Staphylococcus Aureus Bacteremia Antibiotic Treatment Options

NCT01792804 | Completed Phase 3 DMC

• 2 other identifiers: Uni-Koeln-14002013-000577-77
• Study Type: interventional
• Target: 215
• Locations: 5 countries
• Sites: 40

Brief Summary

Increasing resistance to antibiotic agents has been recognized as a major health problem worldwide that will even aggravate due to the lack of new antimicrobial agents within the next decade \[1\]. This threat underscores the need to maximize clinical utility of existing antibiotics, through more rational prescription, e.g. optimizing duration of treatment. Staphylococcus aureus bloodstream infection (SAB) is a common disease with about 200,000 cases occurring annually in Europe \[2\]. A course of at least 14 days of intravenous antimicrobials is considered standard therapy \[3-5\] in "uncomplicated" SAB. This relatively long course serves to prevent SAB-related complications (such as endocarditis and vertebral osteomyelitis) that may result from hematogenous dissemination to distant sites. However, there is insufficient evidence that a full course of intravenous antibiotic therapy is always required in patients with a low risk of SAB-related complications. In a multicenter, open-label, randomized controlled trial we aim to demonstrate that an early switch from intravenous to oral antimicrobial therapy is non-inferior to a conventional 14-days course of intravenous therapy regarding efficacy and safety. An early switch from intravenous to oral therapy would provide several benefits such as earlier discharge, fewer adverse reactions associated with intravenous therapy, increased quality of life, and cost savings.

Conditions

Staphylococcus Aureus Infection

Keywords

Staphylococcus aureus; Bloodstream infection; Oral switch

Outcome Measures

Primary Outcomes (1)

• SAB-related complications

  S. aureus bloodstream infection-related complications (relapsing SAB, deep-seated infection with S. aureus, or attributable mortality) within 90 days

  90 days

Secondary Outcomes (3)

• Length of hospital stay

  90 days

• Survival

  14, 30, and 90 days

• Complications of intravenous therapy

  90 days

Other Outcomes (2)

• Clostridium difficile associated diarrhea (CDAD)

  90 days

• AEs and SAEs

  90 days

Study Arms (2)

Orally administered antibiotic

EXPERIMENTAL

First choice (MRSA and MSSA): trimethoprim-sulfamethoxazole, or Second choice (MSSA): clindamycin, or Second choice (MRSA): linezolid administered for 7-9 days

Drug: Trimethoprim-Sulfamethoxazole; Drug: Clindamycin; Drug: Linezolid

Intravenously administered antibiotic

EXPERIMENTAL

First choice (MSSA): flucloxacillin \[Spain: cloxacillin\], or cefazolin or Second choice (MSSA): vancomycin, or First choice (MRSA): vancomycin, or Second choice (MRSA): daptomycin administered for 7-9 days

Drug: Flucloxacillin; Drug: Cloxacillin; Drug: Vancomycin; Drug: Daptomycin; Drug: Cefazolin

Interventions

Trimethoprim-Sulfamethoxazole DRUG

study drug 1

Orally administered antibiotic

Clindamycin DRUG

study drug 2

Orally administered antibiotic

Linezolid DRUG

study drug 3

Orally administered antibiotic

Flucloxacillin DRUG

study drug 4

Intravenously administered antibiotic

Cloxacillin DRUG

study drug 5

Intravenously administered antibiotic

Vancomycin DRUG

study drug 6

Intravenously administered antibiotic

Daptomycin DRUG

study drug 7

Intravenously administered antibiotic

Cefazolin DRUG

study drug 8

Intravenously administered antibiotic

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age at least 18 years
• Not legally incapacitated
• Written informed consent from the trial subject has been obtained
• Blood culture positive for S. aureus not considered to represent contamination
• At least one negative follow-up blood culture obtained within 24-96 hours after the start of adequate antimicrobial therapy to rule out persistent bacteremia and Absence of a blood culture positive for S. aureus at the same time or thereafter.
• Five to seven full days of appropriate i.v. antimicrobial therapy administered prior to randomization documented in the patient Chart. Appropriate therapy has all of the following characteristics:
• Antimicrobial therapy has to be initiated within 72h after the first positive blood culture was drawn.
• Provided in-vitro susceptibility and adequate dosing (as judged by the PI) preferred agents for pre-randomization antimicrobial therapy are flucloxacillin, cloxacillin, vancomycin and daptomycin. However, the following antimicrobials are allowed:
• MSSR: penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin), β-lactam plus β-lactamase-inhibitors (e.g. ampicillin+sulbactam, piperacillin+tazobactam), cephalosporins (except ceftazidime), carbapenems, clindamycin, fluoroquinolones, trimethoprimsulfamethoxazole, doxycycline, tigecycline, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, ceftobiprole, and macrolides.
• MRSA: vancomycin, teicoplanin, telavancin, fluoroquinolones, clindamycin, trimethoprim-sulfamethoxazole, doxycycline, tigecycline, linezolid, daptomycin, macrolides, ceftaroline, and ceftobiprole.

