# 110 - Tratamento de Acinetobacter sp (CRAB)

And today we are together to talk about a theme that I particularly like a lot, which is about the serious infections of the serious carabinous carabinous malmoney resistant acidetobacter. We will call it the Crabb, which is its acronym in English. Exactly, the English word is Carbapenem resistant acidetobacter, which includes other types of acidetobacter. It is a boring bacteria, but we need to talk about it. Let's go! Just bringing the panorama that we have of the infections of carabinous carabinous malmoney resistant acidetobacter. After the COVID-19 pandemic, we saw a significant increase in the infection rates of carabinous carabinous acidetobacter. Resistence of carabinous acidetobacter goes from 80% to 80% in most of the centers. So we are kind of without a very good treatment option, considering that other drugs do not have a synthetic and co-cinetic profile, so they are good. And some of them are not. It's a boring bacteria, which is a non-fermented non-negative, which is very related to health assistance. So there are some recent review studies that have seen that most patients, when they are infected with carabinous acidetobacter, have acquired it in the hospital environment or are related to other health assistance mechanisms. In other words, in some way they have a contact with health assistance, so maybe they were colonized and then infected by carabinous acidetobacter. So it is that bacteria that we never see someone coming from the community with carabinous acidetobacter, an infection of carabinous carabinous acidetobacter. So usually we are part of a patient who is not the most easy patient. A patient who is already interned, has already taken several antibiotics cycles, so maybe that's why I have already selected this carabinous acidetobacter. Super invaded in an intensive therapy environment, and then it can cause several infections. Pneumonia associated with ventilation, infection of bloodstream, osteomyelitis, very much involved in patients' infections, large burns, and sometimes it is very difficult to say that that sign is actually the pathogen in the determinant of that infection, because many times it can only be colonized. And as he is there in the health assistance environment, he can colonize the patient, so we also face this difficulty and this impact of deciding whether or not the accident has some situations. But in general, it is a very important pathogen that we must try for its presence, especially in places where the rates of infection for accidents are a little higher. And then we will talk about the first problem of the carabinous acidetobacter, as you said, knowing if it is colonization or infection, or sometimes my patient has a risk of developing to infection and my empirical treatment may not work right away. For one of the reasons, as we will talk now about the Crab, if we are talking about the carabinous acidetobacter, which can already have intrinsic resistance, when we are talking about the carabinous acidetobacter, which is resistant to panemic carbon, that is, it can be bringing other resistance mechanisms of carona together. So generally, the Crab is resistant to palmerpene or my mpene, and along with that, it will bring other serine, Betalactamases, or mutation of BBP, or mutation of enzymes, and that's why it can be resistant to my casino, it can be resistant to my other cellulose purines, and then the chance to get it right decreases. That's why we will talk about the treatment and these indications. Just doing a brief review on resistance mechanisms, because it will be important in the choice of drugs, remember that usually when the carabinous acidetobacter is resistant to panemic carbon, it is mainly by oxacilinases. These oxacilinases are Betalactamases of the class D of Ambler, mainly the oxa23, the 40, the 51, which are very common in the acidetobacter, but also other mechanisms, as William said, for example, alteration of BBPs, especially the PbP1, 1a and 3, which would lose its susceptibility to the subactan, and other mechanisms such as the production of Betalactamases metal, the enzymes that are the terror of the infectologists, such as NdmVin, which are increasingly being isolated in the acidetobacter. So, having this resistance scenario, we often have no treatment options. From this, there are recommendations for guidelines, which we are already aware that embody the treatment for the acidetobacter in the world, but that in Brazil, in fact, they are not so effective by the availability of drugs, right, William? So, we are going to use here, as a gardener for our episode today, the IDSA's guideline, an American guideline, but we are going to filter it here, right, and let's go with the drugs that they have, that we don't have. We are already trying to bring it right to our reality here and try to use it to gain time here on this subject. Let's talk about the first premise here, to organize our reasoning. When we are talking about treatment of Acinetobacter and Crab, first thing. Double therapy is a premise here. So, whenever we are talking about treatment, we will prefer double therapy, that is, more of an antibiotic for the treatment of my patient. The first reason is that there is no evidence that the world of therapy is safe enough, or that I have clinical trials to check and find out that maybe this is the best option. According to what Lino said here, Acinetobacter