A Broad-Coverage Antibiotic Combination for Adult Patients With cUTI, cIAI, or HABP/VABP

Transcript

ReachMD Announcer:
Welcome to ReachMD. This medical industry feature titled, “A Broad-Coverage Antibiotic Combination for Adult Patients With cUTI, cIAI, or HABP/VABP” is paid for and brought to you by Merck Sharp & Dohme LLC. This program is intended for health care professionals in the United States, its territories, and Puerto Rico. Here’s your host, Dr. Teena Chopra.

Chapter 1
Dr. Chopra:
Welcome. I’m Dr. Teena Chopra, and I’ll be your host for the program today.

During this presentation, I’ll discuss the case of a critically ill patient who had a type of bacterial nosocomial pneumonia known as ventilated hospital-acquired bacterial pneumonia, or vHABP. In addition, I’ll cover some of the key factors we consider when choosing appropriate therapy in such cases.

Before I get into the specific details of this case, I’ll briefly touch on some of the key challenges posed by difficult-to-treat gram-negative pathogens. It’s also important to mention that good antimicrobial stewardship practices and proper infection control measures are needed to help reduce the development and proliferation of these difficult-to-treat gram-negative organisms.¹

Well, let me start by noting that despite advances in our understanding, hospital-acquired infections, especially those caused by difficult-to-treat gram-negative pathogens, continue to be a significant cause of illness and death in hospitalized patients.²

In vitro data gathered by the Study for Monitoring Antimicrobial Resistance Trends, or SMART, surveillance program show that Pseudomonas aeruginosa was the most prevalent gram-negative pathogen in respiratory tract infections, while E. coli and Klebsiella pneumoniae were the most prevalent gram-negative pathogens in urinary tract and intra-abdominal infections in the US.^3,4

One factor that has complicated the treatment of severe gram-negative infections is the evolving susceptibilities of Pseudomonas aeruginosa and Klebsiella pneumoniae.^5,6

For this reason, additional treatment options are needed, and the development of novel antimicrobials to address many of these infections caused by difficult-to-treat gram-negative pathogens is critical.⁷

Now, hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common nosocomial infections associated with high mortality rates.⁸ We know that patients with ventilated HABP can have an even higher rate of mortality (up to 39%) than either VABP patients (up to 27%) or HABP patients (up to 22%).⁹

Ventilated HABP refers to a case in which a patient with HABP who is not initially ventilated, and is not responding to treatment, subsequently declines to the point where mechanical ventilation is required.^8,10

When we consider the organisms frequently associated with nosocomial pneumonia, we find that Pseudomonas aeruginosa is one of the most common gram-negative pathogens found in cases of HABP/VABP, and it can be particularly challenging to treat in a critically ill patient.^11,12

At this point, I’ll take a moment to provide some background details about our patient case. Clayton is a hypothetical patient similar to many patients treated in our intensive care unit and other ICUs across the country.

Clayton is a 70-year-old male with type 2 diabetes and hypertension who recently underwent coronary bypass surgery for coronary artery disease.

After discharge from the hospital, Clayton was admitted to a long-term acute care hospital, or LTACH, since he required intensive care while recovering from bypass surgery. While in the LTACH, he was treated for a urinary tract infection with a course of oral antibiotics.

After 2 weeks in the LTACH, Clayton developed respiratory symptoms—cough with green purulent sputum, fever and chills, and shortness of breath. A chest X-ray showed a right lower lobe infiltrate, so Clayton was readmitted to the hospital where he was diagnosed with HABP. 

So now I think would be a good point for us to hear about this case from the patient’s perspective.

References:
1. https://www.cdc.gov/DrugResistance/Biggest-Threats.html. Accessed March 2, 2023.
2. Sydnor ER, Perl TM. Clin Microbiol Rev. 2011;24(1):141-173.
3. Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. US-TIX-00567.
4.Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004.US-ZER-01600.
5. Kaye KS, et al. Pharmacotherapy. 2015;35(10):949-962.
6. Villegas MV, et al. Future Sci. OA. 2018;4(9):FSO339.
7. Doi Y. Clin Infect Dis. 2019;69(suppl 7):S565-S575.
8. Kalil AC, et al. Clin Infect Dis. 2016;63:e61-e111.
9. Talbot GH, et al. J Infect Dis. 2019;219(10):1536-1544.
10. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hospital-acquired-bacterial-pneumonia-and- ventilator-associated-bacterial-pneumonia-developing-drugs. Accessed March 2, 2023.
11. Schreiber MP, Shorr AF. Expert Rev Anti Infect Ther. 2017;15(1):23-32.
12. Cilloniz C, et al. Int J Mol Sci. 2016;17(12):2120. doi:10.3390/ijms17122120

Chapter 2
Clayton (the hypothetical patient):
Hello, my name is Clayton. I was born in South Carolina and moved north after graduating from college. I worked for many years in New York as an accountant before retiring about 10 years ago. 

