Early shift to oral antibiotic treatment for pyogenic vertebral osteomyelitis (SAVE): study protocol for an open label, non-inferiority, nation-wide randomized controlled clinical trial.

Background

Pyogenic vertebral osteomyelitis (PVO) is an infection localized to vertebrae and their surrounding structures. PVO is associated with high morbidity and risk of chronic pain and permanent neurological deficits [ 1 ]. The incidence of PVO is increasing worldwide with a recent study showing an increase in incidence from 2.2/100,000 in 1995 to 5.8/100,000 in 2008 in a Danish population [ 2 ]. The 1-year crude mortality rates are reported to be 5–22% [ 3 – 6 ]. Serious long-term consequences include permanent neurological deficits, chronic pain and reduced functional level, all reducing the quality of life [ 5 , 7 ]. In a Danish study the proportion of self-supporters after PVO was only 33% compared to 58% before the diagnosis [ 8 ].

Sparse data are available to guide the choice of treatment modality and duration. Recommendations for antibiotic (AB) therapy have mostly been based on findings from retrospective- and observational studies and expert opinion. The prevailing recommended duration of therapy for PVO has for many years been 6 to 12 weeks [ 1 , 9 ] without clear guidance as to which patient groups would benefit from which duration. Furthermore, intravenous (IV) therapy has been recommended as the primary treatment due to better bioavailability and higher drug concentrations in bone [ 1 , 9 ].

Evidence to support selecting the duration of therapy has emerged during recent years. A randomized controlled trial by Bernard et al. indicated that 6 weeks of AB treatment may be as effective as 12 weeks of AB treatment in a study population with known bacterial etiology and treated with a median of 2 weeks IV antibiotics followed by oral AB combination therapy [ 10 ]. However, the proportion of patients needing surgical treatment or having soft tissue abscess was low. A subsequent study by Park et al. indicated that 6 weeks of therapy is not sufficient in patients with abscesses, methicillin resistant Staphylococcus aureus (MRSA) or end-stage renal disease [ 11 ].

The current Danish National Guideline for treatment of PVO recommends 6 weeks AB treatment, with a 2-week IV AB lead-in followed by 4 weeks oral AB for uncomplicated PVO, and 12 weeks AB treatment with a 4 weeks IV AB lead-in followed by 8 weeks oral AB for complicated PVO [ 12 ]. Complicated cases of PVO are defined as having significant, undrained intraspinal, epidural, paravertebral and/or psoas abscess, the need for surgical intervention, infection with MRSA, end-stage renal disease or a foreign body in the site of infection [ 12 ].

Patients are required to remain hospitalized for at least 2 to 4 weeks for inpatient IV AB therapy or receive IV AB at home, which is also cumbersome and costly. Prolonged hospitalization and IV therapy are costly and entail risks such as IV catheter related infections, vascular injury, thrombosis, and phlebitis as well as other nosocomial infections [ 13 – 16 ]. Furthermore, prolonged hospitalization is associated with functional decline as well as depression and anxiety [ 17 , 18 ].

Oral ABs preclude the need for IV catheters and in-hospital AB treatment. Pharmacokinetic studies have shown that selected oral ABs reach appropriate concentrations in blood and in bone [ 19 ]. Nevertheless, randomized controlled trials to form the basis for accelerated shift to oral ABs for PVO are lacking, as also highlighted by the Infectious Diseases Society of America [ 9 ].

Two landmark studies indicate that early shift to oral ABs for complicated infections can be appropriate. Infectious endocarditis is analogous to PVO in that it is associated with severe morbidity and traditionally has required lengthy admission for IV AB treatment. Data from the POET (Partial Oral versus Intravenous AB Treatment of Endocarditis) study has shown that accelerated step-down from IV to oral ABs administered at home may not only be non-inferior to continued IV ABs but may also carry a significant long-term survival benefit in patients with infectious endocarditis [ 20 , 21 ].

The open-label OVIVA trial published in 2019 reported that oral AB therapy was non-inferior to IV therapy when used during the first 6 weeks of the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomization. However, less than 4% of the study population had PVO [ 22 ].

Thus, the data provided by the POET study and the OVIVA study combined with the increasing incidence of PVO, the burden of prolonged hospitalization imposed on the patient as well as on the healthcare system highlight the need for randomized controlled trials to examine whether early shift to oral ABs is non-inferior to continued IV therapy in patients diagnosed with PVO.

Earlier trials with the same design

A search in the database Clinicaltrials.gov on the term “vertebral osteomyelitis” and with the filters “Adult 18–64 years” AND “Older adult 65+ years” AND “Interventional (Clinical Trial)” yielded 3 results, none of which were trials assessing early switch to oral AB therapy.

The first study compared 6 with 12 weeks of antibiotic therapy for vertebral osteomyelitis. The study was published in 2015 and the impact is as detailed in section 4 [ 10 ].

The second study aimed to examine conservative management (antibiotic therapy alone) to surgical management combined with antibiotic therapy for patients with native vertebral osteomyelitis. According to clinicaltrials.gov, the study is estimated to have been completed in 2021; however, the results of the study are not available. Given the difference in aim, the results of the study would not influence the currently proposed study.

The third study aims to compare ceftriaxone to routinely used antibiotics to see if ceftriaxone is equally as safe and efficacious in curing deep-seated Staphylococcal infections in patients receiving home IV antibiotics. The study is expected to be completed in 2023. No results are currently available. If the study provides compelling data that ceftriaxone is a non-inferior alternative for S. aureus infections and is included in the Danish national guidelines prior to study completion, it will be included as an alternative for IV treatment in this study as well.

Objectives

Primary objective

To investigate whether early transition to oral AB treatment after 1 week of IV treatment is non-inferior to the current national guideline of continued IV AB treatment for 2 to 4 weeks followed by oral AB treatment for PVO with a non-inferiority margin of 10%, as deemed clinically acceptable by the steering committee by comparison of the tolerable risk difference with the benefits of reduced IV exposure and potentially shortened hospitalization including potentially fewer IV catheter complications, nosocomial infections [ 13 , 16 ] and potentially reduced functional decline, depression and anxiety [ 17 , 18 ].

Secondary objectives

To compare the proportion of patients experiencing treatment-related adverse events between treatment arms at 24 weeks after oral AB treatment cessation

To compare the average total number of hospital admission days between treatment arms at 24 weeks after oral AB treatment cessation

To compare self-assessed health related quality of life (EQ5D) at randomization, 1 week and 24 weeks following cessation of antibiotic therapy

To assess the economic impact of early shift from IV to oral AB at 24 weeks following cessation of antibiotic therapy

Assessment of sequencing of microbial cell-free DNA as a diagnostic tool in blood from patients with PVO

Study design

The study will be an investigator initiated, nationwide, multicenter, randomized, controlled, parallel group, open label, non-inferiority trial (Fig. 1 ).

Treatment arms

Arm A: Standard of care (comparator) Uncomplicated PVO: 2 weeks IV ABs followed by oral ABs for 4 weeks Complicated PVO: 2–4 weeks IV ABs followed by oral ABs for 8–10 weeks

Arm B: Early shift to oral ABs (intervention) Uncomplicated PVO: 1 week IV ABs followed by oral ABs for 5 weeks Complicated PVO: 1 week IV ABs followed by oral ABs for 11 weeks

Setting

The study will be conducted at departments of infectious diseases in Denmark and in collaboration with spinal surgery units carrying out infection-related spinal surgery. A list of study sites can be found on the European Union’s Clinical Trials Registry website https://euclinicaltrials.eu/ .

