Efficacy of seven and fourteen days of antibiotic treatment in uncomplicated Staphylococcus aureus bacteremia (SAB7): study protocol for a randomized controlled trial

The extensive use of antibiotics worldwide is closely related to the increasing issues of antimicrobial resistance and antibiotic-associated infections [1, 2]. Long-course antibiotic treatment, as used for blood stream infections, plays a critical role in this context.

Staphylococcus aureus is one of the most frequent causes of bacterial infections in skin, bone, tissue, and blood, with bacteremia being one of the most severe presentations. In Denmark the incidence is around 25 per 100,000 population, corresponding to approximately 1800 cases of S. aureus bacteremia (SAB) each year [3‐5]. SAB is often associated with severe complications, such as secondary deep infections, and a reported mortality rate of 20–25% [5]. However, nearly half of cases are classified as uncomplicated infections associated with a significantly lower risk of relapse and death [6, 7]. Uncomplicated SAB is partly due to in-hospital infections related to invasive procedures and the use of peripheral and central venous catheters, as well as community-acquired skin and soft tissue infections [8, 9].

Present international and Danish guidelines recommend a standard treatment regimen of a minimum of 14 days of intravenous antibiotics for SAB [6]. However, these recommendations are based on only a few randomized clinical studies and, to a greater extent, on individual expert opinion [10]. Only one minor clinical trial has evaluated the length of treatment in SAB, and this found no significant differences in outcome between 2 and 4 weeks of treatment [11]. It is known from case-based studies that 10–14 days of treatment in uncomplicated SAB are associated with few secondary complications and failure to treat events [12‐15]. Interestingly, three observational studies showed that 7 days of treatment in simple catheter-associated SAB were effective and not associated with a higher risk of recurrence if the focus of the infection was eradicated. In all reported cases, follow-up blood cultures were negative and the patients showed no clinical or biochemical signs of adverse events or complications [6, 7, 16]. However, present evidence regarding length of treatment for SAB is limited and further research in the area could potentially modify current clinical practice.

We hypothesize that 7 days of antibiotic treatment in uncomplicated SAB is non-inferior to 14 days of treatment.

We primarily seek to compare 7 and 14 days of antibiotic treatment in patients with uncomplicated SAB in terms of mortality and the prevalence of microbiological and clinical failure to treat and recurrence within 90 days of diagnosis.

The study aims to explore the possibility of reducing the consumption of antibiotics, as well as shortened hospital admission, and thereby potentially decrease the risk of adverse events and microbial resistance development.

The study is a randomized, non-blinded, non-inferiority, interventional study. Confirmation of study eligibility will be performed by entering key variables into a web-based program (REDCap) with subsequent automatic patient randomization into two parallel arms (ratio 1:1): treatment regimens of 7 or 14 days, respectively. Randomization lists will be generated centrally in random blocs and stratified according to catheter-associated infections as well as center/hospital. For a detailed description of the items included in the SAB7 study protocol, please see the SPIRIT table in Additional file 1.

The study has been approved by the relevant regulatory authorities, including The Danish Medicines Agency (EudraCT 2017–003529-13), Research Ethics Committee of the Capital Region of Denmark (H-17027414), and The Danish Data Protection Registry (ID AHH-2017-086, I-Suite no.: 05891). The study will be conducted according to ICH-GCP (guidelines for Good Clinical Practice (GCP)) and monitored by GCP units in Denmark. Informed consent is obtained from all study participants.

The following ten hospitals, representing all five regions of Denmark, will be invited to participate in the study: Hvidovre Hospital, Rigshospitalet, Herlev Hospital, Hillerød Hospital, Roskilde Hospital, Odense University Hospital, Kolding Hospital, University Hospital of Aarhus, Herning Hospital, and University Hospital of Aalborg.

