Piperacillin/Tazobactam vs Meropenem for Bacterial Blood Infections

(PETERPEN Trial)

Recruiting at 17 trial locations

Overseen By Mical Paul, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Rambam Health Care Campus

Disqualifiers: Polymicrobial bacteremia, Septic shock, Endocarditis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

1084 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two antibiotic treatments, piperacillin-tazobactam and meropenem, to determine which is more effective for blood infections caused by specific bacteria resistant to certain common antibiotics. The focus is on infections from E. coli or Klebsiella that do not respond to usual treatments but can be treated with these two drugs. The trial is best suited for individuals recently diagnosed with this type of bacterial infection. Participants should not have mixed infections or severe conditions like septic shock when joining the trial. As a Phase 4 trial, it involves treatments already FDA-approved and proven effective, aiming to understand how they benefit more patients.

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 is the safety track record for these treatments?

Research has shown mixed results regarding the safety of piperacillin-tazobactam. Some studies suggest it can be beneficial, while others indicate it might increase the risk of death in patients with sepsis. It may also result in fewer days without organ failure and less time off ventilators for some patients. However, details about side effects remain unclear.

In contrast, meropenem has been studied in over 6,000 patients with serious bacterial infections. The research suggests it is generally safe and well-tolerated. Although specific details on side effects are limited, it appears to be a safe option for treating bacterial infections.

Both treatments have been widely used, each with its own advantages and disadvantages. These findings are important to consider when deciding whether to join a clinical trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they offer potential advantages over existing options for bacterial blood infections. Unlike some standard treatments, Piperacillin/Tazobactam combines two active ingredients that work together to tackle a broader range of bacteria by inhibiting bacterial cell wall synthesis and beta-lactamase enzymes. On the other hand, Meropenem is a powerful antibiotic that penetrates bacterial cells effectively, targeting enzymes essential for bacterial survival. These unique mechanisms could lead to more effective management of tough bacterial infections, especially those resistant to other antibiotics.

What evidence suggests that this trial's treatments could be effective for bacterial blood infections?

Research shows that meropenem, one of the treatments in this trial, is a powerful antibiotic effective against serious bacterial infections. Studies have found it can shorten hospital stays and improve health outcomes, especially when administered slowly over time. It is often used for severe infections due to its reliability.

In contrast, earlier studies suggest that piperacillin-tazobactam, the other treatment tested in this trial, might be as effective as meropenem for treating mild blood infections. However, some evidence indicates it could slightly increase the risk of death in certain patients. The current research aims to determine if piperacillin-tazobactam is as effective as meropenem for treating specific bacterial infections in the bloodstream. ^{1 3 4 6 7}

Who Is on the Research Team?

Roni Bitterman, MD

Principal Investigator

Rambam Health Care Campus

Mical Paul, MD

Principal Investigator

Rambam Health Care Campus

Leonard Leibovici, MD

Principal Investigator

Rabin Medical Center

Cristina Mussini, MD

Principal Investigator

University of Modena and Reggio Emilia

Noa Eliakim-Raz, MD

Principal Investigator

Rabin Medical Center, Beilinson Campus

Are You a Good Fit for This Trial?

Adults over 18 with bloodstream infections caused by specific bacteria (E. coli or Klebsiella spp.) resistant to certain antibiotics but susceptible to Piperacillin/tazobactam and Meropenem can join. Excluded are those with septic shock, polymicrobial bacteremia, certain severe infections like endocarditis, allergies to study drugs, previous trial participation, or other clinical trials.

Inclusion Criteria

The infection I have is resistant to certain antibiotics but can be treated with PTZ and meropenem.

I have a blood infection caused by E. coli or Klebsiella, possibly with other non-harmful bacteria.

I have a blood infection, whether caught at home or in the hospital.

Exclusion Criteria

It's been over 72 hours since my first blood culture was taken.

I have had very low blood pressure or needed strong medicine to increase it recently.

Polymicrobial bacteremia. Polymicrobial bacteremia will be defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either meropenem or piperacillin-tazobactam for bloodstream infections

14 days

Follow-up

Participants are monitored for microbiological failure, adverse events, and development of resistance

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Meropenem
• Tazobactam

Trial Overview The PETERPEN trial is testing whether Piperacillin/tazobactam is as effective as Meropenem in treating bloodstream infections from cephalosporin-resistant Enterobacteriaceae. It's a head-to-head comparison of these two antibiotic treatments.

How Is the Trial Designed?

Group I: piperacillin tazobactam Experimental Treatment 1 Intervention

Group II: meropenem Active Control 1 Intervention

Meropenem is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Meropenem for:

• Intra-abdominal infections
• Skin and skin structure infections
• Nosocomial pneumonia
• Urinary tract infections
• Meningitis

Approved in United States as Merrem for:

• Complicated skin and skin structure infections
• Intra-abdominal infections
• Bacterial meningitis

Approved in Canada as Meropenem for:

• Intra-abdominal infections
• Skin and skin structure infections
• Nosocomial pneumonia
• Urinary tract infections

Approved in Japan as Meropenem for:

• Intra-abdominal infections
• Skin and skin structure infections
• Nosocomial pneumonia
• Urinary tract infections
• Meningitis

Who Is Running the Clinical Trial?

