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Well, thank you very much uh for this kind of mutation. Um And within the following 2025 minutes, I'll be discussing the uh various therapeutic options. Clinical impact um of the uh metalobalis uh gram negative bacterial infections. Um in gram negative bacteria, carpene resistance is mediated by both um caras which are hydrolytic enzymes. Um hydrolysine carbo antibiotics or non carbose uh mechanisms like pin and efflux mechanisms. And among the carbines, there are three types of uh enzymes which is uh basically K PC uh is a class a type of enzyme, oxo 48 A class D enzyme and finally metalobalis and a class B enzyme. So metal betalactamase are prevalent both in gram negatives and non fermentative like SOAS and acinetobacter. And basically there are three types of metalobalis which are prevalent uh throughout the world. N DM I or rim well, in stenotrophomonas, maltophilia, which is a non fermentative gram negative bacteria. There is a chromosomal betalactamase L1 and it has uh a carbapenemase activity. Well, metall beal omma are notorious enzymes which can produ which can provide resistance against third generation or fourth generation cephalosporins, betalactamase inhibitors, both old and the new ones including PTA Ceftazidim, avibactam and the others. And um most of these bacteria, both enterobacterales or pseudomonas can croce a variety of different enzymes, particularly extended spectrum betalactamase and other types of enzymes. So, this can enhance um uh hydrolytic activity uh against all of these betalactam antibiotics. However, there is only one uh b uh one antibiotic. Betalactam antibiotic, which is a monobactam. A atrium is resistant to the hydrolytic activity of metalobalis. However, atrium can be hydrolyzed by extended spectrum betalactamase. Uh and the chromosome betalactamase which are, you know, 50% within 50% range can be produced by this bacteria. This is a schematic representation of how these betalin uh which I mentioned in my earlier slides are increasing uh during the last uh 50 years or so. So, at the end of 2022 there were almost 5000 different types of betalactamase and they are all increasing. Uh The most rapid increase has been observed in class AC and D but class B enzymes are also uh increasing in a variety of bacteria which are going to discuss right now. Now, if you look at the prevalence of uh the metalobalis in enteric gram negative bacteria among carpene nonsusceptible isolates. So you see particularly in Africa, Middle East and Asia Pacific region, there is a surge of MDM type of um Metal Act. Well, in Europe, um it's uh N DM is also increasing but there is also some contribution by the uh VM type of enzymes. But if you go to the Latin America, um basically, it's all N DM type of enzymes. So we can say particularly in enterobacterales, N DM type of metal betalactam are the primary and the dominant type of uh uh metallo enzymes. Well, if you would like to see these figures on a map on the left hand side, you see enterobacterales and as you see throughout the world, N DM is the most prevalent one. in Indian subcontinent, uh in some countries in eastern Europe and in Africa, this is endemic. Uh but in other countries, it can be um um it can be recognized in various clinical settings. However, there is a different picture in SOAS algis in SOAS algis, the predominant enzyme in is VM type. But of course in Indian subcontinent, which is the origin of the DM type of enzyme. Uh even in pseudomonas, Algis N DM is the primary uh metalloenzyme. Um as I said previously, uh the same organism can croce more than one carbapenemase. And in K PC producers, it's usually v uh type of metalloenzyme. In Oxo 48 producers, it's usually N DM and in N DM producers, it's uh usually Oxo 48. So one or more caras um and other types of uh various betalactam be be lactamases can be uh co-produced at the same time and this will of course, complicate the picture of um imi susceptibility. Uh in these microorganisms. Well, this slide uh shows data from my institution. I work in a tertiary care university hospital in Ankara Turkey. And Turkey is particularly in interact a predominantly oxo 48 type of country. So on the left hand side, you see E coli, uh 94% of re coli are producing a 48 and only a minority of them croce ox a 48 plus N DM or VIM only. However, incl pneumonia, 65% will be a pro will be only producing ox 48 type of enzyme. But as you see, 11% will produce K PC 9% N DM only and 9% will produce ox 48 and a metal enzyme. Uh There are, for example, 2% of these isolates are co producing uh Wim plus. So two metallo enzymes can be produced in a single strain as well. What about the clinical impact? What is the clinical importance of MBL producing enterobacterales infections? Well, the slide indicates first overall the hospitalization rate and the ICU admission is quite high approaching 50% in all these isolates and the mortality is 30% with an attributable mortality even higher. 