Activity Transcript

Matteo Bassetti, MD, PhD: Hello, I am Matteo Bassetti. I am Professor of Infectious Diseases at the University of Genoa, and head of the Infectious Diseases Clinic at the Ospedale Policlinico San Martino in Genoa, Italy. Welcome to this program titled, Expert-to-Expert Updates on New and Emerging Treatments for Nosocomial Pneumonia. I am very pleased to be joined today by Keith Kaye, Professor of Medicine and Director of Research in the Division of Infectious Diseases at the University of Michigan in Ann Arbor. Welcome, Keith.

Keith Kaye, MD, MPH: Thank you.

Dr Bassetti: This is a Medscape Quickfire program. That means that we will have just 90 seconds to answer each other's questions. Let's get started. Keith, the first question to you is regarding the definition of nosocomial pneumonia.

Dr Kaye: When we talk about nosocomial pneumonia, there definitely are different flavors and different categories of this type of pneumonia. The most common one we think of is hospital-acquired pneumonia, which is simply a pneumonia that occurs 48 hours or greater after hospital admission and the symptoms of pneumonia are not present at the time of admission or within those first 48 hours of hospital admission.

The next most common category that we think of is ventilator-associated pneumonia or VAP. This is a pneumonia that arises 48 hours after implementation of mechanical ventilation. There's also a category of ventilated hospital-acquired pneumonia or VHAP, which is a pneumonia that occurs 48 hours after admission. Again, the patient does not have symptoms of pneumonia within those first 48 hours and is not associated with mechanical ventilation. However, this type of pneumonia is often fulminant and after patients develop symptoms, they often require emergent intubation and mechanical ventilation.

Finally, there is non-ventilated ICU-acquired pneumonia or NV-ICUAP. And this is a pneumonia that occurs 48 hours or greater after hospital admission and is managed in the ICU, but the patient typically does not require mechanical ventilation.

Dr Bassetti: Keith, how big is the problem of nosocomial pneumonia in the United States?

Dr Kaye: Well Dr Bassetti, it actually is a very big problem. In fact, HABP or hospital-acquired bacterial pneumonia, is one of the most common nosocomial infections in critically-ill patients and is a major cause of mortality. Up to about 25% of all ICU infections, and more than half of antibiotics prescribed in critical care units, are associated with pneumonia. Mortality rates are actually quite high as well, ranging from about 20% to 50%. As I mentioned before, often the most fulminant serious type of pneumonia in the ICU is this ventilated HABP, followed by ventilator-associated bacterial pneumonia, and finally our lowest mortality rates in non-ventilated hospital-acquired bacterial pneumonia.

A major risk factor for pneumonia in the ICU is mechanical ventilation; about 10% in patients who are intubated we see ventilator-associated bacterial pneumonia. Ventilator-associated bacterial pneumonia is associated with significant bad outcomes in not only increased mortality, as we discussed, but also increased duration of ICU stay and overall hospital stay. These infections are quite costly, at an estimated $40,000 per infection. Late onset pneumonia, particularly in the ICU, is associated with an increased risk for multidrug-resistant organisms.

And now actually Dr Bassetti, I have a question for you. Why are these multidrug-resistant organisms such a major problem and a major focus in hospital-acquired pneumonia and ventilator-associated pneumonia? And what organisms are you most concerned about, or do we most often see? You have 90 seconds to answer.

Dr Bassetti: Thank you, Keith. I think you know the top pathogens implicated in hospital acquired pneumonia are represented generally by Staphylococcus aureus, especially MRSA, but also by Gram-negatives: Pseudomonas, Acinetobacter, Escherichia coli, and Klebsiella, particularly ESBL-producing and extensively drug-resistant Enterobacteriaceae. The incidence of hospital-acquired pneumonia caused by multidrug-resistant organisms is increasing worldwide. So, we have ESBL Enterobacterales and a very important problem sustained by carbapenem-resistant Pseudomonas, Acinetobacter, Enterobacterales.

When you look at the WHO list, carbapenem-resistant strains of Acinetobacter, Pseudomonas, E coli and Klebsiella, they represent the highest priority for new antibiotic development. So, it's very important also to look at the variability in terms of microbiology, because microbiology varies by country, hospital, patient population, but also relates to risk factors like for instance prior antibiotic exposure and by type of ICU patients.