Rambam Health Care Campus

Lead Sponsor

Trials

513

Recruited

350,000+

McGill University Health Centre/Research Institute of the McGill University Health Centre

Collaborator

Trials

476

Recruited

170,000+

Meir Medical Center

Collaborator

Trials

406

Recruited

90,500+

University of Modena and Reggio Emilia

Collaborator

Trials

99

Recruited

33,800+

Hadassah Medical Organization

Collaborator

Trials

729

Recruited

186,000+

Tel Aviv Medical Center

Collaborator

Trials

29

Recruited

8,100+

Soroka University Medical Center

Collaborator

Trials

192

Recruited

57,200+

Jewish General Hospital

Collaborator

Trials

144

Recruited

283,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Rabin Medical Center

Collaborator

Trials

423

Recruited

149,000+

Published Research Related to This Trial

In an emulated trial of 121 patients with bloodstream infections caused by ceftriaxone-nonsusceptible E. coli or Klebsiella spp., the mortality rates for piperacillin-tazobactam (17.1%) and meropenem (15.4%) were similar, suggesting that piperacillin-tazobactam may be a viable alternative to meropenem for treatment.

The mortality rate in this emulated trial was significantly higher than in the original MERINO trial, indicating that patient outcomes may vary based on population characteristics and highlighting the importance of addressing biases in clinical trial methodologies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO). Evans, RN., Harris, J., Rogers, CA., et al.[2022]

Meropenem and heparin maintained over 90% of their initial concentration in most peritoneal dialysis solutions when stored at 4°C for 168 hours, but caution is advised as stability was suboptimal in pH-neutral solutions.

Piperacillin/tazobactam and heparin showed excellent stability across all tested peritoneal dialysis solutions, with heparin retaining over 98% of its anticoagulant activity throughout the study, indicating it is a reliable option for use in combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of Meropenem and Piperacillin/Tazobactam with Heparin in Various Peritoneal Dialysis Solutions. Mendes, K., Harmanjeet, H., Sedeeq, M., et al.[2020]

The combination drug TAZ/PIPC demonstrated strong antibacterial efficacy, with a total efficacy rate of 93.9% in treating various infectious diseases in 33 pediatric cases, showing no cases of treatment failure.

TAZ/PIPC was well-tolerated, with only 11.4% of patients experiencing diarrhea as an adverse reaction, indicating a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Basic and clinical studies on tazobactam/piperacillin in pediatric field]. Motohiro, T., Nagai, K., Yamada, T., et al.[2018]

A 32-year-old Japanese woman developed agranulocytosis after 14 days of treatment with Tazobactam/piperacillin (TAZ/PIPC) for an intraperitoneal infection, highlighting a rare but serious side effect of this medication.

After discontinuing TAZ/PIPC and switching to meropenem, the patient's white blood cell count improved significantly within a week, indicating that monitoring for agranulocytosis is crucial for patients on TAZ/PIPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A puerperal patient with agranulocytosis during tazobactam / piperacillin administration : A case report. Iwazawa, H., Tanaka, H., Tatsumichi, T., et al.[2021]

In a study of 79 ICU patients, 52% of those receiving piperacillin-tazobactam (Piptazo) developed acute kidney injury (AKI), compared to 37.9% in those receiving other broad-spectrum antibiotics, although this difference was not statistically significant.

The study found that higher vancomycin trough concentrations above 20 mcg/mL, the use of nephrotoxic medications, and being of African descent were significantly associated with an increased risk of AKI, regardless of the antibiotic combination used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute kidney injury associated with piperacillin-tazobactam versus other antibiotics combined with vancomycin in critically ill patients: A retrospective cohort study. Almutairi, MS., Alnezary, FS., Chestnutt, J., et al.[2023]

In a study involving 215 patients with bacterial respiratory and urinary tract infections, both piperacillin-sulbactam (PIP-SBT) and piperacillin-tazobactam (PIP-TAZ) showed similar overall efficacy rates of approximately 93%, indicating that both treatments are effective options.

The safety profiles of PIP-SBT and PIP-TAZ were comparable, with only minor differences in adverse events, suggesting that PIP-SBT could be a suitable alternative to PIP-TAZ for treating infections caused by beta-lactamase-producing bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Piperacillin-sulbactam versus piperacillin-tazobactam: a multicentre, randomised, single-blind, controlled clinical trial. Zhiyong, Z., Xiaoju, L., Yanbin, L., et al.[2018]

In a study of 514 clinical isolates of E. coli, only five strains were found to be resistant or intermediate to tazobactam-piperacillin (TZP), indicating that TZP resistance remains rare in clinical settings.