35%. And if you look at the trials, comparing with NBL producing CR E cr E versus Carbenin susceptible isolates causing infections, length of hospital stay rate of admission to the ICU and the 30 day mortality are all higher in those patients infected with MBL producing carbenin resistant enterobacterales infections. At this point, I would like to discuss with you a case which is a real case from my institution. Uh It's a 72 year old male with uh rectal adenocarcinoma. Um The surgeons operated and uh did an anterior resection and end to end anastomosis. And the patient was on preoperative uh antimicrobial prophylaxis with cef reaction and clindamycin. However, the patient developed fever postoperatively uh on the fifth day and the abdominal ultrasonography visualized an abscess uh four centimeter in diameter. So I A drainage catheter is inserted, the culture is taken and the patient was put on piperacillin tazobactam. Empirically. After 48 hours of therapy, the patient developed septic shock with hypotension and spiking fever. And at this time, the cultures from the abdominal drainage uh were available indicating that uh there was an anaerobic bacterium. Bacteria dys fragile is resistant to picta and clindamycin, but sensitive to metroNIDAZOLE. And there was eclampsia in pneumonia which is as you see on the slide, basically resistant to everything including Ceftazidime, avibactam. So at this stage, although no molecular analysis were what was available, we were thinking uh the, the uh possible betalactamase profile of this bacteria. It cannot be a single enzyme which can produce such a high rate of resistance because individual enzymes, for example, ESB LK PC and OXO 48 should have been inactivated by Ceftazidim aact. But since the organism is resistant to Ceftazidim aact we suspected a possible DM or another metallo enzyme. And the um there could be an ESB L as well. Although uh these oxo 48 type of enzymes and N DM can hydrolyze um several of these bacteria as well. So, the suspicion was um a combination of all this and actually the microlab uh within 24 hours revealed that it's an is eclampsia producing oxo 48 plus DM plus CTX M 15, which is an extended spectrum betalactamase. So this is a very difficult case to treat because basically on the antimicrobial susceptibility profile, there is no antibiotic, but let's discuss the options. So what are the options you have in your hand to treat such a patient? But first of all, look at the M IC distribution for meropenem for enterobacterales. So you see those white columns indicate the ox 48 only oxo 48 is a weak inhibitor of carbs. So most of these bacteria, if it's an oxo 48 for example, would be resistant to teen, which can be easily hydrolyzed but susceptible to meropenem and um imipen with an M IC range between one and two. But if it's an OX uh N DM producer, in that case, the M I CS will be very high um for meropenem within the range of 32 or above because high N DM is a very active enzyme against uh carb um antibiotics just as in our case. Now, first, look at the betalactamase inhibitors, which are available today. So, I mean, cact and tazobactam obviously has no activity against any, any type of um, carbs. But the new ones, Avibactam wet and relebactam can have some activity. Well, um, first of all, they have no activity against MBL, but they are basically active, active against K PC and Avibactam has activity against oxo 48 type of enzymes. Well, there are options, there are some new antibiotics and there are some old antibiotics which can be used for the case of N DM and OX 48 and K PC type of carbapenemases. First, there is a new molecule which has been recently approved by I A. It's a AACT and in vitro it's, it has high activity against N DM type of enzymes. And cefiderocol is another option. AYC is a fluorinated tetracycline also has activity against N DM and Tigecycline also active. Um well, the activity is limited. Uh and as you see at the bottom, the yellow color indicates uh an activity scale between 30% of this, 80% of the tested isolates. So it's just like with the case with Cholestin, Fosphomycin and P plazomicin. Uh AAA new aminoglycoside antibiotic, which is available in, in the United States. There is a new agent which has just uh completed its uh phase three trial, Cefepim Tibor bact highly active against Metella enzymes. Uh but unfortunately, the phase three trial did not include any carbenin resistant isolates. So, we are yet to see uh whether this in vitro activity can be translated into clinical trials. This is another figure uh from a very recent paper from uh indicating that Cefiderocol and and AACT are the only approved agents and AACT has only been approved by not FDA uh for, for uh uh MBL uh producing gram negative bacteria. There, there are several other options I already mentioned, Cefepim taniborbactam, but there are others with nebactam and zab bact combinations. Uh but the, the, the trials are still being awaited for MBL uh producing gram negative bacteria. Now, let's talk about the guidelines and the guidelines which I'm going to mention is the most recent one, which is the I DSA Guidelines, Infectious Diseases Society of America uh uh which were updated just three months ago in August 2024 and for carpene resistant enterobacterales with uh with an MBL I DSA proposes Ceftaz abac