 00:09:15,920 --> 00:09:23,120 70% of the time clinicians are choosing intravenous phosphomycin because of resistance to other 132 00:09:23,120 --> 00:09:24,120 agents. 133 00:09:24,120 --> 00:09:25,120 And that's important to know. 134 00:09:25,120 --> 00:09:28,840 They've got resistance to other drugs, so they're pulling it out. 135 00:09:28,840 --> 00:09:33,600 Sometimes it's due to clinical failure of prior therapy or intolerance or adverse effects, 136 00:09:33,600 --> 00:09:40,320 but the vast majority of the time clinicians are using it due to resistance of other antibiotics. 137 00:09:40,320 --> 00:09:47,200 Then when it comes down to dosing, the dosing is actually very interesting because by far 138 00:09:47,200 --> 00:09:55,200 the most common doses that are being used are eight grams every 12 hours, six grams 139 00:09:55,200 --> 00:10:00,640 every eight hours, eight grams every eight hours, four grams every eight hours. 140 00:10:00,640 --> 00:10:06,200 So we have a complete mishmash of dosing, a whole variety of dosing. 141 00:10:06,200 --> 00:10:13,960 And the reason is 100% of the time when intravenous phosphomycin is being used in Canada, it is 142 00:10:13,960 --> 00:10:19,400 infectious disease, microbiology, and clinical pharmacy working together to customize that 143 00:10:19,400 --> 00:10:25,800 dose based on renal function, severity of illness, where that infection is. 144 00:10:25,800 --> 00:10:30,280 So we have a whole range of dosing that is being used. 145 00:10:30,280 --> 00:10:35,680 And then when we get to the types of infections we talked about, it's all types of infections. 146 00:10:35,680 --> 00:10:39,720 But the interesting part is the pathogens treated. 147 00:10:39,720 --> 00:10:45,000 The pathogens that are treated, what we found is that they can be multi-drug resistant gram 148 00:10:45,000 --> 00:10:46,820 positives or gram negatives. 149 00:10:46,820 --> 00:10:53,480 But what we have seen is that the vast majority of the time intravenous phosphomycin has become 150 00:10:53,480 --> 00:11:00,620 the agent of choice to treat carbapenem resistant entero bacterialis infection. 151 00:11:00,620 --> 00:11:07,480 So when clinicians have a CRE infection, we do not have some of these newer agents like 152 00:11:07,480 --> 00:11:15,520 indipendum rilobactam, meropenem baborbactam, ceftazidymabibactam, cefideracol yet. 153 00:11:15,520 --> 00:11:16,640 So what are we doing? 154 00:11:16,640 --> 00:11:23,720 We are using combination treatment for CRE and it's involving intravenous phosphomycin. 155 00:11:23,720 --> 00:11:28,360 So carbapenem resistant E. coli, carbapenem resistant clebsiella. 156 00:11:28,360 --> 00:11:32,880 But we've also seen multi-drug resistant pseudomonas. 157 00:11:32,880 --> 00:11:39,360 Clinicians are using intravenous phospho as part of a combination regimen to treat multi-drug 158 00:11:39,360 --> 00:11:41,820 resistant pseudomonal infections. 159 00:11:41,820 --> 00:11:47,400 And then you asked me in terms of the combination therapy, it is almost always used as part 160 00:11:47,400 --> 00:11:48,880 of combination. 161 00:11:48,880 --> 00:11:56,640 The only time we've seen IV phospho used alone has been in complicated urinary tract infection. 162 00:11:56,640 --> 00:12:01,600 And that's because of the Zeus study that was published in the US using it alone compared 163 00:12:01,600 --> 00:12:04,520 to Piptazole for complicated UTI. 164 00:12:04,520 --> 00:12:08,940 But in the other indications, it's used in combination. 165 00:12:08,940 --> 00:12:11,160 What is it used in combination with? 166 00:12:11,160 --> 00:12:13,000 A lot of meropenem. 