has several resistance mechanisms. If we are talking about Crab, resistant to paramedics, most of my paramedics or my other antibiotics, if I use TAS, if I use Meropenem, I will be wrong. So, as it has several resistance mechanisms, most of my empirical treatments of my patients, the chance of not covering the patient is very high, so it is the premise of double therapy. It is a recommendation, but I remember that it is not a recommendation with such a good degree of evidence. There are several studies that sought the benefit of this therapy combined with the treatment of Crab. And the problem of all these studies, in fact, is the heterogeneity of the patients, the heterogeneity of the adopted schemes, the adopted comparators, and the doses used that varied a lot among the patients. The lack of a drug that has a pharmacosinetic-pharmacodinamic profile is really great for us to choose what to treat, and as many times it has implications with high mortality and has a study that demonstrated a better clinic in these patients, the guideline recommends doing combined therapy. And what would be the basis of this combined therapy? It is basically the Subactan that you must have heard of. The Subactan is a beta-lactamic inhibitor of beta-lactamase, which here in Brazil only comes with subactan ampicillin, which you must have also heard of, and which we use for several treatments of other infections. So when we are talking about subactan ampicillin, when I recommend this drug, it is because of the subactan effect that it is a beta-lactamase inhibitor that will saturate the Pbps, and that's why the subactan has this effect and the recommended drug. Ampicillin itself does not have an effect against the acinet, it is not recommended, but it is the drug that we can extract the subactan that has an effect against the acinet. In detail, when we talk about subactan ampicillin, the total daily dose is 9g of subactan, which usually gives confusion. So when it is prescribed it is 9g of subactan component, you have to take into account. Use recommendations. Most people, right, the oncologists, use 8 in 8, 3g of 8 in 8 hours of subactan component, or continuous infusion throughout the day is 9g. And because of this recommendation of subactan, there are several studies, both in relation to the better clinic, clinic cure, mortality reduction and microbiological eradication, and the subactan showed very efficient in relation to its comparators, or it was equal or better than with respect to these effects. So that's why it is recommended to use the subactan for the treatment of the acinet. We have some questions. The first would be the reduction of susceptibility, and we see there that less than 50% of the subactan acinet are sensitive to subactan. When it is sensitive, we have a laboratory problem. It is difficult to perform an anti-biogram of the subactan for the acinet, so we have a rate of use of the majors, which would be when a result comes sensitive, but actually resistant, from up to 10% to 15%. So that's why we can't use the subactan alone, due to both resistance and due to the possibility of lab error. And then most of these studies tested the subactan, in fact, with high doses, varying from 4 to 9g a day. In relation to the comparators that were used for the treatment of the acinet, it is usually colicina or subactan combinations with some other thing. And despite that, seven clinical studies that we have, only one, showed a significant improvement in this combined therapy with the subactan. But we will recommend, due to the high mortality rate, that the infections by the acinet have... Usually we do not have good options, so the subactan, in fact, would be the pillar of the treatment. So much so that, out there, recently, a new drug has been approved, right, William? Exactly, Helena. We do not have it here, we will not talk much about it, but it is cool to know that it exists. Which is the subactan, the Urlobactan, which, in the guideline, also recommends to be used in double therapy. But it is a drug that the two drugs would have an effect, would have its benefits. And that's why it ends up being recommended, it makes sense that it would be its first line of therapy associated with a second drug. So even this new drug, still indicated in the guideline, giving all the rescues that I have brought so far. That's because the Urlobactan subactan was approved in 2023 by the FDA. Your approval study is called "Trile Attack", right? And in this study were included the patients with a documented infection by the acinetobacter balmone-resistant carapenemico, pneumonia and blood corneal infections, with the intention of evaluating mortality in 28 days, and the comparator was colistina. But as it is a new drug, both arms received an imi-pennence and lasatina together. That's why it has this recommendation that whenever you use the Urlobactan subactan, use the imi-pennence, since there is no study that used the Urlobactan subactan alone. And what would be the Urlobactan? The Urlobactan is a beta-lactamase inhibitor, not a new beta-lactamate. And the master's play is to be able to inhibit the oxacilinases, these D-class enzymes that the acinetobacter produces. So, that's why its use in the treatment of infections by the acinetobacter. Just an add-on, remember that the Urlobactan does not work against the beta-lactamase metal, so those Ndm, Vim, Imp enzymes that are frequent in the acinetobacter, not