Uncomplicated SAB is defined according to the guidelines of the Infectious Disease Society of America [17]. Briefly, patients are required to be free of signs of infectious endocarditis and have a negative follow-up blood culture, a physical examination without signs of metastatic foci, absence of fever 48–72 h after initiation of appropriate antibiotic therapy, and no implantable devices. Prosthetics in joint and bones implanted > 6 months prior to SAB will be accepted if the patients show no clinical signs of infection involving the prosthetics. Inclusion and exclusion criteria are listed in detail in Table 1. Eligible patients must fulfill all of the inclusion and none of the exclusion criteria (Fig. 1). Cases are identified through the respective departments of microbiology and infectious diseases at each center. All participants are hospitalized at enrollment.

Patients will receive antibiotic treatment adhering to local and national guidelines as well as according to the susceptibility of the respective isolate. Participation in the study will only affect treatment duration and will have no influence on the choice of treatment with respect to type and dose of antibiotic agent. Patients entering the study have already received 7 days of antibiotic treatment. According to randomization, patients will (i) discontinue antibiotic treatment at day 7 or (ii) continue antibiotic treatment for a total of 14 days. Antibiotics considered appropriate for empiric treatment of SAB are listed in Table 2.

A summary of collected data is presented in Fig. 3. Study participants will be followed by doctors at the respective centers for 6 months after the SAB diagnosis (Figs. 2 and 3). Hospitalized patients will be assessed in accordance with the study protocol and local hospital standards. Day 0 is defined as the initiation of antibiotic therapy with antimicrobial effects against SAB (Fig. 1). Days 1–6 serve as a screening period to determine study eligibility. Eligible patients will be included in the trial and randomized at day 7. To evaluate outcome efficacy patients will undergo three follow-up examinations on day 14 and weeks 12 and 26, respectively. The first follow-up visit will consist of a physical examination, whereas the second and third follow-up visits will consist of a clinical consultation or a standardized telephone interview (Fig. 2). In addition to the scheduled follow-up visits, patients will at discharge be thoroughly instructed on contacting the treating physician if they develop symptoms or fever at any time between follow-up visits. Any signs of fever must lead to a clinical evaluation, blood testing, and blood culture. Follow-up data and laboratory tests are described in Fig. 3. Additional follow-up regarding comorbidity and other clinical variables is conducted by the use of hospital and national databases. All data are registered in an electronic case report form.

Based on local and national databases, we expect a failure to treat and relapse rate of < 5% for patients with uncomplicated SAB alive at day 7 and a 90-day all-cause mortality rate of approximately 7%, corresponding to a recovery rate of 88% [20]. However, available data on recurrence and death in this select group of patients is sparse. Consequently, an adaptive trial design is used in which the event rate is reassessed and the sample size and the non-inferiority margin adjusted if appropriate. The reassessment will occur at the second interim analysis when 100 patients have entered the study and completed 90 days of follow-up. Reassessment after the second interim analysis may lead to one of four changes to the study: 1) sample size and non-inferiority margin will remain unchanged because the event rate is 12%; 2) sample size and non-inferiority margin will be lowered because the event rates is < 12%; 3) sample size will be increased because the event rate is > 12% while the non-inferiority margin will remain unchanged; or 4) the trial will be terminated due to safety concerns.

The regulatory authorities will be informed of the result of the pilot phase and interim analysis and potential adjustments to sample size.

Non-inferiority is defined as a difference in primary endpoint of up to 10%. Assuming a treatment response of 88%, statistical power of 80%, a statistical significance level of 5% and a 2% loss to follow-up rate, 284 randomized patients are require in order to exclude predefined difference in the two groups. Sample size was estimated using simulation, with the assumption of a 12% failure in both groups and a non-inferiority margin of 10%.

We will perform two interim analyses when 30 and 100 patients have completed the study, respectively. This serves to evaluate the primary and secondary endpoints and potential adverse events by an independent data and safety monitoring board (DSMB).

The Haybittle-Peto method is applied to demonstrate overwhelming differences between the two treatment groups that necessitate premature termination of the trail. A significant p value of 0.001 in the interim analyses will correspond to a p value of 0.05 in the final analysis.