Population

All patients diagnosed with PVO will be assessed for eligibility. Patients will be eligible for inclusion if they fulfill all the inclusion and none of the exclusion criteria.

Inclusion criteria

Age ≥18 years

Diagnosed with PVO by a physician based on clinical symptoms and findings consistent with PVO in combination with diagnostic imaging (MRI, PET/CT, or PET/MRI)

The physician responsible for the patient decides to treat the patient for PVO.

At time of randomization, CRP has decreased to < 75% of peak value or to < 20 mg/l.

At the time of randomization, patient has received maximum 7 days of appropriate IV AB for PVO.

Exclusion criteria

Previous episodes of PVO within the past 24 months

Spinal implants inserted prior to current episode of PVO

Hypersensitivity to an AB intended for use in the patient and no alternative drugs available

Oral ABs not possible due to suspicion of reduced absorption

Oral Abs not possible due to verified or expected bacterial susceptibility or due to expected toxicity of available regimen

Identification of fungus, mold, TB, Brucella, Actinomyces, Nocardia, and P. aeruginosa as etiology

Severe immunocompromise defined as primary immunodeficiencies, uncontrolled HIV/AIDS, organ transplant recipients, hematological malignancies, patients having undergone DMARD therapy, biological therapy, or chemotherapy within the last 6 months and/or patients currently being treated with prednisolone >= 20 mg daily (or equipotent doses of other corticosteroids) >14 days

Verified or expected reduced compliance (for example iv drug use)

Pregnancy

Breastfeeding

Women of childbearing potential, who at the time of inclusion are not using and/or who will not use an effective anticonception method during the treatment period

Patients not capable of providing informed consent at time of screening for inclusion

Diagnosed or suspected concomitant or unrelated infections necessitating IV AB therapy beyond 7 days of duration at the time of randomization

A positive blood-culture taken 48–72 h after initiation of appropriate therapy in patients having S. aureus bacteremia

Renal failure and hepatic failure are not exclusion criteria, provided an appropriate antibiotic regimen for both IV and PO can be identified prior to randomization.

Methodology

Diagnostic procedures

The diagnosis of PVO will be made by a physician based on clinical suspicion, laboratory results, and radiological findings on MRI and or PET/CT and/or PET/MRI.

Screening for inclusion and consent provision

Patients will be screened for inclusion as soon as possible and no later than 7 days after initiation of appropriate antibiotics for PVO. The patient will be approached by good clinical practice (GCP) trained study personnel and provided with written information about the study, the document “Forsøgspersoners rettigheder i et biomedicinsk forskningsprojekt” (in English: “Study participants rights in a biomedical research project”) and a consent form. A subsequent meeting will be agreed upon, where the patient’s understanding of the written information will be ascertained and any questions regarding the study, the patient may have, will be answered by the site principal investigator or a physician to whom the task has been delegated. If the patient wishes to participate in the study, they will be asked to provide written informed consent.

Additional consent provisions for collection and use of participant data and biological specimens

We will examine whether sequencing of microbial cell-free DNA as a diagnostic tool will be useful to identify bacterial etiology more accurately and quickly than conventional culture. The method has shown promise in small studies with respect to sensitivity and specificity [ 23 ]. In addition, the detection of circulating microbial DNA has been shown to occur earlier than the blood cultures become positive by growing the microbes [ 24 ]

Furthermore, we plan to carry out future investigations to assess for the presence of genetic variants related to immune dysfunction, antibiotic absorption-and metabolism, and bone remodeling [ 25 – 30 ].

For these purposes, separate patient consent forms will be obtained.

Selection of AB regimen and definition of starting date of appropriate AB therapy

Antibiotics used for treatment of patients in the study have been authorized for sale in Denmark. The appropriate antibiotic regimen will be selected prior to randomization and was until the 12 th of March 2025 in accordance with Appendix 1 and has since been in accordance with the updated Danish National Guideline (DNG) for Diagnosis and Treatment of Spondylodiscitis [ 12 ]. If compliance with Appendix 1 or subsequently the DNG is not possible, or there is any uncertainty about selection of regimen or dosage, the patient’s microbiology data will be assessed by the regional member of the Treatment Committee (TC) who will consult with other members of the TC if necessary. In these cases, the TC will decide which AB regimen the patient is to receive. The first day of antibiotics for PVO will be defined as Day 1 of appropriate AB therapy in accordance with Appendix 1 or subsequently the DNG if possible, or as agreed with the TC. The duration therapy will be counted from this day. For patients having infection within the spinal canal, who have begun relevant antibiotic treatment for PVO, but who have not initially received the appropriate antibiotic in the appropriate dose for intraspinal infection, Day 1 will be defined either as the first day of appropriate treatment for PVO without intraspinal infection or as the first day of appropriate treatment for PVO with intraspinal infection at the discretion of the treating clinicians.

If new microbiology data emerges that would render the chosen regimen inadequate, a new appropriate regimen will be selected as described above. In this case, the date of initiation of the new appropriate regimen will be the new Day 1 upon which duration will be defined.

For patients undergoing therapeutic surgery or radiologically assisted abscess evacuation for PVO or psoas abscess, the starting timepoint of appropriate IV AB therapy will be immediately following surgery or radiologically assisted procedure.

The number of days will be counted in complete days of prescribed antibiotic therapy. For example, if the patient is prescribed benzylpenicillin four times daily, 1 day of AB therapy will be completed after four prescribed doses. If the patient is prescribed intravenous vancomycin or similar drug, where coverage is defined by number of days with adequate trough levels, 1 day of AB will be dependent on having adequate trough levels as defined in the summary of product characteristics.

Randomization

Randomization will take place after inclusion in the study and selection of both IV and oral AB regimen. A centralized internet-based computer-generated randomization schedule has been prepared by a statistician. The schedule has been uploaded to REDCap and can only be accessed by the statistician. Thus, the investigators cannot predict block patterns. Patients will be randomized 1:1 in permuted blocks of 2 and 4 and stratified according to disease severity (complicated or uncomplicated PVO) and region to mitigate center-to-center variation in practice. Randomization will be done by the principal investigator or on-site study personnel to whom the task has delegated.

Patient monitoring and follow-up (Table 1 )

During in-patient treatment and care

Patients will be monitored by the clinical team according to clinical standards and individual needs. Blood samples, further microbiological and radiological work-up will likewise be individualized, with a minimum of hematology, CRP, and kidney function once weekly on any given day in accordance with standard of care. The site’s study-physician and research-nurse will maintain contact with the clinical team to identify potential endpoints and adverse events and to verify that the chosen AB therapy is implemented.

During out-patient treatment and care

During the period of out-patient AB therapy, patients will be asked to call the study team if they experience new symptoms or worsening of existing symptoms.

Patients will be monitored with blood samples once per week.

All patients will be contacted weekly by the study team to assess their symptoms including presence of fever, pain status, and presence of serious adverse events (SAE), as well as adherence to medication using Morisky short score [ 31 ] and self-reported number of missed doses. In accordance with clinical standards, the treating physician will assess whether a physical consultation at the outpatient clinic is warranted at all time points according to clinical indication.

