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Study protocol
Protocol of a short post-surgical antibiotic therapy in spine infections - prospective, randomized, unblinded, non-inferiority trials(SASI trials)
Ilker Uçkay
Uniklinik Balgrist
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5552-0973
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Trials.
Background There are several open scientific questions regarding the optimal antibiotic treatment of spine infections (SI) with or without an implant. The duration of post-surgical antibiotic therapy is debated.Methods We will perform and perform two unblinded randomized -controlled RCTs. We hypothesize that shorter durations of systemic antibiotic therapy after surgery for SI are non-inferior (10% margin, 80% power, ɑlpha 5%) to existing (long) treatment durations. The RCTs allocate the participants in two arms of 2 x 59 episodes each: 3 vs. 6 weeks of targeted post-surgical systemic antibiotic therapy for implant-free spine infections (two positive microbiological samples); or 6 vs. 12 weeks for implant-related spine infections. This equals a total of 236 adult SI episodes (randomization schemes 1:1) with a minimal follow-up of 12 months. All participants have a concomitant multidisciplinary surgical, re-educational, internist and infectious diseases care. We perform three interim analyses that are evaluated, in a blinded analysis, by an independent Study Data Monitoring Committee. Besides the primary outcome remission, we also assess adverse events of antibiotic therapy, changes of the patient’s nutritional status, the influence of immune suppression, total costs, functional scores, and the timely evolution of the (surgical) wounds. We define infection as the presence of local signs of inflammation (pus, wound discharge, calor, rubor) together with microbiological evidence of the same pathogen(s) in at least two intraoperative samples; and remission as absence of clinical, laboratory and/or radiological evidence of (former or new) infection.Discussion Provided that there is adequate surgical debridement, both RCTs enable to potentially prescribe less antibiotics during the therapy of SI; with potentially less adverse events and reduced overall costs.
Keywords
spine infections; osteomyelitis; spondylodeses; antibiotic duration; remission; failure; financial costs; adverse events
Figure 1
Figure 2
Figure 3
Due to technical limitations, Table 1 is only available as a download in the supplemental files section.
Table 2 - List of allowed antibiotic treatments (empirical or targeted)
|
Antibiotic Agent |
Allowed Dosing Regimens |
Allowed Total Daily Dose* |
|
Levofloxacin PO |
500 mg q.12h |
750 to 1000 mg |
|
Ciprofloxacin PO |
500 mg q.12h |
750 to 1500 mg |
|
Amoxicillin/clavulanate PO |
500/125 mg q.12h. or q.8h |
1000/250 mg to 1500/375 mg |
|
Amoxicillin/clavulanate IV |
1000/200 mg q.12h or q.8h |
2000/400 mg to 3000/600 mg |
|
Cefuroxim IV |
1500 mg q.8h |
4500 mg |
|
Ceftriaxon IV |
2000 mg q.24 h |
2000 mg |
|
Co-trimoxazol PO |
960 mg q.12h or q.8h |
1920 mg to 2880 mg |
|
Clindamycin PO |
300 mg or 450 mg q.6h |
1200 mg to 1800 mg |
|
Doxycyclin PO |
100 mg q.12h |
200 mg |
|
Linezolid PO |
600 mg q.12h |
1200 mg |
|
Linezolid IV |
600 mg q.12h |
1200 mg |
|
Metronidazol PO |
500 mg q.8h or 500 mg q.6h |
1200 mg to 2000 mg |
|
Metronidazol IV |
500 mg q.8h or q.6h |
1500 mg to 2000 mg |
|
Vancomycin IV |
15 mg/kg q.12h |
Target serum levels, 10-20 mg/L |
|
Meropenem IV |
1 g or 2 g q.12h or q.8h |
2 g to 6 g |
|
Piperacillin/tazobactam IV |
4000/500 mg q.8h |
1200/1500 mg (12 g/1.5 g) |
PO = oral therapy; IV = Intravenous therapy: * to be adapted to renal insufficiency
Table 3 - Time table of the study
|
Activity |
|
2019 |
2020 |
2021 |
2022 |
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P |
S |
A |
W |
P |
S |
A |
W |
P |
S |
A |
W |
P |
S |
A |
W |
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Permission ethics committees |
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Ongoing recruitment of new sites |
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Clinical study |
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Database |
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Interim statistical analysis |
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Final statistical analyses |
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Writing-up of results and manuscript |
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P = spring, S = summer, A = autumn, W = winter
This is a list of supplementary files associated with this preprint. Click to download.
