You’re listening to ReachMD. This medical industry feature, titled “Evidence for a Potential Treatment Option for Adult Patients With HABP/VABP in the ICU,” is paid for and brought to you by Merck. This is not a certified continuing medical education program, and it’s intended for health care professionals in the United States, its territories, and Puerto Rico.
And now, here’s your host, Dr Charles Turck.
Welcome to ReachMD. I’m Dr Charles Turck, and joining me today to discuss the management of adult patients with hospital-acquired and ventilator-associated bacterial pneumonia is Dr Michael Niederman. Dr Niederman is a Pulmonary and Critical Care Medicine specialist working in New York City. Improving the management of patients with nosocomial pneumonia has been an important focus of his career for the last 30 years. During this time, he has authored numerous papers on this topic, participated as an investigator in several registration trials, and served on both US and European HABP/VABP guideline committees.
We’re delighted to have you with us, Dr Niederman. Welcome!
Thank you. I’m happy to be here.
Well, we’re certainly happy to have you. So to get us started, Dr Niederman, can you tell us about the different categories of nosocomial pneumonia?
I’d be happy to. Hospital-acquired bacterial pneumonia, or HABP, is pneumonia caused by bacteria not incubating at the time of admission and that occurs 48 hours or more after admission.1 A second category is ventilator-associated bacterial pneumonia, or VABP for short, which is pneumonia caused by bacteria that arises more than 48 hours after intubation.1 And a third category, which is really a subtype of HABP, is ventilated hospital-acquired bacterial pneumonia, or vHABP, which can occur in patients with HABP who clinically deteriorate, subsequently develop acute respiratory failure, and therefore require ventilation.1,2 Taken together, HABP and VABP are the most common hospital-acquired infections in the ICU in the United States.3
According to the findings from a recently published multicenter retrospective cohort study of more than 17,000 hospitalized adult patients with culture-positive HABP, VABP, or vHABP, there are important differences between patients who suffer from HABP, VABP, and vHABP.In this study, patients with vHABP had the highest risk of death. Additionally, patients with vHABP had the highest comorbidity burden, the highest prevalence of P aeruginosa infection, and the greatest use of vasopressors.4 Clearly, patients with vHABP tend to have poor outcomes. For these reasons, further studies are needed to improve both our understanding and management of these distinct conditions, particularly vHABP.
Thank you for that overview, Dr Niederman. Can you tell us what are the most common gram-negative bacterial pathogens found in patients in the ICU?
Sure. But first, I think it’s important to remind the audience that a variety of microorganisms can cause lower respiratory tract infections, including nosocomial pneumonia.5 Physicians like myself who routinely treat nosocomial pneumonia in the ICU tend to be most concerned about certain gram-negative bacteria. INFORM, which is the International Network For Optimal Resistance Monitoring, has provided important data on this topic. In 2018-2020, INFORM collected 4680 bacterial isolates from intensive care unit (ICU) patients and 16,263 isolates from non-ICU patients at 70 US medical centers.6 This study found that Pseudomonas aeruginosa (23.5 percent) was the most common gram-negative organism in ICU isolates, followed by Escherichia coli (18.8 percent) and Klebsiella pneumoniae (14.4 percent).6
And are there some particular challenges that are posed by critically ill patients with HABP, vHABP, or VABP?
Yes, many of these patients tend to be older, frail, and have multiple comorbidities that put them at increased risk for negative outcomes. Now, there is evidence that early appropriate antimicrobial therapy is critical to help improve clinical outcomes in these patients, as inappropriate initial antibiotic therapy has been associated with an increased risk of mortality.1,7,8 And as we think about these critically ill patients, we should also take into account the evidence that patients with vHABP may have a higher rate of 28-day mortality than those with HABP or VABP.9 So the timely administration of effective antimicrobial therapy for these critically ill patients is important. Prompt identification of the causative pathogen and its antimicrobial susceptibility can be challenging based on specimen collection method and how the lab is resourced. In fact, one recent study found the median testing turnaround times from respiratory specimen collection to identification and antimicrobial susceptibility testing were approximately 1.5 and 2.5 days, respectively.10 Pathogens were more likely to be recovered from mechanically ventilated patients and endotracheal aspirate specimens.10
Now with those challenges in mind, Dr Niederman, how can we improve our approach to the management of these serious infections?
Well, effective environmental and infection control measures coupled with antimicrobial stewardship and knowledge of the local ecology are key components of a strategy to help reduce the development of antimicrobial resistance.11,12 The use of antibiograms, including hospital-wide and ICU-specific antibiograms,13 as well as new technologies that enable more rapid detection of some implicated pathogens, can aid in therapy choices and reduce the amount of time before the patient receives appropriate antibiotic therapy.14
And when we consider antibiotic treatment of HABP, vHABP, and VABP, it’s critical to have antimicrobials that are active against the confirmed or suspected gram-negative pathogens.
Thanks for breaking that down for us, Dr Niederman. And for those just tuning in, you’re listening to ReachMD. I’m Dr Charles Turck, and today I’m speaking with Dr Michael Niederman about the management of adult patients with hospital-acquired and ventilator-associated bacterial pneumonia.
Now, this is a good time to discuss ZERBAXA, a combination of ceftolozane, which is a novel cephalosporin antibiotic, and a beta-lactamase inhibitor called tazobactam. But before we continue our discussion, let’s review the HABP/VABP indication for ZERBAXA (ceftolozane and tazobactam) injection for intravenous use.
ZERBAXA is indicated for the treatment of adult patients (18 years and older) with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
And now, let’s hear some Important Safety Information.