Additional investigations and diagnostics including additional blood samples, samples for microbiology and imaging as well as further monitoring and follow-up will be carried out according to clinical indication.

Following cessation of oral AB

Patients will be monitored as follows:

After 1 week (+/−- 3 days): Clinical assessment, WBC, CRP, blood culture

After 4 weeks (+/−- 5 days): Clinical assessment, WBC, and CRP

After 12 weeks (+/−- 10 days): Clinical assessment, WBC, and CRP

After 24 weeks (+/−- 10 days): Clinical assessment, WBC, and CR

Further examinations and tests, including additional blood samples, cultures, and imaging, will be carried out on clinical indication.

Health-related quality of life will be assessed using the EQ5D questionnaire (a standardized measure of health-related quality of life developed by the EuroQol group https://euroqol.org/ ) (Appendix 2) [ 32 ] at the following time-points in both treatment arms: At randomization, at 1 week, and 24 weeks following cessation of AB therapy. The questionnaire will be administered either by self-complete at the hospital or by in-person or telephone interview carried out by study personnel. The validated language versions used will be Danish and English.

Patients will be included at randomization and are followed until 24 weeks after end of antibiotic treatment according to study procedures. Any patient lost to follow-up (LTFU) will have their electronic patient record examined to identify the occurrence of all elements of the composite primary endpoint.

Criteria for discontinuing allocated intervention and implications for analyses

Patients will discontinue the study if PVO is disproven. If they experience a primary outcome or if the allocated AB treatment strategy is deemed clinically unacceptable, unfeasible, or inadequate, or if the patient experiences a sudden unexpected serious adverse reaction (SUSAR), the allocated treatment will be discontinued. Further treatment and care will be provided in accordance with clinical standards.

Patients have the right to withdraw from the intervention at any time and instead receive routine clinical treatment and care in accordance with clinical standards.

All patients will remain in the study for follow-up and will be included in the intention to treat analysis. Data to assess the primary endpoint can be found in routinely used patient records.

Drug accountability and handling of investigational medicinal products

As the investigational medicinal products (IMP) used in this study are all off the shelf items, dispensing of IMP to the patient will be recorded in the electronic medical journals in accordance with clinical standards, as will administration of IMPs during admission, likewise in accordance with clinical standards.

Duration of oral antibiotic therapy

Follow-on oral ABs after the initial 6–12 weeks of trial-antibiotic therapy may be prescribed in either arm if deemed indicated by the treating physician. However, the choice of agent and duration is not governed by trial protocol.

Concomitant care and co-interventions

If a participant requires IV antibiotic therapy for an unrelated intercurrent illness during the oral antibiotic-treatment, or if the patient experiences vomiting or is unable to swallow, or concerns arise about absorption of oral medication, then IV antibiotic therapy may be given for up to five days. If IV antibiotic therapy is given for more than 5 days, the patient will have met a secondary endpoint and will be excluded from the per protocol analysis but will still contribute to the intention-to treat analysis.

Other interventions for other medical conditions are allowed during the study.

Endpoints

Primary endpoint

The primary endpoint will be a composite of the following events occurring from randomization to 24 weeks after completion of oral AB treatment:

All-cause mortality

Unplanned surgical intervention in relation to the spine for treatment of PVO

Relapse of bacteremia with the primary pathogen

Relapse of bacteria with the initial pathogen being cultured from relevant material from infected areas in relation to the spine or iliopsoas muscle (detected by culture)

Renewed course of IV ABs given for >7 days for treatment of PVO

Secondary endpoints

Occurrence of each component of the composite primary endpoint from randomization to 24 weeks after completion of oral AB treatment

Median duration of hospital admission(s) from randomization to 24 weeks after completion of oral AB treatment (admission defined as overnight stay at the department)

Number of readmissions from randomization to 24 weeks after completion of oral AB treatment

Proportion of patients receiving additional oral AB therapy beyond the duration defined in the protocol

Proportion of patients having early termination of allocated treatment strategy due to adverse events, patient preference, or any other reason

Proportion of patients experiencing complications associated with IV treatment (e.g., catheter infections, phlebitis, bleeding, venous thrombosis, need for replacement of catheter) from the time of initiation of IV treatment for PVO to 24 weeks after completion of oral AB treatment

Proportion of patients experiencing severe adverse events from ABs from randomization to 1 week after completion of oral AB treatment according to plan.

Proportion of patients diagnosed with Clostridioides difficile associated diarrhea from randomization to 24 weeks after completion of oral AB treatment

Quality of life scores (EQ-5D) at the following timepoints: Randomization, 1 week after the end of AB therapy, and 24 weeks after the end of oral AB therapy

Resource allocation/cost assessment determined by a combination of EQ5D, DALYs, Days of hospital admission, and antibiotic prescribing costs

CRP and WBC at randomization as well as CRP and WBC, weekly during treatment and at weeks 4, 12, and 24 after completion of oral AB treatment

Presence of microbial cell-free DNA in blood samples at the time of inclusion

Sample size and statistical considerations

The study is designed as a non-inferiority study to assess whether the proportion of patients who have not experienced a primary endpoint at 24 weeks after cessation of oral AB is non-inferior in patients who have undergone early shift to oral AB compared to the proportion in patients who have continued IV treatment followed by shift to oral therapy as per national guidelines.

The primary endpoint is a composite endpoint comprising all-cause mortality, relapse of the initial pathogen(s), re-initiation of IV Abs, and unplanned surgery.

Previous studies have found 1-year all-cause mortality to be 5–22% [ 3 , 4 , 6 , 22 , 33 ] and 90-day mortality to be 14%. Relapse of the initial pathogen to be 0–3% [ 4 ] and unplanned surgery after 1 year of follow-up to be 17% [ 4 ].

The patient population in this study is a selected population, as it excludes patients having severe immunocompromise, patients having other relevant sites of infection requiring prolonged IV AB therapy (for example patients having endocarditis), patients having recurrence of S. aureus bacteremia despite relevant treatment, patients having previously inserted spinal implants, and patients who are not able to give informed consent. Additionally, patients are required to have AB response according to biochemical parameters at the time of randomization. Adverse outcomes in similar trials with comparable populations have found overall lower occurrence of adverse outcomes, including lack of cure and death 3,6, than retrospective observational studies have found 1,2,5. In their study with a similar population, Bernard et al. found that 13–16% of patients could not be classified as alive and cured at 1 year follow up 6. Considering these factors, the expected proportion having met the composite primary endpoint at 24 weeks after cessation of oral AB therapy is estimated to be 13%.

The study will include patients with complicated vertebral osteomyelitis and patients with uncomplicated vertebral osteomyelitis. This grouping defines the total antibiotic treatment duration in accordance with the Danish National Guidelines, based on data from Park et al. [ 11 ]. The data from this paper does not examine differences in duration of intravenous treatment, but rather focuses on recurrence in relation to total duration of antibiotic treatment. As such, we expect similar risk of primary endpoint occurrence in the two treatment arms in the groups, which is reflected in our sample size calculation.

The non-inferiority margin (Δ) has been set to 10% based on what has been deemed clinically acceptable by the steering committee by comparison of the tolerable risk difference with the benefits of reduced IV exposure and potentially shortened hospitalization including potentially fewer IV catheter complications, nosocomial infections [ 13 , 16 ] and potentially reduced functional decline, depression and anxiety [ 17 , 18 ].

