Susceptibility Testing of Biofilm to Guide Treatment of Periprosthetic Joint Infections

NCT04488458 | Unknown

• 1 other identifier: 2020-01471
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The overall purpose of this clinical treatment research project is to explore novel diagnostics that can guide the treatment of infections associated to orthopaedic implants, in order to improve patient outcomes and reduce the development of antibiotic resistance. The project aims are: (i) To improve the current diagnostic approaches and treatments of periprosthetic joint infections (PJI) (ii) To investigate the pathogenesis of PJI through the characterization of the virulence carried by the causative pathogens This multidisciplinary project addresses implant-associated infection and its contribution to increasing antibiotic resistance. Both lead to longer hospital stays, higher medical costs and increased morbidity and mortality. Antibiotic resistance is globally considered as one of the greatest and most urgent risk in medicine. Implant-associated infections are commonly caused by biofilms. Biofilms can be described as 'a community of bacterial cells connected by their secreted extracellular matrix'. Since antibiotics are designed to fight planktonic free-living bacteria, studying antibiotic resistance in biofilm communities poses a paradigm shift. Furthermore, bacteria in biofilms are up to 1000 times more resistant to antibiotics than planktonic bacteria. Mechanisms involved in a biofilm infection also play a crucial role in the development of antibiotic resistance. Hospital-acquired infections are the fourth leading cause of disease and 70% are associated with medical implants and caused by staphylococcal biofilms. In addition, the level of antimicrobial resistance in bacteria causing implant-associated infections has increased worldwide, leaving patients with fewer treatment options. In this study the investigators will randomize patients with PJI to either standard MIC susceptibility or MIC and MBEC susceptibility guided treatment with oral antibiotic combinations; (i) Non cell wall active standard of care antibiotic combination (MIC-guided) for 6 weeks. (ii) Or; non cell wall active antibiotic combination according to a MBEC-based decision algorithm for 6 weeks. In this pilot project, the primary endpoint is how often treatment changes with the MBEC susceptibility testing compared to only MIC-susceptibility testing.

Conditions

Prosthetic Joint Infection; Prosthetic Infection; Hip Prosthesis Infection; Knee Prosthesis Infection

Keywords

staphylococci; biofilm; antimicrobial resistance; periprosthetic infection

Outcome Measures

Primary Outcomes (1)

• Number of changes in antimicrobial regimen other than standard of care

  Proportions of antimicrobial regimens other than standard of care through application of proposed MBEC-algorithm.

  6 weeks

Secondary Outcomes (9)

• Repeat procedure, relapse or reinfection

  12 months

• Oxford Hip Score

  12 months

• EQ-5D

  12 months

• Time to revision

  12 months

• Inpatient care

  Up to 12 months

Other Outcomes (1)

• Correlation between the virulence properties of the causative bacteria and patient outcome (infection resolution versus recurrent infection)

  36 months

Study Arms (2)

MBEC and MIC susceptibility testing

EXPERIMENTAL

For all administered antimicrobials staphylococcal strains must be susceptible in disc diffusion tests/MIC, regardless of MBEC-level. Antibiotic combinations will be selected from 5 already recommended non-cell wall active anti-staphylococcal antibiotics with high per-oral bio-availabilities and acceptable bone penetration used in the treatment of PJIs: rifampicin, fusidic acid, ciprofloxacin/levofloxacin and clindamycin. MBEC cut-off for replacement with 2nd or 3rd line antibiotic: RIF MBEC/MIC \> 8; LEV MBEC/MIC \> 5; FUS MBEC/MIC \> 3; CLI MBEC/MIC \> 4; LIN MBEC/MIC \> 2; T/S MBEC \> MIC Second line of treatment: RIF and Fusidic acid 500 mg TID (ter in die) RIF and Clindamycin 450 - 600 mg TID LEV and Fusidic acid 500 mg TID LEV and Clindamycin 450 mg TID Third line of treatment: Linezolid 600 mg BID (bis in die) Sulfamethoxazole/Trimethoprim 800/160 mg TID Clindamycin 450 mg TID and Fusidic acid 500 mg TID

Diagnostic Test: MIC or MBEC+MIC based treatment algorithm

MIC susceptibility testing

ACTIVE COMPARATOR

If the causative bacterium is susceptible according to MIC diagnostics, the patient will follow the first line of treatment: Rifampicin 750-900 mg/day + Levofloxacin 750 mg BID

Diagnostic Test: MIC or MBEC+MIC based treatment algorithm

Interventions

MIC or MBEC+MIC based treatment algorithm DIAGNOSTIC_TEST

i) Non cell wall active standard of care antibiotic combination (MIC-guided) for 6 weeks. ii) Non cell wall active antibiotic combination according to a MBEC-based decision algorithm for 6 weeks.

MBEC and MIC susceptibility testing; MIC susceptibility testing

Eligibility Criteria

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

You may qualify if:

• first PJI in hip or knee according to Musculoskeletal Infection Society (MSIS) definitions
• first DAIR
• mono-microbial staphylococcal infection
• days of intravenous treatment with either cloxacillin or vancomycin
• standardized administration of local antibiotics

You may not qualify if:

• allergy/previous toxic event/unacceptable drug interaction to most effective antibiotic combination according to either MIC or MBEC
• severe drug interactions to MBEC-guided compound

Sponsors & Collaborators

• Vastra Gotaland Region: lead
• Göteborg University: collaborator

Study Sites (1)

Ortopedi, Sahlgrenska University Hospital

Mölndal, Sweden

RECRUITING

Related Publications (2)

• Zaborowska M, Tillander J, Branemark R, Hagberg L, Thomsen P, Trobos M. Biofilm formation and antimicrobial susceptibility of staphylococci and enterococci from osteomyelitis associated with percutaneous orthopaedic implants. J Biomed Mater Res B Appl Biomater. 2017 Nov;105(8):2630-2640. doi: 10.1002/jbm.b.33803. Epub 2016 Oct 25.

  PMID: 27779811 BACKGROUND

• Tillander JAN, Rilby K, Svensson Malchau K, Skovbjerg S, Lindberg E, Rolfson O, Trobos M. Treatment of periprosthetic joint infections guided by minimum biofilm eradication concentration (MBEC) in addition to minimum inhibitory concentration (MIC): protocol for a prospective randomised clinical trial. BMJ Open. 2022 Sep 15;12(9):e058168. doi: 10.1136/bmjopen-2021-058168.

  PMID: 36109038 DERIVED

MeSH Terms

Interventions

Microbial Sensitivity Tests

Intervention Hierarchy (Ancestors)

Microbiological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Drug Evaluation, Preclinical; Evaluation Studies as Topic

Central Study Contacts

Ola Rolfson, Professor

CONTACT

+46 313430852; ola.rolfson@vgregion.se

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2020
• First Posted: July 28, 2020
• Study Start: August 15, 2021
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2023
• Last Updated: August 24, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)