Targeted Antibiotic Therapy for Pneumonia

Recruiting at 11 trial locations

Overseen By Michael Rothberg, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Disqualifiers: ICU admission, Comfort care, Cystic fibrosis, Recent discharge, Known pathogen, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days

12500 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to reduce the exposure of broad-spectrum antimicrobials by optimizing the rapid detection of CAP pathogens and improving rates of de-escalation following negative cultures. To accomplish this, we will perform a 3-year, pragmatic, multicenter 2 X 2 factorial cluster randomized controlled trial with four arms: a) rapid diagnostic testing b) pharmacist-led de-escalation c) rapid diagnostic testing + pharmacist-led de-escalation and d) usual care

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Meropenem-Vaborbactam for treating pneumonia?

Meropenem-Vaborbactam has shown effectiveness in treating infections caused by carbapenem-resistant Enterobacteriaceae (CRE), particularly those involving Klebsiella pneumoniae, which is a common cause of pneumonia. It has been demonstrated to be effective in treating complicated urinary tract infections and other invasive infections, suggesting its potential usefulness in treating pneumonia caused by similar resistant bacteria. ^{1 2 3 4 5}

How does targeted antibiotic therapy for pneumonia differ from other treatments?

Targeted antibiotic therapy for pneumonia is unique because it focuses on using specific antibiotics that are effective against multidrug-resistant bacteria, like Pseudomonas aeruginosa, which are difficult to treat with standard antibiotics. This approach may involve newer antibiotics such as ceftolozane-tazobactam and ceftazidime-avibactam, which are designed to combat resistant strains more effectively. ^{6 7 8 9 10}

Research Team

Michael Rothberg, M.D.

Principal Investigator

The Cleveland Clinic

Eligibility Criteria

This trial is for adults over 18 with pneumonia, admitted to a participating hospital without intensive care in the first 24 hours, not on comfort care only, without cystic fibrosis or recent discharge from acute care. It excludes those known to have a specific pathogen causing their illness.

Inclusion Criteria

I am 18 years old or older.

Admitted to a participating (i.e. enrolled and randomized) hospital

I have been diagnosed with pneumonia.

Exclusion Criteria

I was discharged from the hospital within the last week.

I was admitted to the ICU within 24 hours of being hospitalized.

I am only receiving treatments to ease symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rapid diagnostic testing and/or pharmacist-led de-escalation for community-acquired pneumonia

21 days

Daily monitoring by clinical pharmacist on weekdays

Follow-up

Participants are monitored for safety and effectiveness after treatment, including infection with resistant organisms and 30-day readmission

6 months

Treatment Details

Interventions

• Pharmacist-led de-escalation
• Rapid Diagnostic Testing

Trial Overview The study tests if rapid diagnostic testing and pharmacist-led de-escalation can reduce broad-spectrum antimicrobial use in community-acquired pneumonia. It's a 3-year trial with four groups: one gets rapid tests, another gets pharmacist help, one gets both, and the last follows usual care.

Participant Groups

Group I: Rapid diagnostic testing (RDT) Active Control 1 Intervention

Rapid diagnostic testing: Eligible patients at hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. If the patient is not being admitted to the ICU, and the patient has an admitting diagnosis of pneumonia, the form will append orders for viral testing and UAT testing to providers in hospitals randomized to receive it.

Group II: Pharmacist-led de-escalation Active Control 1 Intervention

Pharmacist-led de-escalation: Another CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for \> 48 hours and generate a list for the clinical pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily on weekdays at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. The validated measures of clinical stability in patients with CAP are a) resolved vital sign abnormalities b) normal mental status c) ability to eat. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page.

Group III: Rapid diagnostic testing (RDT) and Pharmacist-led de-escalation Active Control 2 Interventions

Rapid diagnostic testing: Eligible patients at hospitals randomized to this arm will undergo testing for viral pathogens (from November-April) and pneumococcal UAT testing. If the patient is not being admitted to the ICU, and the patient has an admitting diagnosis of pneumonia, the form will append orders for viral testing and UAT testing to providers in hospitals randomized to receive it. Pharmacist-led de-escalation: Another CDSS algorithm will identify CAP patients who meet study criteria and have negative culture results for \>48-hours and generate a list for the clinical pharmacist, who will be a member of the study team. The alerts will be audited by the pharmacist daily on weekdays at a centralized location. The pharmacist will attempt to determine whether each patient is clinically stable. If the patient appears stable, the pharmacist will communicate their recommendations for de-escalation to the clinical providers via a phone call or page.

Group IV: Usual care (no intervention) Active Control 1 Intervention

Usual care

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

Meropenem-vaborbactam is effective against complicated urinary tract infections and acute pyelonephritis caused by carbapenem-resistant Enterobacteriaceae, as shown in the Phase III trial TANGO I.

The drug is safe, well tolerated, and has better pharmacokinetic and pharmacodynamic profiles compared to other antibiotics targeting the same resistant bacteria, making it a valuable option for treating infections caused by K. pneumoniae carbapenemase-producing CRE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meropenem-vaborbactam: a new weapon in the war against infections due to resistant Gram-negative bacteria. Patel, TS., Pogue, JM., Mills, JP., et al.[2019]

Meropenem-vaborbactam is an effective treatment for complicated urinary tract infections caused by carbapenem-resistant Enterobacteriaceae (CRE), particularly those producing Klebsiella pneumoniae carbapenemase (KPC), showing higher treatment success rates compared to traditional therapies.

