Seven Versus Fourteen Days of Treatment in Uncomplicated Staphylococcus Aureus Bacteremia (SAB7)

Efficacy of Seven and Fourteen Days of Antibiotic Treatment in Uncomplicated Staphylococcus Aureus Bacteremia: A Randomized, Non-blinded, Non-inferiority Interventional Study

Introduction: Staphylococcus aureus bacteremia (SAB) plays an important role in long-course antibiotic therapy. Current international guidelines recommend fourteen days of intravenous antibiotic treatment for SAB in order to minimize risks of secondary deep infections and complications. However, patients with simple SAB are known to have a low risk of complications. Reducing treatment length in uncomplicated SAB would reduce the total consumption of antibiotics, adverse events and duration of hospital admission. SAB7 seeks to determine if seven days of antibiotic treatment in patients with uncomplicated SAB is non-inferior to fourteen days of treatment.

Method: The study is designed as a randomized, non-blinded, non-inferiority interventional study. Primary measure of outcome will be failure to treatment or recurrence of SAB twelve weeks after termination of antibiotic treatment. As a measure of secondary outcome the prevalence of severe adverse effects will be evaluated, in particular secondary infection with Clostridium difficile, mortality as well as public health related costs. Patients identified with uncomplicated SAB, are randomized 1:1 in two parallel arms to seven or fourteen days of antimicrobial treatment, respectively. Endpoints will be tested with a statistical non-inferiority margin of 10%.

Conclusion: SAB 7 will determine if seven days of antibiotic treatment in patients with uncomplicated SAB is sufficient and safe, potentially modifying current treatment recommendations.

Study Overview

• Status: Unknown
• Conditions: Staphylococcus Aureus Bacteremia
• Intervention / Treatment: Drug: Antibiotic therapy duration for 7 days

• Study Type: Interventional
• Enrollment (Anticipated): 284
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen
    • Hvidovre, Copenhagen, Denmark, 2650
      • Recruiting
      • Hvidovre Hospital
      • Contact: Louise Ussing, MD; Phone Number: 26457710; Email: louise.thorlacius-ussing@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18 years
• Blood culture positive for Staphylococcus aureus
• Antibiotic treatment with antimicrobial activity to S. aureus administrated within 12 hours of the first positive blood culture
• Temperature < 37,5 degrees celsius at randomization
• S. aureus negative follow-up blood culture obtained 48-96 hours after microbiological verified SAB.
• Patients written consent obtained

Exclusion Criteria:

• Persistence of S. aureus bacteremia before randomization (S. aureus positive follow-up blood culture obtained 48-96 hours of the first positive blood culture)
• Polymicrobial infection
• Antibiotic treatment whit no antimicrobial activity to S. aureus administrated more than 12 hours of the first positive blood culture
• Endocarditis or other intracardiac infection demonstrated with transthoracic or transesophageal echocardiography
• Previous history of endocarditis
• Pacemaker or other intracardiac implant
• Failure to remove a likely focus of infection, such as central venous catheter within 72 hours of the first positive blood culture.
• Prosthetics in joints and bones or vascular grafts
• Pneumonia or infection involving bone or joints
• Previously bone/join infection
• S. aureus infection within the last 90 days
• Pregnancy or breastfeeding
• Neutropenia (blood neutrophils < 1,0 x 109/l)
• Untreated cancer
• Chemotherapy within 90 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Antibiotic therapy duration for 7 days	Drug: Antibiotic therapy duration for 7 days; Antibiotic therapy for seven days
NO_INTERVENTION: Antibiotic therapy duration for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
90-day survival without clinical or microbiological failure to treatment or relapse	up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiologically failure to treatment	Verified S. aureus infection of the same genotype as the initial infection	less than 7 days after treatment termination
Microbiologically relapse	Verified S. aureus infection of the same genotype as the initial infection	more than 7 days after treatment termination
Clinical failure to treatment or relapse	Initiation of anti-staphylococcal therapy for more than 48 hours due to suspected recurrence.	Up to day 90
Mortality	All-cause mortality	Days 14, 28, 90 and 180
Severe adverse events	grade 3 or above adverse events	Up to 26 weeks
Acute renal injury	A 1.5 fold increase in creatinine or a 25% decrease of the glomerular filtration rate (GFR)	Up to 26 weeks
Clostridium difficile infection	Microbiologically verified C. difficile infection	Up to 26 weeks
Multidrug-resistance organism	Microbiologically verified multidrug-resistance organism	Up to 26 weeks
Health-associated costs	Public health related cost estimated from a general consideration of the expenses associated with hospitalization for SAB.	Up to 26 weeks