the main ones, but end up happening, would not be inhibited by the Urlobactan subactan. So, for this type of resistance, we still have some problems in the treatment. Exactly, Lina, I think that when we have the drug in Brazil, we can even record a new episode, discuss more about what the indications would be, but basically that's it. So, summarizing what we have said here, so far, recommended double therapy. If possible, your first option will be the Ampsubactan because of the Subactan. And what are the other drugs that we can use? I think that maybe the first drug we're going to talk about is Polymixinab, which is a drug that, in the guideline, it says that Polymixinab can be considered as a combination with another agent to treat the crab. Always remember that international guidelines kind of suck in Polymixinab because their reality is different, right? They have, for other infections, Hepatazidimabactan, Hepatolusanitazobactan, easily available. Outside, there's the Urlobactan subactan. So, in our reality, in Brazil, Polymixinab is still a super useful drug and very prescribed by us effectologists. So, we're talking about Polymixinab, but between Polymixinab and Colistinab. That's right. I'm just going to give you a brief review of the differences between Polymixinab and Colistinab. The two are Polymixinab, right? The Colistinab is Polymixinab and Polymixinab is Polymixinab. They have some differences, mainly, co-cinetics, ok? Regarding the spectrum of action, there is no difference between the two. Remember that Polyb is already an active drug, while the Colistinab is a pro-drug, which needs to be activated. It has a renal activation. So, when we think about treating serious infections, systemic infections, we need a drug that is already active with a good level of serics enough to be able to make a faster microbiological error. So, it would be Polymixinab. While the Colistinab and Polymixinab are more reserved, there are more recommendations for urinary infections treatment, since it will have a renal activation and there it will be active in a large amount. Speaking of that, we use Polymixinab for most of the questions, but there is a problem in literature that most of the studies are with Colistinab, because out there, in European countries and in the United States, there is more Colistinab than Polymixinab. Other differences between the two are different effects. Colistinab has greater neurotoxicity rates in relation to Polymixinab, ok? In other words, you can use it for treatment in infectious diseases, both PolyB and PolyE. We will be talking here more about Polymixinab and Colistinab, but the two are more reserved, ok? Exactly. Those who work in Suzhou know that Polymixinab is a antibiotic that is not difficult to find. So, in most of our hospitals, we can find it. That is why we already talk about it here and mention it right away. So, it is a antibiotic that is not difficult to get. But let's go to the problems of Polymixinab. First, it makes it very clear not to use it in monotherapy. One of the reasons here. In the currently recommended prescription levels of Polymixinab, its serial level to have a bactericidal effect is variable from patient to patient. This can be great in various situations. In other words, you can be giving Polymixinab to your patient and it can be varying in the serial level and you are not having the bactericidal effect you wanted to have there. Another thing, to make it a good pulmonary level, it is also variable. And as we have already talked about at the beginning, usually the senetum and epineumonia, or PAV, epineumonia necessary for ventilation, are recurrent infections. In other words, one of the main focus, the serial level, the level to get there is also great. And finally, which is the classic of Polymixinab, I always joke that polyben is an agrotox that we use eventually, I don't know how to kill the bacteria, is that if it is giving a good serial level, it will bring nephrotoxicity, that is, if an antibiotic is not causing nephrotoxicity, maybe the dose is wrong, right? So it is a classic antibiotic caused by nephrotoxicity. Our, that's the thing, you prescribe PolyB on a page, in the second, you call nephrologist. - Exactly. - You are not following it anymore, right? But sometimes it is the only option that is left, that's why we use it a lot, right? And there is another problem with polymixinab in relation to senetum, which is the difficulty of testing the mica, of getting a mica cured for polymixinab. So sometimes we have the difficulty of being able to do the laboratory exam, here in São Paulo, however, but in other places like that, having the difficulty of doing the test for polymixinab, and then you get without knowing, in fact, what it gives to the patient. But it is not our reality here, in most of the places we have this test, and then polymixinab will be the basic drug for treatment, right? Since it is what we have available, it has sensitivity, despite all the problems that William said. And with what we do not combine polymixinab, right? The evidence field in the treatment of crab is kind of nebulous, but what we have as a result, that the guidelines already say, do not do, is not to give polymixinab with meropenem. So if you are going to treat infection by senetum, resistant to carapenemic, unlike many times this treatment of infection by crab, product of HPC, is there resistant to meropenem, but we give meropenem