167 00:12:13,000 --> 00:12:17,080 It's being used to treat CRE with meropenem. 168 00:12:17,080 --> 00:12:24,640 It's being used to treat CRE with meropenem and tigecycline, meropenem and an aminoglycoside 169 00:12:24,640 --> 00:12:27,160 to treat CRE. 170 00:12:27,160 --> 00:12:34,160 The intravenous phosphomycin with a carbapenem with inhaled colistin, inhaled aminoglycoside. 171 00:12:34,160 --> 00:12:41,800 So it's really being used a lot as a CRE regimen where clinicians are choosing meropenem and 172 00:12:41,800 --> 00:12:49,120 intravenous phosphomycin, maybe in adding in tigecycline, maybe adding an aminoglycoside 173 00:12:49,120 --> 00:12:51,320 or inhaled colistin. 174 00:12:51,320 --> 00:12:58,200 But for the most part, this is a big CRE treatment as part of combination therapy. 175 00:12:58,200 --> 00:12:59,200 Okay. 176 00:12:59,200 --> 00:13:02,420 And like you mentioned, I mean, we don't have too many drugs on the market that can help 177 00:13:02,420 --> 00:13:03,720 us in those situations. 178 00:13:03,720 --> 00:13:07,180 So that's really important for us clinicians. 179 00:13:07,180 --> 00:13:12,120 And in terms of, I think when we talked about the indications, we can see that penetration 180 00:13:12,120 --> 00:13:18,040 into multiple spaces, you know, so it can be widely used, which is actually a really 181 00:13:18,040 --> 00:13:21,960 important property, I think, of IV phosphomycin. 182 00:13:21,960 --> 00:13:26,800 In terms of the antimicrobial susceptibility, so do most like across the country, or you 183 00:13:26,800 --> 00:13:32,360 can speak specifically at your center, do most of us have this on formulary, first of 184 00:13:32,360 --> 00:13:37,840 all, and then the second thing about antimicrobial susceptibility is, do we have breakpoints 185 00:13:37,840 --> 00:13:39,280 that we're looking at? 186 00:13:39,280 --> 00:13:41,640 And will this be reported by the labs? 187 00:13:41,640 --> 00:13:46,240 So now we're on to a really touchy subject and it's our listeners are going to get all 188 00:13:46,240 --> 00:13:47,240 upset. 189 00:13:47,240 --> 00:13:53,300 I know phosphomycin is an interesting drug because yes, we have health counter approvals 190 00:13:53,300 --> 00:13:55,880 for a whole range of indications. 191 00:13:55,880 --> 00:14:00,080 It's on many and most hospital formularies. 192 00:14:00,080 --> 00:14:07,240 It is being used quite ubiquitously in some centers, less often in other centers. 193 00:14:07,240 --> 00:14:13,480 It's being used by infectious diseases, medical microbiology, and clinical pharmacy working 194 00:14:13,480 --> 00:14:14,480 together. 195 00:14:14,480 --> 00:14:21,560 We know that over half of the patients who get intravenous phosphomycin are bacteremic. 196 00:14:21,560 --> 00:14:25,840 We know that more than half of the patients who are treated with IV phosphor are in the 197 00:14:25,840 --> 00:14:27,120 ICU. 198 00:14:27,120 --> 00:14:30,740 So it's being used in really, really, really sick people. 199 00:14:30,740 --> 00:14:35,520 The vast majority of the time it's being used as directed therapy, meaning we actually have 200 00:14:35,520 --> 00:14:36,760 a pathogen. 201 00:14:36,760 --> 00:14:43,240 So we have a clinical diagnosis and we have a bacteriological diagnosis and now IV phosphors 202 00:14:43,240 --> 00:14:45,000 being used in combination. 203 00:14:45,000 --> 00:14:49,920 But then comes the rub, the susceptibility testing. 204 00:14:49,920 --> 00:14:55,640 Susceptibility testing with intravenous phosphomycin is a real dog's breakfast and the reason is 205 00:14:55,640 --> 00:14:59,280 auger dilution is the world standard. 