Collaborators and Investigators

• Sponsor: Thomas Benfield

Publications and helpful links

General Publications

• Banaei N, Anikst V, Schroeder LF. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015 Jun 11;372(24):2368-9. doi: 10.1056/NEJMc1505190. No abstract available.
• Kaasch AJ, Fatkenheuer G, Prinz-Langenohl R, Paulus U, Hellmich M, Weiss V, Jung N, Rieg S, Kern WV, Seifert H; SABATO trial group (with linked authorship to the individuals in the Acknowledgements section). Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial. Trials. 2015 Oct 9;16:450. doi: 10.1186/s13063-015-0973-x.
• Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Torok ME, Walker S, Wertheim HF, Wilson P, Llewelyn MJ; UK Clinical Infection Research Group. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011 Mar;11(3):208-22. doi: 10.1016/S1473-3099(10)70285-1.
• Blyth CC, Darragh H, Whelan A, O'Shea JP, Beaman MH, McCarthy JS. Evaluation of clinical guidelines for the management of Staphylococcus aureus bacteraemia. Intern Med J. 2002 May-Jun;32(5-6):224-32. doi: 10.1046/j.1445-5994.2001.00205.x.
• Benfield T, Espersen F, Frimodt-Moller N, Jensen AG, Larsen AR, Pallesen LV, Skov R, Westh H, Skinhoj P. Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia between 1981 and 2000. Clin Microbiol Infect. 2007 Mar;13(3):257-63. doi: 10.1111/j.1469-0691.2006.01589.x.
• Zeylemaker MM, Jaspers CA, van Kraaij MG, Visser MR, Hoepelman IM. Long-term infectious complications and their relation to treatment duration in catheter-related Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2001 Jun;20(6):380-4. doi: 10.1007/pl00011278.
• Raad II, Sabbagh MF. Optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia: a study of 55 cases and review. Clin Infect Dis. 1992 Jan;14(1):75-82. doi: 10.1093/clinids/14.1.75.
• Fowler VG Jr, Sanders LL, Sexton DJ, Kong L, Marr KA, Gopal AK, Gottlieb G, McClelland RS, Corey GR. Outcome of Staphylococcus aureus bacteremia according to compliance with recommendations of infectious diseases specialists: experience with 244 patients. Clin Infect Dis. 1998 Sep;27(3):478-86. doi: 10.1086/514686.
• Mylotte JM, McDermott C, Spooner JA. Prospective study of 114 consecutive episodes of Staphylococcus aureus bacteremia. Rev Infect Dis. 1987 Sep-Oct;9(5):891-907. doi: 10.1093/clinids/9.5.891.
• Ehni WF, Reller LB. Short-course therapy for catheter-associated Staphylococcus aureus bacteremia. Arch Intern Med. 1989 Mar;149(3):533-6.
• Larsen AR, Stegger M, Sorum M. spa typing directly from a mecA, spa and pvl multiplex PCR assay-a cost-effective improvement for methicillin-resistant Staphylococcus aureus surveillance. Clin Microbiol Infect. 2008 Jun;14(6):611-4. doi: 10.1111/j.1469-0691.2008.01995.x. Epub 2008 Apr 3.
• Mejer N, Westh H, Schonheyder HC, Jensen AG, Larsen AR, Skov R, Benfield T; Danish Staphylococcal Bacteraemia Study Group. Stable incidence and continued improvement in short term mortality of Staphylococcus aureus bacteraemia between 1995 and 2008. BMC Infect Dis. 2012 Oct 17;12:260. doi: 10.1186/1471-2334-12-260.
• Mylotte JM, McDermott C. Staphylococcus aureus bacteremia caused by infected intravenous catheters. Am J Infect Control. 1987 Feb;15(1):1-6. doi: 10.1016/0196-6553(87)90069-1.
• Iannini PB, Crossley K. Therapy of Staphylococcus aureus bacteremia associated with a removable focus of infection. Ann Intern Med. 1976 May;84(5):558-60. doi: 10.7326/0003-4819-84-5-558.
• Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhoj P, Frimodt-Moller N. Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 cases. Arch Intern Med. 2002 Jan 14;162(1):25-32. doi: 10.1001/archinte.162.1.25.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2018
• Primary Completion (ANTICIPATED): May 1, 2021
• Study Completion (ANTICIPATED): November 1, 2021

Study Registration Dates

• First Submitted: November 10, 2017
• First Submitted That Met QC Criteria: May 1, 2018
• First Posted (ACTUAL): May 2, 2018

Study Record Updates

• Last Update Posted (ACTUAL): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 14, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Sepsis; Bacteremia; Staphylococcal Infections; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: H-17027414; 2017-003529-13 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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