This novel combination not only has lower toxicity but also presents a stronger defense against developing antimicrobial resistance, making it a preferred option for managing serious infections caused by KPC-producing CRE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meropenem-vaborbactam for adults with complicated urinary tract and other invasive infections. Albin, OR., Patel, TS., Kaye, KS.[2019]

Vaborem, a combination of vaborbactam and meropenem, is effective against Carbapenem-resistant Enterobacterales (CRE) infections, particularly those caused by Klebsiella pneumoniae carbapenemase (KPC), and is expected to improve patient outcomes by reducing treatment failures and the need for chronic renal replacement therapy.

In a cost-effectiveness analysis based on a 5-year model in Italy, Vaborem demonstrated a gain of 0.384 quality-adjusted life years (QALYs) at an incremental cost of €3549, resulting in a cost-effectiveness ratio of €9246/QALY, indicating it is a cost-effective treatment option compared to the best available therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of Vaborem in Carbapenem-resistant Enterobacterales (CRE) -Klebsiella pneumoniae infections in Italy. Mennini, FS., Gori, M., Vlachaki, I., et al.[2021]

Meropenem-Vaborbactam (Vabomere) is effective against infections caused by carbapenem-resistant Enterobacteriaceae, showing promising results in clinical settings.

The combination of Meropenem and Vaborbactam enhances the efficacy of treatment by overcoming resistance mechanisms, making it a valuable option for patients with limited antibiotic choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meropenem-Vaborbactam (Vabomere™): Another Option for Carbapenem-Resistant Enterobacteriaceae. Lee, Y., Kim, J., Trinh, S.[2020]

In a post hoc analysis of the TANGO-II trial, meropenem-vaborbactam (MV) showed a 42.9% absolute increase in clinical cure rates compared to best available therapy (BAT) for patients with KPC-producing Enterobacteriaceae infections, indicating its superior efficacy.

MV was associated with fewer adverse events and a 29.0% reduction in mortality, suggesting it is a well-tolerated and effective treatment option for serious carbapenem-resistant infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Meropenem-Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis. Bassetti, M., Giacobbe, DR., Patel, N., et al.[2020]

Recent advancements in the treatment of castration-resistant prostate cancer (CRPC) have introduced four new therapies that improve patient outcomes, emphasizing the importance of understanding the disease's biology and the role of the androgen receptor as a therapeutic target.

Patient selection, timing of therapy, and cost-effectiveness are critical factors in the management of CRPC, as the introduction of novel treatments, including immunotherapy and specific androgen receptor inhibitors, has changed the standard care approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for the management of castration-resistant prostate cancer. Haddad, H., Garcia, JA.[2012]

Cabazitaxel, abiraterone, and enzalutamide show comparable overall survival outcomes for patients with metastatic castrate-resistant prostate cancer, with no significant differences found in median survival rates among the treatments.

However, cabazitaxel is associated with a higher risk of certain adverse events, such as anemia, diarrhea, and pyrexia, compared to abiraterone and enzalutamide, indicating a need for careful consideration of side effects when choosing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of cabazitaxel for patients with metastatic castrate-resistant prostate cancer who have been previously treated with a docetaxel-containing regimen. Fryzek, JP., Reichert, H., Summers, N., et al.[2021]

In a phase I trial involving 22 patients with hormone-resistant prostate cancer, the combination of docetaxel (DTX) and zoledronic acid (ZOL) administered bi-weekly showed promising anti-tumor activity, particularly with the sequence of DTX followed by ZOL.

Sequence A (DTX followed by ZOL) resulted in disease control in 6 out of 9 patients and a decrease in biological markers, while sequence B did not demonstrate any anti-tumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Facchini, G., Caraglia, M., Morabito, A., et al.[2020]

Multidrug resistance (MDR) in Pseudomonas aeruginosa poses a significant challenge for selecting effective antibiotic treatments, necessitating careful consideration of both empiric and definitive therapy options.

Newer antibiotics like ceftolozane-tazobactam and ceftazidime-avibactam show promise against MDR-PSA, but more clinical data is needed to establish their effectiveness in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approach to the Treatment of Patients with Serious Multidrug-Resistant Pseudomonas aeruginosa Infections. O'Donnell, JN., Bidell, MR., Lodise, TP.[2021]

In a study of 70 patients with ventilator-associated pneumonia (VAP), switching to trimethoprim-sulfamethoxazole (TMP-SMX) from β-lactam antibiotics did not lead to higher mortality rates at 30 days or at the end of treatment, indicating its safety as a treatment option.

The findings suggest that using TMP-SMX as a de-escalation strategy from broader-spectrum antibiotics is a viable approach that warrants further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trimethoprim-sulfamethoxazole as de-escalation in ventilator-associated pneumonia: a cohort study subanalysis. Strazzulla, A., Postorino, MC., Youbong, T., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Meropenem-vaborbactam: a new weapon in the war against infections due to resistant Gram-negative bacteria. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Meropenem-vaborbactam for adults with complicated urinary tract and other invasive infections. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of Vaborem in Carbapenem-resistant Enterobacterales (CRE) -Klebsiella pneumoniae infections in Italy. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Meropenem-Vaborbactam (Vabomere™): Another Option for Carbapenem-Resistant Enterobacteriaceae. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Meropenem-Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Novel agents for the management of castration-resistant prostate cancer. [2012]

7. United States pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of cabazitaxel for patients with metastatic castrate-resistant prostate cancer who have been previously treated with a docetaxel-containing regimen. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Approach to the Treatment of Patients with Serious Multidrug-Resistant Pseudomonas aeruginosa Infections. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Trimethoprim-sulfamethoxazole as de-escalation in ventilator-associated pneumonia: a cohort study subanalysis. [2021]