206 00:14:59,280 --> 00:15:03,200 And we do auger dilution in Winnipeg, you know, in our lab. 207 00:15:03,200 --> 00:15:07,080 The labs don't want to do that and they don't do auger dilution. 208 00:15:07,080 --> 00:15:08,680 So what do they do? 209 00:15:08,680 --> 00:15:12,680 They've been trying other things predominantly e-test. 210 00:15:12,680 --> 00:15:21,680 And what we have seen is in 70% of the cases when intravenous phosphomycin is used, the 211 00:15:21,680 --> 00:15:27,520 lab has used some sort of antimicrobial susceptibility testing. 212 00:15:27,520 --> 00:15:31,720 It could be disc diffusion, but usually it's e-test. 213 00:15:31,720 --> 00:15:35,820 And that's what they've done to try and guide susceptibility testing. 214 00:15:35,820 --> 00:15:37,840 The problem is breakpoints. 215 00:15:37,840 --> 00:15:44,360 You know, if you look at the CLSI breakpoints, we only have urinary breakpoints for E. coli 216 00:15:44,360 --> 00:15:46,120 and enterococcus. 217 00:15:46,120 --> 00:15:52,520 And this is because there's an oral phosphomycin indicated for acute uncomplicated cystitis. 218 00:15:52,520 --> 00:16:00,480 So the breakpoints are for UTI pathogens only, E. coli and enterococcus, UCAS, because intravenous 219 00:16:00,480 --> 00:16:03,840 phospho is available in Europe. 220 00:16:03,840 --> 00:16:06,060 It is not available in the U.S. 221 00:16:06,060 --> 00:16:10,880 We have UCAS breakpoints for IV phosphomycin. 222 00:16:10,880 --> 00:16:16,160 And I think some Canadian clinicians look at the UCAS breakpoints in order to guide 223 00:16:16,160 --> 00:16:17,160 them. 224 00:16:17,160 --> 00:16:18,880 But it's a real dog's breakfast. 225 00:16:18,880 --> 00:16:23,280 No one wants to really do auger dilution susceptibility testing. 226 00:16:23,280 --> 00:16:24,840 They're asking us what to do. 227 00:16:24,840 --> 00:16:30,160 Many people send us the isolates to do auger because we have a national IV phosphomycin 228 00:16:30,160 --> 00:16:32,760 susceptibility testing service. 229 00:16:32,760 --> 00:16:37,360 But of the times it's used, clinicians are trying to do some sort of testing. 230 00:16:37,360 --> 00:16:41,360 They're either sending the isolate test to do auger dilution, or they're doing some sort 231 00:16:41,360 --> 00:16:48,600 of in-house testing with disc testing or E-test to try and get an idea of susceptibility testing. 232 00:16:48,600 --> 00:16:50,820 But then I go back to how they're using it. 233 00:16:50,820 --> 00:16:53,640 They're using it as combination therapy. 234 00:16:53,640 --> 00:16:55,680 They're almost never using it alone. 235 00:16:55,680 --> 00:17:02,460 So when you're treating a CRE and you're using optimized doses and pharmacodynamics of Meropenem, 236 00:17:02,460 --> 00:17:08,360 you're adding in tigecycline, maybe even an amino glycoside like amicacin, and adding 237 00:17:08,360 --> 00:17:10,480 IV phosphomycin. 238 00:17:10,480 --> 00:17:16,880 I'm not sure that they know or we know what really that MIC value really means because 239 00:17:16,880 --> 00:17:22,640 you're adding it for the purposes of synergy to try and optimize bacterial eradication. 240 00:17:22,640 --> 00:17:28,520 So yeah, like you said, so more importantly, I think is what our microbiological cure rates 241 00:17:28,520 --> 00:17:29,800 and our clinical cure rates. 242 00:17:29,800 --> 00:17:34,080 I think that's what we can focus on because for us clinicians, obviously, if we're using 243 00:17:34,080 --> 00:17:39,360 combination therapy like that, like you mentioned, sometimes it is to overcome some resistance 244 00:17:39,360 --> 00:17:40,360 patterns. 