Two mechanisms of TZP resistance were identified: one strain showed hyperproduction of the TEM-1 β-lactamase, while two intermediate strains exhibited both high β-lactamase production and increased activity of the AcrAB efflux pump, highlighting the complexity of resistance development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contribution of β-lactamase and efflux pump overproduction to tazobactam-piperacillin resistance in clinical isolates of Escherichia coli. Suzuki, Y., Sato, T., Fukushima, Y., et al.[2021]

A study involving 600 hospitalized adult patients showed that the generic piperacillin/tazobactam (Astaz-P) is as effective as the original version (Tazocin) in treating infections, with comparable clinical outcomes and mortality rates (74.0% vs. 74.7% for outcomes and 18.3% vs. 18.0% for mortality).

There were no significant differences in adverse effects between the two groups, confirming that Astaz-P is a safe alternative to Tazocin for infection treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of generic formulation of piperacillin/tazobactam (Astaz-P) for treatment of infected patients at Siriraj Hospital. Charoenpong, L., Tongsai, S., Thamlikitkul, V.[2018]

Meropenem demonstrated superior activity compared to imipenem against common nosocomial pathogens, showing two- and eight-fold greater effectiveness against Escherichia coli and Klebsiella pneumoniae, respectively.

A significant proportion of Klebsiella pneumoniae (40.5%) and other isolates were found to produce extended-spectrum beta-lactamases (ESBL), highlighting the need for ongoing surveillance to guide effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Susceptibility of bacterial isolates from Turkey--a report from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program. Eraksoy, H., Basustaoglu, A., Korten, V., et al.[2022]

Over 90% of clinical bacterial isolates produce beta-lactamase, leading to increased resistance against common antibiotics like ampicillin and piperacillin, highlighting a significant challenge in treating bacterial infections.

The new beta-lactamase inhibitor tazobactam, when combined with piperacillin (TAZ/PIPC), demonstrated stronger antibacterial activity and a lower frequency of resistant bacteria emergence in both laboratory and mouse models, suggesting it is an effective strategy to combat beta-lactamase-mediated resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Development of beta-lactamase inhibitors]. Hyodo, A., Higashitani, F., Nishida, K., et al.[2018]

Tazobactam/piperacillin (TAZ/PIPC) demonstrated a 100% efficacy rate in treating various infections in 10 pediatric patients, with excellent clinical responses in 5 cases and good responses in another 5.

The treatment was generally safe, with only mild skin rash reported in one patient, which resolved quickly after stopping the medication, indicating that TAZ/PIPC is a promising antibiotic for children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fundamental and clinical studies on tazobactam/piperacillin in the pediatric field]. Kitamura, K., Nishimori, H., Ihara, T., et al.[2018]

A retrospective study involving 136 pediatric cancer patients with febrile neutropenia found that both meropenem and piperacillin-tazobactam (PIP/TAZ) monotherapies had similar success rates (92.4% for meropenem and 91.9% for PIP/TAZ) in treating infections, indicating their comparable efficacy.

No serious adverse effects were reported for either treatment, suggesting that both meropenem and PIP/TAZ are safe options for the initial management of febrile neutropenia in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meropenem versus piperacillin-tazobactam as empiric therapy for febrile neutropenia in pediatric oncology patients. Sezgin, G., Acipayam, C., Ozkan, A., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12323782/

Initial Meropenem Plasma Concentration and Its Correlation ... Meropenem, a carbapenem antibiotic, is known for its potent antibacterial activity and broad-spectrum efficacy, frequently employed in anti- ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39864658/

A systematic review and meta-analysis The primary outcomes included all-cause mortality and clinical improvement, while secondary outcomes encompassed hospital and intensive care ...

3. jintensivecare.biomedcentral.com jintensivecare.biomedcentral.com/articles/10.1186/s40560-020-00442-7

Clinical outcomes of empirical high-dose meropenem in ... Empirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients.

4. academic.oup.com academic.oup.com/cid/article/47/Supplement_1/S41/305563

Update on the Efficacy and Tolerability of Meropenem in the ... Compared with clindamycin/tobramycin, meropenem is associated with a reduced length of hospital stay and a shorter duration of therapy among patients with ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1341321X25000303

Impact of prolonged versus intermittent infusion ... Prolonged infusion of meropenem is more effective than intermittent infusion in reducing mortality, improving clinical outcomes, and enhancing microbial ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7060146/

Real-world Multicenter Analysis of Clinical Outcomes and ... MEV was used in 40 patients with complicated MDR infections and was successful in 70.0% (28/40). Clinical failure was largely attributed to failure to resolve ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2016/050706s037lbl.pdf

Label: MERREM IV (meropenem for injection), There is limited safety data available ... Counsel patients that antibacterial drugs including MERREM IV should only be used to treat bacterial infections.