You’re listening to ReachMD. This medical industry feature, titled “A Broad-Coverage Combination Antimicrobial for Treatment of Adult Patients With cUTI, cIAI, and HABP/VABP” is paid for and brought to you by Merck.1 This is not a certified continuing medical education program. This program is intended for health care professionals in the United States, its territories and Puerto Rico.
The list of references for the information discussed today are available in the transcript, which can be accessed on the site where you have listened to this podcast. Here’s your host, Dr Jennifer Caudle.
Welcome to ReachMD. I’m your host Dr Jennifer Caudle and joining me today to discuss the management of hospitalized adult patients with certain gram-negative infections is Dr Keith Kaye, an infectious disease specialist who has devoted much of his career to the prevention, diagnosis, and treatment of hospital-acquired infections.
Dr Kaye, welcome!
Thank you! I’m very happy to be here.
Well, we’re certainly happy to have you. So, to get us started, can you tell us about some of the risks posed by difficult-to-treat gram-negative pathogens for complicated urinary tract infections, or cUTIs, complicated intra-abdominal infections, or cIAIs, and hospital-acquired or ventilator-associated bacterial pneumonia, also known as HABP and VABP?
Certainly. Difficult-to-treat gram-negative pathogens, such as Pseudomonas aeruginosa strains that have certain resistance mechanisms as well as extended-spectrum β-lactamase (or ESBL)-producing Enterobacteriaceae, these have been associated with increased morbidity and mortality.2-5 And recently the CDC released an update on the threats posed by many of these pathogens in the US. This was released in November 2019.4 Unfortunately, hospital-acquired infections continue to be a significant cause of illness and death although, even despite advances in our understanding of the contributing factors of these diseases.6 And for this reason, additional and different treatment options are definitely needed.7
This is a good time to discuss RECARBRIO, a combination of imipenem, a penem antibacterial; cilastatin, a renal dehydropeptidase inhibitor; and relebactam, a novel beta-lactamase inhibitor. Relebactam helps restore the activity of imipenem.1 Now before we continue our discussion, let’s review the Indications for RECARBRIO.
RECARBRIO (imipenem, cilastatin, and relebactam) for injection1 is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP and VABP), caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.
RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis, and Pseudomonas aeruginosa.
Approval of the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO 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 discuss some Selected Safety Information for RECARBRIO, which you’ll hear more of throughout this podcast.
Hypersensitivity Reactions: RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately.
Coming back to you, Dr Kaye, in what ways can we improve our approach to the diagnosis and treatment of serious hospital-acquired infections?
Well, first, I would like to remind listeners that antimicrobial stewardship paired with knowledge of your local ecology, as well as infection control and environmental hygiene are always going to be key pillars of a strategy used to help reduce the development of antimicrobial resistance.4,8
Now from a management perspective, development of antimicrobials is critical.4 For example, RECARBRIO, which is an antimicrobial that combines a novel BLI, relebactam, with imipenem, a broad- coverage carbapenem, exhibits in vitro activity against certain gram-negative pathogens, including some Enterobacteriaceae that produce ESBLs and KPCs.1 It’s also shown activity against P. aeruginosa isolates with the most prevalent mechanisms of resistance, including upregulation of AmpC and PDC; PDC is a class C beta-lactamase, which is Pseudomonas-derived cephalosporinase. In addition, it often shows activity against isolates with resistance due to loss of outer membrane porin and upregulation of efflux pumps.1 RECARBRIO is not active against isolates containing certain types of beta-lactamases, including metallo-beta-lactamases, oxacillinases with carbapenemase activity, and certain alleles of Guiana extended-spectrum beta-lactamase, also known as GES.1 Importantly, the clinical significance of in vitro data is unknown.1
And with that background in mind, let’s dive into some of the clinical data. Now what can you tell us about the registration trial supporting the approval of RECARBRIO for the treatment of HABP/VABP?
Well, let me start by providing a brief overview of this clinical study, which is known as RESTORE-IMI-2. This was a multinational, noninferiority, double-blind study in which 535 hospitalized adults with HABP/VABP were randomized 1:1 to receive either RECARBRIO 1.25 grams or piperacillin/tazobactam 4.5 grams. Each of these drugs was administered intravenously every 6 hours for 7 to 14 days.1,5
Now the primary efficacy endpoint was 28-day all-cause mortality.5 Importantly, this endpoint was assessed in the modified intent-to-treat, or MITT, population, which included all randomized patients who received at least 1 dose of the trial therapy and in whom gram-positive cocci were not the only bacteria shown on Gram stain of their baseline lower respiratory tract specimen.1
Patients were stratified according to whether they had nonventilated HABP or ventilated HABP/VABP.5 For those who may not be familiar with the term, ventilated HABP refers to a type of bacterial pneumonia in which a patient with HABP declines to the point where mechanical ventilation becomes required. 9,10 The patients were also stratified by severity of illness and the risk of mortality using the APACHE II score.5,11
The study population consisted of patients at increased risk of mortality.5 For example, at randomization, 66 percent were in the ICU, almost 50 percent were ventilated, and 77 percent were in the hospital for 5 days or longer.1,5
Thank you for that overview, Dr Kaye. Can you share the key efficacy data from this clinical study?
