Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis

Abstract

Background: Studies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial.

Objectives: To assess systematically the effectiveness and safety of high dose tigecycline in the treatment of severe infections.

Methods: Pubmed, Web of Science, Embase, MEDLINE, Cochrane Library and ClinicalTrials were searched up to February 20, 2019 for studies that compared the effectiveness and safety of high dose tigecycline with standard dose tigecycline or other non-tigecycline-containing regimens in the treatment of severe infections. Rates for all-cause mortality, clinical cure, microbiological eradication and adverse events were analysed.

Results: Ten studies with 593 patients were included. The results indicated that using high dose tigecycline resulted in better outcomes compared with controls with lower all-cause mortality (OR 0.44, 95% CI 0.30-0.66, p < 0.0001), higher clinical cure (OR 3.43, 95% CI 2.09-5.63, p < 0.00001), higher microbiological eradication (OR 2.25, 95% CI 1.44-3.50, p = 0.0003), and without increasing adverse events rates. Subgroup analysis showed that high dose tigecycline reduced all-cause mortality in nosocomial acquired pneumonia (OR 0.39, 95% CI 0.22-0.70, p = 0.002), bloodstream infections (OR 0.19, 95% CI 0.06-0.58, p = 0.004) and mixed infections (OR 0.20, 95% CI 0.07-0.59, p = 0.003), with no statistical differences in complicated intra-abdominal infections (OR 2.04, 95% CI 0.80-5.23, p = 0.14). In carbapenem-resistant pathogens, the microbiological eradication rate in those given high dose tigecycline did not differ from controls (OR 1.07, 95% CI 0.44-2.60, p = 0.87), although mortality was reduced (OR 0.20, 95% CI 0.09-0.45, p = 0.0001). The main limitation of the review is that most of the included studies are observational studies with small sample sizes and high risks of bias.

Conclusions: High dose tigecycline treatment is effective and safe for severe infections owing to its lower all-cause mortality, higher clinical cure, microbiological eradication and comparable adverse events. However, as a result of the high risks of bias of the included studies, well-designed randomised clinical trials are warranted to establish the effectiveness and safety of high dose tigecycline compared with standard dose tigecycline and other commonly used antibiotics.

Keywords: Carbapenem resistance; Gram-negative bacteria; Infectious disease; Multidrug resistance; Tigecycline.

Fig. 1

Flow chart indicating the process of literature search and review for effectiveness and safety of high dose tigecycline for the treatment of severe infections based on eligible criteria

Fig. 2

Funnel plot of all-cause mortality in high dose tigecycline (HDT) regimens compared with controls

Fig. 3

All-cause mortality of the high dose tigecycline (HDT) regimens compared with controls. HAP hospital-acquired pneumonia, VAP ventilator-associated pneumonia, BSI bloodstream infection, cIAI complicated intra-abdominal infections, CR carbapenem resistant

Fig. 4

Clinical cure rate and microbiological eradication rate of high dose tigecycline (HDT) regimens compared with controls. CR carbapenem resistant

Fig. 5

Adverse events of the high dose tigecycline (HDT) regimens compared with controls

Fig. 6

Cumulative meta-analysis assessing the effect of high dose tigecycline on all-cause mortality of severe infections. The sequential monitoring boundary, which assumes a 42% control event rate and a 12% relative risk reduction with 80% power and two-sided α of 5%, has been crossed, indicating that the cumulative evidence is conclusive