245 00:17:40,360 --> 00:17:46,440 And so, and if we don't have reliable break points, then really we're looking at how well 246 00:17:46,440 --> 00:17:48,040 did our patients do. 247 00:17:48,040 --> 00:17:54,000 And so in the clear registry, you guys look at outcomes and I believe both at micro and 248 00:17:54,000 --> 00:17:55,320 clinical cure rates. 249 00:17:55,320 --> 00:17:59,120 And so what type of information has been inputted? 250 00:17:59,120 --> 00:18:05,200 So I'm very thankful to our clinicians who are participating in clear. 251 00:18:05,200 --> 00:18:10,440 I'm giving you data right now and about 76 patients who've been treated with intravenous 252 00:18:10,440 --> 00:18:17,360 phosphomycin and the clinicians who are submitting the data in Canada, it's about half infectious 253 00:18:17,360 --> 00:18:22,840 disease medical microbiology, half of clinical pharmacists who are specializing in ID or 254 00:18:22,840 --> 00:18:23,840 antimicrobial stewardship. 255 00:18:23,840 --> 00:18:25,280 So I'm very thankful to them. 256 00:18:25,280 --> 00:18:30,580 And what they're telling us is that in their hands coast to coast, even though they're 257 00:18:30,580 --> 00:18:37,240 using the drug, typically when there's resistance to other agents, patients are bacteremic frequently, 258 00:18:37,240 --> 00:18:40,120 frequently in the ICU, they're quite ill. 259 00:18:40,120 --> 00:18:47,040 They've showed us that the microbiological eradication or success is in the range of 260 00:18:47,040 --> 00:18:48,840 78%. 261 00:18:48,840 --> 00:18:55,440 So 78% of the time from a microbiological perspective, the organism is either eradicated 262 00:18:55,440 --> 00:19:01,640 or what we call presumed eradicated, meaning you're using it for hospital acquired pneumonia 263 00:19:01,640 --> 00:19:04,200 and the pneumonia is improved. 264 00:19:04,200 --> 00:19:09,460 You don't even have any sputum or tracheal aspirate fluid to submit. 265 00:19:09,460 --> 00:19:10,960 So it's presumed eradicated. 266 00:19:10,960 --> 00:19:18,700 So surprisingly quite high eradication rates despite the types of patients and the types 267 00:19:18,700 --> 00:19:21,280 of infections that are being treated. 268 00:19:21,280 --> 00:19:26,600 And then clinically that's obviously correlating because clinically their patients are improving. 269 00:19:26,600 --> 00:19:32,320 And like you mentioned, whether that's very sick, ill patients in the ICU versus even 270 00:19:32,320 --> 00:19:35,760 an uncomplicated cystitis type of picture. 271 00:19:35,760 --> 00:19:40,200 So definitely a wide range of patients that they're seeing it used in. 272 00:19:40,200 --> 00:19:45,880 Rapina, I will say that, you know, one of the differences between you and me is I'm 273 00:19:45,880 --> 00:19:47,520 interested in killing bugs. 274 00:19:47,520 --> 00:19:49,960 You know, I'm a microbiologist at a pharmacologist. 275 00:19:49,960 --> 00:19:51,640 I like to kill bugs. 276 00:19:51,640 --> 00:19:57,640 So I'm delighted that phospho is very rapidly bactericidal and in combination is killing 277 00:19:57,640 --> 00:20:01,960 these organisms and the microbiological success rates are high. 278 00:20:01,960 --> 00:20:06,000 However, you know, clinicians like you're interested in clinical success, right? 279 00:20:06,000 --> 00:20:07,560 I'm not killing the pathogen. 280 00:20:07,560 --> 00:20:09,600 I want to see how my patients are doing. 281 00:20:09,600 --> 00:20:12,000 So patients are doing quite well. 282 00:20:12,000 --> 00:20:15,520 You know, our clinical successes are in the mid sixties. 