Piperacillin/Tazobactam vs Meropenem for Bacterial Blood Infections

(PETERPEN Trial)

Recruiting at 13 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

Trial Summary

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 Piperacillin/Tazobactam vs Meropenem for bacterial blood infections?

Research shows that Piperacillin/Tazobactam is effective against various bacteria, including those that produce beta-lactamase (an enzyme that makes bacteria resistant to some antibiotics), and is particularly active against Pseudomonas aeruginosa. Meropenem is also highly effective against resistant bacteria like Escherichia coli and Klebsiella pneumoniae, making both drugs valuable options for treating serious infections. ^{1 2 3 4 5}

What safety information is available for Piperacillin/Tazobactam and Meropenem?

Piperacillin/Tazobactam can cause side effects like diarrhea, liver dysfunction, and in rare cases, agranulocytosis (a drop in white blood cells). It may also lead to acute kidney injury, especially when used with vancomycin. Meropenem is generally considered safe, but like all antibiotics, it can have side effects, which should be discussed with a healthcare provider. ^{1 6 7 8 9}

How does the drug Piperacillin/Tazobactam differ from other treatments for bacterial blood infections?

Piperacillin/Tazobactam is unique because it combines a broad-spectrum penicillin with a beta-lactamase inhibitor, making it effective against bacteria that produce enzymes (beta-lactamases) which typically resist antibiotics. This combination is particularly useful for treating serious infections caused by resistant bacteria. ^{1 2 10 11 12}

What is the purpose of this trial?

Data regarding optimal treatment for extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae blood-stream infection are lacking. Observational studies show conflicting results when comparing treatment with combination beta-lactam-beta-lactamase inhibitor and carbapenems. The investigators aim to evaluate the effect of definitive treatment with meropenem vs. piperacillin-tazobactam on the outcome of patients with bacteremia due to cephalosporin-non-susceptible Enterobacteriaceae. The investigators hypothesize that piperacillin-tazobactam is non-inferior to meropenem.

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

References

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

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO). [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

[Basic and clinical studies on tazobactam/piperacillin in pediatric field]. [2018]

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

Stability of Meropenem and Piperacillin/Tazobactam with Heparin in Various Peritoneal Dialysis Solutions. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Susceptibility of bacterial isolates from Turkey--a report from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

[Development of beta-lactamase inhibitors]. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Piperacillin-sulbactam versus piperacillin-tazobactam: a multicentre, randomised, single-blind, controlled clinical trial. [2018]

7. Japan pubmed.ncbi.nlm.nih.gov

A puerperal patient with agranulocytosis during tazobactam / piperacillin administration : A case report. [2021]

8. Thailand pubmed.ncbi.nlm.nih.gov

Meropenem versus piperacillin-tazobactam as empiric therapy for febrile neutropenia in pediatric oncology patients. [2022]

9. Saudi Arabia 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. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Contribution of β-lactamase and efflux pump overproduction to tazobactam-piperacillin resistance in clinical isolates of Escherichia coli. [2021]

11. Thailand pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of generic formulation of piperacillin/tazobactam (Astaz-P) for treatment of infected patients at Siriraj Hospital. [2018]

12. Japan pubmed.ncbi.nlm.nih.gov

[Fundamental and clinical studies on tazobactam/piperacillin in the pediatric field]. [2018]