Multicentre randomised double-blind placebo controlled trial of combination vancomycin and cefazolin surgical antibiotic prophylaxis: the Australian surgical antibiotic prophylaxis (ASAP) trial

Abstract

IntroductionResistant Gram-positive organisms, such as methicillin-resistant staphylococci, account for a significant proportion of infections following joint replacement surgery. Current surgical antimicrobial prophylaxis guidelines recommend the use of first-generation or second-generation cephalosporin antibiotics, such as cefazolin. Cefazolin, however, does not prevent infections due to these resistant organisms; therefore, new prevention strategies need to be examined. One proposed strategy is to combine a glycopeptide antibiotic with cefazolin for prophylaxis. The clinical benefit and cost-effectiveness of this combination therapy compared with usual therapy, however, have not been established.Methods and analysisThis randomised, double-blind, parallel, superiority, placebo-controlled, phase 4 trial will compare the incidence of all surgical site infections (SSIs) including superficial, deep and organ/space (prosthetic joint) infections, safety and cost-effectiveness of surgical prophylaxis with cefazolin plus vancomycin to that with cefazolin plus placebo. The study will be performed in patients undergoing joint replacement surgery. In the microbiological sub-studies, we will examine the incidence of SSIs in participants with preoperative staphylococci colonisation (Sub-Study 1) and incidence of VRE acquisition (Sub-Study 2). The trial will recruit 4450 participants over a 4-year period across 13 orthopaedic centres in Australia. The primary outcome is the incidence of SSI at 90 days post index surgery. Secondary outcomes include the incidence of SSI according to joint and microorganism and other healthcare associated infections. Safety endpoints include the incidence of acute kidney injury, hypersensitivity reactions and all-cause mortality. The primary and secondary analysis will be a modified intention-to-treat analysis consisting of all randomised participants who undergo eligible surgery. We will also perform a per-protocol analysis.Ethics and disseminationThe study protocol was reviewed and approved by The Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/102) on 9 July 2018. Study findings will be disseminated in the printed media, and learnt forums.Trial registration numberACTRN12618000642280

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“…These are already the most commonly used antibiotics in Brazil, according to a study that included data from ICUs, surgical clinics, and pediatrics from a teaching hospital in 2018 (Da Silva et al, 2021). Surgical sectors can consume more first-generation cephalosporins, as this class is used for surgical prophylaxis (Peel et al, 2019). In 2019, ANVISA issued a warning about the safety profile of fluoroquinolones, discouraging their use (Agência Nacional de Vigilância Sanitária, 2019).…”

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“…8 Moreover, vancomycin remains the first choice of antimicrobial prophylaxis in centers with a high prevalence of MRSA. 9,10 On the other hand, the present survey raised a concern for potential GNB infections, as broader anti-GNB antimicrobial prophylaxis was prescribed in 30% of centers. This choice is in line with several studies pointing out that GNB also became significant causative agents of BSI in solid organ transplant (SOT) recipients, especially within the first days after transplantation.…”

Timing and duration of antibiotic prophylaxis is associated with the risk of infection after hip and knee arthroplasty

“…7 A randomized clinical trial is underway to explore dual routine use of prophylactic cephazolin and vancomycin, given increasing concern about antibiotic-resistant SSI. 38 Further research is recommended, including economic evaluation due to the high cost and burden of SSI, 32 and to explore the reduction in SSI risk we observed with the use of rivaroxaban for VTE prophylaxis. 23 This study has provided evidence of the association between cephalosporin dosing and timing, and the risk of SSI.…”