Linezolid or Vancomycin Surgical Site Infection Prophylaxis

Anesthesia and surgical guidelines recommend the administration of a surgical antibiotic prophylaxis for patients undergoing "clean" surgery. The prescribed antibiotic should target the bacteria most commonly found in surgical site infections (SSIs) and the duration of administration should not exceed 24 hours to minimize the ecological risk of bacterial resistance emergence.

Surgical site infections are devastating complications occurring after surgery. They can lead to prolonged and burdensome duration of hospitalization, resulting in impaired outcomes and additional costs.

Many infections are associated with Gram positive bacteria, mainly Staphylococcus aureus and Staphylococcus spp with negative coagulase. Large European cohorts reported that less than 10% of SSIs were associated with Gram negative bacteria, justifying the use of 1st and 2nd generation cephalosporin, clindamycin and vancomycin as surgical antibiotic prophylaxis.

Guidelines provide a framework for the administration of surgical antibiotic prophylaxis but protocols are discussed at the local level with an agreement between surgeons, anesthesiologists, infectious diseases specialists, microbiologists and pharmacists. They are subject to economic analyses, including head-to-head comparisons of different options. Their effectiveness is regularly re-evaluated by measuring the rates of SSIs and the microorganisms responsible for infectious complications after surgery.

The majority of interventions required the use of first or second generation cephalosporins as surgical antibiotic prophylaxis. For patients with allergy to beta-lactams, clindamycin and vancomycin are proposed as alternatives. In the patients with methicillin-resistant S. aureus (MRSA) colonization or if those at risk of developing MRSA-associated SSI (hospital ecology, previous antibiotic treatment), only vancomycin is recommended. Actually, clindamycin was found to be less effective than beta-lactams or vancomycin in reducing the risk of SSI; the reported odds ratios (OR) for SSIs as compared to cefazolin range from an OR of 1.38 (95%CI 1.11 to 1.71) to OR 3.45 (95% CI 1.84 to 6.47).

Vancomycin is a large glycopeptide molecule, effective against a wide variety of Gram positive bacteria. The pharmacokinetics and pharmacodynamics (PK/PD) of vancomycin is complex, involving multicompartmental models. Its tissue absorption varies according to the level of tissue inflammation. It is exclusively administered via intravenous route. This is a difficult molecule to handle: specific international guidelines for its management have been published. In surgical antibiotic prophylaxis, French guidelines recommend a single loading dose infusion of vancomycin. It is recommended that loading doses of vancomycin should be administered as a low-rate infusion to mitigate infusion-related adverse events such as red-man syndrome (rate of 10-15 mg/min representing ≥1 hour for 1000 mg). Despite decades of use, vancomycin dosing regimens are still debated. Vancomycin dosing is commonly based on the actual patient body weight, although the volume of distribution of vancomycin is not proportional to weight. Therefore, as loading dose should lead to a rapid attainment of therapeutic concentrations, high doses (30 mg/kg) have been proposed for surgical antibiotic prophylaxis with a capping threshold of 2000 mg to avoid overdosing and risk of acute renal failure. These doses rapidly achieve the area under the curve (AUC) over the minimal inhibitory concentration (MIC) (AUC/MIC) targets, assuming a MIC ≤1mg/L for MRSA. Such high doses require prolonged infused time (at least two hours) and the administration should be terminated 30 minutes prior to surgery. This recommendation can lead to suboptimal administration times, delays in surgery and may also preclude the use of vancomycin in outpatient surgery. A U.S cohort reported that vancomycin was administered in 64% of cases outside national and institutional standards and incomplete administration of vancomycin has been associated with higher rates of SSI. Furthermore, in a nationwide US sample published, half of the patients receiving vancomycin were underdosed, which was associated with an increased risk of SSI.

Linezolid is a synthetic antibiotic from the oxazolidinone class. By binding to the rRNA on the 30S and 50S ribosomal subunits, it inhibits the bacterial synthesis. It is therefore a bacteriostatic antibiotic approved for the treatment of both methicillin susceptible S. aureus (MSSA) and MRSA infections. It also covers a broad spectrum of Gram positive bacteria. Its pharmacokinetics allows rapid intravenous infusion, with achievement of peak plasma concentrations within 30 minutes. Linezolid has also been shown to penetrate rapidly into bone and soft tissue of the surgical site during hip surgery. A large Cochrane meta-analysis reported that linezolid was superior to vancomycin in skin infections, including MRSA infections, albeit with low quality evidence.

We therefore hypothesized that linezolid can be used instead of vancomycin for beta-lactam allergic patients and patients at risk of MRSA-associated SSI in general surgery.

• Assessment of SSIs rates in all patients after 365 days [Time frame: 365 after surgery]
• Comparaison of treatment compliance [Time frame: Day-365]
• Number of days from hospital admission to surgery, from surgery to discharge, from inclusion to discharge [Time frame: Day-365]
• Mortality rates In-hospital, at day-30, at day-90 and at day-365; [Time frame: day-30, at day-90 and at day-365]
• Antibiotic-free days during the 30-days following surgery [Time frame: Day-30]
• Rates of Gram positive and Gram negative infections of any sites requiring antibiotic treatments [Time frame: Day-365]
• Rates of MSSA and MRSA infections [Time frame: Day-365]
• Preference-based utility score [Time frame: Day-365]
• Total costs of care during the 30-day study period and associated costs over the 365-day study period in all patients; [Time frame: 30-Day and 365-day]