1. On behalf of the ASID CRN Gram negative working group
Meropenem versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections caused by Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens in low-risk patients: Protocol for a Pilot Randomised Controlled Trial (the “MERINO-2” Trial)
Harris PNA1,2, Davis JS3,4, Harris-Brown T1, Lipman J5, Paterson DL1,2
1University of Queensland, UQ Centre for Clinical Research, Herston, QLD, 2Dept. of Microbiology, Central Laboratory, Pathology Queensland, Brisbane, QLD, 3Dept. of Infection and Immunity, John Hunter Hospital, Newcastle, NSW, 4Menzies School of Health Research, 5Dept. of Intensive Care, Royal Brisbane and Women’s Hospital, QLD
On behalf of the ASID CRN Gram negative working group
BACKGROUND
Some Gram-negative bacteria possess chromosomal AmpC β-lactamases which may be expressed at high-levels, leading to resistance to many β-lactam agents. Such resistant variants may be selected during antibiotic therapy and lead to clinical failure. This has been best described in Enterobacter bacteraemia treated with 3rd generation cephalosporins. As carbapenems are stable to the activity of AmpC, these agents are often considered optimal therapy for bloodstream infections caused by AmpC-producers, yet may cause selection pressure for carbapenem-resistance. Piperacillin-tazobactam (PTZ) has an uncertain role in this context, as many AmpC-producers will test susceptible to PTZ but the risk of selection for AmpC hyper-producing variants and clinical failure is not well characterised. We aim to test the hypothesis that PTZ is non-inferior to carbapenems in the treatment of bloodstream infection caused by AmpC-producers in order to define a useful ‘carbapenem-sparing’ option for these infections.
METHODS
OUTCOME MEASURES
Multi-centre international pilot study to generate data to inform a definitive trial; N=100 patients
Primary Outcome:
To compare the frequency within each treatment arm of reaching a composite end-point of: Death OR Microbiological failure OR Clinical failure OR Microbiological relapse within 30 days post randomisation (definitions below)
Secondary Outcomes:
Time to clinical and microbiological resolution
Length of hospital (or ICU) stay
Requirement for subsequent ICU admission
Risk of microbiological failure arising from AmpC-mediated resistance
Risk of colonisation or infection with multi-drug resistant bacteria or Clostridium difficile infection
Identified participants who meet inclusion/initial screening criteria
Inclusion Criteria:
1. Bloodstream infection with Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp. or Serratia marcescens
2. Bacterial isolate confirmed as piperacillin/tazobactam and meropenem susceptible
3. No more than 72 hours since the first positive blood culture collection
4. Patient or approved proxy able to give written informed consent
5. Patients aged >18 years (21 in Singapore)
Exclusion Criteria:
1. Patient not expected to survive more than 4 days
2. Patient allergic to a penicillin or a carbapenem
3. Patient with significant polymicrobial bacteraemia
4. Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).
5. Pregnancy or breastfeeding
6. Pitt bacteraemia score of >4
7. Neutropenia (neutrophil count <1.0) from cytotoxic chemotherapy
8. Solid organ transplant
9. Likely source to be from:
a. The central nervous system
b. Infected orthopaedic implant, septic arthritis or osteomyelitis
c. Undrained intra-abdominal, pleural or visceral collection(s)
d. Endovascular infection
e. Line source - not removed
Definitions
Death: up to 30 days post randomisation
Clinical failure: ongoing fever (Tmax >38°C) OR leucocytosis (white blood cell count >12x109/L) day 5
Microbiological failure: positive blood cultures or any sterile site with same species as initial (index) blood culture on day 3-5 post randomisation
Microbiological relapse: growth from blood culture or any sterile site of the same organism as in the initial (index) blood culture after day 5 but before day 30
Randomized 1:1 ratio
*Piperacillin-tazobactam
4.5g Q6h
*Meropenem 1g Q8h
Clinical parameters recorded daily up to day 4; Daily BCs if febrile – all have day 3 BC collected
Follow-up at 30 days to determine outcomes
Excluded
Well-designed studies are required to provide guidance for the optimal treatment of resistant Gram-negative bacteria. Clinician-initiated randomised trials, that align with normal clinical care, are feasible and not excessively costly. Such studies are an optimal approach to help define carbapenem-sparing options for these significant infections and support antimicrobial stewardship
*Treatment will be for a minimum of 4 days and a maximum of 14 days, dependent upon clinical review
For further information regarding this poster please contact:
Patrick Harris
The study has received funding from the RBWH Foundation and the John Hunter Hospital Charitable Trust