together, because there are some studies showing benefits, in the senetum area there is not that. All studies were negative. Adding meropenem has no change in improving the clinic, in microbiological eradication, or mortality. So polycomeru here is not the maximum, ok? I think we can even have this second point here, when we talk about carapenemic, that we talk about crab resistant, carapenemase, they will be resistant. Studies that tried to associate with carapenemic, as well as meropenem, did not bring a benefit. So here we will not recommend, at the moment, you try to associate, like what we do with HPC, that even if it is resistant, there is this discussion, that maybe there is a benefit, double dose, carapenemic, but here it is not the case. So I have meropenem, I was not doing anything there in this case. And then what do we do in the day-to-day? At least me, right? Generally, when we have a serious infection, by asinine, carapenemic, we combine polycomapsubactan. Generally, this is the treatment scheme, that we have preferred, to treat a fever, to treat a blood flow infection. We make B-pollimixin, with that high dose of ampicillin subactan. Even if the ampicillin subactan, comes resistant in the antibiogram, for all these issues, of residual activity, saturation of PPP, in high dose, we usually prescribe. This scheme, because in fact, is what still has a better, philopharmaconsinetic, with a rate of sensitivity, but satisfactory, in relation to polymixin. Exactly, Lino. And now I think we can jump to the next class, which is another option, in our arsenal. So, there is the class of tetracycline, and here, I think, our main representative, in our context, in Brazil, Lino is the tetracycline. Yes, the tetracycline, which is a silcycline, which usually also, has a good sensitivity, there, in most of the places, to treat infections, by accident. The problem, of using the tetracycline, is its philopharmaconsinetic, once again. So much in relation to levels, that we have erratic levels, and it is very difficult, to reach an adequate level, for the treatment of bacteria, by accident. And the same thing, occurs to drug levels, in the epithelial fluid, we have a difficulty, to reach these levels. So, many times, we can't treat these infections, adequately. That's why, societies recommend it. So, when we use the tetracycline, it will always be an associated drug, you will always use it, as an option, between two drugs, that you will be using. As Lino said, for the urinary infection, it may be an option, that you don't want to use, because it won't do a good level, in the urine, it's very difficult. For the lung, there are some recommended, double dose, so, you will keep it, in that bigger dose, to be able to, maybe, make a better lung level. And, if you treat, maybe, other infections, abdominal, maybe, you can use, in your usual dose. But, like, it's a drug, that we also have around, right Lino? It's not so difficult to find, in SUS, you also have. It may be that, I always joke, that the tetracycline, it's a coringa, it takes a negative, it can take the HPC, it can take the senet. But, at the same time, it may not be taking anything, right? That's it. And that's what we're going to treat, we're going to treat, with 200 milligrams of attack, followed by 100 milligrams, of 12 in 12 hours, ok? The problem of this dose, is the amount of nausea, that the patient will have, right? Nausea is very often, using tetracycline, and it's a dose-dependent dose, so, you increase the dose like this. Very difficult, your patient, won't complain about nausea, but many times, it's the option, that we have one more time. Remember that, on the website, the FDA has a box warning, of the use of tetracycline, there are some studies, that showed the increase, of mortality, in patients, that used it, only for their use. And in the studies, of treatment, of Asinetobacter baumani, which is only 5, in 2 of them, there was the worst mortality, with tetracycline. So, it's an option, that usually we reserve, for cases, not so serious, or an infection, of leprosy, treatment of an injury, due to increased blood pressure, than serious cases. Exactly. So, at least, it's an option, right? It's what we sometimes have, maybe that, that, especially if you want to, to help the function, of your patient, and avoid polyb, can be this letter, in the manga, that you have there. And, like, practically, our options, kind of, ended up here, right? We have, maybe, the last drug, that we could say, that maybe, has some benefit, that is Cephiderochol, but then, we enter a problem, to get the drug here. I don't know, if you've heard, but Cephiderochol, we don't have in Brazil yet, but it's widely available, it's super difficult. It's a Cephalosporine Ciderophora, that, already had its role, investigated, in the treatment, of infections, for Acinetobacter. And, why would it be so attractive, like this? As it uses a, a iron channel, to enter the bacteria, different from other purines, that other antibiotics, use them, and it keeps stability, against several enzymes, including, against Betalactamazes, it would be a great option, for the treatment of Acinet, right? There are two studies, the two studies, of approval of Cephiderochol, of the trials, which are aspects, and the Credibocer, in aspects, there was not much difference, of mortality, but in Credibocer, I just wanted to raise, that has an interesting data, despite a small