With a one-sided alpha of 2.5%, 90%, power and 10% expected loss to follow-up, a total sample size of 530 patients will be included and randomized.

The primary endpoint will be analyzed as a binary variable, with statistical comparisons based on differences in proportions. A Generalized Linear Model (GLM) from the binomial family with an identity link will be used. The analyses will be adjusted for the stratification variables. To account for potential deviations from the model’s assumptions, robust standard errors will be applied to ensure valid statistical inference. Non-inferiority will be considered to have been confirmed if the upper limit of the 97.5% one-sided confidence interval for the difference in proportions does not include ∆.

The primary outcome analysis is an intention-to-treat analysis including all randomized participants in the treatment arm to which they were randomized. A secondary per-protocol analysis will be carried out including only participants who have received the intended durations of IV therapy ± 1 day and oral AB therapy with ≥80% of prescribed oral doses taken.

For exploratory purposes, the analyses will be repeated with the inclusion of interaction terms between treatment arm and (1) complicated vs. uncomplicated status, (2) region, (3) age groups (patients younger than 70 years vs patients equal to or older than 70 years) and, if feasible, (4) type of bacteria ( S. aureus , Enterobacteriaceae, culture-negative), and (5) comorbidity score in five separate analyses. Statistical significance for these analyses will be assessed using two-sided test of the interaction coefficients at the 5% significance level.

Missing primary endpoint data will be addressed by worst case imputation meaning that missing data in the intervention arm will be analyzed as an endpoint, while missing data in the standard of care arm will be analyzed as no endpoint.

Furthermore, survival models (Kaplan-Meier curves and Cox regression models) will be performed to further examine possible differences in timing of adverse outcomes. One-sided test at significance level α = 5% will be used.

Secondary endpoints

A competing risk approach will be used to estimate cumulative incidence functions of each component of the composite endpoint. A test of similar medians in the two arms will be used to test differences of duration of hospital admissions. As for endpoints 3–9, chi 2 tests will be carried out to test for difference between treatment arms. Repeated measures of quality of life (EQ-5D) (endpoint 10) based on the Danish EQ5D-5L value set will be analyzed using linear mixed models, due to possible deviations from normal distributions of the residuals a robust variance estimator will be implemented. Study patients having incomplete EQ5D-5L datasets will be excluded from these analyses. CRP and WBC (Endpoints 12) will also be analyzed using linear mixed models. For all secondary analyses, two-sided tests with significance level α = 5% will be used. However, due to multiple testing, statistically significant results for secondary analyses might be due to Type I error and should therefore be interpreted with caution.

Statistical analyses will be done using R version 4.5.1.

The statistician carrying out the analyses is independent from the sponsor institution and will remain blinded to treatment arm.

Minimizing bias

Staff and participants are not blinded to the treatment allocation, since we consider IV placebo treatment, including the placement and possible complications of IV catheters, as unethical in this setting.

Stratification

At randomization, patients will be stratified according to region as well as according to whether they are treated for complicated or uncomplicated PVO.

Endpoint Committee

An end-point committee (EC), comprising two infectious diseases specialists Senior Consultant Rikke Krogh-Madsen, Copenhagen University Hospital, Hvidovre and Senior Consultant Merete Storgaard, Århus University hospital, Skejby, as well as spinal surgeon Professor Senior Consultant Benny Dahl, Copenhagen University Hospital Rigshospitalet, will be charged with adjudicating whether selected elements of the primary endpoint have occurred in accordance with the Endpoint Committee Charter (Appendix 4).

Data and safety monitoring

The trial is not a clinical trial of a specific investigational medical product. All antibiotics used in the trial have well described safety profiles and are approved for treating infections in adults. The purpose of the trial is to compare the effectiveness of known and approved oral antibiotics with the effectiveness of known and approved intravenous antibiotics in a real-life setting. The indication for prescription of the used antibiotics, the target population, and the dosage are in accordance with current clinical practice and guidelines. Therefore, a risk-adjusted approach to safety monitoring is employed, whereby SAE are registered and reported to the sponsor, to ensure that any difference in serious adverse reactions (SAR) is identified and to ensure that any arising suspected unexpected serious adverse reactions (SUSAR)s are identified [ 34 ].

Safety monitoring and reporting

For definitions of SAE and SUSAR, please refer to section “Definitions” 10.

The safety follow-up period will last until 1 week after the last planned dose of oral antibiotics has been taken.

Registration and reporting of SAE/SAR

SAE arising after randomization will be registered at follow-up during in-person consultation or telephone consultation through spontaneous report by the patient, through asking and by examination of medical records for information regarding admittance to hospital since or death.

SAE will be recorded electronically in the electronic Case Report Form (eCRF) and reported to the sponsor. The electronic record will include date of onset, criteria for seriousness, and date of resolution.

Recorded SAE/SAR will be followed up until resolution or until the final follow-up study visit. If SAE/SAR has not been resolved at this time, the patient will be referred for appropriate follow-up in accordance with clinical standards.

Causality of SAE will be assessed by the site principal investigator and by the sponsor.

SAE will be reported by investigators to the sponsor within 24 h from knowledge of the SAE.

Expectedness of serious adverse reactions will be assessed by the sponsor by examining the Summary of Product Characteristics of the investigational medicinal product in question.

SAE that will not be reported by the investigator to the sponsor are events directly related to PVO including complications to surgery related to PVO and complications of PVO. Furthermore, hospitalization for the sole purpose of standard patient follow-up where out-patient consultation is not possible and hospitalization for the purpose of examinations, including radiology, that do not lead to the diagnosis of a condition requiring further hospitalization will be exempted from reporting.

Registration and reporting of suspected unexpected serious adverse reactions

The sponsor will be registered in the EudraVigilance system and will report suspected unexpected serious adverse reactions (SUSAR) through the EudraVigilance system and comply with timelines stated in article 42 of the Clinical Trials directive ( https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32014R0536 ).

An annual safety report will be submitted on a yearly basis through the CTIS system covering all the IMPs involved.

Reporting to the data and safety monitoring committee

An independent Data and Safety Monitoring Committee (DSMC) have been established to monitor safety data and carry out unblinded interim analyses. To ensure independence, the DSMC will be comprised of two physicians with relevant experience including infectious diseases Senior Consultant Court Pedersen, Odense University Hospital, and Professor, Senior Consultant Emil Fosbøl, Copenhagen University Hospital, Rigshospitalet, and Statistician Inge Petersen, Odense University Hospital.

Interim analyses for futility (inferiority)

We expect the primary outcome to occur in 68 patients (11% of 530) with an equal distribution between treatment arms. Interim analyses will be scheduled to be carried out by the DSMC once 20% ( n = 106) and 50% ( n = 265) study patients have reached 24 weeks following planned cessation of oral antibiotic therapy. Haybittle-Peto stopping rules ( p < 0.0005) will be used for as stopping criteria at the interim analyses [ 35 ].

Reporting of SAE to the DSMC

If the PI or sponsor assesses that an SAE may be relevant to patient safety, a detailed expedited report will be made of the event to the DSMC.

