Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)

Assistance Publique - Hôpitaux de Paris

Status and phase

Not yet enrolling

Phase 3

Conditions

Hematologic Malignancy

Tumor

Allogeneic Stem Cell Transplantation

Septic Shock

Sepsis

Treatments

Drug: Aminoglycosides intervention

Behavioral: Lack of protective isolation intervention

Other: No systematic aminoglycosides intervention - standard arm

Other: Protective isolation intervention - standard arm

Study type

Interventional

Funder types

Other

Identifiers

NCT05443854

APHP180690

Details and patient eligibility

About

Sepsis remains the leading cause of ICU admission in neutropenic patients. This condition remains associated with a high morbidity and mortality, with hospital mortality of 60% when vasopressors are required.

Full protective isolation (including geographic isolation, technical isolation, high-efficiency air filtration, and digestive decontamination) proved to be efficient in patients with profound and prolonged neutropenia with regard to infection rate. However, these studies are biased and were performed up to 40 years ago. More recent studies, performed in patients with less profound neutropenia, or performed without digestive decontamination or with partial protective isolation led however to negative results. More importantly, isolation has been demonstrated to limit access to patients' room and to be associated with suboptimal monitoring, with increased rate of severe and avoidable adverse events. This may explain the uneven use of protective isolation in hematology ward and expert's suggestion to appraise protective isolation benefits using large well conducted RCT.

In neutropenic patients with suspected sepsis, urgent broad antibiotic therapy is mandatory and failure to initiate adequate antibiotic therapy within 1 hour has been associated with a 10 fold increase in adjusted mortality. Current IDSA guidelines recommend using preferentially large anti-pseudomonas beta-lactam therapy. Routine antibiotic combination using aminoglycosides is controversial and not recommended. On one hand, meta-analyses suggested not-only a lack of benefit from this association but also increased rate of renal failure and a trend towards a higher mortality rate with aminoglycosides use. On the other hand, subgroup analysis and low-level evidences studies suggest however a benefit from aminoglycosides in critically-ill patients, patients with severe sepsis, or those with documented gram negative infection. Along this line, both the recent Cochran systematic review and the recent French guidelines focusing on neutropenia management in critically-ill patients advocated additional trials in this field focusing in the sickest patients.

The current study aims to assess benefits of protective isolation and systematic use of aminoglycosides combination antibiotic therapy in critically-ill patients with cancer-related neutropenia and sepsis or septic shock. To do so, the investigators intend to perform a 2x2 factorial design randomized pragmatic trial comparing on one hand benefits of protective isolation (versus no protective isolation) and in the other hand benefits of systematic aminoglycosides antibiotics combination (versus no systematic combination).

Enrollment

340 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age ≥ 18 years
Sepsis or septic shock as defined by SEPSIS3 definition
Underlying tumor, allogeneic stem cell transplantation or hematological malignancy
Neutropenia (defined by either absolute neutrophil count <500/mm3 or leucocytes <1000/mm3) related to an underlying malignancy or its treatment
Informed or deferred consent

Exclusion criteria

Pregnancy and breastfeeding
Moribund patients (death expected within 48 hours by attending physician)
Previous participation to this study
No affiliation to social security
Patients under legal protection according to French Law
Patient having received more than 1 injection of aminoglycosides in the 3 days preceding ICU admission
Contraindication to aminoglycosides as mentioned in SpC section 4.3:
- Hypersensitivity to amikacin, to other antibiotics from the aminoglycoside family, or to any excipient from the amikacin used.
- Patients with documented allergy to aminoglycosides
- Myasthenia gravis
- Concomitant administration of intravenous Polymyxin- Delay between admission for a new sepsis and inclusion>24 hours or (in patients previously admitted in the ICU for another reason) delay between new sepsis in study inclusion >24h

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Factorial Assignment

Masking

None (Open label)

340 participants in 4 patient groups

Aminoglycosides intervention

Experimental group

Description:

Systematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered. Recommended duration will be of three days or until microbiological documentation.

Treatment:

Drug: Aminoglycosides intervention

Lack of protective isolation intervention

Experimental group

Description:

Protective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained.

Treatment:

Behavioral: Lack of protective isolation intervention

No systematic aminoglycosides intervention

Other group

Description:

Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines - standard arm

Treatment:

Other: No systematic aminoglycosides intervention - standard arm

Protective isolation intervention

Other group

Description:

Protective isolation will be provided systematically as currently practiced in participating centers - standard arm