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Hello, I am Maba. I am Professor of Infectious Diseases in the University of Genova and also Chief of the Infectious Disease Department in San Martino University Hospital in Genoa Italy. So my task today is gonna be discussing with you about the uh clinical signs and symptoms caused by MBL. So, uh metal metal is producing bacteria in order in order to improve early detection rate. So let's start my presentation. So uh these are my disclosures regarding advisor, consultant, speaker group. Uh First of all, it's important to underline that antimicrobial resistance is a globally unfolding crisis that every sorry that every health care professional should know. Uh So that, that uh uh every healthcare professional can add up to a bird. So we know that the number are impressive. There has been uh a global increase in consumption of uh antibiotic or prescribed antibiotics in the past 20 years, around 50%. And the resistance rate in the key pathogens like acinetobacter and KSA reach very, very high levels, more than 50% and all, all over the world, there are approximately 5 million people that die every year for the A Mr. So uh the situation this is the situation now. But when we look at the situation in 2050. So there are a couple of uh interesting articles and one has been published very recently uh by in, in Lancet. And as you can see in 2050 without intervention, there will be around 40 million people all over the world that will die for I Mr. So this is gonna be the first cause of uh that more than uh that's for uh cancer and any other type of uh uh different diseases. So uh I Mr would be uh more problematic in the future than, than today. So when you look at the uh projection of what uh will happen in the future regarding the particular death rate for uh 100,000 attributable to a Mr all over the age, I like to show you the data in 9090 in 2021 and and what will happen in 2050. So you can see very well that this is the or the death rate due to anti resistant bacteria. And in 1990 you can see that uh in uh us, but even in Europe mortality was in between uh 9 to 10% 9 to 12 in us, you can see is around 12 to 15. So in any case, mortality rate was lower than 15%. So this is the situation in 2021. So, I mean uh now that we are facing in our hospital So look in the United States each level around 20%. So in Europe, particularly in Italy, but you know, in the eastern part of Europe mortality range between 20 to more than 30% particularly in the Romania or in Greece. But even in all the part of eastern Europe, but look at the situation in South America but even in India or in some part in the, in, in, in the, in the, in the in other countries in Asia. But uh uh and this is gonna be very problematic in, in 20 in 2050. So which are the contributor, contributing factors to the emergence and spread of. Uh I Mr. So, first of all, we know that I Mr is strictly related to one another prescription of antibiotics. The second reason is probably related to the fact that patients not taking an antibiotic as prescribed. So they stop antibiotic before the, the before the end because they feel better and they stop after three or four days. And this is uh obviously a reason why bacteria uh become resistant and then there is an unnecessary use of antibiotics in agriculture. But even in uh in veterinarian, and this uh obviously uh promote the spread and infusion of uh resistant bacteria in, in in the hospital. We know that another reason is related to the poor infection control, particularly in hospitals and clinics, but also the poor hygiene and sanitation practices. But another important reason is that the lack of uh rapid la la laboratory test that obviously this increase uh the number of empirical therapy because there is a lot of uh uh diagnostics uh uh and diagnosis and uh what's regarding what, what happened with, with COVID. So the COVID uh there has been uh an E disruption and there was a an of use and uh obviously also this uh problem promote I Mr. So actually one of the main problem that we are facing all over the world is represented by the carapin resistance. So these are the last data coming from the aerobact trial, Aerobact two trial which uh uh Alexis the published uh last year in uh in intensive care medicine. And you can see that the level of carbenin resistance in different bats. So in CSA reach uh more than 37% of the cases in Samonas, more than 33%. And in a tobacco we have in Europe actually more than 80%. So the data are not uh different compared to the epic two, the, the IC two trial published in 2020 in Jama. And you can see that the the the resistance in gel was even higher uh reaching uh uh more or less 60%. So the one is a little lower and then I see that the bacter more or less around 80%. So when you look at the distribution of the clinically relevant, acquired carbon negative, you can see very well that we have different classes of uh uh Beales, we have the class A that are mainly represented D and KBC. We have the class B that are the metal and the class D and you can see very well that the class B are present in club but also in that are quite uh common in, in, in those pathogens. So when we look at the uh gran negatives and uh at the different uh betalactamase, you can see very well in this nice scheme that we have set betalactamase mainly represent by the class A, the ESB L and the K PC by the class B, mainly by AC and by the class D maybe the op A 48. So then we have the metall IC galactose and today we have to discuss about metalobalis and are part of the class B and we have three main uh mechanism, three main names. One is I MP and DM and V. So what do we know about Metallo in general? So metall metall tamas carrying islets increased from around 4% to more than 12% from the period 2007, 2009 to the period 20 0 14, 2016. You can see very well here, the increase of metal. So obviously K PC remain one of the main mechanism of resistance and even ox. But look the, the, the AMB L genes increased significantly uh with an increase of more or less three times in uh less than 10 years and 26 is are in two Carma gene were known in the period of 2014, 2016. Most of, most of it include the gene thing called in ox 48 plus uh emet. So we can have a mix of two different type of uh of metals including uh emet plus, maybe another type of uh uh carapin in, in, in