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Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 06 Jan, 2020
Published
On 06 Feb, 2020
No community comments so far
Editorial decision: Accept
On 02 Jan, 2020
Editor assigned
On 30 Dec, 2019
Submission checks complete
On 29 Dec, 2019
No comments provided
Reviewer #3 agreed
On 19 Dec, 2019
Review #3 received
Received 19 Dec, 2019
Editorial decision: Minor revision
On 19 Dec, 2019
Reviewer #2 agreed
On 12 Dec, 2019
Review #2 received
Received 12 Dec, 2019
Review #1 received
Received 12 Dec, 2019
Reviewer #1 agreed
On 18 Nov, 2019
Reviewers invited
Invitations sent on 04 Nov, 2019
Editor assigned
On 06 Sep, 2019
Submission checks complete
On 29 Aug, 2019
First submitted
On 27 Aug, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
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This preprint is under consideration at Trials. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Study protocol
Protocol of a short post-surgical antibiotic therapy in spine infections - prospective, randomized, unblinded, non-inferiority trials(SASI trials)
Ilker Uçkay
Uniklinik Balgrist
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5552-0973
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 06 Jan, 2020
Published
On 06 Feb, 2020
No community comments so far
Editorial decision: Accept
On 02 Jan, 2020
Editor assigned
On 30 Dec, 2019
Submission checks complete
On 29 Dec, 2019
No comments provided
Reviewer #3 agreed
On 19 Dec, 2019
Review #3 received
Received 19 Dec, 2019
Editorial decision: Minor revision
On 19 Dec, 2019
Reviewer #2 agreed
On 12 Dec, 2019
Review #2 received
Received 12 Dec, 2019
Review #1 received
Received 12 Dec, 2019
Reviewer #1 agreed
On 18 Nov, 2019
Reviewers invited
Invitations sent on 04 Nov, 2019
Editor assigned
On 06 Sep, 2019
Submission checks complete
On 29 Aug, 2019
First submitted
On 27 Aug, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Trials.
Background There are several open scientific questions regarding the optimal antibiotic treatment of spine infections (SI) with or without an implant. The duration of post-surgical antibiotic therapy is debated.Methods We will perform and perform two unblinded randomized -controlled RCTs. We hypothesize that shorter durations of systemic antibiotic therapy after surgery for SI are non-inferior (10% margin, 80% power, ɑlpha 5%) to existing (long) treatment durations. The RCTs allocate the participants in two arms of 2 x 59 episodes each: 3 vs. 6 weeks of targeted post-surgical systemic antibiotic therapy for implant-free spine infections (two positive microbiological samples); or 6 vs. 12 weeks for implant-related spine infections. This equals a total of 236 adult SI episodes (randomization schemes 1:1) with a minimal follow-up of 12 months. All participants have a concomitant multidisciplinary surgical, re-educational, internist and infectious diseases care. We perform three interim analyses that are evaluated, in a blinded analysis, by an independent Study Data Monitoring Committee. Besides the primary outcome remission, we also assess adverse events of antibiotic therapy, changes of the patient’s nutritional status, the influence of immune suppression, total costs, functional scores, and the timely evolution of the (surgical) wounds. We define infection as the presence of local signs of inflammation (pus, wound discharge, calor, rubor) together with microbiological evidence of the same pathogen(s) in at least two intraoperative samples; and remission as absence of clinical, laboratory and/or radiological evidence of (former or new) infection.Discussion Provided that there is adequate surgical debridement, both RCTs enable to potentially prescribe less antibiotics during the therapy of SI; with potentially less adverse events and reduced overall costs.
Figure 1
Figure 2
Figure 3
Due to technical limitations, Table 1 is only available as a download in the supplemental files section.
Table 2 - List of allowed antibiotic treatments (empirical or targeted)
|
Antibiotic Agent |
Allowed Dosing Regimens |
Allowed Total Daily Dose* |
|
Levofloxacin PO |
500 mg q.12h |
750 to 1000 mg |
|
Ciprofloxacin PO |
500 mg q.12h |
750 to 1500 mg |
|
Amoxicillin/clavulanate PO |
500/125 mg q.12h. or q.8h |
1000/250 mg to 1500/375 mg |
|
Amoxicillin/clavulanate IV |
1000/200 mg q.12h or q.8h |
2000/400 mg to 3000/600 mg |
|
Cefuroxim IV |
1500 mg q.8h |
4500 mg |
|
Ceftriaxon IV |
2000 mg q.24 h |
2000 mg |
|
Co-trimoxazol PO |
960 mg q.12h or q.8h |
1920 mg to 2880 mg |
|
Clindamycin PO |
300 mg or 450 mg q.6h |
1200 mg to 1800 mg |
|
Doxycyclin PO |
100 mg q.12h |
200 mg |
|
Linezolid PO |
600 mg q.12h |
1200 mg |
|
Linezolid IV |
600 mg q.12h |
1200 mg |
|
Metronidazol PO |
500 mg q.8h or 500 mg q.6h |
1200 mg to 2000 mg |
|
Metronidazol IV |
500 mg q.8h or q.6h |
1500 mg to 2000 mg |
|
Vancomycin IV |
15 mg/kg q.12h |
Target serum levels, 10-20 mg/L |
|
Meropenem IV |
1 g or 2 g q.12h or q.8h |
2 g to 6 g |
|
Piperacillin/tazobactam IV |
4000/500 mg q.8h |
1200/1500 mg (12 g/1.5 g) |
PO = oral therapy; IV = Intravenous therapy: * to be adapted to renal insufficiency
Table 3 - Time table of the study
|
Activity |
|
2019 |
2020 |
2021 |
2022 |
|||||||||||
|
|
P |
S |
A |
W |
P |
S |
A |
W |
P |
S |
A |
W |
P |
S |
A |
W |
|
Permission ethics committees |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Ongoing recruitment of new sites |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Clinical study |
|
|
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|
Database |
|
|
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|
|
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|
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|
|
|
|
|
|
|
Interim statistical analysis |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Final statistical analyses |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Writing-up of results and manuscript |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
P = spring, S = summer, A = autumn, W = winter