N, that the patients, who had an infection, for Acinet, and used Cephiderochol, died more, than the arm, comparator. Maybe this is due, because in this group, of patients, there were more serious patients, with a Ceptic shock, in an intensive therapy environment, but, already on the back, this alert, that if we go to use Cephiderochol, we have to pay attention to this, including, the European guideline, does not put Cephiderochol, as a good treatment option, for CREB, ok? It is a drug, that appears attractive, when we go to study in vitro, there are so many mechanisms, that make it attractive, but in vivo, clinical studies, did not demonstrate so much benefit, what I have already seen, some pathologists, questioning, exactly why you said, sometimes, the profile, of the population studied, which is not legal, but, based here, on the guideline, it puts, prefer to use other drugs, before, will prefer PolyB, will prefer, tetracycline, before you use, Cephiderochol, but it is an option, that also, there is in the list. And if you are going to use, use with, combined therapy also, they do not put, for use, isolated from Cephiderochol. Let's talk here, so now, maybe, our last drugs, that are not recommended, that also, in vitro, may have some benefit, but in vivo, there is no clinical study, that demonstrates, help. Let's talk here, of rifampicin, right Lina? That, the studies, for use, of rifampicin, in a CREB treatment, were not satisfactory, there was no difference, neither positive, nor negative, when we, use rifampicin, combined, in the treatment, of Acinetobacter baumana, those studies, also used, subiotimus, the size, of the studies, were small, so, the panel, does not recommend, the use of rifampicin, as a component, of this therapy, for CREB. Just to open a parenthesis here, when we talk, of rifampicin, of families, of rifampicin, in a general way, okay? And let's now, for another, therapy form, that also, is not recommended, which is, antibiotic, inhalatory, or antibiotic nebulization, for nothing, not to treat, anxiety, of the doctor. True, and then, there are some studies, for treatment, of Acinetobacter, with polymixin, in the inhalatory, okay? And it was not seen, in fact, beneficial, for treatment, of these patients. And, another issue, is the risk, of adverse effects, especially, bronchospasm, which can be, these ideas, then, I think, this was just, an episode, the vast majority, has no benefit, at least here, Acinetobacter, is already very clear, there is no benefit, in you wanting to associate. There is even the issue, I have already seen people prescribing, sometimes, there is the issue of the form, of the nebulizer, that you will use, your ultrasonic, of the conformation, of the drug, there are situations, very specific, that have benefits, and it is not like this, I will break a ball, put it in the inhaler, which will work out. No, there are specific forms, to do, the vast majority, when they do, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, I personally, do not recommend, that he, in a serious way. I think, in the guideline, he does not mention, because usually, when there is resistance, is the endemic carbon, it already brings, mainly, the change of enzymes, 16S, RNA, which is one of the main forms, of resistance, the glycoside, so he does not mention, as Lino brought, it can also be a drug, and that, maybe, still, is still left there. I think that, we stay here, let's just make a summary, of how you would treat, Sinetobacter, resistant to, endemic carbon, in a serious infection. Exactly, I think the first thing, is to know if that infection, really. If possible, try to differentiate, we know that it is never easy, it can be just a colonizer, it can be just found, but remember, that you will be using, like combinations, and antibiotics, with toxic risks, or, you will be giving a lot of volume, to your patient. If you ask, if the cost of benefits, we treat, really worth it. That's right. And then, did you think it was worth treating? Let's do a therapy, combined, in which, the basis of the scheme, will be an ampicillin, Subactan, even if it comes, resistant to anti-biogram, you will use, that high dose, Subactan. 9 grams of Subactan. And, together, with Subactan, you choose another, active drug, that, in general, here in Brazil, will be left as an option, the polymixin. Remember, I went to a serious, systemic infection, out of intracurricular treatment, by Polymixin B, by the best pharmacosinetic profile. Naurina, Colichina. And then, you combine, Polymixin, with Subactan ampicillin, and, in most cases, this will be the treatment, that we indicate, for patients, remembering the risks, of nephrotoxicity, and we are giving, a high dose, of Subactan ampicillin, which is Betelactamic, so, there are also, associated risks. And, the other option, for you to associate, is active Cycline, in the case of tetracycline, that, if it is for blood flow, reconsider it, sometimes, it is a drug, that will not make, a level serious, to treat your patient. If it is for urine, also, maybe, it is not an option. If it is, this is your case, preferably, use high doses, of Cicline, and, if it is for lung, already have, the formal recommendation, of being double dose. And the rest, is not indicated, formally. We wait for the new drugs, Lina. Yeah. Please, take the Subactan, of the Subactan, arrive soon, in Brazil. Thank you very much, and see you next time. Bye. [BLANK_AUDIO]