283 00:20:15,520 --> 00:20:20,560 As you know, patients get better for a whole and worse for a whole variety of reasons, 284 00:20:20,560 --> 00:20:25,280 including the heart failure that they have and the MI that they've had and the stroke 285 00:20:25,280 --> 00:20:26,280 that they've had. 286 00:20:26,280 --> 00:20:32,840 So clinical success is much more complicated, but surprisingly the clinical success rates 287 00:20:32,840 --> 00:20:37,320 have been in the mid sixties, which is quite high again, considering these patients are 288 00:20:37,320 --> 00:20:42,220 very sick, will back to make in the ICU and complicated infection. 289 00:20:42,220 --> 00:20:47,840 So the drug is doing well on the eradication side and clinically it's doing quite well 290 00:20:47,840 --> 00:20:50,440 on the clinical success side as well. 291 00:20:50,440 --> 00:20:51,640 That's fantastic. 292 00:20:51,640 --> 00:20:53,280 And so what are some of the side effects? 293 00:20:53,280 --> 00:20:57,520 Cause I know an earlier on in the podcast episode, you mentioned that there might be 294 00:20:57,520 --> 00:20:59,480 some side effects that we have to worry about. 295 00:20:59,480 --> 00:21:01,080 Maybe we can just touch on that. 296 00:21:01,080 --> 00:21:04,160 Cause I'm sure listeners are curious about that as well. 297 00:21:04,160 --> 00:21:05,600 So no surprise. 298 00:21:05,600 --> 00:21:11,600 This is a very safe drug and we thought this would occur because we have 25 years of experience 299 00:21:11,600 --> 00:21:12,600 from Europe. 300 00:21:12,600 --> 00:21:18,280 It's been used extensively in places like Germany and Austria and Spain and France and 301 00:21:18,280 --> 00:21:20,320 many European countries. 302 00:21:20,320 --> 00:21:26,040 So the vast majority of patients have no side effects, but the one side effect that has 303 00:21:26,040 --> 00:21:34,280 come up is hypocholemia and it's important that clinicians monitor potassium levels and 304 00:21:34,280 --> 00:21:38,040 potentially supplement potassium. 305 00:21:38,040 --> 00:21:42,560 There's a sodium load that comes with the drug because it comes with a sodium, there's 306 00:21:42,560 --> 00:21:44,600 sodium in the formulation. 307 00:21:44,600 --> 00:21:48,900 We had three patients with hypernatremia. 308 00:21:48,900 --> 00:21:53,880 So it's important to monitor sodium cause there's a sodium load, but the big deal really 309 00:21:53,880 --> 00:22:01,220 is hypocholemia monitoring potassium levels, knowing where they are and potentially supplementing. 310 00:22:01,220 --> 00:22:05,520 But interestingly enough, in no case was the drug discontinued. 311 00:22:05,520 --> 00:22:11,040 You know, I always look at serious adverse effects and did the clinicians stop using 312 00:22:11,040 --> 00:22:14,160 the drug as a result of adverse effects? 313 00:22:14,160 --> 00:22:20,960 And the answer is no, but they've documented hypocholemia and in some cases have been supplementing 314 00:22:20,960 --> 00:22:22,960 with potassium. 315 00:22:22,960 --> 00:22:25,760 And did clinicians mention at like what stage? 316 00:22:25,760 --> 00:22:27,560 So is this early on in the course? 317 00:22:27,560 --> 00:22:29,920 Is it kind of very? 318 00:22:29,920 --> 00:22:30,920 It's a great question. 319 00:22:30,920 --> 00:22:31,920 They did not. 320 00:22:31,920 --> 00:22:36,880 They did not ask him that the balancing act I have with clear is that clinicians have 321 00:22:36,880 --> 00:22:40,680 been very clear to me about clear. 322 00:22:40,680 --> 00:22:44,840 And they said, look, if this thing takes me any more than three minutes to enter a patient 323 00:22:44,840 --> 00:22:49,520 case on my iPhone, my iPad, my desktop, no way. 324 00:22:49,520 --> 00:22:54,960 So we have 17 drop down questions, point, click, point, click, point, click. 