Patients with renal impairment: Dose adjustment is required for adult patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane/tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
So, Dr Niederman, with that important safety information in mind, let’s take a look at the clinical data on ZERBAXA. What can you tell us about the ASPECT-NP trial?
The ASPECT-NP trial was the registration trial supporting the approval of ceftolozane/tazobactam at 3 grams every 8 hours for the treatment of HABP and VABP.15 This was a multinational, noninferiority, double-blind study in which 726 adult patients hospitalized with vHABP or VABP were randomized 1:1 to receive either 3 grams of ceftolozane/tazobactam or 1 gram of meropenem. Each of these drugs was administered intravenously every 8 hours, over 1 hour infusion, for 8 to 14 days.15
The primary efficacy endpoint was 28-day all-cause mortality. This endpoint was assessed in the intent-to-treat, or ITT, population, which included all randomized patients.15
Now I do think it’s important to understand why ASPECT-NP is unique among HABP/VABP registration trials. First, all patients were intubated and mechanically ventilated at randomization,15 and nearly all patients—92 percent—were treated in the ICU. Additionally, 77 percent had been hospitalized for 5 days or longer, and nearly half—49 percent—were ventilated for 5 days or longer, 44 percent of patients were on vasopressors,15 and about one-third of the patients had an APACHE II score of 20 or higher, indicating a high severity of illness for many patients enrolled in this trial.
And with all that being said, can you share the key efficacy data from this trial?
Certainly. Ceftolozane/tazobactam achieved the primary endpoint of noninferiority to meropenem in day 28 all-cause mortality, which was 24 percent in the ceftolozane/tazobactam group versus 25.3 percent in the meropenem group. In the vHABP subgroup of patients, there was a favorable response for ceftolozane/tazobactam in day 28 all-cause mortality, which was found to be 24.2 percent compared with 37 percent in those treated with meropenem. In the VABP subgroup, day 28 all-cause mortality was 24 percent for ceftolozane/tazobactam versus 20.3 percent for meropenem.15
Thanks for reviewing that clinical data, Dr Niederman. Now let’s review additional Important Safety Information for ZERBAXA.
Clostridioides difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Adverse reactions in adult patients with HABP/VABP: The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%).
Now we’re almost out of time for today Dr Niederman, so before we close, how would you summarize the potential role of ZERBAXA in the management of appropriate adults with HABP or VABP?
There are clearly clinical scenarios where agents such as ceftolozane/tazobactam with activity against Pseudomonas aeruginosa can have an important role. Based on findings from ASPECT-NP, which as we noted earlier was unique among HABP/VABP registration trials in that 100 percent of patients were mechanically ventilated upon randomization, ceftolozane/tazobactam at 3 grams every 8 hours achieved the primary endpoint of noninferiority to meropenem in day 28 all-cause mortality.15 In the vHABP subgroup—which was a large, pre-defined subgroup—there was a favorable response for ceftolozane/tazobactam in all-cause mortality through day 28, which was 24.2 percent for ceftolozane/tazobactam compared to 37 percent for meropenem.15 In the VABP subgroup, day 28 all-cause mortality was 24 percent for ceftolozane/tazobactam versus 20.3 percent for meropenem.15These are important findings.3 So I would summarize by saying ceftolozane/tazobactam at 3 grams is an important option in our armamentarium and has a role in the treatment of appropriate adults with HABP, VABP, and vHABP.
Those are some great takeaways from our discussion. And I’d like to thank my guest, Dr Michael Niederman, for joining me to share key data on ZERBAXA. Dr Niederman, it was great speaking with you today.
Before administering ZERBAXA (ceftolozane and tazobactam), please read the Prescribing Information, which can be accessed on the site where you have listened to this podcast.
The list of references for the information discussed today are available in the transcript, which also can be accessed on that site. This program was brought to you by Merck. If you missed any part of this discussion, please visit ReachMD dot com slash industry feature. This is ReachMD. Be Part of the Knowledge.
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- Kalil AC, Metersky ML, Klompas M, et al. Clin Infect Dis. 2016;63(5):e61-111.
- FDA Guidance for Industry. Updated June 2020. Accessed October 5, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hospital-acquired-bacterial-pneumonia-and-ventilator-associated-bacterial-pneumonia-developing-drugs
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- Zilberberg MD, Nathanson BH, Puzniak, et al. Crit Care Med. 2022;50(3):460-468.
- Noviello S, Huang DB. Diagnostics (Basel). 2019;9(2):37. doi:10.3390/diagnostics9020037
- Sader HS, Mendes RE, Streit JM, et al. Diagn Microbiol Infect Dis.2022;102(1):115557. doi:10.1016/j.diagmicrobio.2021.115557
- Schreiber MP, Shorr AF. Expert Rev Anti Infect Ther. 2017;15(1):23-32.
- Tsalik EL, Li Y, Hudson LL, et al. Ann Am Thorac Soc. 2016;13(3):401-413.
- Talbot GH, Das A, Cush S, et al. J Infect Dis. 2019;219(10):1536-1544.
- MacVane SH, Oppermann N, Humphries RM. J Clin Microbiol. 2020;58(11):e01468-20.
- CDC. Antibiotic resistance threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. Accessed September 19, 2022.
- Maillard JY, Bloomfield SF, Courvalin P, et al. Am J Infect Control. 2020;48(9):1090-1099.
- Klinker KP, Hidayat LK, DeRyke CA, et al. Ther Adv Infect Dis. 2021;8:1-9. doi:10.1177/20499361211011373
- Vasala A, Hytönen VP, Laitinen OH. Front Cell Infect Microbiol. 2020;10:308. doi:10.3389/fcimb.2020.00308
- Kollef MH, Nováček M, Kivistik Ü, et al. Lancet Infect Dis. 2019;19(12):1299-1311.