plus A or it could be Austria aact. Of course, at the time of, of, of this writing, uh FDA has not been approved um Austria avibactam. So they use Ceftaz avibactam plus Austrian or Cefiderocol. If it's a non uti urinary tract or nonbacteremic infection, then you can use acyline. But since these two antibiotics have very low level in the urine and in the blood, you cannot use them for bacteremia or urinary tract infection. I DSA proposes Cefiderocol is the only choice for difficult to treat resistant soas, aeruginosa and discovers MBL producing soas Agios as well. But there are no specific recommendations for MBL producing carbenin resistant acinetobacter bowmanii or stenotrophomonas maltophilia. So let's have a closer look to all these antibiotics which are available for treating MBL producing bacteria of a avibactam. First avibactam is a non betalactam betalactamase inhibitor. It has broad spectrum of activity. ESP LMC oxo 48 um K PC of course, but it's not active against metal enzymes and no anaerobic activity, no activity against acetobacter. Well, the classical molecule is Ceftaz Iam, which has been available for quite long time right now, more than more than six years. And it's been approved for all complicated urinary tract infections, complicated intraabdominal infections and uh pneumonia. Um and in a variety of infections such as ventriculitis sal salvage therapy in those patients who have been not been effectively treatment with other antibiotics. But Ceftaz aact of course, has no activity against metal om is producing bacteria. Whereas on the other hand, atrium, which is a monobactam antibiotic has in vitro activity against metall beal omma. It cannot be hydrolyzed by metalobalis. However, this antibiotic can be inactivated by extended spectrum, betalactamase K PC type of carbs and MC chromosome betalactamase. But when you combine avibactam with aab avibactam will protect a uh to be hydrolyzed by E SPLS K PC and MC and osteon will not be hydrolyzed by metal beal omy. So it's going to be an ideal combination for metalobalis producing gram negative bacteria plus minus ESP L or other types of uh enzymes. Well, before astronomy back then was available, the regular combination was to use Ceftazidim avibactam plus Austrian. And in the in vitro data, uh the combination worked very well against MBL positive enterobacterales, soas and stenotrophomonas. Um And the clinical data indicated a reliable clinical cure rate in in a month which is around 80% and around 20% mortality rate in those patients who have bacteremia. Recently, just a month ago, there was a comparative study called revisit study which compared Austrian avibactam plus minus metroNIDAZOLE for intraabdominal infections. Of course, for anaerobic bacteria and meropenem plus minus cholestin in serious gram negative infections, including those patients infected with the metalloenzyme producing bacteria. There were 422 patients. The randomization, one was 12 to 1 and um 271 isolate at least produced one um enzyme and most of these bacteria were enterobacterales. However, the problem was that only 80% of these bacteria tested for carbapenemase and only there were 19 carbapenemase were detected. Unfortunately, five of these 19 were a metal metalloenzyme. So four in the Austrian Iam group, one in the meropenem group. So, although this is a large trial, unfortunately, it doesn't give us enough information about the efficacy of and abiam for um metil enzyme producers. And if you look at the patients either with complicated intraabdominal infection or have to have the clinical cure rate and 20 day mortality were both comparable um uh comparable with um Merom and the atrium avibactam. And for safety issue, um there was no problem with Austrian and avibactam. It was similar to a monotherapy. Well, the second agent is Cefiderocol, which is a cho cephalosporin, which means the drug is carried into the cell through bacterial iron transport system. So it's not affected by purine mutations and efflux, its main target is PVP three. And in vitro activity is excellent. Uh 99% of these isolates producing M cesp L or metallo enzymes including C. So alsa acinetobacter, bowmannii and sto maltophilia are susceptible to this agent. However, there is no gram positive or anaerobic activity and the approval for complicated urinary tract infections. And he or when there were two trials with Cefiderocol, the first trial uh was interacted with low number of accrual of patients. And the second trial which was called credible trial comparing cefiderocol versus best available therapy for carbapenem resistant gram negative bacteria. And in these trials, there were higher numerical efficacy against MBL producers uh to clinical cure rate, microbiological eradication. And there was a lower uh 28 day mortality. One concern was that in those patients with acinetobacter infections, there were high higher deaths and there were uh re uh resistance problem uh among those Indian producers. So, although in vitro, it was, it was ideal drug, it seemed to be ideal drug. Uh in vivo did not uh do very well. Actually, in this particular trial, the third drug is AYC, which is a, a novel