Broad-spectrum Antibiotic Prophylaxis in Tumor and Infected Orthopedic Surgery (BAPTIST)

Broad-spectrum Antibiotic Prophylaxis in Tumor and Infected Orthopedic Sur-gery - the Prospective-randomized, Microbiologist-blinded, Stratified, Superiority Trials - BAPTIST Trials

The perioperative antibiotic prophylaxis is evidence-based in orthopedic surgery. While its duration ranges from a single dose to three doses throughout the world, the choice of the prophylactic agents is undisputed. Worldwide, the surgeons use 1st or 2nd-generation cephalosporins (or vancomycin in some cases).

However, there are particular clinical situation with a high risk of antibiotic-resistant surgical site infections (SSI); independently of the duration of adminis-tered prophylaxis. These resistant SSI's occur in contaminated wounds, or during surgery under current therapeutic antibiotics, and base on "selection" by antibiotics used for therapy or for prophylaxis.

Study Overview

• Status: Recruiting
• Conditions: Microbial Colonization; Surgical Site Infection; Antibiotic Resistant Infection
• Intervention / Treatment: Drug: Standard antibiotic prophylaxis

Detailed Description

The perioperative antibiotic prophylaxis is evidence-based for the majority of orthopedic surgeries. While the debate of its duration and timing (single-dose versus triple-dose; before or after the intraoperative microbiological sampling) may continue, no clinicians doubt on the efficiency of the recommended prophylactic agents; that are mostly 1st or 2nd-generation cephalosporins, co-amoxiclav or other exceptional agents in cases of (pseudo)-allergy. However. and traditionally, up to the half of all detected pathogens of orthopedic SSI's are not covered by the prior prophylactic regimens: e.g. SSIs due to methicillin-resistant cocci or non-fermenting Gram-negative rods in orthopedic surgery.

Additionally, orthopedic surgeons operating selected patient populations (neoplasms, open fractures, postoperative wound dehiscence9, diabetic foot infections or already infected body sites) experience a high risk of prophylactic-resistant pathogens, or pathogens resistant to current therapeutic antibiotics regimens. At least 10% of all new intraoperative tissue samples, during iterative surgical debridement, yield (new) pathogens unknown to the clinicians.

This is due to selection by prophylactic or therapeutic antibiotics, which only kill the previously detected pathogens, but left over newly introduced contaminants, remnant parts of partially-diagnosed polymicrobial infections; ultimately leading to a new SSIs occurring during therapy for the first infection at the orthopedic site. This selection is unpredictable involving both Gram-positive skin pathogens as well as (multi) resistant Gram-negative rods.From a microbiological point of view, only a maximal Gram-negative coverage, alongside with a large Gram-negative coverage, would cover these selections.

The literature is in-existing how to prevent these selections. Most clinicians just continue with the standard prophylactic recommendation, or the current thera-peutic antibiotic regimen. Theoretically, clinicians cannot exclude that these selected patient populations eventually might profit from a broad-spectrum prophylaxis.

The BAPTIST trials only concern the perioperative antibiotic prophylaxis in selected situations of orthopedic surgery: tumor surgery, debridement for postoperative dehiscent wounds, debridement under antibiotics, open fractures, skin colonization with multidrug-resistant bacteria, plus, as a control; spine surgery in selected multimorbid patients. The investigators alternately randomize the standard prophylaxis (or by continuing the current antibiotic treatment) to the additional broad-spectrum single-shot of vancomycin 1g IV & single-shot of gentamicin 5 mg/kg intravenously; before an eventual intraoperative sampling. End-of-Treatment (EOT) and/or Test-of-Cure (TOC) occur latest at the 6-week's surgical control visit. The rest of the hospital stay, treatment, the use of negative-pressure vacuum therapy, other interventions, local antibiotic therapies; therapies or procedure are at the discretion of the treating clinicians.

The investogators will randomize surgical interventions defined by the inclusion criteria in a prospective-alternating scheme (1:1) according to the scheduled position in the operating theatres. The anesthetists (or the nurses at the hospitalization units) the will administer the standard prophylaxis (or the therapeutic antibiotics) alone, or with the addition of the single-shot broad-spectrum prophylaxis regimen composed of vancomycin and gentamicin. In case of clinical suspicion of infection or massive contamination, the surgeons will perform at least three microbiological intraoperative tissue samples. Each surgery counts as an independent event. If a patient is debrided several times, he/she can have different prophylaxis regimens during each of the interventions. After the prophylactic regimen, the clinicians are free to continue with a targeted or empirical therapeutic antibiotic regimen. The antibiotic therapy per se is not an objective of this current trials.

The treatment period includes the following daily study visits:

• Visit 1 - Enrollment (Day 1)
• EOT (end of microbiological cultures) - Day 14 (+/- 3 days)
• TOC (clinical surgical control) - Day 42 (+/- 14 days)
• Follow-up (telephone) for implant-related surgery - 1 year (+/- 2 months)

• Study Type: Interventional
• Enrollment (Anticipated): 414
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Zurich, Switzerland, 8008
    • Recruiting
    • Balgrist University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Age ≥ 18 years
• Surgery under current or recent therapeutic antibiotics (antibiotic-free window <14 days and past antibiotic prescription >4 days)
• Surgery for open fractures and wounds; including 2nd and 3rd looks
• Potentially contaminated wound revision in the operating theatre
• Tumor (oncologic) surgery (if prior radiotherapy and/or bone involvement)
• Spine surgery with ASA-Score >= 3 points, sacral involvement, or re-vision surgery
• Known skin colonization with multidrug-resistant Gram-negative bacteria