All my children are grown and married now, so it’s just my wife and myself at home. I’ve had diabetes and high blood pressure for some time. I didn’t have any other major health problems until the last year or so when I started to have episodes of angina. I was diagnosed with coronary heart disease, which led to bypass surgery.

After the surgery I had some complications and spent 5 days in the ICU, and I was then moved to the long-term acute care hospital, or LTACH, to continue my recovery, which was expected to take several additional weeks. 

While in the LTACH, I was treated for a urinary tract infection. Toward the end of my second week, I started coughing, I had fever and difficulty breathing.

At that point, I was transferred back to the hospital, and over the next day the coughing got worse. I was worried, and I didn’t know how things would turn out.

Chapter 3
Dr. Chopra:
Once back in the hospital, the patient was treated with IV antibiotics for suspected HABP. His oxygen demands increased, and he was started on high-flow nasal cannula. Sputum was sent for Gram stain and culture. 

When the Gram stain results came back, they showed abundant gram-negative rods. After 24 hours, the patient showed evidence of worsening hypoxia, hypotension, and respiratory distress.

Blood pressure had dropped to 90/60, heart rate had increased to 140 beats per minute, and the respiratory rate was 37 breaths per minute. Oxygen saturation, or SpO₂, was 84% despite supplemental oxygen. 

The patient’s condition was clearly declining, so at this point he was moved to the ICU, where he was intubated, administered fluids, and started on vasopressor therapy.

At the time of intubation, a deep tracheal aspirate was taken and sent for culture. 

The patient’s deteriorating condition suggested that the infection was not responding to the initial IV antibiotics, so we needed to modify this patient’s antibiotic therapy.

It is extremely important to choose timely, appropriate antibiotic therapy in cases of bacterial nosocomial pneumonia because a delay in effective therapy has been associated with increased mortality.^1,2

As discussed earlier, ventilated HABP patients such as this patient have mortality rates that are higher than those of patients with HABP.³ So the timely choice of an appropriate antibiotic is especially important.

There are several considerations that we took into account when modifying antimicrobial therapy for this patient. 

Pseudomonas aeruginosa is one of the most prevalent gram-negative pathogens in HABP/VABP.^4,5 So when choosing the next antibiotic, we should consider the possibility that Pseudomonas aeruginosa might be the causative pathogen.

Also when selecting antibiotic therapy, we consult our hospital antibiogram, which provides valuable data on the susceptibility of various pathogens, including Pseudomonas, to commonly prescribed antibiotics.

An additional consideration in this case was a report from the patient’s LTACH that several recent infections in that facility were caused by Pseudomonas aeruginosa that was nonsusceptible to carbapenems.

In choosing the next antibiotic to administer to this critically ill patient, there are various factors I took into account, such as his underlying comorbidities, recent history of antibiotic use, hospitalization for major surgery, and recent stay in an LTACH. 

I also considered the most likely causative pathogens, such as Pseudomonas aeruginosa, as well as the possibility of Pseudomonas aeruginosa expressing certain resistance mechanisms might be implicated.

So, taking all these factors into account, I decided to initiate treatment with RECARBRIO™, which is imipenem, cilastatin, and relebactam, at a dose of 1.25 grams IV every 6 hours, which is the FDA-approved dose for treatment of adult patients with normal renal function with HABP/VABP.⁶

The culture and sensitivity results later confirmed that RECARBRIO was an appropriate option in this case.

Now, I would like to share with you the Indications and some Selected Safety Information for RECARBRIO which is imipenem, cilastatin, and relebactam. 

[Voiceover]
Indications and Usage
RECARBRIO™ is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/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.

Selected Safety Information
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.

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 (for example, 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.

Additional Selected Safety Information for RECARBRIO will continue later in this video.

Dr. Chopra:
At this point, I’d like to provide a brief overview of RECARBRIO, which is a combination of imipenem, a penem antibacterial; cilastatin, a renal dehydropeptidase inhibitor; and relebactam, a novel beta-lactamase inhibitor, or BLI.⁶

The bactericidal activity of imipenem results from binding to penicillin-binding protein (PBP) 2 and PBP 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of PBPs, which leads to the disruption of bacterial cell wall synthesis.⁶

Relebactam protects imipenem from degradation by certain serine beta-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs), and Pseudomonas-derived cephalosporinase (PDC, AmpC-type).⁵ Imipenem/relebactam has demonstrated in vitro activity against some Enterobacteriaceae isolates genotypically characterized for some beta-lactamases and certain extended-spectrum beta-lactamases, or ESBLs.⁶

Imipenem/relebactam is not active against most isolates containing metallo-beta-lactamases (MBLs), some oxacillinases with carbapenemase activity, as well as certain alleles of GES.⁶

Relebactam was shown to help restore the in vitro activity of imipenem in isolates collected from intra-abdominal and urinary tract infections in the United States from 2015 to 2017 for the SMART surveillance program.^1,7