those particular cases, the oxy 48. So in 2023 wh O identified and measured creatine the activity of traditional antibiotics against MDL. So MBL gene ly mobile and accelerating, they spread all over the world. Metal metal is producing bacteria often coar multiple resistant mechanism including uh the MC and ESB L and the stenotrophomonas is intrinsically resistant to most metacam agents due to the production of two metal ainas along with the other mechanism. Sorry we have in the big five caras three of them are represented by the meals. And the first point we have a PC ox 48. But then look at the I MPV. Men in the M that are, they represent the most common Carma is isolate globally all over the world. So this is uh the situation regarding the different metal aromas that are spreading uh all over the world. You can see that uh mainly we have N DM. You know, that is in uh with this kind of uh of color, you know, this is uh an orange between orange and pink. So China but also Middle East. And they obviously there are in India are more problematic like in the eastern part of Europe, including Romania and, and, and you know, very, very important. So then we have all the countries in which we have fe you cannot study is more problem for instance, for them. And then we have I NP in Australia and other countries. So it's very important not only uh uh to know where you are, but also which are the main betalactam or the main carbo pinas that are circulating in your country and even in your hospital. So when you look at 10, at, at the $10 rules for antibiotic use clinical in patients particular uh MDR, I really believe there are 10 very important points to be considered. First of all, we know how important is to start with an early appropriator particularly for septic patients in order to reduce the mortality. The second point is uh uh to consider the impact on bacterial resistance, the so called collateral damage. S it is important to improve diagnosis and diagnostics, particularly with the new tactics, investing in a rapid diagnostic test. But then is also important uh to do an adequate certification in order to know if the patient is for a metal or for another type of carbs or for a different type of uh mechanism of resistance, then it is important also the combination when needed to use the combination of two active antibiotics for the negatives, which is the role of the established antibiotics. Very important. Some oral antibiotic, oral antibiotics are important and then grab optimization to optimize the PK PD rules. Then it is very important in MDR to be escalate, rapidly duration. Shelter in Jan is better, the longer and then last point is gonna be the role of new antibiotics. So we know very well that uh uh the uh appropriate versus appropriate therapy uh is very important. And this is a study that uh mental ao that clear demonstrate that in uh all the different type of infections start with an appropriate therapy, reduce significantly the mortality. It's not only important to start on a weight therapy, but it is also important to start on the gra therapy on time. So this is the importance of treating it right the first time. So this is a study that uh uh we published with a friend for K A in 2020 which we analyze the mortality rate at 30 days for K PC bacteremia. And you can see that start the treatment within uh 24 hours after uh the blood culture were done. And you can see that the mortality was significantly lower than if you start the mortality later. Uh after two days, three days or more days, uh the inappropriate initial antibiotic therapy leads in general to an increased mortality particularly in uh in a gran negative infections. And you can see very well. This is the most important risk factor for mortality. Uh is represented by the inappropriate initial antibiotic therapy. Inappropriate initial therapy is a modifiable risk factor for mortality. And it is important to do all the four in order to modify uh the inappropriate uh initial antibiotic therapy. So this is a nice study that was published this year in a scientific report which they analyzed the impact of MDR, the multi drug resistance on the outcomes uh uh in hematological cancer patients with the bacterial bursting infections. And you can see very well that looking significantly. And the carbo panel resistant strains demonstrate that there was the i mortality, the IgE mortality. You look at what you know, if you have in a concentration, a carb panel resistant gram negative, this is the mortality, 60% increase in 30 days mortality. So in general, in general, mortality doubles with the infections caused by carboplatin resistant pathogens and uh particularly by metalloma. So this is the study that demonstrated if you have eclampsia, susceptible to carboplatin mortality is more or less 20%. If you have a AAA eclampsia resistant to car mortality reach uh immortality again than 40%. And the same is in SOAS which you can see many of them are metal, uh metal activ AO in you in which you can see very well that the mortality uh double in MDR SOAS compared to the non Mr. So in particular, the infections caused by metalobalis and T bacteral are associated with an increase in mortality. So look at that the in hospital mortality for patients presenting MDM enterobacterales infections specifically in the ICU in South Africa and the known MDM uh enterobacterales. There was a a an a significant increase in the men in, in, in, in the l of hospital stay but also in the L of ICU stay. And at the end was an increase uh in in the ratio for in hospital uh mortality. This is adjusted ra uh and the same is for 14 days mortality. Look at again in this second study conducted in Greece. And even in this other study in this Multicenter study conducted in Japan, you can see very well the I NP versus non I MP mortality uh more than two times uh two times higher and also the length of hospital stay, you can see very well longer for I MP compared to no I MP. So when we look specifically the Metalobalis, uh it is very important to try to early identify patients that present at risk for MDR negative infections. And um it's very important to consider uh some specific respect for MBL, the MBL outbreaks, obviously, but also travel to eye endemic areas. I show you the areas in which we have one N DM. Obviously, if you have a, a patient that uh come back from India, is