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

Abstract

Introduction: Prosthetic joint infections (PJIs) are disastrous complications for patients and costly for healthcare organisations. They may promote bacterial resistance due to the extensive antibiotic use necessary in the PJI treatment. The PJI incidence is estimated to be 1%-3%, but the absolute numbers worldwide are high and increasing as large joint arthroplasties are performed by the millions each year. Current treatment algorithms, based on implant preserving surgery or full revision followed by a semitailored antibiotic regimen for no less than 2-3 months, lead to infection resolution in approximately 60% and 90%, respectively. Antibiotic choice is currently guided by minimum inhibitory concentrations (MICs) of free-living bacteria and not of bacteria in biofilm growth mode. Biofilm assays with relatively rapid output for the determination of minimum biofilm eradication concentrations (MBECs) have previously been developed but their clinical usefulness have not been established.

Methods and analysis: This single-blinded, two-arm randomised study of hip or knee staphylococcal PJI will evaluate 6-week standard of care (MIC guided), or an alternative antibiotic regimen according to an MBEC-guided-based decision algorithm. Sixty-four patients with a first-time PJI treated according to the debridement, antibiotics, and implant retention principle will be enrolled at a single tertiary orthopaedic centre (Sahlgrenska University Hospital). Patients will receive 14 days of standard parenteral antibiotics before entering the comparative study arms. The primary outcome measurement is the proportion of changes in antimicrobial regimen from first-line treatment dependent on randomisation arm. Secondary endpoints are unresolved infection, how microbial properties including biofilm abilities and emerging antimicrobial resistance correlate to infection outcomes, patient reported outcomes and costs with a 12-month follow-up.

Ethics and dissemination: Approval is received from the Swedish Ethical Review Authority, no 2020-01471 and the Swedish Medical Products Agency, EudraCT, no 2020-003444-80.

Trial registration number: ClinicalTrials.gov ID: NCT04488458.

Keywords: bacteriology; hip; infection control; knee.

Conflict of interest statement

Competing interests: All governmental and foundational fundings have been paid to the institutions of authors MT, JANT and SS as disclosed above. OR is an unpaid committee member of the International Society of Arthroplasty Registries Steering committee and is receiving institutional research support from Pfizer and has received a few lecture payments from LINK Sweden. SS is an unpaid member of the Reference group on Clinical Bacteriology in the Swedish Society of Clinical Microbiology and is also receiving research grants from the Healthcare Committee, Region Västra Götaland, Gothenburg, Sweden.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Decision tree on antibiotic combinations other than standard of care in the comparator study arm. MBEC threshold for substituting with second-line or when applicable third-line antibiotic combinations; RIF: MBEC/MIC>8, LEVO: MBEC/MIC>5, FUS: MBEC/MIC>3, CLI: MBEC/MIC>4, LZD: MBEC/MIC>2, SXT: MBEC>MIC. *Interpreted as more effective than. CLI, clindamycin; FUS, fusidate; LEVO, levofloxacin; LZD, linezolid; MBEC, minimum biofilm eradication concentration; MIC, minimum inhibitory concentration; RIF, rifampin; SXT, trimethoprim/sulfamethoxazole.

Figure 2

Representation of the custom-made microbroth dilution plate for the determination of minimum inhibitory concentration and minimum biofilm eradication concentration. The susceptibility plate contains nine antimicrobial agents in doubling increasing concentrations (mg/L): levofloxacin (LEVO), clindamycin (CLI), oxacillin+2% NaCl (OXA+), fusidate (FUS), linezolid (LZD), rifampin (RIF), trimethoprim/sulfamethoxazole (SXT), vancomycin (VAN) and cefoxitin (FOX). In the first column, two wells for positive and negative controls are included, and the last four wells are empty since these pegs containing biofilms are used for colony-forming unit counting.

Figure 3

Schematic summary and timeline of the study. Informed consent will be obtained and block randomisations undertaken during the postoperative hospital stay. The oral antibiotic regimen will take 6 weeks, and the patient will be followed up to 1 year postoperatively for relapse or reinfection events. DAIR, debridement, antibiotics and implant retention; MBEC, minimum biofilm eradication concentration; MIC, minimum inhibitory concentration; SOC, standard of care.