325 00:22:54,960 --> 00:22:56,400 So there's virtually no writing. 326 00:22:56,400 --> 00:22:57,400 It's all point, click. 327 00:22:57,400 --> 00:22:59,640 And it's what is the infection? 328 00:22:59,640 --> 00:23:00,640 What's the pathogen? 329 00:23:00,640 --> 00:23:05,020 What dose are using or using in combination clinically, microbiologically is a working 330 00:23:05,020 --> 00:23:06,020 side effect. 331 00:23:06,020 --> 00:23:09,680 So all I have is, you know, was there a side effect? 332 00:23:09,680 --> 00:23:11,080 Yes, no. 333 00:23:11,080 --> 00:23:12,080 What was it? 334 00:23:12,080 --> 00:23:13,080 Click hypocholemia. 335 00:23:13,080 --> 00:23:18,720 So I don't know when, and I don't know at which point they intervene. 336 00:23:18,720 --> 00:23:24,300 So those are the limitations of clear, but the whole goal of it is if a clinician wants 337 00:23:24,300 --> 00:23:28,720 to submit data and we're delighted they do, it's quick. 338 00:23:28,720 --> 00:23:30,200 Yeah, exactly. 339 00:23:30,200 --> 00:23:32,740 And really we're looking at like, what's the indication? 340 00:23:32,740 --> 00:23:34,600 And there's a lot of case by case, right? 341 00:23:34,600 --> 00:23:39,840 So assessments and that, like when we're using any other drug and probably similarly, I don't 342 00:23:39,840 --> 00:23:42,440 know if they comment on duration. 343 00:23:42,440 --> 00:23:45,000 Have they commented on duration of use? 344 00:23:45,000 --> 00:23:46,600 Yes, they have. 345 00:23:46,600 --> 00:23:52,960 And you know, no surprise, close to half of the patients have received greater than 10 346 00:23:52,960 --> 00:23:54,640 days of therapy. 347 00:23:54,640 --> 00:23:56,880 And the other quarter has been seven to 10 days. 348 00:23:56,880 --> 00:23:59,960 And the other quarter has been less than seven days. 349 00:23:59,960 --> 00:24:04,660 And it's not that surprising that a lot of patients get longer therapy. 350 00:24:04,660 --> 00:24:10,840 And the reason is if we look at our top indications, the most common reason it's being used is 351 00:24:10,840 --> 00:24:18,880 bacteremia and sepsis, ventilatory associated bacterial pneumonia, hospital associated bacterial 352 00:24:18,880 --> 00:24:20,840 pneumonia, endocarditis. 353 00:24:20,840 --> 00:24:27,440 And these are due to multi-drug resistant pathogens where clinicians may want to treat 354 00:24:27,440 --> 00:24:32,560 a little bit longer when you've got a CRE or a multi-drug resistant pseudomonas. 355 00:24:32,560 --> 00:24:39,280 So treatment duration is frequently quite long, despite that it's a pretty safe drug. 356 00:24:39,280 --> 00:24:45,000 And so for our prescribers and our listeners out there who are pharmacists, who are physicians, 357 00:24:45,000 --> 00:24:50,600 medical students and training residents, are there any specific resources that they can 358 00:24:50,600 --> 00:24:52,880 look in terms of for this drug? 359 00:24:52,880 --> 00:24:58,480 So obviously, I mean, this would be one of the resources listening to the podcast episode, 360 00:24:58,480 --> 00:25:04,840 but are there other brochures, posters, publications that they can search and get more information? 361 00:25:04,840 --> 00:25:05,840 Yes. 362 00:25:05,840 --> 00:25:07,080 Thank you for asking that. 363 00:25:07,080 --> 00:25:14,100 So Dr. Rupina, my vision with CLEAR has been that a new intravenous antimicrobial comes 364 00:25:14,100 --> 00:25:19,480 to Canada, is Health Canada approved, comes onto the shelf so clinicians can use it. 365 00:25:19,480 --> 00:25:23,820 And it's maximally on the CLEAR registry for two to three years. 