Exclusion Criteria:

• Inability to understand the study procedure for linguistic or cognitive rea-sons
• Surgery without intraoperative microbiological samples
• Allergy or major intolerance to vancomycin and/or gentamicin
• Anticipated clinical follow-up of less than 6 weeks after inclusion
• Pregnant or breastfeeding women
• Known carriage of multiresistant Gram-negative bacteria in the urine or anal region

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard prophylaxis arm; The standard prophylaxis consists of one to three intravenous doses of cefuroxime 1.5 g intravenously; or cefuroxim 3g if obesity > 120 kg or a BMI > 35 kg/m2; or vancomycin 1 g or clindamycin 600 mg in case of intolerance to cephalosporins In patients alrady under current therapuetic antibiotic therapy, continuation of that therapuetic antibiotic regimen	Drug: Standard antibiotic prophylaxis; One to three intravenous doses of cefuroxime 1.5 g intravenously; or 3g if obesity; or vancomycin 1 g or clindamycin 600 mg; if allergy. Continuation of eventual current therapeutic antibiotc regimens for any infection
Experimental: Innovative prophylaxis arm; Additional single-shot perioperative antibiotic prophylaxis with Broad-spectrum prophylaxis: vancomycin 1 g & gentamicin 5 mg/kg.	Drug: Standard antibiotic prophylaxis; One to three intravenous doses of cefuroxime 1.5 g intravenously; or 3g if obesity; or vancomycin 1 g or clindamycin 600 mg; if allergy. Continuation of eventual current therapeutic antibiotc regimens for any infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Surgical Site Infections (SSI) at 6 weeks for surgeries without implant; and 1 year for surgeries with implant	Assessment of SSI at the clinical controls according to clinical criteria in the literature (pus, discharge, pain, inflammation, several deep tissue microbiological cultures	6 weeks postoperatively, or 1 year postoperatively in case of implant-related orthopedic surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of antibiotic-resistant pathogens in the deep surgical site of the study patients; in relation to the prior antibiotic prophylaxis or the current therapeu-tic antibiotic therapy	Assessments of antibiotic resistance of pathogens according to standard susceptibilty testing in the Microbiological Laboratory	6 weeks postoperatively, or 1 year postoperatively in case of implant-related orthopedic surgery
Incidence of revision surgery for non-infections reasons within 6 weeks	Unplanned revision surgery in the operating theatre for any reasons	6 weeks postoperatively
Proportion of the change of antibiotic therapy based on intraoperative findings	Asssesment in the medical files. Have therapeutic antibiotics been changed according to new intraoperative bacterial culture findings	6 weeks postoperatively
Incidence of dverse events and global costs of therapeutic antibiotics (if any)	If there is therapeutic antibiotc treatment necessary, the investigators assess the drugs, the adverse events and the global costs related to the antibiotc treatment. The costs are the global (overall) hospitalizations costs in Swiss Francs.	6 weeks postoperatively, or 1 year postoperatively in case of implant-related orthopedic surgery
Incidence of non-SSI infections within 6 weeks (e.g. urine infections)	Assessment of all nosocomial and community-acquired infections ocrruging in the immediate postoperative period and relate them to prior perioperative antibiotic prophylaxis	6 weeks postoperatively
Incidence of skin and body colonization with Gram-negative multi-resistant bacteriaweeks (if there are any samples)	Assessment of the impact of the priorantibiotic prophylaxis on the body colonization with multiresistant bacteria of concern for infection control	4-6 weeks postoperatively

Collaborators and Investigators

• Sponsor: Balgrist University Hospital

Publications and helpful links

General Publications

• Uckay I, Hoffmeyer P, Lew D, Pittet D. Prevention of surgical site infections in orthopaedic surgery and bone trauma: state-of-the-art update. J Hosp Infect. 2013 May;84(1):5-12. doi: 10.1016/j.jhin.2012.12.014. Epub 2013 Feb 14.
• Wuarin L, Abbas M, Harbarth S, Waibel F, Holy D, Burkhard J, Uckay I. Changing perioperative prophylaxis during antibiotic therapy and iterative debridement for orthopedic infections? PLoS One. 2019 Dec 18;14(12):e0226674. doi: 10.1371/journal.pone.0226674. eCollection 2019.
• Jamei O, Gjoni S, Zenelaj B, Kressmann B, Belaieff W, Hannouche D, Uckay I. Which Orthopaedic Patients Are Infected with Gram-negative Non-fermenting Rods? J Bone Jt Infect. 2017 Jan 15;2(2):73-76. doi: 10.7150/jbji.17171. eCollection 2017.
• Muller D, Kaiser D, Sairanen K, Studhalter T, Uckay I. Antimicrobial Prophylaxis for the Prevention of Surgical Site Infections in Orthopaedic Oncology - A Narrative Review of Current Concepts. J Bone Jt Infect. 2019 Oct 15;4(6):254-263. doi: 10.7150/jbji.39050. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: August 11, 2022
• First Submitted That Met QC Criteria: August 12, 2022
• First Posted (Actual): August 16, 2022

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 27, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Selection; Perioperative antibiotic prophylaxis; High Risk patients; Ranndomized-Controlled Trial
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Disease Attributes; Wound Infection; Infections; Communicable Diseases; Surgical Wound Infection; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: BASEC 2022-00800

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators might share anonomyzed key elements (data) upon scientific request to the corresponding person
• IPD Sharing Time Frame: After the intermi analyses
• IPD Sharing Access Criteria: The ivestigators might bilaterally share anonomyzed key elements (data) upon scientific request to the corresponding person
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No