Comparing the efficacy of ceftazidime avibactum plus aztreonam therapy versus meropenem polymyxin combination therapy for gram negative sepsis by metallo-beta-lactamase producers in intensive care unit:A randomised control trial

COMPARING THE EFFICACY OF CEFTAZIDIME AVIBACTUM PLUS AZTREONAM THERAPY VERSUS MEROPENEM POLYMYXIN COMBINATION THERAPY FOR GRAM NEGATIVE SEPSIS BY METALLO-BETA-LACTAMASE PRODUCERS  IN INTENSIVE CARE UNIT: A RANDOMISED CONTROL TRIAL

Introduction:  Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Gram negative bacteria mainly CRE  are an important cause of sepsis. Metallo-beta-lactamase (MBL)–producing Enterobacterales, are endemic in the Indian subcontinent [1] but are increasingly reported as cause of healthcare-associated infections in Europe and worldwide [2] Recognition of this condition and initiation of treatment thus merits a prompt, appropriate response and in turn  results in reduction of proportional mortality rate. Inflammatory biomarkers have a major role in diagnosis of sepsis. Thus we did a  study  on comparing the efficacy of ceftazidime avibactam plus aztreonam versus meropenem polymyxin combination therapy for gram negative sepsis and prognostication of gram negative sepsis by the use of novel biomarkers like procalcitonin(PCT),CRP and neutrophil to lymphocyte ratio(NLR).

AIMS AND OBJECTIVE

The primary objective will be –

·       To compare the cure rate among two groups by culture negative report.

 The secondary objectives will be-

·       To observe the Procalcitonin (PCT) and Proadrenomedullin levels in both the groups.

·       To compare the neutrophil to lymphocyte ratio(NLR) in both the groups..

·       To determine the length of ICU stay in both groups.

·       To find out the 28-day all-cause mortality in both groups.

MATERIAL AND METHODS

RESEARCH QUESTION

Is Ceftazidime-Avibactam plus Aztreonam is a better combination than Meropenem Polymyxin combination for managing  gram negative sepsis caused by Metallo-beta-lactamase (MBL) producers ?

 HYPOTHESIS

We hypothesize that Ceftazidime Avibactam plus Aztreonam and  Meropenem Polymyxin combination therapy both are equally efficacious in treating gram negative sepsis caused by Metallo-beta-lactamase ( MBL).

 Study Setting:

The study will be carried out in AICU(adult intensive care unit), Department of Anaesthesiology & Critical Care, AIIMS Jodhpur.

Case enrolment - Department of Anaesthesiology & Critical Care, AIIMS Jodhpur

Study Design:

Prospective randomised open labelled comparative trial.

Study population

Patients admitted in AICU with culture proven gram negative Metallo-beta-lactamase (MBL) sepsis

Inclusion Criteria

·       Patients aged 

18 years.

·       Patients having gram negative infections caused by MBL producers according to culture report.

Exclusion Criteria

·       The patient/relatives who refuse to give informed consent

·       Age less than 18 years

·       Patients having gram negative  infections caused by CRAB/Non MBL.

·       Pregnant females.

·       Moribund and Brain dead patients.

·       Patients with known allergy to given drug regime.

 Randomization: Once the culture report is received.

 Duration of study: All eligible patients after CTRI registration , till sample size is achieved or 6 months, whichever is earlier (sample size of 40 patients in each group).

   METHODOLOGY

This shall be a prospective open labelled randomised  comparative trial in AICU of AIIMS,Jodhpur for a duration of 6 months or till sample size is achieved.The patients of culture proven gram negative sepsis caused by MBL producers shall be randomized on receiving proven gram negative culture report and then culture reports to be sent every 72 hours till negative. All patients are to be followed up until 28 days after the admission.

 Bacterial Isolates Identification and Susceptibility Testing

Blood isolate identification to be performed by matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI Biotyper) or VITEK 2 automated machine. Metallo-beta-lactamase (MBL) identification by  phenotyping method  and Antimicrobial susceptibility test to be performed with VITEK 2 machine. Minimum inhibitory concentrations (MICs) to be classified according to breakpoints established by the CLSI (Clinical and laboratory standards institute)

 Antibiotic Therapy

Patients are to be treated with antibiotic regimens chosen by randomization after culture proven gram negative report by MBL producers in AICU.CEFTAZIDIME –AVIBACTAM (CAZ-AVI) to be administered at the dose of 2.5 g every 8 hour  and AZTREONAM( ATM) at the dose of 2 g every 8 hours. Colistin(polymyxin E)  to be administered with a loading dose of 9M IU followed by 4.5M IU every 12 hours or Polymyxin B to be administered with a loading dose of 20,000-25,000 Units/kg  followed by 12,500-15,000 units/kg every 12 hours  and meropenem 2 g every 8 hours. Loading doses are to be used for the antibiotics initially. All maintenance doses to be adjusted for creatinine clearance.