SAE that will not undergo expedited reporting to the DSMC include the following:

Complications to surgery related to PVO

Complications of PVO

Drug reactions for concurrent medications given for routine clinical care as detailed in the Danish Medicines Agency’s Product Resume ( https://produktresume.dk/AppBuilder/search )

Intercurrent illness deemed causally unrelated to the patient’s antibiotics for PVO

GCP monitoring

GCP monitoring will be carried out by the Danish GCP-units on a risk-based schedule.

Data collection

Prior to study initiation, each site will receive a set of standard operating procedures detailing how to screen patients, solicit informed consent, randomize, obtain and enter study data into the electronic Case Report Form (eCRF), carry out study specific procedures (e.g., acquiring blood samples for sensitive PCR based diagnostics and immunogenetic analyses), reporting of potential primary outcomes in need of adjudication (i.e., non-fatal events) to the sponsor and the EC, and how to use the EQ5D questionnaire and Morisky score.

Throughout the study, the site investigator will obtain data from the patients’ electronic patient chart and enter them in an eCRF. The eCRF will be on the internet-based electronic data capture tool RedCap hosted by the Capital Region of Denmark.

The data entered in the eCRF will include the following:

At inclusion in the study:

Inclusion- and exclusion criteria

Registration of study samples for MCF DNA and Biobank

Before randomization:

SAVE Antibiotic Plan

CRP levels at peak and randomization

At randomization

Stratification

Baseline demographics including age and sex

Comorbidities and calculated Charlson comorbidity index

Clinical features at first hospital contact

EQ5D at randomization

Following randomization

Clinical features at randomization

Results of MRI and/or PET/CT and/or PET/MRI indicating PVO

Results of other imaging examinations, including imaging carried out by the radiological department and cardiological department

Results of blood cultures

Results of invasive samples

Positive findings from other microbiological examinations

Results of routine blood tests at randomization including hemoglobin, WBC, thrombocytes, creatinine, estimated glomerular filtration rate (eGFR), and CRP

Surgical intervention, including date, indication, type, inserted foreign bodies, and planned surgical revision

Antibiotics given from admission to start of SAVE antibiotic plan

Whether there have been any changes in antibiotics since the beginning of the SAVE Antibiotic plan

Follow-up during SAP treatment, Week 1 follow-up after end of SAP, Week 4 follow-up after end of SAP, and Week 12 follow-up after end of SAP

Follow-up time

Clinical features

Routine biomarkers including CRP hemoglobin, WBC, thrombocytes, creatinine, and eGFR

Whether any endpoint has occurred

Any change in SAVE AB treatment plan

Whether the patient has been readmitted to hospital following discharge and the reason

Number of days patient was admitted to hospital

Complications to IV catheters

Serious adverse events that take place during the safety follow-up period

Whether the patient has been excluded following consent and for what reason

EQ5D 1 week after end of SAP

Week 24 follow-up after end of SAP

Follow-up time

Clinical features

Routine biomarkers including CRP hemoglobin, WBC, thrombocytes, creatinine, and eGFR

Whether any endpoint has occurred.

Any change in SAVE AB treatment plan

Any new radiological examinations

Any new microbiological findings including blood cultures, cultures from samples from infected areas in relation to the spine and other positive microbiological findings including positive PCR for C. difficile

AB treatment since randomization

Surgical procedures

Whether the patient has been readmitted to hospital following discharge and the reason

Number of days patient was admitted to hospital

Complications to IV catheters

EQ5D 24 weeks after end of SAP

The EQ5D questionnaire will be completed at the following timepoints: Randomization, 1 week after the end of AB therapy and 24 weeks after the end of AB therapy.

Data management

Patient data will be collected and entered in the eCRF in the REDCap database by trained local study investigators or designated research staff. Each site will also keep a screening log and an ID log.

The REDCap database is managed and secured by the IT-services of the Capital Region of Denmark. The Trial Master File and material containing patient information will be kept at local study sites at secured facilities and in accordance with GDPR regulations.

Confidentiality

All personal data are entered and maintained within the REDCap tool hosted by the Capital Region of Denmark. Only authorized trial personnel including local study investigators, members of the Steering Committee, and the DSMC can access the stored information using personal usernames and passwords. Only the members of the Coordinating Centre team at the sponsors institution have full data access to the REDCap database.

Collection and storage of biological specimens in a biobank for molecular and genetic analyses in this trial/future use

The following blood samples will be collected within 24 h after inclusion in the study at selected sites:

6-ml EDTA

3-mL serum glass Gold with separator gel

10-mL Streck DNA Complete BCT CE glass

Blood samples will be stored in a refrigerator until shipment and sent to the Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet. Samples for future analyses will be stored at – 80 °C in a research-biobank until analysis according to a specified study. After conclusion of the study, the blood samples will be stored in a biobank for an additional 10 years at conditions specified by the Danish data protection legislation in case new technology allows for new and more advanced immune-genetic analyses. At end of storage, the samples will be sent for destruction at a facility for biological waste management. Samples for MCF DNA will be processed at the Statens Serum Institut and Department of Microbiology, Copenhagen University Hospital, Rigshospitalet.

Provisions for post-trial care

Study participants will be insured by the Patient Insurance Association and protected by the “Patients’ Rights Act” and “Act on Patient Safety in the Danish Health Care System.” Following completion of the last follow-up visit in the trial, the patient will continue to be followed up and cared for by relevant clinical entities in accordance with local clinical standards.

Oversight and monitoring

The Steering Committee will be responsible for trial completion, data analysis, and interpretation. The Steering Committee will have the authority and responsibility to terminate the study, e.g., by recommendation from the DSMC. The Steering Committee and local investigators will meet every 6 months to discuss study progress. The Coordinating Centre (Copenhagen University Hospital, Rigshospitalet) is responsible for the overall organization of the trial, day-to-day management support, and coordination with the local investigators. In turn, the local investigators are responsible for setting up and day-to-day local execution of the trial. Zahra Persson Theilgaard is the primary investigator and trial manager assisted by a research nurse (Fig. 2 ).

Good Clinical Practice monitoring will be carried out by the GCP Unit of the University of Copenhagen.

Discussion, ethical considerations, and overall risk and benefit assessment

There is currently insufficient evidence to clarify whether early switch to oral AB is non-inferior to current national guidelines.

There is a risk that early switch will lead to increased frequency of treatment failure and overall prolonged therapy. However, considering current data on oral antibiotic therapy for similar infections [ 20 , 22 ] as well as trial procedures including limiting the study population to patients with clear improvement, frequent follow up including monitoring adverse and serious adverse events, we perceive this risk to be minimal.

For patients randomized to oral AB, participation in the study will provide the opportunity to shorten the duration of hospitalization considerably. Patients randomized to standard IV therapy will only experience minimal changes in in monitoring and follow-up compared to current clinical practice.

All investigators have agreed that they will ensure that this study is conducted in full conformity with relevant regulations and with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996 as well as in adherence with the protocol. The trial is in full compliance with the Helsinki Declaration.

The study and the patient information and consent forms have been approved by the Danish Medical Research Ethics Committee and the Danish Medicines Agency (EU CT Number 2023–507617-96-01).

Substantial modifications to the protocol as defined by the Clinical Trial Regulation Chapter 1 article 2 [ 2 , 14 ] will be submitted to the above-mentioned authorities for approval. Protocol modifications will be communicated to trial participants, journals, and trial registries as appropriate.

All principal investigators have signed a declaration of interest (DOI). None have reported a conflict of interest. All DOIs have been submitted to the Danish Medical Research Ethics Committee.