important to suspect that the patient can be maybe colonized by a via metal or specifically by MDM. So also the medical theories but also very important to consider the prior colonization. And also very important to consider the prior antibiotic use, particularly gabapentin. And also the healthcare exposures in the endemic areas uh in the management of MBL. And in general, the management of uh uh in the context of MBL circulation is very important to have a uh a, a, a AAA combined approach of another great antimicrobial ship program with the right the right dose. But at the same time, it's very important that the antimicrobial ship program interact directly with the diagnostic steer program with the eye test for the right patient, the right time. And also it's very important to have the interpretation. I really believe this is very important in order to have rapid test to diagnose uh M BI or other mechanism of resistance. So, in general, in the management of the patients in the hospital, if II, in order to start the uh an appropriate therapy is very important to consider in a septic patients, the local epidemiological contest. So if there is a circulation of metalobalis of carb resistant and uh uh gram negative nonfermentative and fermentative. So then consider risk factors for carbenin or for ESP L and then also consider the associated comorbidities and put all together like a puzzle. And uh after obtaining adequate capture and uh and after having the rapid diagnosis test, II think it's important to start an empirical therapy in order to cover MDR and in order to rapidly deescalate based on the rapid uh diagnostic test. So the rapid molecular diagnostic test to identify pathogen are very important. So there are some example of these tests are lateral flow assay, syndromic assay for genes or rapid antimicrobial som test and test often indicate the presence of or or other kin A or ESP L that idolizes. And there is also widespread use of a rapid test is umed by cost and availability. And also it is very important to uh have caution in interpreting the result. So which is the challenging the the challenges in the region of MDR gra negatives. So anabolism is I can expect to increase in the coming years. More than 60% of infection in uh in critical a caused by gra negative in particular called eclipse Enterobacter infections are more species specific resistant mechanism, ES PLC E and the MLS, the increased set of beacon is including carane produced by gra negative random many traditional antibiotics red MDR due to the production of an MDR, increased the likelihood of in appropriate initial antibiotic regimen, which increased the risk of morbidity and also of uh mortality. So we know that uh the mortality attributable to uh different carbenin resistant negative is totally different. You know, look at the attributable mortality for the different type of uh of the karma. So here we have the karma pens rejectable negative. And look at here the mortality around 14% for K PC, 26% for metal metal is 36.4% for carb. So the 32 and for acid metacin more than 43. So this is the existing mortality. Look at the existing mortality for metallo 35% compared to a one. So very uh uh important data published by Marco Falco in uh 2023. Now, I have a very simple clinical case in order to summarize all the contrast that we discussed today, we have a a male cystic hold with multiple comorbidities, atrial fibrillation, diabetes and chronic renal disease. And in 2021 he, he experienced severe pneumonia and needing a invasive mechanical ventilation, tracheoscopy and uh tracheoesophageal fistula. The patient underwent a fist and correction with the um blood cell occluder device. But from 2021 to 2024 multiple episodes device, dislocation and a in justice pneumonia needed hospitalization. In 2024 dislocation of uh unplug occluded device needing replacement. And there was an ICU admission during the postoperative period uh with some important ICU complication, delirium CBC and intestinal ischemia and the surveillance screening weekly. Uh and there was a surveillance weekly done with the recal track class, urine cultures and blood cultures. So going to the patients. So we have a patient that during the IC admission experience, 40 degrees of fever with the BP, 90/60 we need for vasopressor with some important uh data, a very high increase in the C RP and uh also very high increase in uh PCT and lactate. So we have a very sick patient. Uh and uh they ask for an IV consultation. So the surveillance culture show very well that the patient present in the respiratory tract, eclampsia, pneumonia producing MDM and difficult to treat. You know, the patient was also colonized in the rectal, the rectal swab with N DM, eclampsia and the urine culture were positive for N DM eclampsia. So we have a patient that is highly colonized by N DM. So, and uh here is a colonization driven empirical therapy. So in a patient that becomes septic like this patient, which the risk score is higher than seven and in which we have aaca so positive for MDN. The suggestion like in this case is uh to start caza plus asterum or if available, uh avibactam plus or plus abacta. So if the sub is positive for 48 may be CASA or if it is positive for uh K PC CAA me or so, if the patient is colonized by acinetobacter colon ce containing regimen, if the patient is less than seven is not colonized and is not in septic shock, uh it is important to continue with the standard treatment. And obviously, this is gonna be uh an early escalation one, the data from the rapid test will be available. So going back to depression. The blood culture show eclampsia and eclampsia. They note in the, in the rapid test, the presence of and and uh there was a recent uh a recent intestinal ischemia, possible intestinal cause translocation of the. And um at the end, even the blood culture should become positive. And uh the blood culture show associated to cedar and uh to tigecycline. And this is a case of or so, thanks for uh giving me the opportunity to present it. And um my personal consideration and the conclusion for MBL is that um enterobacterales for enterobacterales, actually, the best treatment options are presented if presence of MBL by septa eact plus atrium, uh or as ABAC will eventually get for soas the best for metal loss is represented by uh probably by. Thank you very much for your attention.