   Proadrenomedullin assay procedure

Blood samples to be collected in serum separator tubes. All samples to be clotted for 2 hours  at room temperature (22°C) before centrifugation for 15 minutes. Then the serum to be removed and stored at -80°C until it is assayed.The proadrenomedullin level to be  estimated by ELISA kit.

Study Outcome Variables

The main outcome variable shall be comparing the cure rate among two groups which is to be determined by  culture negative report .All cultures to be sent before initiation of antibiotics and cultures to be repeated every 72 hours till negative report.

The main secondary outcome variable shall be to find the prognostic value of Proadrenomedullin ,PCT and neutrophil to lymphocyte ratio  in gram negative sepsis.

The other secondary  outcome variables shall be the 28-day all-cause mortality, defined as the occurrence of death within 28 days from day of admission, length of hospital stay (LOS) after admission and to detect the number of metallo-beta-lactamase (MBL) producers and carbapenem resistant Enterobacteriaceae(CRE) in blood samples.

Clinical data to be collected within 24 hours after culture proven gram negative sepsis.

Patient variables to be collected shall include age, sex, underlying diseases, previous anti- microbial therapy , mean arterial pressure, need for ICU admission, laboratory findings including WBC count, proadrenomedullin level ,NLR,CRP, PCT,LFT,RFT and serum creatinine.

Other variables to be  considered are presence of septic shock, Sequential Organ Failure Assessment (SOFA) score,APACHE II score, mechanical ventilation, source of infection (defined according to Centers for Disease Control and Prevention definitions ), control of removable source of infection, and acute kidney injury (AKI). Control of removable source of infection is defined as removal of any pre-existing contaminated intravascular device and  drainage of intra-abdominal abscesses or other fluid collections thought to be the source of infection and incidence of acute kidney injury (AKI). AKI is defined as an abrupt (within 48 hours) increase in serum creatinine of 0.5 mg/dL or a 50% increase above baseline for at least 2 repeated measurements. Cultures to be repeated after From previous studies the clinical cure rate was found out to be 92% in ceftazidime avibactum and aztreonam group and 71.4% in colistin (polymyxin E) group ,so taking in account the sample size comes to 35  in each group as effect size is 0.20  and power of study is 80% and patient assumed to be lost in follow-up is 10%,so the sample size finally coming to be 40 in each group.

Data to be analysed using the SPSS latest version. Continuous variables are to be reported as mean ± standard deviation or median and interquartile range according to their distribution. The normality of distributions to be assessed by the Kolmogorov-Smirnov test. Continuous variables are to be compared by the Student t test or the Mann-Whitney U test, as appropriate. Categorical data are to be expressed as frequency distributions, and Fisher exact test to be used to determine if differences exists between groups.

According to the study outcome, univariate and multivariate analyses are to be performed using Cox proportional hazards regression to identify associations between exposures and mortality until day 28 or clinical failure respectively. All variables to be considered for the multivariate model and CEFTAZIDIME-AVIBACTAM + AZTREONAM is to be tested against POLYMYXIN  PLUS MEROPENEM COMBINATION THERAPY.72 hours after initiation of treatment.

ETHICAL CONSIDERATIONS

 Informed written consent will be taken as per the attached proforma from all the study subjects. No pressure or coercion will be exerted on subjects for participation in study.

 Enrolment in the study will not pose any additional risk to the patient and will not increase the cost of the treatment.

  Confidentiality and privacy will be maintained at all stages.

BIBLIOGRAPHY

1.     Snyder BM, Montague BT, Anandan S, et al. Risk factors and epidemiologic pre- dictors of bloodstream infections with New Delhi metallo-b-lactamase (NDM-1) producing Enterobacteriaceae. Epidemiol Infect 2019; 147:e137.

2.     European Centre for Disease Control and Prevention. Regional outbreak of New Delhi metallo-betalactamase-producing carbapenem-resistant Enterobacteriaceae, Italy, 2018–2019. Available at: https://www.ecdc.europa. eu/sites/default/files/documents/04-Jun-2019-RRA-Carbapenems%2C%20 Enterobacteriaceae-Italy.1. Accessed 25 May 2020.