Comparison of Cloxacillin and Benzylpenicillin in Penicillin Susceptible S. Aureus Bacteraemia (COMeBAC)

Randomized Controlled Clinical Trial Comparing Treatment With Cloxacillin Versus Benzylpenicillin in Bacteraemia Caused by Penicillin-susceptible Staphylococcus Aureus (PSSA)

The goal of this study is to investigate if benzylpenicillin is a better treatment option than cloxacillin in patients with penicillin-susceptible Staphylococcus aureus bacteraemia.

Study Overview

• Status: Recruiting
• Conditions: Staphylococcal Bacteraemia; Staphylococcus (S.) Aureus Infection; Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia); Staphylococcus Aureus Bacteraemia
• Intervention / Treatment: Drug: Penicillin G_1200mg; Drug: cloxacillin

Detailed Description

The overall research idea of is a RCT is to test the hypothesis that benzylpenicillin is superior to cloxacillin in the treatment of PSSA bacteraemia.

Population: Adult patients (>18 years) with PSSA bacteraemia will be eligible for enrolment in the study. Exclusion criteria are allergy to penicillin, inability to give informed consent, and concomitant growth of other clinically significant bacteria in blood cultures. We are planning a nation-wide study.

Intervention: Benzylpenicillin treatment of PSSA bacteraemia will be evaluated. As soon as S. aureus has been identified in blood cultures and the susceptibility testing indicates penicillin susceptibility (Two-three days from start of treatment), patients will be randomized to continue therapy with either cloxacillin or benzylpenicillin. The duration of treatment depends on the type of infection, and details about length of therapy and dosage will be decided by the specific patient diagnosis (i.e., endocarditis, arthritis). Repeated blood cultures and echocardiography are important in the diagnostic work-up of S. aureus bacteraemia and will be included in the study protocol. Patients will also be monitored regarding adverse events, such as liver and renal impairment, rash, diarrhoea, thrombophlebitis et c., and treatment failure, relapse, and mortality.

Control: The study drug (benzylpenicillin) will be compared to cloxacillin, which is the current drug of choice for methicillin susceptible S. aureus in Sweden. Both drugs will be used at clinically recommended doses, with appropriate adjustments for renal impairment if needed. Outcome: Primary outcome is; to be alive for 90 days without any complications. Complications are defined as having any of relapse (90 days after antibiotic finished), need of change or addition of antibiotics due to side effects or treatment failure or adverse events.

• Study Type: Interventional
• Enrollment (Estimated): 420
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Malin Hagstrand Aldman, PhD; Phone Number: +46768766308; Email: malin.hagstrand-aldman@skane.se
• Study Contact Backup: Name: Lisa I Påhlman, PhD, MD; Email: Lisa.pahlman@med.lu.se

Study Locations

• Sweden
  • Lund, Sweden, 22467
    • Recruiting
    • Skånes universitetssjukhus, Region Skåne
    • Contact: MD, PhD, Malin Hagstrand Aldman, PhD, MD; Phone Number: +46768766308; Email: malin.hagstrand-aldman@skane.se
    • Principal Investigator: Malin Hagstrand Aldman, PhD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Aged ≥18 with penicillin susceptible S. aureus bacteraemia (PSSA), and able to provide written informed consent.

Exclusion Criteria:

• allergy to penicillin,
• inability to give informed consent,
• concomitant growth of other clinically significant bacteria in blood cultures

• neutropenia

  -≥ 96h with prior antibiotics

• When the per oral follow up medication can not be flukloxacillin or penicillinV/Amoxicillin (ie prosthetic joint infection)
• Patients in terminal palliation, where death is expected within 7 days.
• Where the treating physician believes cloxacillin is not a first-line treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Benzylpenicillin treatment	Drug: Penicillin G_1200mg; benzylpenicillin preferred dosing 1gx4; Other Names: benzylpenicillin; bensylpenicillin
Active Comparator: cloxacillin	Drug: cloxacillin; cloxacillin 2gx4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at 90 days without any treatment complications	Complications are defined as having any of; relapse within 90 days after treatment finish, need of change or addition of antibiotics due to side effects or treatment failure or adverse events.	From enrollment to 90 days after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 90 days	All cause mortality within 90 days from enrollment	From enrollment to 90 days after end of treatment
Relapse 90 days after end of treatment	Relapse with positive culturing from sterile sites or high suscpition of clinical relapse	From enrollment to 90 days after end of treatment
Cumulative frequency of side effects within 90 days	all side effects registered as a cumulative frequence	From enrollment until 90 days.
Cumulative frequence of change or addition of antibiotic treatment due to sideeffects or treatment failure	Every time additional antibiotics or change in antibiotic treatment is made due to either side effects or treatment failure (according to treating doctor)	from enrollment to end of treatment duration up to 90 days
Decrease of Bacterial DNA in blood samples	Bacterial DNA tested the first 5 days during study treatment.	From enrollment and first 5 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days with intravenous antibiotics	Differences between treatment groups	From enrollment and until end of treatment
Different outcome measures stratified by diagnosis	90 days mortality, relapse 90 days after end of treatment, cumulative side effects stratified by diagnosis	From enrollment and up to 90 days after end of treatment

Collaborators and Investigators

• Sponsor: Region Skane
• Investigators: Principal Investigator: Malin Hagstrand Aldman, PhD, MD, Lund University

Publications and helpful links

Helpful Links

• CTIS

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2025
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: November 26, 2024
• First Submitted That Met QC Criteria: December 5, 2024
• First Posted (Actual): December 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: cloxacillin; Staphylococcus aureus bacteraemia; Penicillin treatment; benzylpenicillin; Penicillin susceptible S. aureus
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Pathological Conditions, Signs and Symptoms; Bacteremia; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amides; beta-Lactams; Lactams; Penicillins; Oxacillin; Penicillin G; Cloxacillin
• Other Study ID Numbers: 2023-506860-15-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: To share the IPD is not supported by the Swedish ethical comite.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No