Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem

Conditions

Gram-Negative Bacterial Infections

Keywords

Gram-Negative Bacterial Infections, Resistant Bacteria, Drug Resistance, Bacterial, Colistin

Brief summary

The purpose of this study is to determine whether the addition of meropenem to colistin is better than colistin alone in the treatment of clinically significant infections caused by multi-drug resistant bacteria

Nutman A, Temkin E, Lellouche J, Amar Ben Dalak M, Kaplan E, Lurie-Weinberger M, Dishon Benattar Y, Neuberger A, Stern A, Daitch V, Eliakim-Raz N, Durante-Mangoni E, Bernardo M, Iossa D, Daikos G, Skiada A, Pavleas I, Friberg L, Theuretzbacher U, Leibovici L, Paul M, Carmeli Y, AIDA Study Group.

2025-11-05

10.1186/s13756-025-01651-1

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

Daitch V, Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Cavezza G, Adler A, Dickstein Y, Pavleas I, Zampino R, Bitterman R, Zayyad H, Koppel F, Zak-Doron Y, Levi I, Babich T, Turjeman A, Ben-Zvi H, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L.

2021-03-315 citations

10.1186/s12879-021-05995-y

Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial

Yaakov Dickstein, Jonathan Lellouche, Maayan Ben Dalak Amar, David A. Schwartz, Amir Nutman et al. (68 authors)

Clinical Infectious Diseases2018-11-15119 citations

10.1093/cid/ciy988

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.

Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Pafundi PC, Adler A, Dickstein Y, Pavleas I, Zampino R, Daitch V, Bitterman R, Zayyad H, Koppel F, Levi I, Babich T, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L.

2018-02-16435 citations

10.1016/s1473-3099(18)30099-9

Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol

Yaakov Dickstein, Leonard Leibovici, Dafna Yahav, Noa Eliakim‐Raz, George L. Daikos et al. (24 authors)

BMJ Open2016-04-0145 citations

10.1136/bmjopen-2015-009956

Interventions

DRUGColistin

IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.

DRUGMeropenem

IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Adult inpatients * Clinically significant, microbiological-documented infection caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria and identified according to CDC criteria- blood stream infections, hospital acquired pneumonia, ventilator associated pneumonia, and urinary tract infections * Patient recruitment will occur only after microbiological documentation and susceptibility testing. Patients will be included within 96 hours of the time the index culture was taken (typically within 48 hours of isolate identification), regardless of the antibiotic treatment administered during this time period.

Exclusion criteria

* Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection * Pregnant women * Epilepsy or prior seizures * Known allergy to colistin or a carbapenem

Design outcomes

Primary

Measure	Time frame	Description
Clinical success	14 days	defined as a composite of all of the following, all measured at 14 days: * Patient alive * Systolic blood pressure \>90 mmHg without need for vasopressor support * Stable or improved SOFA score, define as: * for baseline SOFA ≥ 3: a decrease of at least 30%; * for baseline SOFA \<3: stable or decreased SOFA score * For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved * For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile

Secondary

Measure	Time frame	Description
Clinical success with modification	14 days	Clinical success, but with modification to the antibiotic treatment not permitted by protocol
Time to defervescence	28 days	defined as time to reach a temperature of \<38°C with no recurrence for 3 days
Time to weaning	28 days	Time to weaning from mechanical ventilation in VAP for patients weaned alive
Time to hospital discharge	28 days	Time to hospital discharge for patient discharged alive
Secondary outcomes and adverse events	14 and 28 days	14 and 28-day all-cause mortality. If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy).
Superinfections	28 days	Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
New resistant infection	28 days	Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance
CDAD	28 days	Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test
Microbiological failure	28 days	Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples. * For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response * For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response * For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time

Countries

Greece, Israel, Italy

Outcome results

None listed