In a recent trial conducted in the United States in the ICU between 2015 to 2017, in which they isolated several different pathogens, Staphylococcus aureus represents the major pathogen, followed by Pseudomonas and then by Klebsiella and Enterobacter, E coli, and other pathogens.

Obviously, this is a picture of the United States, but maybe it's important also to look at the other studies because the epidemiology range and change according to the different countries.

But now, Keith, I have a very interesting question to you because cefiderocol was recently approved by the FDA earlier this year, and my question is what were the key findings from the pivotal phase 3 trial regarding cefiderocol? Please give.

Dr Kaye: Cefiderocol is a novel siderophore cephalosporin, which means that it crosses the bacterial membrane using active ion transport channels, almost like a Trojan horse. It is very stable against all Ambler classes of beta-lactamases, including metallo-beta-lactamases. And most importantly, it has very broad Gram-negative activity to Acinetobacter, Pseudomonas, CRE, even to Stenotrophomonas.

The pivotal phase 3 trial that Dr Bassetti was talking about was the APEKS-NP trial, which was a nosocomial pneumonia trial, where cefiderocol was compared with meropenem. Meropenem was dosed at 2 grams intravenously every 8 hours. Primary outcome was 14-day all-cause mortality. Non-inferiority endpoints were reached for cefiderocol, with mortality rates of about 12%. Secondary outcomes of clinical and microbiological eradication were also similar. Cefiderocol was safe, with really similar safety outcomes compared with meropenem.

Dr Bassetti: So, Keith, is there any difference in terms of clinical cure rates by pathogens in the same study?

Dr Kaye: Well, to answer that briefly, there were no statistically significant differences, although numerically cefiderocol did have lower clinical cure rates for Pseudomonas and Acinetobacter. But again, these were statistically not significant.

Matteo, you are the lead author on another cefiderocol randomized controlled trial, the CREDIBLE-CR study. Can you please summarize the efficacy and safety results? And also, can you please note any pathogen-specific differences in outcomes?

Dr Bassetti: Thank you very much, Keith, for your question because I think this is a really interesting study. It was a randomized, open-label phase 3 trial of cefiderocol for serious Gram-negative infections, in which they were randomized, and then 52 patients with serious Gram-negative infections, including 45% with nosocomial pneumonia. The most common pathogens were carbapenem-resistant organisms -- Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa.

The randomization was 2:1 to intravenous (IV) cefiderocol, 2 grams every 8 hours, or best available therapy for a range period of time between 7 and 14 days. For nosocomial pneumonia pathogens, clinical cure at the test of cure achieved in 50% of the cefiderocol group, and in 53% of the best available therapy without any differences. All-cause mortality at the end of this study among nosocomial pneumonia patients was 42% for cefiderocol group and 18 for best available therapy. There was a higher mortality, with cefiderocol primarily found in a subset of patients infected by Acinetobacter species, particularly during the early and late period of study.

Keith, we have another new antibiotic that is represented by imipenem-relebactam. That has a study published earlier this year from the phase III study in hospital-acquired pneumonia and ventilator-associated pneumonia. What are the key findings for this trial? Is there anything new, anything interesting in this trial?

Dr Kaye: Yeah. And just to remind our listeners that the novel thing about imipenem-relebactam is the relebactam, which is a novel beta-lactamase inhibitor. Again, it inhibits KPC for example, and it's combined with our old friend, our old carbapenem friend, imipenem-cilastatin. This was a nosocomial pneumonia study that involved over 500 patients from 27 countries. About half of the enrolled patients had ventilated HABP or VABP, and of that, greater than 40% were 65 years of age or older, and about two-thirds of subjects were managed in the ICU.

Patients were randomized to either the imipenem-relebactam or piperacillin-tazobactam, again for treatment of 7 to 14 days. Imipenem-relebactam was non-inferior to piperacillin-tazobactam for 28-day all-cause mortality, and key secondary end points also were favorable.

Early clinical response was similar in the 2 arms. This was important also, that there were some differences in types of infection and by pathogen. In ventilated HABP, the sort of emergent serious pneumonia that we often see in these studies, imipenem-relebactam was not statistically significantly associated with better outcomes or lower mortality. However, when you look by pathogen, imipenem-relebactam did not perform as well as piperacillin-tazobactam against Pseudomonas aeruginosa, but this difference did not reach statistical significance. Imipenem-relebactam and piperacillin-tazobactam had similar safety profiles as well.