366 00:25:23,820 --> 00:25:29,000 After that, two, three years later, we've educated clinicians on how and why they're 367 00:25:29,000 --> 00:25:33,520 using these drugs and now they're just routine drugs in practice. 368 00:25:33,520 --> 00:25:36,960 They come off the registry and new ones come onto the registry. 369 00:25:36,960 --> 00:25:39,000 So it's a rolling model. 370 00:25:39,000 --> 00:25:45,240 So what we've tried to do successfully, and we've done that with IV FOSFO, is once we 371 00:25:45,240 --> 00:25:52,480 hit somewhere around 20 to 30 patients treated, submit an AMI poster, and we present the data 372 00:25:52,480 --> 00:25:59,200 at the National AMI CACMED meeting, which is, you know, typically in March or April. 373 00:25:59,200 --> 00:26:01,960 So clinicians can see how it's going. 374 00:26:01,960 --> 00:26:06,760 Typically once we hit around 50 patients, we write up a publication. 375 00:26:06,760 --> 00:26:11,700 So once we were about 20, we had an AMI poster in 2022. 376 00:26:11,700 --> 00:26:13,120 We hit 50 patients. 377 00:26:13,120 --> 00:26:19,000 We published a paper in the Journal of Global Antimicrobial Resistance in 2023. 378 00:26:19,000 --> 00:26:25,500 Then typically once we get to higher 60, 70, we put together a second AMI poster. 379 00:26:25,500 --> 00:26:28,960 So we had an AMI poster in 2023. 380 00:26:28,960 --> 00:26:33,880 And then once we hit 100, and I'm hoping to get to 100 patients soon, we will write the 381 00:26:33,880 --> 00:26:40,240 final, you know, it's the final story, how are Canadian physicians using IV FOSFO. 382 00:26:40,240 --> 00:26:43,940 So we've committed to a third AMI poster. 383 00:26:43,940 --> 00:26:50,200 We're writing up the abstract right now, and we'll submit that to AMI before Christmas. 384 00:26:50,200 --> 00:26:55,880 And then I'm hoping that by the time we put that poster together in March of 2024, then 385 00:26:55,880 --> 00:27:01,840 we'll write up the final publication of how clinicians are using intravenous FOSFO mice. 386 00:27:01,840 --> 00:27:04,800 And my goal is really to hit 100 patients. 387 00:27:04,800 --> 00:27:10,100 So I'm encouraging all your listeners, you know, please hit those links. 388 00:27:10,100 --> 00:27:15,760 If you're not a participant of CLEAR, you just send George Zanell an email, Google me, 389 00:27:15,760 --> 00:27:18,760 and you'll see my email address and it's free. 390 00:27:18,760 --> 00:27:20,480 I just send you all the links. 391 00:27:20,480 --> 00:27:22,440 And then you also get all the data. 392 00:27:22,440 --> 00:27:28,380 What I do is we crunch the data and I send all of the PowerPoint slides of how these 393 00:27:28,380 --> 00:27:30,640 drugs are being used to all CLEAR participants. 394 00:27:30,640 --> 00:27:31,960 We're up to 400. 395 00:27:31,960 --> 00:27:34,200 Rupina, I'm delighted to say. 396 00:27:34,200 --> 00:27:35,200 That's great. 397 00:27:35,200 --> 00:27:41,680 Half are kind of AMI members, you know, pediatric, adult infectious disease specialists, microbiologists. 398 00:27:41,680 --> 00:27:46,280 The other half are clinical pharmacists and stewardship infectious diseases, coast to 399 00:27:46,280 --> 00:27:47,280 coast. 400 00:27:47,280 --> 00:27:49,080 So if you're a CLEAR member, you know, it's free. 401 00:27:49,080 --> 00:27:50,400 You get all the data. 402 00:27:50,400 --> 00:27:55,060 And if you're willing to be one of the submitters, you just hit one of those links. 403 00:27:55,060 --> 00:27:59,040 We always send you the links every two, three months and you enter the data and here we 404 00:27:59,040 --> 00:28:00,040 go. 405 00:28:00,040 --> 00:28:04,440 So please continue to submit the IV FOSFO mice and treatment experiences. 