Aminoglycosides in Early Sepsis (AGES)

University Hospital, Akershus

Status and phase: Not yet enrolling; Phase 4

Conditions: Sepsis

Treatments: Drug: Piperacillin-tazobactam; Drug: Gentamicin + narrow spectrum betalactam; Drug: Cefotaxime

Study type: Interventional

Funder types: Other

Identifiers

NCT06712641

2024-519797-39-00

Details and patient eligibility

About

Norwegian guidelines for empirical antibiotic therapy in suspected community acquired sepsis recommend the combination of narrow spectrum betalactam and aminoglycoside as the first choice, but broad spectrum betalactams are considered equally appropriate, effective, and safe. However, fear of renal complications due to gentamicin and concern for lacking evidence for efficiency commonly leads to the use of broad spectrum betalactam therapy, a larger driver of antibiotic resistance.

In patients with suspected community acquired sepsis, the investigators hypothesize that empirical combination therapy with narrow spectrum betalactams and aminoglycosides is safe and non-inferior to empirical therapy with broad spectrum betalactams. More specifically, the investigators hypothesize that the proportion of patients with acute kidney injury or death will be similar between these two treatment groups. Furthermore, the investigators hypothesize that the aminoglycoside-based regimen has lesser impact on the gut microbiome. Antimicrobial resistance is one of the most urgent health threats of our time, and Norwegian hospitals were required but failed to reduce the use of broad-spectrum antibiotics with 30% by the end of 2020. In this context, novel initiatives aiming at reducing use of antibiotics are direly needed.

Enrollment: 1,900 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Hospitalized
• Adults 18 year or older
• Clinical suspicion of community acquired sepsis with indication for empirical antibiotic therapy
• National Early Warning Score 2 (NEWS2) ≥ 5
• Signed informed consent must be obtained and documented according to ICH GCP, and national/local regulations

Exclusion criteria

• Established chronic kidney failure (eGFR < 30 ml/min/1.73m2)
• Presentation with septic shock with multiorgan failure
• Suspicion of condition necessitating specific antimicrobial therapy (e.g. atypical pneumonia, fungal infection, parasitic infection, mycobacterial infection)
• Current or recent use of nephrotoxic drugs (e.g cisplatin within previous 2 months)
• Suspected or confirmed carrier of extended spectrum betalactamase (ESBL) producing bacteria, methicillin-resistant Staphylococcus aureus (MRSA), or other drug-resistant microbes necessitating specific antimicrobial therapy
• Multiple myeloma
• Renal transplantation
• Renal replacement therapy
• Myasthenia gravis
• Known hypersensitivity to any of the study drugs
• Pregnancy

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

1,900 participants in 2 patient groups

Gentamicin + narrow spectrum betalactam

Active Comparator group

Description:

Empirical therapy for suspected community-acquired sepsis with gentamicin + narrow spectrum betalactam (either one of penicillin, ampicillin, or cloxacillin)

Treatment:

Drug: Gentamicin + narrow spectrum betalactam

Cefotaxime or piperacillin-tazobactam

Active Comparator group

Description:

Empirical therapy for suspected community-acquired sepsis with broad spectrum betalactam (either one of cefotaxime or piperacillin-tazobactam)

Treatment:

Drug: Cefotaxime

Drug: Piperacillin-tazobactam