Dr Kaye: But I want to ask you a question now. The cephalosporin/beta-lactamase inhibitor combinations ceftazidime-avibactam and ceftolozane-tazobactam were approved to treat nosocomial pneumonia within the past couple of years, but I think a lot of clinicians have become more familiar with them more recently. Can you give us a 90-second rundown on these agents, and what clinicians really need to know?

Dr Bassetti: Thank you Keith. If I will try to do this, it's not easy in 90 seconds, but we have newer cephalosporin/beta-lactamase inhibitor combinations for nosocomial pneumonia. We know that we have ceftazidime-avibactam. That is an old cephalosporin plus a novel beta-lactamase inhibitor. It was approved by the FDA for nosocomial pneumonia at a dose of 2.5 grams every 8 hours. And then we have ceftolozane. That is a novel cephalosporin class and established beta-lactamase inhibitor, FDA-approved for nosocomial pneumonia with a dose of 3 grams every 8 hours.

So, the 2 studies, the first was called REPROVE, and the study was the one in which ceftazidime-avibactam has been compared with meropenem. And in the overall population, there was no difference in the primary end point, and even in a subpopulation of ventilate, and the ceftazidime at the end was non-inferior to meropenem across all the endpoints. For this reason, the drug has been approved in this indication.

The second trial is the ASPECT nosocomial one, nosocomial pneumonia, in which ceftolozane-tazobactam has been compared with meropenem. And you can see very well that the overall all-cause mortality at day 28 was not, there were no differences between ceftolozane-tazobactam and meropenem but there was an important difference in 2 subsets of patients -- in patients with ventilated HAP that you very well described in the definition, and then in the patient that presented with prior treatment failure; in these 2 populations, there was an advantage in using ceftolozane-tazobactam.

Dr Bassetti: I think that is the last question to you that is regarding antibiotic resistance. That is a so important problem. The question is how can critical care specialists better work with ID specialists and their antibiotic stewardship team to optimize the management of hospital-acquired pneumonia while at the same time limiting the collateral damage of antibiotic therapy?

Dr Kaye: Well, that's an excellent question Matteo, and I'm going to try to keep my answer brief, because I want to hear your thoughts on this as well. First of all, I think hospital medicine, particularly in the ICU with complex patients with serious infections, care is really a team sport. It's not just about one star taking on the world. And I think here on a team approach, that the ID physician and antimicrobial stewardship pharmacists can help out with treatment algorithms, particularly around duration of therapy and de-escalation.

There's literature out there about biomarkers and clinical scores to help guide therapy or stop antibiotics early when they're no longer indicated. We talked about rapid diagnostic testing as well. I particularly think that many of the new antibiotics that we talked about today, there need to be important understanding of where these best fit for treatment in the ICU. Matteo, how about your thoughts about the role of the ID physician and stewardship team in the ICU?

Dr Bassetti: Keith, I agree with you. I think the most important point in antimicrobial stewardship, particularly in the ICU, is the multi-disciplinary approach. I think having rounds together, discussing the patient, having at the same time also the report of the PK/PD specialists, I mean the pharmacologists, would be really great. I think this is the only way we have to develop an adequate algorithm in which we have guidelines, in which we have the clinical score, the biomarkers. And then I think we have 2 very important points to be focused. The first one is de-escalation. So, I agree we have to agree also to start with the combination therapy, maybe with more than 2 antibiotics, but then we have to deescalate when we have the culture available, even the rapid tests, if available.

Then the duration of the therapy, I think we have to use the biomarkers in order to decrease the duration of the treatment, because for the majority of the infections and particularly for pneumonia, 8, maximum 10 days is probably enough for managing these difficult-to-treat infections.

Then I think it's also important in my opinion to use the new antibiotics, because sometimes the antimicrobial stewardship programs are developed more to control the cost, but then I think it's important not only to control the cost, but even to give to our patient the best antibiotic treatment if they need it.

So, thank you, Keith, because I think you did a great job. We are officially out of time, and this has been a lot of fun and great discussion. And thank you for joining me today for this interesting talk. And thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation for credit. Thank you again.

This transcript has been edited for style and clarity.