Trial status

The study began patient inclusion on 14th February 2024 with implementation of protocol version number 2.0.

The duration of the study is expected to be 5.5 years in total (5 years of inclusion and 6 months of follow up). The last visit of the last patient will define the end of the trial (Table 2 ).

The current protocol version no 4.3. date 23.09.2025.

Protocol amendments made after trial initiation are delineated in Appendix 6.

Dissemination

Information about the study will be publicly available on Copenhagen University Hospital, Rigshospitalet’s website.

Regardless of outcome, the results of this study will be made available to the public, preferably by publication in a high-impact, peer-reviewed medical journal.

As soon as possible and no later than 1 year after the trial has ended, the trial results (positive, negative, or inconclusive) will be submitted to the CTIS portal. Subsequently the data will be published on clinicaltrialsregister.eu.

Authorship eligibility and access to trial data is as defined by the site agreements signed by the Sponsor, the site Principal Investigator and a representative of the site. As stated in the agreement, publication of results from the Trial will be governed by requirements for authorship promulgated by the International Committee of Medical Journal Editors (ICMJE). The sponsor has no publication veto.

Supplementary Information

Additional file 1. SPIRIT checklist.

Additional file 2. Appendixes.

Acknowledgements

The authors would like to thank statistician Inge Petersen, Odense University Hospital, for her invaluable technical support in designing and planning statistical analyses.

Definitions

Glossary

Adverse event: Any untoward occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Appropriate antibiotic: Antibiotic therapy for pyogenic vertebral osteomyelitis in accordance with Appendix 1 until the updated Danish National Guideline (DNG) for Diagnosis and Treatment of has been published (expected in 2024 or early 2025) on http://www.infmed.dk . Once the DNG has been published, it will be the reference for appropriate antibiotic therapy. If selection of antibiotic regimen in accordance with appendix 1 or subsequently the DNG is not possible, appropriate antibiotic therapy will be as recommended by the Treatment Committee.

Biological therapy: https://pro.medicin.dk/Laegemiddelgrupper/Grupper/315347 .

Chemotherapy: https://pro.medicin.dk/Laegemiddelgrupper/Grupper/291000 .

Complicated pyogenic vertebral osteomyelitis (PVO)

The presence of a significant, undrained, intraspinal, epidural, paravertebral and/or psoas abscess

and/or

Requiring a therapeutic surgical intervention

and/or

Patient undergoing dialysis.

and/or

Methicillin resistant S. aureus as etiological agent

Conventional Disease Modifying Anti Rheumatic Drugs (DMARDs): https://pro.medicin.dk/Laegemiddelgrupper/Grupper/315513 .

Day 1: Day of first dose of appropriate antibiotic therapy for PVO.

Days of antibiotic therapy:These are counted in a full days’ worth of prescribed antibiotics from the first administered dose. For example, a patient prescribed with cefuroxime 1.5 g three times per day, will have completed day one after 3 doses. Analogously, 7 days of antibiotics will in this case comprise 21 doses, and 14 days of antibiotics will comprise 42 doses, regardless of time of day, at which antibiotics begin.

Early Shift to oral antibiotic therapy:Reduction of intravenous therapy to 1 week.

Hematological malignancies: Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), Hodgkins lymphoma (HL), non-Hodgkins lymphoma (NHL) or other Leukemia.

Potent immunosuppressive agents:Prednisolone 20 mg (or equipotent doses of other corticosteroids) >14 days, biological therapy, conventional DMARDs, targeted synthetic DMARDs and chemotherapy (see separate definitions).

Serious Adverse Event: A serious adverse event is defined as any untoward medical occurrence (i.e. not necessarily linked to medication) where the outcome is:

Death

Life threatening condition

Unplanned hospitalization or prolonged hospitalization. Exempt from this definition will be:

Hospitalization for the sole purpose of standard patient follow-up where out-patient consultation is not possible.

Hospitalization for the purpose of examinations, including radiology, that do not lead to the diagnosis of a condition requiring further hospitalization.

Persistent or significant disability.

Other important medical events where the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes.

Congenital anomaly.

Birth defect.

Suspected Unexpected Serious Adverse Reactions: A serious adverse reaction that is suspected to be related to one of the investigational medicinal products and that is unexpected in relation to the reference safety information (product summary as detailed in the Summary of Product Characteristics (SmPC)).

Targeted synthetic DMARDs: https://pro.medicin.dk/Laegemiddelgrupper/Grupper/318875 .

Treatment Committee (TC):A committee comprising 5 clinical microbiologists, one from each region in Denmark (Capital Region, Region Zealand, - Southern Denmark, - Central Jutland, - Northern Jutland), as well as three infectious diseases consultants.

Uncomplicated PVO:Cases that do not fulfill the criteria for complicated PVO.

Uncontrolled HIV/AIDS: HIV-infection with a CD4 cell count below 300 cells/µL and HIV RNA > 50 copies/mL

Contributors

Coordinating Center, Sponsor institution. Department of Infectious Diseases

Copenhagen University Hospital, Rigshospitalet

Blegdamsvej 9

DK-2100 Copenhagen

Denmark

Correspondence to:

Coordinating Investigator

Zahra Persson Theilgaard

Consultant, PhD

Department of Infectious diseases, Copenhagen University Hospital, Rigshospitalet

Blegdamsvej 9

DK-2100 Copenhagen

Denmark

Phone: +4535451501

zahra.persson.theilgaard@regionh.dk

Sponsor:

Anne-Mette Lebech, Professor, Senior Consultant, MD, PhD, DSc

Department of infectious diseases, Copenhagen University Hospital, Rigshospitalet

Blegdamsvej 9

DK-2100 Copenhagen

Denmark

Phone: +4535451498

Email: anne-mette.lebech@regionh.dk

Project Coordinator

Hansina Debes

Nurse, MSc in Health Science

Department of Infectious diseases, Copenhagen University Hospital, Rigshospitalet

Blegdamsvej 9

DK-2100 Copenhagen

Denmark

Phone: +453547100

Email: hansina.debes@regionh.dk

Steering Committee

The steering committee comprises specialists in infectious diseases and clinical microbiology who have taken a particular interest in developing a national collaboration to promote clinical research in pyogenic vertebral osteomyelitis.

