Authors: Marin Kollef (Washington University School of Medicine, St. Louis, MO, USA) & Ignacio Martin-Loeches (Trinity College Dublin, Ireland)
The recent European Congress of Clinical Microbiology and Infectious Disease (ECCMID; 11–16 April, Amsterdam, the Netherlands) saw the first presentation of the results from ASPECT-NP, a randomized, multi-center Phase III trial evaluating Merck’s (NJ, USA) ZERBAXA® (ceftolozane–tazobactam) for the treatment of patients with ventilated nosocomial pneumonia.
In light of this we spoke to investigators Marin Kollef (Washington University School of Medicine, St. Louis, MO, USA) and Ignacio Martin-Loeches (Trinity College Dublin, Ireland) about the rationale behind this trial, its design and the key findings.
First, could you introduce yourself and give a brief summary your career to date?
Ignacio Martin-Loeches: I am a consultant in critical care medicine. I work in a university and teaching hospital in Dublin (Ireland) that is an affiliated center with Trinity College Dublin. I also have a double affiliation with the University of Barcelona (Spain), and I have my research group there. So, I do my clinical work in Dublin, but I have part of my research in Barcelona.
Marin Kollef: I’m director of the Medical Critical Care and Respiratory Care Services of Barnes-Jewish Hospital (MO, USA), a 1500 bed academic center, and a Professor at Washington University in St. Louis. I primarily do critical care, and I have for about 35 years. I’ve specialized in infectious diseases and do a lot of clinical research related to infectious diseases that occur in patients in the intensive care unit (ICU) setting.
Could you just introduce the ASPECT-NP study and tell us a bit about the rationale behind it?
Ignacio Martin-Loeches: The reason for this study was because we desperately need more drugs for bacteria that are becoming resistant to antibiotics. This is a difficult problem because we know that there is increasing resistance, however, if you have a patient in your daily practice that is very sick, you need to save the life of that patient.
We are developing more multidrug resistance and there are two major groups of pathogens that are a real concern for hospitals in general and ventilated patients in particular, and those are Enterobacteriaceae, especially Klebsiella, and Pseudomonas, which have traditionally been the major threats in the ICU. The rationale of this study is to provide a drug that is going to be more powerful than the drugs that we have currently for Pseudomonas aeruginosa but can also treat other bacteria such as Enterobacteriaceae.
The study is a classical design – it is a randomized, double blind trial. The uniqueness of this study is that it was done in truly critically ill patients who were all mechanically ventilated. The vast majority were patients who had ventilator-associated pneumonia. However, we also had a cohort of patients that occur less frequently but have a high rate of failure, these patients had hospital-acquired pneumonia but had failed treatment on the ward and had to be transferred to the ICU to be ventilated. That all the patients were ventilated is important because sometimes as an ICU doctor we use the word ‘critical care’ in a very loose way. But I think that when you have a patient with a tube inserted in their airway, no one is going to argue that they are not a critically ill patient.
Marin Kollef: The ASPECT-NP study was an important trial. In the past many of the nosocomial pneumonia trials were not designed adequately from the standpoint of populations that were enrolled in the study, or sometimes it wasn’t clear whether the patients had pneumonia or not. In addition, the other problem in prior trials was the dosing of the antibiotics, especially new drugs, and there are some glaring examples where drugs were under-dosed for pneumonia for example, tigecycline.
So, to design the ASPECT-NP study we made sure that we learned from these prior trials and first to ensure the dose of ceftolozane and tazobactam was suitable for pneumonia. To do this, a number of studies were carried out measuring the lung concentrations of the antibiotic after it was given intravenously, and it became clear that in order to get the best coverage for the organisms in the lung a 3g dose was better than the 1.5g dose.
The second aspect that’s important is that, as mentioned, all participants were ventilated patients, which meant that they were seriously ill and thus we probably had a much greater likelihood of enrolling pneumonia patients than in individuals who are not intubated. It was a more homogenous group of patients that we were able to enroll into the study. In addition, they’re sicker, so if there was going to be any kind of problem with the trial you would be more likely to see it and act on it.
Could you outline the findings you’re presenting here?
Marin Kollef: This was a registration trial – registration trials are indicated by the US FDA and the EMA with the purpose to demonstrate that a compound is safe and that it is as good as something that is already out there in society – the bar is set to show non-inferiority.