Absolutely. RECARBRIO was noninferior to piperacillin/tazobactam for the 28-day all-cause mortality, which was the primary endpoint of the study.5
Now let’s review additional selected safety information for RECARBRIO.
Seizures and Other Central Nervous System (CNS) Adverse Reactions: CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (eg, brain lesions or history of seizures) and/or compromised renal function. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued.
Increased Seizure Potential Due to Interaction with Valproic Acid: Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems.
Clostridioides difficile–Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued.
You’re listening to ReachMD. I’m your host Dr Jennifer Caudle, and here with me today is Dr Keith Kaye to talk about RECARBRIO, a potential treatment option for adults with cUTI, cIAI, or HABP/VABP due to the indicated pathogens.
Now Dr Kaye, I believe RECARBRIO has also been evaluated in another trial known as RESTORE- IMI-1. Can you tell us a little more about that trial?
Of course. This study by Motsch and colleagues was published in Clinical Infectious Diseases in 2020. RESTORE-IMI-1 was a noninferential, prospective, double-blind trial that compared imipenem/cilastatin/relebactam as monotherapy to dose-optimized colistin plus imipenem in 47 hospitalized adult patients. The patients had bacterial infections that were imipenem- nonsusceptible, but were susceptible to imipenem plus relebactam as well as to colistin.12
This clinical study had several limitations, including its small sample size, which was based on logistical feasibility as opposed to statistical considerations. Thus, it was a noninferential, descriptive, estimation trial, and formal statistical testing for efficacy endpoints was not performed. RESTORE-IMI-1 was intended to generate limited clinical data in the target population as part of a streamlined drug development program.12
That’s great, and thank you for sharing that information, Dr Kaye. And now let’s review more Selected Safety Information for RECARBRIO.
Development of Drug-Resistant Bacteria: Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Adverse Reactions: The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI patients treated with RECARBRIO were diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), phlebitis/infusion site reactions (2%), pyrexia (2%), and hypertension (2%). The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%).
So now that we’ve reviewed the Indications and Selected Safety information along with clinical data, Dr Kaye, how would you sum up the potential role of imipenem/cilastatin/relebactam in the management of adults with HABP/VABP, cUTI, and cIAI?
So first, I would say that because hospital-acquired infections are often caused by difficult-to- treat gram-negative pathogens, we are always in need of additional therapeutic options such as imipenem/cilastatin/relebactam.6,7 I’ve given a profile of this drug. I consider imipenem/cilastatin/relebactam a potential treatment option for certain adult patients with either HABP/VABP, cUTI, or cIAI.1 Of note, IDSA recent guidance included imipenem/cilastatin/relebactam as a treatment option for adults with certain difficult-to-treat gram-negative bacterial pathogens.13
Those are all great takeaways from our discussion, Dr Kaye. I’d like to thank you for joining me to share key data on this therapy. Thank you so much.
Before administering RECARBRIO (imipenem, cilastatin, and relebactam) 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.
The preceding program was brought to you by Merck.
And if you missed any part of this discussion, please visit reachmd.com. This is ReachMD. Be Part of the Knowledge.
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All rights reserved. US-TIX-00341 07/21
- RECARBRIO® (imipenem, cilastatin, and relebactam). Prescribing Information. 2020. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
- https://www.cdc.gov/hai/organisms/pseudomonas.html Accessed April 20, 2021.
- https://www.cdc.gov/hai/organisms/ESBL.html#:~:text=In%202017%2C%20there%20were%20an,%3A%2 02019%20AR%20Threats%20Report%5D Accessed April 20, 2021.
- https://www.cdc.gov/DrugResistance/Biggest-Threats.html Accessed April 11, 2021.
- Titov I, Wunderink RG, Roquilly A, et al. Clin Infect Dis. 2020. doi:10.1093/cid/ciaa803
- Sydnor ER, Perl TM. Clin Microbiol Rev. 2011;24(1):141-173.
- Meletis G. Ther Adv Infect Dis. 2016;3(1):15-21.
- Maillard J, Bloomfield SF, Courvalin P, et al. Am J Infect Control. 2020;48(9):1090-1099.
- Kalil AC, Metersky ML, Klompas M, et al. Clin Infect Dis. 2016;63(5):e61-111.
- https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hospital-acquired- bacterial-pneumonia-and-ventilator-associated-bacterial-pneumonia-developing-drugs Accessed April 20, 2021.
- Parajuli BD, Shrestha GS, Pradhan B, et al. Indian J Crit Care Med. 2015;19(2):87-91.
- Motsch J, De Oliveira CM, Stus V, et al. Clin Infect Dis. 2020;70(9):1799-1808.
- Tamma PD, Aitken SL, Bonomo RA, et al. Clin Infect Dis. 2021;72(7):e169-e183.