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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT02176122
Other study ID # ACTRN12613000532707
Secondary ID
Status Terminated
Phase Phase 4
First received June 24, 2014
Last updated November 22, 2017
Start date February 2014
Est. completion date August 7, 2017

Study information

Verified date November 2017
Source The University of Queensland
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

No randomized controlled trials (RCTs) have yet been performed comparing different treatment options for AmpC or ESBL-producing Enterobacteriaceae. During the last 10 years we have seen an exponentially increasing rate of carbapenem resistance worldwide, including Australia and New Zealand. The investigators urgently need data from well-designed RCTs to guide clinicians in the treatment of antibiotic resistant Gram-negative infections. The investigators face a situation where a commonly used antibiotic for these infections (meropenem) may be driving carbapenem resistance. For this reason, the investigators are seeking to compare a carbapenem-sparing regimen with a carbapenem for the treatment of these infections. Formal evaluation of safety and efficacy of generic antibiotics in the treatment of infection is of immense clinical and public health importance, and no formal trial has yet been conducted to address these issues. The international collaboration between teams of clinician researchers, some of whom are leaders in their field, makes it highly likely that the outcomes of this trial will have a significant impact on clinical practice.

The investigators' hypothesis is that piperacillin/tazobactam (a carbapenem-sparing regimen) is non-inferior to meropenem (a widely used carbapenem) for the definitive treatment of bloodstream infections due to third-generation cephalosporin non-susceptible E. coli or Klebsiella species.


Description:

Escherichia coli and Klebsiella spp. are common causes of bacteraemia, and may acquire genes encoding extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases (1). ESBL or AmpC producers are typically resistant to third generation cephalosporins such as ceftriaxone, but susceptible to carbapenems (1). Observational studies have been performed evaluating antibiotic choices for ESBL producers (2-9). In no study has the outcome of treatment for serious infections for ESBL producers been significantly surpassed by carbapenems (2-9).

Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible organisms, widespread use of carbapenems may cause selection pressure leading to carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant organisms are treated with "last-line" antibiotics such as colistin. Some new beta-lactam antibiotics and beta-lactamase inhibitors, which are active against ESBL, AmpC and some carbapenemase producing organisms, are in advanced clinical development (10). However, these antibiotics are likely to be expensive and may best be held in reserve for infections where there are no alternatives. Therefore, we see a need for establishing the efficacy of a generically available alternative to carbapenems for serious infections.

The susceptibility of ESBL producers and AmpC producers to piperacillin/tazobactam is less predictable than that of carbapenems. By definition, ESBLs are inhibited by beta-lactamase inhibitors such as tazobactam (1). However, E. coli or Klebsiella may produce multiple beta-lactamase types some of which are resistant to inhibition by tazobactam. Additionally, in some cases outer membrane protein loss may contribute to resistance to tazobactam. By definition, AmpC is not inhibited by beta-lactamase inhibitors such as tazobactam. However, despite these limitations, approximately 50% or more of ceftriaxone non-susceptible E. coli or Klebsiellae remain susceptible in vitro to piperacillin/tazobactam (1).

No randomised controlled trials have yet been performed comparing different treatment options for ceftriaxone resistant Enterobacteriaceae. The largest observational study with an analysis by treatment outcome was published in February 2012 by Rodriguez-Bano and colleagues (9). They performed a post-hoc analysis of six published cohorts of patients with bacteraemia due to ESBL producing E. coli. Two nonmutually exclusive cohorts (empirical therapy and definitive therapy) were constructed and analysed separately. In both cohorts, carbapenems were not superior to beta-lactam/beta-lactamase inhibitor combinations (BLBLIC). Specifically, in the definitive therapy cohort, mortality rates at 30 days were not significantly different - 9.3% for those who received a BLBLIC and 16.7% for those who received a carbapenem (p>0.20) (9).


Recruitment information / eligibility

Status Terminated
Enrollment 391
Est. completion date August 7, 2017
Est. primary completion date July 7, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria:

- Bloodstream infection with E. coli or Klebsiella spp. with proven non-susceptibility to third generation cephalosporins and susceptibility to meropenem and piperacillin-tazobactam from at least one blood culture draw. This will be determined in accordance with laboratory methods and susceptibility breakpoints defined by EUCAST standards (www. eucast.org). Bacterial identification to species level will be performed using standard laboratory methods (e.g. MALDI-TOF) and susceptibility testing (e.g. Vitek2)

- No more than 72 hours has elapsed since the first positive blood culture collection.