chemically, it's similar to Tigecycline, but it's orally bioavailable 28% oral availability. Uh However, the uh concentration in blood and urine like Tigecycline are limited. It is active against a variety range of enzymes. ESB LK PCA and N DM. So the estimate guidelines which were published 2022 recommended this agent against MBL producing carbenin resistant enterobacterales. I DSA recommended only as an alternative. Um Well, in vitro, it is up to two F four fold. More active against CR E and acinetobacter bowmannii. There is uh significant anti M RSA and VRE activity. However, there is no activity against the Moosa and the main indication for this agent for uh complicated intraabdominal infection by both FD A&E A. Well, this is a summary of the indications um where AYC can be used. So, in those patients with complicated intraabdominal infections previously colonized or suspected to be colonized by ESB L or CR E. Um if the patient was treated with broad spectrum antibiotics within the last three months, recent hospitalization or invasive procedure, recent travel to endemic areas with MDR problem, long term care, patients, recent uh C difficile infection and penicillin, allergy could all be or individually an indication for AYC for intraabdominal infections. Well, there are other options as well which are less reliable, but it's, it's of course, an option first aminoglycosides, the old one is Amikacin. From time to time. You can come across an uh MBL producing uh gram negative which is sensitive to amikacin and you can use it for urinary tract infection. Cleomycin is a new aminoglycoside, um which is approved for urinary tract infections only and only in United States nowhere else. Um but these agents are not active against N DM producing bacteria. And of course, there is concern about nephrotoxicity and increased mortality. Well, if none of these new agents are available in a setting, then your choice would be colistin provided that of course, your bacterium is sensitive to colistin. But remember in our case, it, there was a high resistance to colistin as well. So it wasn't an option but it can be used in various settings because it normally it has high in vitro activity versus MBL producing microorganisms. Well, smis uh recommends monotherapy with cholestin against Cr E and Carbenin resistant acac bowmannii aza. It's in combination. Whereas in ids AIDS A says Colistin is an unreliable drug and should not be used. It's a sharp uh contradiction between estate and I DSA guidelines. Um Tetracycline as we are all aware that has high in activity versus MBL producing bacteria, but the blood and urine concentrations are pretty low. So it cannot be used for bacteremia and urinary tract infections. SM recommends it in high dose which is double dose uh for carbenin resistant acinetobacter which is resistant to sulbactam in vitro and it could be used in combination with other antibiotics, either cholestin, sulbactam, carbs, et cetera. However, there have been concern in several clinical trials indicating that there is an increased risk of mortality. And unfortunately, the, the the reliable clinical evidence from comparative trials are lacking uh with, with this antibiotic. And finally, Fosfomycin, which is, um which has in vitro activity for uh most of the MBL producing bacteria, Um except MDR pseudomonas algis and MDR acetobacter Bowmanii. Both I DSA and SME recommends this agent in combination versus carbenin resistant enterobacteriales. Uh There is concern, however, in certain parts of the world, particularly in the, in the in Asia and Southeast Asia, there is emergence of resistance through a gene called fos aging. Um And uh particularly if you use fosfomycin monotherapy for for treatment, this uh the the resistance can develop very quickly. So it should be always used uh in combination against C A. So, in conclusions, um MBL producing bacterial infections are a significant problem and an an emerging problem. Uh globally, the their clinical impact and uh treatment opportunities is challenging. Uh There, there is a significant clinical impact and there are not very uh many options for for the treatment. Um Although there are several in vitro effective drugs, uh most of the clinical data with these drugs are lacking, we don't know what is the uh optimal duration of therapy with the wi with these agents with the new agents or the old agents. There are new drugs which are being uh tested in various phases uh in the clinical trials. But we are yet to see uh randomized clinical trials, which are designed particularly targeting the MBL producing bacterial infections. So at the moment, we are left with only meticulous antimicrobial stewardship practices, which should include the role of rapid diagnostic tests to identify MBL producing bacteria as early as possible. Um Regarding the previous antimicrobial use and the relationship of emerging MBL producing bacterial infections. And of course, there is a need to know about the local epidemiology in order to treat these patients empirically until uh exact data from the clinical microbiology lab is available. I think I'll stop here. Thank you very much for listening to me.