Anne-Mette Lebech, Professor, Senior Consultant, MD, PhD, DSc

Department of Infectious Diseases

Copenhagen University Hospital, Rigshospitalet

Zahra Persson Theilgaard, Consultant, MD, PhD

Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet

and Department of Internal Medicine, Infectious Diseases Unit, Zealand University Hospital,

Roskilde

Isik Somuncu Johansen, Professor, Senior Consultant, MD, DSc

Department of Infectious Diseases

Odense University Hospital

Nina Weis, Professor, Senior Consultant, MD, PhD

Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, and

Department of Clinical Medicine,

Faculty of Health and Medical Sciences,

University of Copenhagen

Pernille Ravn, Associate Professor, Senior Consultant, MD, PhD,

Department for Infectious Diseases

Copenhagen University Hospital, Herlev and Gentofte

Nis Pedersen Jørgensen, Consultant, MD, PhD

Department of Infectious Diseases

Aarhus University Hospital, Skejby

Kristian Schønning, Senior Consultant, Associate Professor, MD, DMSc

Department of Clinical Microbiology

Copenhagen University Hospital, Rigshospitalet

Collaborating Units and Local Investigators

Iben Ørsted, Senior Consultant, MD

Department of Infectious Diseases

Aalborg University Hospital

Kristina Öbrink-Hansen, Senior Consultant, MD, PhD

Department of Infectious Diseases

Gødstrup Hospital

Nis Pedersen Jørgensen, Consultant, MD, PhD

Department of Infectious Diseases

Århus University Hospital, Skejby

Morten Svensson, Senior Consultant, MD

Department of Infectious Diseases

Copenhagen University Hospital, Herlev and Gentofte

Peter Bernhard, Senior Consultant, MD PhD,

Department of Pulmonology and Infectious Diseases

North Zealand Hospital, Hillerød

Andreas Knudsen, Consultant, MD, PhD, DSc

Department of Pulmonology and Infectious Diseases

Copenhagen University Hospital, Bispebjerg

Nina Weis Professor, Senior Consultant, MD, PhD

Department of Infectious Diseases

Copenhagen University Hospital, Hvidovre

Isik S. Johansen, Professor, Senior Consultant, MD, DSc

Department of Infectious Diseases

Odense University Hospital

Zahra Persson Theilgaard, Consultant, MD, PhD.

Department of Medicine, Infectious Diseases Unit

Zealand University Hospital, Roskilde

Lone Wulff Madsen, Associate Professor, MD, PhD

Medical Department

Syghus Lillebelt, Kolding Hospital

Martin Skov Pedersen, MSc, PhD

Statens Serum Institut

Marc Stegger, Msc

Department of Microbiology and Infection Control

Statens Serum Institut

Treatment Committee

Kristian Schønning, Senior Consultant, Associate Professor, MD, DMSc

Department of Clinical Microbiology

Copenhagen University Hospital, Rigshospitalet

Jørgen Engberg, Senior Consultant, MD, DMSc

Department of Clinical Microbiology

Slagelse Hospital

Flemming Rosenvinge, Senior Consultant, MD

Department of Clinical Microbiology

Odense University Hospital

Thomas Greve, Senior Consultant, MD, PhD

Department of Clinical Microbiology

Århus University Hospital, Skejby

Jurgita Samulioniene, Senior Consultant, MD

Department of Clinical Microbiology

Ålborg University Hospital

Kurt Fuursted, Senior Consultant, DSc

Department for Bacteria, Parasites and Fungi

Statens Serum Institute

Andreas Knudsen, Consultant, MD, PhD, DSc

Department of Pulmonology and Infectious Diseases

Copenhagen University Hospital, Bispebjerg

Isik S. Johansen, Professor, Senior Consultant, MD, DSc

Department of Infectious Diseases

Odense University Hospital

Zahra Persson Theilgaard, Consultant, MD, PhD

Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet

and Department of Internal Medicine, Infectious Diseases Unit, Zealand University Hospital,

Roskilde

Data and Safety Monitoring Committee

Court Petersen, Professor, Senior Consultant, MD, DMSc

Department of Infectious Diseases

Odense University Hospital

Court Petersen, Professor, Senior Consultant, MD, DMSc

Department of Infectious Diseases

Odense University Hospital

Emil Loldrup Fosbøl, Professor, Senior Consultant, Ph.D.

Department of Cardiology

Copenhagen University Hospital, Rigshospitalet.

Endpoint Committee

Rikke Krogh-Madsen, Associate Professor, Senior Consultant, MD, PhD

Department of Infectious Diseases

Copenhagen University Hospital, Hvidovre

Merete Storgaard, Associate Professor, Senior consultant, MD, PhD

Department of Infectious Diseases

Århus University hospital, Skejby

Benny Dahl, Professor, Senior Consultant, MD, PhD, DMSc

SpineUnit, Department of Orthopedic Surgery

University Hospital of Copenhagen, Rigshospitalet

Roles and responsibilities

The steering committee members have developed the protocol in collaboration with input from the local investigators. The steering committee is responsible for the design and conduct of the trial as well as for trial completion, data analysis and interpretation. Appendix 1 has been developed by the treatment committee, while the sponsor has coordinated the effort. Thus, the study sponsor has been one of the key stakeholders of protocol development. It is the responsibility of the coordinating center to oversee, facilitate and coordinate conduct of the trail and ensure that sites receive appropriate information and feedback. Data collection and management as well as oversight of study sites has been delegated to the coordinating investigator.

Disclaimer

The funders have not had any role in study design, nor do they have any role in data collection, analysis, or interpretation or in the decision to submit for publication. Study patients will not receive any kind of payment for participating in the study.

Abbreviations

Antibiotic

Adverse event

C-reactive protein

Data and Safety Monitoring Committee

Electronic Case Report Form

Intravenous

Magnetic Resonance Imaging

Methicillin Resistant Staphylococcus Aureus

Positron Emission Tomography/Computed Tomography

Positron Emission Tomography/Magnetic Resonance Imaging

Pyogenic Vertebral Osteomyelitis

Serious adverse event

Suspected unexpected serious adverse reaction

Tuberculosis

Treatment Committee

White blood cell count

Authors' contributions

AML and ISJ conceptualized the study. AML, ISJ, NW, PR, and ZPT designed the study. AML is overall responsible for study conduct as representative of the sponsor institution. ZPT is the coordinating investigator and has been responsible for drafting and updating the study protocol. All authors have provided feedback and critical review of the study protocol and current manuscript. All authors read and approved the final manuscript.

Funding

Open access funding provided by Copenhagen University. Funding to cover all aspects of the trial has been received from the Novo Nordisk Foundation, Sygeforsikringen “danmark” and Regionernes Medicin-og Behandlingspulje. The grants will be administered through research accounts at Copenhagen University Hospital, Rigshospitalet, and will cover expenses related to study administration and procedures, laboratory procedures and salary.

Data availability

Beginning 6 months and ending 3 years after publication, an anonymized dataset can be shared with qualified researchers, who provide a methodologically sound proposal for a post hoc study assessed and approved by the members of the Steering Committee. The study protocol, informed consent form, clinical study report and analytic code can also be shared upon request.

Declarations

Ethics approval and consent to participate

The study has received approval from the Danish Medical Research Ethics Committees and the Danish Medicines Agency. Date of approval 27-11-2023, reference number EU CT Nr 2023–507617-96-01. Written, informed consent to participate will be obtained from all study participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Isik Somuncu Johansen and Anne-Mette Lebech shared last authorship.

References

1. Zimmerli W. Clinical practice. Vertebral osteomyelitis. N Engl J Med. 2010;362(11):1022–9.

2. Kehrer M, Pedersen C, Jensen TG, Lassen AT. Increasing incidence of pyogenic spondylodiscitis: a 14-year population-based study. J Infect. 2014;68:313–20.

3. Kehrer M, Pedersen C, Gorm Jensen T, Hallas J, Lassen AT. Clinical study increased short-and long-term mortality among patients with infectious spondylodiscitis compared with a reference population. Spine J. 2015;15:1233–40.

4. Geisler Crone C, Mose Tetens M, Bengaard Andersen A, Obel N, Lebech AM. Clinical characteristics of pyogenic vertebral osteomyelitis, and factors associated with inadequate treatment response. Int J Infect Dis. 2021;1;108:487–93.