- Patient is aged 18 years and over

- The patient or approved proxy is able to provide informed consent.

Exclusion Criteria:

- Patient not expected to survive more than 4 days

- Patient allergic to a penicillin or a carbapenem

- Patient with significant polymicrobial bacteraemia (that is, a Gram positive skin contaminant in one set of blood cultures is not regarded as significant polymicrobial bacteraemia).

- Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).

- Pregnancy or breast-feeding.

- Use of concomitant antimicrobials in the first 4 days after enrolment with known activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole may be continued as Pneumocystis prophylaxis).

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Meropenem
Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.
Piperacillin-tazobactam combination product
Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.

Locations

Country Name City State
Australia Brisbane Private Hospital Brisbane Queensland
Australia Mater Misericordiae Health Services Brisbane Ltd. Brisbane Queensland
Australia St. Andrew's War Memorial Hospital Brisbane Queensland
Australia Monash Health Clayton Victoria
Australia Peter MacCallum Cancer Centre East Melbourne Victoria
Australia Barwon Health Geelong Victoria
Australia Royal Brisbane and Women's Hospital Herston Queensland
Australia The Alfred Hospital Melbourne Victoria
Australia Fiona Stanley Hospital Perth
Australia Royal Perth Hospital Perth Western Australia
Australia Shellharbour Hospital (Illawarra Shoalhaven Local Health District) Shellharbour New South Wales
Australia Westmead Hospital Westmead New South Wales
Australia Wollongong Hospital Wollongong New South Wales
Australia Princess Alexandra Hospital Woolloongabba Queensland
Canada Sunnybrook Research Institute Toronto
Italy Teaching Hospital - Sant'Orsola Malpighi Bologna
Italy Dipartimento di Scienze Biomediche e Cliniche "L. Sacco". Azienda Ospedaliera - Polo Universitario Milan
Italy "Sapienza" University of Rome Rome
Italy Catholic University Rome Rome
Italy Sanremo Hospital Sanremo
Italy Santa Maria Misericorida University Hospital Udine
Lebanon The American University of Beirut Beirut
New Zealand Middlemore Hospital Papatoetoe
New Zealand The North Shore Hospital Westlake
Saudi Arabia King Fahad Specialist Hospital Dammam
Saudi Arabia King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Riyadh
Singapore National University Hospital Singapore
Singapore Tan Tock Seng Hospital Singapore
South Africa Groote Schuur Hospital Cape Town
South Africa Charlotte Maxeke Johannesberg Academic Hospital Johannesburg
Turkey Istanbul Medipol Üniversitesi Medipol Mega Hastaneler Kompleksi (Medipol Mega Hospitals Complex) Istanbul

Sponsors (5)

Lead Sponsor Collaborator
The University of Queensland Australasian Society for Infectious Diseases, Australian Society for Antimicrobials, International Society of Chemotherapy, Queensland Clinical Trials & Biostatistics Centre

Countries where clinical trial is conducted

Australia,  Canada,  Italy,  Lebanon,  New Zealand,  Saudi Arabia,  Singapore,  South Africa,  Turkey, 

Outcome

Type Measure Description Time frame Safety issue
Primary Mortality at 30 days To compare the 30-day mortality post bloodstream infection of piperacillin/tazobactam and meropenem. 30 days
Secondary Time to clinical and microbiologic resolution of infection defined as number of days from randomisation to resolution of fever (temperature > 38.0o C) and leucocytosis (white blood cell count >12x109/L) PLUS sterilisation of blood cultures. on or before study day 4
Secondary Clinical and microbiologic success defined as survival PLUS resolution of fever and leucocytosis PLUS sterilisation of blood cultures day 4
Secondary Microbiologic resolution of infection defined as sterility of blood cultures collected on or before day 4 day 4
Secondary Microbiologic relapse defined as growth of a meropenem resistant Gram negative bacillus from any clinical specimen collected or a positive stool test (according to local lab diagnostic procedures) for C. difficile, from day 4 of study drug administration to day 30 day 30
Secondary Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile To compare the risk of superinfection with a carbapenem resistant organism with each regimen. day 30
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