Background: We intended to compare the efficacy and safety outcomes of colistin versus tigecycline as monotherapy or combination therapy against multi-drug resistant (MDR) and extensively drug-resistant (XDR) pathogens. Methods: A search was conducted in PubMed, Cochrane CENTRAL, EMBASE, and in the grey literature (i.e., ClinicalTrials.gov and Google Scholar) up to May 2021. Outcomes were clinical response, mortality, infection recurrence, and renal and hepatic toxicity. We pooled odd ratios (OR) using heterogeneity-guided random or fixed models at a statistical significance of p < 0.05. Results: Fourteen observational studies involving 1163 MDR/XDR pathogens, receiving tigecycline versus colistin monotherapy or combination, were included. Base-case analyses revealed insignificant differences in the clinical response, reinfection, and hepatic impairment. The 30-day mortality was significantly relatively reduced with tigecycline monotherapy (OR = 0.35, 95% CI 0.16–0.75, p = 0.007). The colistin monotherapy significantly relatively reduced in-hospital mortality (OR = 2.27, 95%CI 1.24–4.16, p = 0.008). Renal impairment rates were lower with tigecycline monotherapy or in combination, and were lower with monotherapy versus colistin-tigecycline combination. Low-risk of bias and moderate/high evidence quality were associated with all studies. Conclusions: Within the limitations of this study, it can be concluded that there were no statistically significant differences in main efficacy outcomes between colistin and tigecycline monotherapies or combinations against MDR/ XDR infections, except for lower rates of 30-day mortality with tigecycline and in-hospital mortality with colistin. Tigecycline was associated with favourable renal toxicity outcomes.
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