We enrolled over 700 patients who were ventilated and couldn’t receive antibiotics directed against their pneumonia for more than 24 hours, and we found in the trial that the primary endpoint, which was 28 day mortality in the intent-to-treat population, was no different to the standard-of-care – at about 25% in both arms. Having said that, it was interesting because within the ventilated hospital-acquired pneumonia subgroup, which is different than the ventilator-associated pneumonia subgroup, they actually had a higher survival rate in the ceftolozane–tazobactam arm compared with the meropenem arm. I think there’s some interesting data suggesting that there might be some groups in the population where ceftolozane–tazobactam may do better.
But to answer your question, a registration trial is just meant to show non-inferiority and we were able to do that. The FDA are reviewing the data, they should have their final report in the early summer, and we’re expecting that they’ll approve the drug for use in the USA.
Ignacio Martin-Loeches: The study compared our standard-of-care, meropenem, with a comparator, ceftolozane–tazobactam, which is a cephalosporin with a β-lactamase inhibitor. Ceftolozane–tazobactam was used at a dose that was not used in the previous studies, which was 3g; 2g of ceftolozane, 1g of tazobactam. This is again quite unique and that was supported by some previews, pharmacokinetic and pharmacodynamic studies, showing that to reach a high level of concentration in the lungs, we need 3g.
The randomized study had approximately 300+ patients in both arms and the results that I presented were for those patients that were pathogen positive. We saw that two major results, one is the clinical cure and the second is the microbiological eradication. In the clinical cure both regimens are comparable, including in the major threats that are Pseudomonas and Enterobacteriaceae.
In the microbiological eradication we have two groups, we have the microbiological intent-to-treat (mITT) population and the microbiologically evaluable (ME) population. In the ME, we saw that the eradication of Pseudomonas was larger with ceftolozane–tazobactam, as compared with meropenem, with a microbiological eradication rate of over 70% versus approximately 50%. So, we know that it is a very important antipseudomonal drug, but also for Enterobacteriaceae we saw that the microbiological eradication rates for ceftolozane–tazobactam were comparable to meropenem. This is going to be very helpful that can use a drug that is a great antipseudomonal but not leave behind the other major threats.
Finally, when we analyzed the epidemiology of patients included in this study, who were from all over the world, we expected that Pseudomonas would be the most prevalent pathogen; however, we discovered that Klebsiella had a higher rate than Pseudomonas. This is the first time that we have seen in these global studies that Klebsiella is higher than Pseudomonas and perhaps that is a very slight shift in the epidemiology of pathogens in lung infections.
Could you outline some of the impacts these findings might have for patients and clinicians in the future?
Ignacio Martin-Loeches: To me the most important thing is that we are going to have an alternative to meropenem. Previously meropenem was our final and our only drug, now we might have an alternative. The vast majority of the antibiotics that we are using in clinical practice are very broad, including amoxicillin. In many cases we are also using piperacillin-tazobactam, especially when we don’t have ESBL. But now with the MERINO trial and other trials, we have seen that ESBL is becoming a major threat and piperacillin-tazobactam is probably not the right choice.
We were suspecting that in our study population ESBL-producing bacteria were in up to 30% of the patients – for these patients normally we’d have no other option but meropenem. But now ceftolozane–tazobactam presents an alternative, and the most interesting part of this study in my opinion is that it will no longer be just meropenem for everyone.
Thinking about the process of developing and evaluating new antibiotic agents – how important is clinical trial design?
Marin Kollef: The design of the trial is absolutely important because as we’ve seen in the past if the trial is not designed correctly sometimes a drug may be approved that subsequently will be found to have problems and cause some harm. This again is related to the dosing of the drug, having adequate numbers of patients and studying the types of patients that the drug will be used in. For example, if we only conducted the trial in non-ventilated patients and got the approval there, and then clinicians were using the drug in ventilated populations we might not really know how the drug will act in these populations, so I think it’s critical that the critical trial reflects the clinical use. In the past there have been times where that hasn’t happened.
Are there any other trials assessing this drug combination in other patient populations?
