BackgroundThe effectiveness of infection prevention and control measures combating multidrug-resistant organisms (MDROs) in healthcare settings remains controversial.MethodsPubMed, Embase, MEDLINE, Cochrane Library, and CINAHL were searched from inception to June 1, 2024. The interventions encompassed standard precautions (SP), contact precautions (CP), hand hygiene (HH), environmental cleaning (ENV), antimicrobial stewardship programs (ASP), decolonization (DCL), and chlorhexidine baths (CHG). The primary outcome were the acquisition, infection, and colonization of MDROs. Secondary outcomes were all-cause mortality and MDROs-associated bacteraemia. Effect indicators were expressed as rate ratios (RRs) with 95% confidence intervals (CIs).ResultsThe study included a total of 97 articles, comprising 19 RCTs and 78 non-RCTs. The results showed that the most effective combination interventions for the acquisition, infection, and colonization of MDROs compared to SP varied as follows: CP + CHG (RR, 0.38 [0.18, 0.79]), SP + CP + ENV (RR, 0.04 [0.02, 0.08]), and SP + CHG (RR, 0.28 [0.14, 0.56]). In subgroup analyses, CP + CHG (RR, 0.36 [0.20,0.64]) was the most effective intervention for the acquisition of MDROs in the ICU setting, whereas SP + CP + ASP (RR, 0.35 [0.14,0.92]) was the most effective hospital-wide. Across subgroups, SP + CP + ENV (RR, 0.04 to 0.09 [95% CI, 0.01 to 0.99]) was identified as the most effective intervention for MDROs infections. In the ICU setting, SP + CHG (RR, 0.28 [0.14,0.56]) demonstrated the highest effectiveness in reducing the colonization of MDROs, whereas SP + CP + ENV + CHG (RR, 0.15 [0.06,0.38]) was the most effective on a hospital-wide scale. SP + CP + DCL (RR, 0.28 [0.24, 0.32]) was associated with reduced CRE colonization. The results of this study were robust according to the sensitivity analysis. None of the analyses related to secondary outcomes were statistically significant. In terms of article quality assessment, 94.7% of the RCTs were medium to high risk, while 92.31% of the non-RCTs. The primary limitation of the RCTs were related to the randomization process, whereas the non-RCTs were primarily affected by confounding bias.ConclusionsEffective interventions differ based on carriage status, intervention setting, and the resistant strain. Additionally, contact precautions is a crucial component of these combinations. Consequently, healthcare organizations can select appropriate interventions based on their unique resistance profiles to optimize precision and resource efficiency.