406 00:28:04,440 --> 00:28:08,600 If you have treated or will treat, hit the link three minutes and you're done. 407 00:28:08,600 --> 00:28:09,920 Easy peasy. 408 00:28:09,920 --> 00:28:11,520 That sounds fantastic. 409 00:28:11,520 --> 00:28:16,400 And with that, I think you've answered my all my questions that I had for IV FOSFO mice 410 00:28:16,400 --> 00:28:18,440 in and we're so grateful. 411 00:28:18,440 --> 00:28:23,520 And I speak for probably all clinicians out there and prescribers that there is available 412 00:28:23,520 --> 00:28:30,120 data within Canada about this real life usage, because I think it's really difficult sometimes 413 00:28:30,120 --> 00:28:36,120 looking at data from, you know, international data that maybe you cannot correlate with 414 00:28:36,120 --> 00:28:42,600 your patient population, but this is really real life, real time data that's being submitted. 415 00:28:42,600 --> 00:28:47,600 And we all look forward to seeing the posters and the publications and the data submitted 416 00:28:47,600 --> 00:28:49,280 at AMI next year. 417 00:28:49,280 --> 00:28:52,440 So Rupina, two quick things before we sign off. 418 00:28:52,440 --> 00:28:54,080 One is a big thank you to you. 419 00:28:54,080 --> 00:28:58,800 You know, I think the goal is that every Canadian, if they're going for a walk or hiking, they 420 00:28:58,800 --> 00:29:04,400 need to have Dr. Rupina podcast in their ear because these are fantastic podcasts. 421 00:29:04,400 --> 00:29:05,400 That's what I do. 422 00:29:05,400 --> 00:29:12,000 And secondly, a big thank you to every clinician in Canada who is willing to press that link 423 00:29:12,000 --> 00:29:17,400 and then three minutes entering the data on one of these drugs, FOSFO, Dalbal Vansin, 424 00:29:17,400 --> 00:29:19,200 Ceftovipros of Tulzaintazo. 425 00:29:19,200 --> 00:29:22,480 So a huge thank you to Canadians for making this successful. 426 00:29:22,480 --> 00:29:27,840 And a shout out to my colleague, an ID doc in Vancouver, Dr. Ted Steiner, who was really 427 00:29:27,840 --> 00:29:30,880 instrumental in getting me to get this going. 428 00:29:30,880 --> 00:29:31,880 So thank you, Ted. 429 00:29:31,880 --> 00:29:33,600 Yeah, no, that's fantastic. 430 00:29:33,600 --> 00:29:38,360 And we want to thank you as well because first of all, for supporting the podcast and coming 431 00:29:38,360 --> 00:29:40,080 on for a second episode. 432 00:29:40,080 --> 00:29:46,200 And I know we have some future episodes on other medications such as Ceftovipro coming 433 00:29:46,200 --> 00:29:47,400 up in the next season. 434 00:29:47,400 --> 00:29:52,400 So I think all of our listeners will be very excited to hear more about all the data that's 435 00:29:52,400 --> 00:29:53,660 been collected and clear. 436 00:29:53,660 --> 00:29:55,180 So thank you so much. 437 00:29:55,180 --> 00:29:56,440 Thank you. 438 00:29:56,440 --> 00:30:00,660 Thank you, Dr. Rapina and Dr. Zanel for the valuable review. 439 00:30:00,660 --> 00:30:13,880 To join the clear registry, email Dr. Zanel at ggzanel, z-h-a-n-e-l, at pcsinternet.ca. 440 00:30:13,880 --> 00:30:16,000 Links are in the episode description. 441 00:30:16,000 --> 00:30:18,920 This concludes season two of the Canadian Breakpoint. 442 00:30:18,920 --> 00:30:24,600 We'd like to thank all of our listeners, all of our fabulous guests, as well as Bayou Mérillou 443 00:30:24,600 --> 00:30:28,520 and Verity Pharmaceuticals for their support with the podcast. 444 00:30:28,520 --> 00:30:31,160 Have a wonderful holiday season and a festive new year. 445 00:30:31,160 --> 00:30:58,200 And we'll see you again in 2024 at the Canadian Breakpoint.