Marin Kollef: There have already been trials in urinary tract infection and complicated intrabdominal – for those indications ceftolozane–tazobactam has already been approved for the US and Europe. In these indications the dosing is only 1.5g every 8 hours and that is because antibiotics penetrate differently into the lung than they do in other tissues.
This is not a new drug, we’ve been using it for nearly 5 years in the US and off-label many of us have been using the drug at a 3g dose, but with this ASPECT-NP trial we now have data that can help justify the 3g dosing.
Could you give a broader perspective on new drugs and/or drug combinations for hospital-acquired pneumonia and ventilator-associated pneumonia?
Ignacio Martin-Loeches: We do have some new drugs; piperacillin-tazobactam, ceftazidime–avibactam and of course meropenem. We have these three drugs that at the moment that are going to make our life much easier because we are going to have a choice when we are prescribing to critically ill patients. But is this enough? The answer is probably not. We know that there is only a matter of time until the drugs become less effective and we will have to try and optimize them by ‘games’ such as prolonged infusions.
We don’t have enough compounds but I also think that we also need to keep a wise balance – we need to treat patients that are very sick but we must also try not to increase the antibiotic pressure because we know that antibiotics are precious and we will need this drug for someone else. This is something that I say to my registrars when I am practicing in my unit in Dublin. If you have a patient with a high temperature, you are going to use paracetamol, if you have a patient with high blood sugar, you are going to use insulin – this is fine because it will only impact that patient. But when a patient has an infection and is given an antibiotic you are not only treating that patient, you are treating the whole unit. That antibiotic is not going only to impact to that patient, it is going to change the ecology of your unit.
With ventilator-associated pneumonia, why is that an area of unmet need?
Marin Kollef: For both ventilator-associated pneumonia and ventilated hospital pneumonia it’s an unmet need because we generally see the most resistant organisms within that population when you look at the whole – it has to do with the fact that these are patients who are often in hospital for a while and have had a lot antibiotic therapy, so they’re more likely to have resistant organisms.
The other reason it’s important is that if you make a mistake treating these patients, they are not likely to be salvageable. Unfortunately, clinicians out there and hospitals sometimes try to get by with the least expensive way of administering the drug, in fact the most expensive drugs are drugs that cause problems. So, you really want to try and optimize the clinical outcomes and that was central in the ASPECT trial. Getting the dose right and having the right trial design were all incredibly important for this.
Finally, with growing resistance, where do you think the field will be in 5–10 years’ time?
Marin Kollef: I think there are a couple of areas. With growing antimicrobial resistance we still have the need for new drugs to come out, including non-traditional antibiotics. We’ve started to see monoclonal antibodies directed against bacteria and against some of their virulence factors and I think we’ll start to see other non-traditional methods coming out to enhance treatment for these organisms.
I also think that diagnostics are going to evolve – rapid diagnostics have really improved quite a bit in the last 5–10 years. The challenge is that they can be somewhat costly but there are newer technologies that are being developed and prices are dropping. With regards to genome sequencing, I think in the next 5–10 years our ability to stratify hosts and bugs will improve and using this we can really direct our treatment depending on the genomic results. This personalized medicine approach is a little way down the road, but I think that’s where we’re heading.
Ignacio Martin-Loeches: I think that in the next years we are going to come with more and better antibiotics, both broad- and narrow-spectrum.
I also think that the use of rapid diagnostics needs to come together with the new development of antibiotics. Rapid diagnostics is is an area that is really exploding and there is huge competition – this is good for us, the more competition the better because we are going to have an excellent care in our patients!
It is interesting to see the number of companies doing blood cultures, it is huge and I’m glad. However, I think that there are still not enough companies focused on respiratory samples. Pneumonia is one of the most frequent infections and it is the infection that worries us in critical care the most, so I would encourage the industry to put resources in respiratory sampling. Then diagnostics will be a fantastic way and to protect the right antibiotics for the right patient.
Do you have any other comments you’d like to add?
Ignacio Martin-Loeches: I think that the new launch of a new antibiotic is always a show for the companies, but at the same time as healthcare professionals we need to be less ashamed of cheering these successes because at the end of the day it is in our best interest and the patient’s best interest. I am sure that in the months following a launch we will have questions about who the right patient is, what the archetype of this patient is etc., but ultimately a new drug gives us new options.
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