Clinical trial NCT01792804: Staphylococcus Aureus Bacteremia Antibiotic Treatment Options
Official title: Early Oral Switch Therapy in Low-risk Staphylococcus Aureus Bloodstream Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Staphylococcus Aureus Infection
Keywords: Staphylococcus aureus
Bloodstream infection
Oral switch
Lead sponsor: Heinrich-Heine University, Duesseldorf
Sponsor class: OTHER
Collaborators: name: German Research Foundation
First posted: 2013-02-15
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 1. WHO. WHO Global Strategy for Containment of Antimicrobial Resistance.: World Health Organization, 2001.
2. Kern WV. Management of Staphylococcus aureus bacteremia and endocarditis: progresses and challenges. Curr Opin Infect Dis 2010;23(4):346-58.
3. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006;57(4):589-608.
4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):e18-55.
5. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49(1):1-45.

Eligibility criteria: Inclusion Criteria:

* 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:

  1. Antimicrobial therapy has to be initiated within 72h after the first positive blood culture was drawn.
  2. 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.

Exclusion Criteria:

* 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
* Presence of a prosthetic joint (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled:

  * prosthetic joint was implanted at least 6 months prior, and
  * catheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
  * joint infection unlikely (no clinical or imaging signs)
* Presence of a pacemaker or an automated implantable cardioverter Defibrillator (AICD) device (if not removed 2 days or more before randomization). This is not an exclusion criterion, if all of the following conditions are fulfilled:

  * pacemaker or AICD was implanted at least 6 months prior, and
  * catheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
  * no clinical signs of infective endocarditis, and
  * infective endocarditis unlikely by echocardiography (preferably TEE), and
  * pocket infection unlikely (no clinical or imaging signs)
* Failure to remove any intravascular catheter which was present when first positive blood culture was drawn within 4 days of the first positive blood culture
* Severe liver disease. This is not an exclusion criterion, if the following condition is fulfilled:

  - catheter-related infection, skin and soft tissue infection, or surgical wound infection is present
* End-stage renal disease. This is not an exclusion criterion, if all of the following conditions are fulfilled:

  * catheter-related infection, skin and soft tissue infection, or surgical wound infection is present (as defined below), and
  * no clinical signs of infective endocarditis, and
  * infective endocarditis unlikely by echocardiography (preferably TEE), and
  * in patients with a hemodialysis shunt with a non-removable foreign body (e.g. synthetic PTFE loop): no clinical signs of a shunt infection
* Severe immunodeficiency

  * primary immunodeficiency disorders
  * neutropenia (\<500 neutrophils/μl) at randomization or neutropenia expected during intervention phase due to immunosuppressive treatment
  * uncontrolled disease in HIV-positive patients
  * high-dose steroid therapy (\>1 mg/kg prednisone or equivalent doses given for \>4 weeks or planned during intervention)
  * immunosuppressive combination therapy with two or more drugs with different mode of action
  * hematopoietic stem cell transplantation within the past 6 months or planned during treatment period
  * solid organ transplant
  * treatment with biologicals within the previous year
* Life expectancy \< 3 months
* Inability to take oral drugs
* Injection drug user
* Expected low compliance with drug regimen
* Participation in other interventional trials within the previous three months or ongoing
* Pregnant women and nursing mothers
* For premenopausal women: Failure to use highly-effective contraceptive methods for 1 month after receiving study drug. The following contraceptive methods with a Pearl Index lower than 1% are regarded as highly-effective:

  * oral hormonal contraception ('pill')
  * dermal hormonal contraception
  * vaginal hormonal contraception (NuvaRing®)
  * contraceptive plaster
  * long-acting injectable contraceptives
  * implants that release progesterone (Implanon®)
  * tubal ligation (female sterilisation)
  * intrauterine devices that release hormones (hormone spiral)
  * double barrier methods
* Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
* Persons held in an institution by legal or official order

Primary outcomes:
measure: SAB-related complications
timeFrame: 90 days
Secondary outcomes:
measure: Length of hospital stay
timeFrame: 90 days
measure: Survival
timeFrame: 14, 30, and 90 days
measure: Complications of intravenous therapy
timeFrame: 90 days
Other outcomes:
measure: Clostridium difficile associated diarrhea (CDAD)
timeFrame: 90 days
measure: AEs and SAEs
timeFrame: 90 days
Locations:
city: Annecy
country: France
facility: Annecy
city: Chambéry
country: France
facility: Chambéry
city: Grenoble
country: France
facility: Grenoble
city: La Roche-sur-Yon
country: France
facility: La Roche-sur-Yon
city: Nantes
country: France
facility: Nantes
city: Orléans
country: France
facility: Orléans
city: Paris
country: France
facility: Paris 5
city: Paris
country: France
facility: Paris 1
city: Paris
country: France
facility: Paris 3
city: Paris
country: France
facility: Paris 2
city: Paris
country: France
facility: Paris 4
city: Quimper
country: France
facility: Quimper
city: Rennes
country: France
facility: Rennes
city: Saint Etienne
country: France
facility: St. Etienne
city: Tours
country: France
facility: Tours
city: Berlin
country: Germany
facility: Berlin
city: Cologne
country: Germany
facility: Uniklinik Köln
city: Dusseldorf
country: Germany
facility: Düsseldorf
city: Frankfurt/Main
country: Germany
facility: Frankfurt
city: Freiburg
country: Germany
facility: Freiburg
city: Hannover
country: Germany
facility: Hannover
city: Jena
country: Germany
facility: Jena
city: Krefeld
country: Germany
facility: Krefeld
city: Leverkusen
country: Germany
facility: Leverkusen
city: Lübeck
country: Germany
facility: Lübeck
city: Ulm
country: Germany
facility: Ulm
city: Amsterdam
country: Netherlands
facility: VUmc Amsterdam
city: Amsterdam
country: Netherlands
facility: Amsterdam
city: Breda
country: Netherlands
facility: Breda
city: Groningen
country: Netherlands
facility: Groningen
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Tilburg
country: Netherlands
facility: Tilburg
city: Utrecht
country: Netherlands
facility: Utrecht
city: Utrecht
country: Netherlands
facility: Diakonessenhuis Utrecht
city: Barcelona
country: Spain
facility: Barcelona II
city: Barcelona
country: Spain
facility: Barcelona I
city: Palma de Mallorca
country: Spain
facility: Palma
city: Sevilla
country: Spain
facility: Sevilla II
city: Sevilla
country: Spain
facility: Sevilla
city: Nottingham
country: United Kingdom
facility: Nottingham
Study officials:
affiliation: Heinrich-Heine University, Duesseldorf
name: Achim J Kaasch, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.