5. Dragsted C, Aagaard T, Ohrt-Nissen S, Gehrchen M, Dahl B. Mortality and health-related quality of life in patients surgically treated for spondylodiscitis. J Orthop Surg (Hong Kong). 2017;25(2):2309499017716068. 10.1177/2309499017716068. PMID: 28639530.

6. Kinamon T, Dagher M, Park L, Ruffin F, Fowler VG, Maskarinec SA. Risk factors and outcomes of hematogenous vertebral osteomyelitis in patients with Staphylococcus aureus bacteremia. Clin Infect Dis. 2023;77(9):1226. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10640688/ . Cited 2025 Jan 21.

7. Aagaard T, Roed C, Dahl B, Obel N. Long-term prognosis and causes of death after spondylodiscitis: A Danish nationwide cohort study. 2015;48(3):201–8. http://dx.doi.org.ep.fjernadgang.kb.dk/103109/2374423520151103897 .

8. Kehrer M, Hallas J, Bælum J, Jensen TG, Pedersen C, Lassen AT. Reduced ability to work both before and after infectious spondylodiscitis in working-age patients. Infect Dis. 2017;1;49(2):95–103.

9. Berbari EF, Kanj SS, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis. 2015;61(6):e26-46.

10. Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet. 2015;385(9971):875–82. 10.1016/S0140-6736(14)61233-2. Epub 2014 Nov 5. PMID: 25468170.

11. Park KH, Cho OH, Lee JH, Park JS, Ryu KN, Park SY, et al. Optimal duration of antibiotic therapy in patients with hematogenous vertebral osteomyelitis at low risk and high risk of recurrence. Clin Infect Dis. 2016;62(10):1262–9.

12. Spondylodiscitis Diagnostik og behandling version 2, 2025. 2025. Available from: https://infmed.dk/site/tools/download.php?UID=c9fbe386d5fd577eb77cf6f9085bfada8e6a3153 . Cited 2025 Mar 21.

13. Miliani K, Taravella R, Thillard D, Chauvin V, Martin E, Phanie Edouard S, et al. Peripheral venous catheter-related adverse events: evaluation from a multicentre epidemiological study in France (the CATHEVAL Project). 2017.

14. Kornbau C, Lee KC, Hughes GD, Firstenberg MS. Central line complications. Int J Crit Illn Inj Sci. 2015;5(3):170.

15. Forrester JD, Maggio PM, Tennakoon L. Cost of health care-associated infections in the United States. J Patient Saf. 2022;18(2):E477–9.

16. Nosocomial infections in medical intensive care units in the United States. Available from: https://oce-ovid-com.ep.fjernadgang.kb.dk/article/00003246-199905000-00020/HTML . Cited 2023 Feb 27.

17. Walker IV FB, Novack DH, Kaiser DL, Knight A, Oblinger P. Anxiety and depression among medical and surgical patients nearing hospital discharge. J Gen Intern Med. 1987;2(2):99–101.

18. Chen Y, Almirall-Sánchez A, Mockler D, Adrion E, Domínguez-Vivero C, Romero-Ortuño R. Hospital‐associated deconditioning: not only physical, but also cognitive. Int J Geriatr Psychiatry. 2022;37(3):1–13.

19. Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012;54(3):393–407. 10.1093/cid/cir842. Epub 2011 Dec 12. PMID: 22157324; PMCID: PMC3491855.

20. Iversen K, Ihlemann N, Gill SU, Madsen T, Elming H, Jensen KT, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. New England J Med. 2019;380(5):415–24.

21. Pries-Heje MM, Wiingaard C, Ihlemann N, Gill SU, Bruun NE, Elming H, et al. Five-year outcomes of the partial oral treatment of endocarditis (POET) Trial. New England J Med. 2022;386(6):601–2.

22. Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, et al. Oral versus intravenous antibiotics for bone and joint infection. New England J Med. 2019;380(5):425–36.

23. Eichenberger EM, De Vries CR, Ruffin F, Sharma-Kuinkel B, Park L, Hong D, et al. Microbial cell-free DNA identifies etiology of bloodstream infections, persists longer than conventional blood cultures, and its duration of detection is associated with metastatic infection in patients with Staphylococcus aureus and gram-negative bacteremia. Clin Infect Dis. 2022;74(11):2020.

24. Goggin KP, Gonzalez-Pena V, Inaba Y, Allison KJ, Hong DK, Ahmed AA, et al. Evaluation of plasma microbial cell-free DNA sequencing to predict bloodstream infection in pediatric patients with relapsed or refractory cancer. JAMA Oncol. 2020;6(4):552.

25. Howard P, Covino M, Daly AK. Relevance of pharmacogenomics to the safe use of antimicrobials. Antibiotics (Basel). 2023;12(3):425. 10.3390/antibiotics12030425. PMID: 36978292; PMCID: PMC10044203.

26. Wang CW, Arni I, Preclaro C, Lin WH, Chung WH. An updated review of genetic associations with severe adverse drug reactions: translation and implementation of pharmacogenomic testing in clinical practice. Front Pharmacol. 2022;13:886377. 10.3389/fphar.2022.886377. PMID: 35548363; PMCID: PMC9081981.

27. Stocco G, Lucafò M, Decorti G. Pharmacogenomics of antibiotics. Int J Mol Sci. 2020;21(17):1–20.

28. Haugaard AK, Marquart H V., Kolte L, Ryder LP, Kehrer M, Krogstrup M, et al. Quantitative B-lymphocyte deficiency and increased TCRγδ T-lymphocytes in acute infectious spondylodiscitis. Sci Rep. 2018;8(1):15174.

29. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473.

30. Oton-Gonzalez L, Mazziotta C, Iaquinta MR, Mazzoni E, Nocini R, Trevisiol L, et al. Genetics and epigenetics of bone remodeling and metabolic bone diseases. Int J Mol Sci. 2022;23(3):1500.

31. Treibich C, Ventelou B. Validation of a short-form questionnaire to check patients’ adherence to antibiotic treatments in an outpatient setting. Eur J Public Health. 2017;27(6):978–80.

32. Feng YS, Kohlmann T, Janssen MF, Buchholz I. Psychometric properties of the EQ-5D-5L: a systematic review of the literature. Qual Life Res. 2021;30(3):647–73.

33. Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet. 2015;385(9971):875–82.

34. Lægemiddelstyrelsen (The Danish Medicines Agency). Lægemiddelstyrelsens vejledning om risikotilpasset bivirkningsregistrering og rapportering i kliniske forsøg med lægemidler under forordning (EU) nr. 536/2014. Version 1.0. 2023;1–16. Available from: https://laegemiddelstyrelsen.dk/da/nyheder/2023/risikotilpasset-bivirkningsregistrering-og-rapportering-i-kliniske-forsoeg-med-laegemidler-er-nu-muligt/~/media/8E1AFBB2C13C47E19D088765F917116C.ashx . Accessed Sept 2024.

35. Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet. 2005;365(9471):1657–61.

Associated Data

Supplementary Materials

Additional file 1. SPIRIT checklist.

Additional file 2. Appendixes.

Data Availability Statement

Beginning 6 months and ending 3 years after publication, an anonymized dataset can be shared with qualified researchers, who provide a methodologically sound proposal for a post hoc study assessed and approved by the members of the Steering Committee. The study protocol, informed consent form, clinical study report and analytic code can also be shared upon request.