Among 193 Pseudomonas aeruginosa isolates that were nonsusceptible to imipenem, 85% were found to be susceptible to imipenem plus relebactam. In addition, among 54 Enterobacteriaceae isolates positive for KPC, 96.3% were found to be susceptible to imipenem/relebactam, while only 3.7% were susceptible to imipenem.⁷ The clinical significance of in vitro data is unknown.⁶

Now let’s take a look at the clinical data. The efficacy of imipenem/cilastatin/relebactam in the treatment of HABP/VABP was assessed in a phase 3 noninferiority clinical trial known as RESTORE-IMI-2. In this trial, 535 hospitalized adults with HABP/VABP were randomized 1:1 to receive either imipenem/cilastatin/relebactam 1.25 grams or piperacillin/tazobactam 4.5 grams. Each drug was administered intravenously every 6 hours over a 30-minute infusion period for 7 to 14 days.^6,8 At the outset of the trial, patients were stratified according to whether they had nonventilated HABP or ventilated HABP/VABP and by an APACHE II score <15 or ≥15.⁸

The primary efficacy endpoint was 28-day all-cause mortality in the modified intent-to-treat, or MITT, population.⁸

At randomization, 66% of patients were admitted to the ICU, and almost half of the patients had ventilated HABP/VABP.⁸

The study population consisted largely of patients at increased risk of adverse treatment outcomes and death, which was reflected in the high proportion of elderly patients, those enrolled in the ICU, and patients who had APACHE II scores greater than or equal to 15.^1,8

In this trial, imipenem/cilastatin/relebactam achieved the primary endpoint of noninferiority vs piperacillin/tazobactam in day 28 all-cause mortality in the MITT population. Day 28 all-cause mortality was 15.9% with RECARBRIO and 21.3% with piperacillin/tazobactam.⁶

Imipenem/cilastatin/relebactam also demonstrated a favorable response vs piperacillin/tazobactam in certain high-risk subgroups.

In patients with ventilated pneumonia, either VABP or vHABP, the day 28 mortality was 19.7% in patients treated with imipenem/cilastatin/ relebactam compared with 30.9% in those treated with piperacillin/tazobactam.⁶ In patients with HABP, the day 28 mortality was 12.7% in those treated with imipenem/cilastatin/relebactam compared with 11.5% in those treated with piperacillin/tazobactam.⁶

For patients with APACHE II scores ≥15, day 28 all-cause mortality was 20% in patients treated with imipenem/cilastatin/relebactam, compared with 35.4% in the piperacillin/tazobactam group.⁶ In patients with APACHE II scores <15, day 28 all-cause mortality rates were 12.2% for those treated with imipenem/cilastatin/relebactam, compared with 8.6% for those in the piperacillin/tazobactam group.⁶

Let’s take a moment now to consider some additional selected safety information for RECARBRIO. 

[Voiceover]
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.

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%).

Dr. Chopra:
Before we close this presentation, I would like to emphasize the importance of the local microbiology lab, since susceptibilities can vary from hospital to hospital. Additionally, susceptibility testing of all antibiotics should be considered, as these results can be used to help inform and guide treatment decisions.^9,10

Finally, I consider RECARBRIO a welcome addition to our antibiotic armamentarium. RECARBRIO may be an appropriate option for adult patients with HABP/VABP, and for adult patients with cUTI and cIAI where treatment options are limited. 

I thank you for taking the time to view this presentation and hope that you found the content informative.

[Voiceover]
Before prescribing RECARBRIO™ (imipenem, cilastatin, and relebactam) for injection, please read the accompanying Prescribing Information at merck.com: https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf

ReachMD Announcer:
This program was sponsored by Merck. If you missed any part of this discussion, visit ReachMD.com/IndustryFeature. This is ReachMD. Be Part of the Knowledge.

References:
1. Data on file. Overview of SMART Surveillance. Merck and Co., Inc. 
2. Tsalik EL, et al. Ann Am Thorac Soc. 2016;13(3):401-413.
3. Talbot GH, et al. J Infect Dis. 2019;219(10):1536-1544.
4. Schreiber MP, Shorr AF. Expert Rev Anti Infect Ther. 2017;15(1):23-32.
5. Cilloniz C, et al. Int J Mol Sci. 2016;17(12):2120. doi:10.3390/ijms17122120
6. RECARBRIO^® (imipenem, cilastatin/relebactam). Prescribing Information. 2019-2022. Merck & Co., Inc., Rahway, NJ, USA.
7. Karlowsky JA, et al. J Glob Antimicrob Resist. 2020;21:223-228.
8. Titov I, et al. Clin Infect Dis. 2020. doi:10.1093/cid/ciaa803
9. https://www.cdc.gov/DrugResistance/Biggest-Threats.html. Accessed March 2, 2023.
10. Kirby JE, et al. J Clin Microbiol. 2019;57(12):e01270-19.

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