You may not qualify if:

• Polymicrobial bloodstream infection, defined as isolation of pathogens other than S. aureus from a blood culture obtained in the time from two days prior to the first positive blood culture with S. aureus until randomization. Common skin contaminants (coagulase-negative staphylococci, diphtheroids, Bacillus spp., and Propionibacterium spp.) detected in one of several blood cultures will not be considered to represent polymicrobial infection
• Recent history (within 3 months) of prior S. aureus bloodstream infection
• In vitro resistance of S. aureus to all oral or all i.v. study drugs
• Contraindications for all oral or all i.v. study drugs
• Previously planned Treatment with active drug against S. aureus during Intervention Phase (e.g. cotrimoxazol prophylaxis)
• Signs and symptoms of complicated SAB as judged by an ID physician. Complicated infection is defined as at least one of the following:
• deep-seated focus: e.g. endocarditis, pneumonia, undrained abscess, empyema, and Osteomyelitis
• septic shock, as defined by the AACP criteria (23), within 4 days before randomization
• prolonged bacteremia: positive follow-up blood culture more than 72h after the start of adequate antimicrobial therapy
• body temperature \>38 °C on two separate days within 48h before randomization
• Presence of the following non-removable foreign bodies (if not removed 2 days or more before randomization):
• prosthetic heart valve
• deep-seated vascular graft with foreign material (e.g. PTFE or dacron graft). Hemodialysis shunts are not considered deep-seated vascular grafts.
• ventriculo-atrial shunt
• prosthetic joint was implanted at least 6 months prior, and

Sponsors & Collaborators

• Heinrich-Heine University, Duesseldorf: lead
• German Research Foundation: collaborator

Study Sites (40)

Annecy

Annecy, 74000, France

Location

Chambéry

Chambéry, 73000, France

Location

Grenoble

Grenoble, 38700, France

Location

La Roche-sur-Yon

La Roche-sur-Yon, 85000, France

Location

Nantes

Nantes, 44000, France

Location

Orléans

Orléans, 45100, France

Location

Paris 5

Paris, 75010, France

Location

Paris 1

Paris, 92100, France

Location

Paris 3

Paris, 92110, France

Location

Paris 2

Paris, 93000, France

Location

Paris 4

Paris, 94010, France

Location

Quimper

Quimper, 29107, France

Location

Rennes

Rennes, 35000, France

Location

St. Etienne

Saint-Etienne, 42800, France

Location

Tours

Tours, 37000, France

Location

Berlin

Berlin, 12157, Germany

Location

Uniklinik Köln

Cologne, 50935, Germany

Location

Düsseldorf

Düsseldorf, 40225, Germany

Location

Frankfurt

Frankfurt am Main, 60590, Germany

Location

Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Hannover

Hanover, 30625, Germany

Location

Jena

Jena, 07743, Germany

Location

Krefeld

Krefeld, 47805, Germany

Location

Leverkusen

Leverkusen, 51375, Germany

Location

Lübeck

Lübeck, 23562, Germany

Location

Ulm

Ulm, 89081, Germany

Location

VUmc Amsterdam

Amsterdam, 1081, Netherlands

Location

Amsterdam

Amsterdam, 1105 AZ, Netherlands

Location

Breda

Breda, 4814 CK Breda, Netherlands

Location

Groningen

Groningen, 9700 RB, Netherlands

Location

UMC Groningen

Groningen, 9700, Netherlands

Location

Tilburg

Tilburg, 5022GC, Netherlands

Location

Utrecht

Utrecht, 3584 CX, Netherlands

Location

Diakonessenhuis Utrecht

Utrecht, 5022, Netherlands

Location

Barcelona II

Barcelona, 08035, Spain

Location

Barcelona I

Barcelona, 08036, Spain

Location

Palma

Palma de Mallorca, 07010, Spain

Location

Sevilla II

Seville, 41071, Spain

Location

Sevilla

Seville, 41071, Spain

Location

Nottingham

Nottingham, NG7 24 H, United Kingdom

Location

Related Publications (3)

• Kaasch AJ, Lopez-Cortes LE, Rodriguez-Bano J, Cisneros JM, Dolores Navarro M, Fatkenheuer G, Jung N, Rieg S, Lepeule R, Coutte L, Bernard L, Lemaignen A, Kosters K, MacKenzie CR, Soriano A, Hagel S, Fantin B, Lafaurie M, Talarmin JP, Dinh A, Guimard T, Boutoille D, Welte T, Reuter S, Kluytmans J, Martin ML, Forestier E, Stocker H, Vitrat V, Tattevin P, Rommerskirchen A, Noret M, Adams A, Kern WV, Hellmich M, Seifert H; SABATO study group. Efficacy and safety of an early oral switch in low-risk Staphylococcus aureus bloodstream infection (SABATO): an international, open-label, parallel-group, randomised, controlled, non-inferiority trial. Lancet Infect Dis. 2024 May;24(5):523-534. doi: 10.1016/S1473-3099(23)00756-9. Epub 2024 Jan 17.

  PMID: 38244557 DERIVED

• Kaasch AJ, Rommerskirchen A, Hellmich M, Fatkenheuer G, Prinz-Langenohl R, Rieg S, Kern WV, Seifert H; SABATO trial group. Protocol update for the SABATO trial: a randomized controlled trial to assess early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection. Trials. 2020 Feb 12;21(1):175. doi: 10.1186/s13063-020-4102-0.

  PMID: 32051007 DERIVED

• 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.

  PMID: 26452342 DERIVED

MeSH Terms

Conditions

Staphylococcal Infections; Sepsis

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination; Clindamycin; Linezolid; Floxacillin; Cloxacillin; Vancomycin; Daptomycin; Cefazolin

Condition Hierarchy (Ancestors)

Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Lincomycin; Lincosamides; Pyrrolidines; Glycosides; Carbohydrates; Acetamides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Oxacillin; Penicillins; beta-Lactams; Lactams; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Glycopeptides; Glycoconjugates; Peptides; Amino Acids, Peptides, and Proteins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Cephalosporins; Thiazines

Study Officials

• Achim J Kaasch, MD

  Heinrich-Heine University, Duesseldorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2013
• First Posted: February 15, 2013
• Study Start: December 1, 2013
• Primary Completion: March 26, 2020
• Study Completion: March 26, 2020
• Last Updated: May 27, 2020

Record last verified: 2020-05

Locations

NL (8); ES (5); FR (15); DE (11); GB (1)