Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis

Summary

Background

Multidrug resistance among bacteria increases the need for new antimicrobial drugs with high potency and stability. Tigecycline is one candidate drug, and a previous meta-analysis of only published randomised controlled trials suggested that it might as effective as comparator treatments; we did a meta-analysis to include new and unpublished trials to assess its efficacy for the treatment of adult patients with serious bacterial infection.

Methods

We searched PubMed, Cochrane Central Register, and Embase up to March 30, 2011, to identify published studies, and we searched clinical trial registries to identify completed unpublished studies, the results of which were obtained through the manufacturer. Eligible studies were randomised trials assessing the clinical efficacy, safety, and eradication efficiency of tigecycline versus other antimicrobial agents for any bacterial infection. The primary outcome was treatment success in patients who received at least one dose of the study drug, had clinical evidence of disease, and had complete follow-up (the clinically assessable population). Meta-analysis was done with random-effects models because of heterogeneity across the trials.

Findings

14 randomised trials, comprising about 7400 patients, were included. Treatment success was lower with tigecycline than with control antibiotic agents, but the difference was not significant (odds ratio 0·87, 95% CI 0·74–1·02). Adverse events were more frequent in the tigecycline group than in the control groups (1·45, 1·11–1·88), with significantly more vomiting and nausea. All-cause mortality was higher in the tigecycline group than in the comparator groups, but the difference was not significant (1·28, 0·97–1·69). Eradication efficiency did not differ between tigecycline and control regimens, but the sample size for these comparisons was small.

Interpretation

Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections. Our findings show that assessment with unpublished studies is needed to make appropriate decisions about new agents.

Funding

None.

Introduction

Infections with resistant pathogens are associated with increased mortality, morbidity, and length and cost of hospital stay. Antimicrobial resistance has been progressive in Gram-negative pathogens, such as extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa, and in Gram-positive bacteria, such as meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. Classic agents used to treat these pathogens have become outdated and new antibiotics available might have already become targets for bacterial mechanisms of resistance.1, 2 Therefore, development of new antibiotics with high potency, stability against the mechanisms of resistance, and favourable pharmacokinetic and pharmacodynamic characteristics has become an urgent priority.

Tigecycline is the first representative of the glycylcycline class of antibacterial agents. The US Food and Drug Administration (FDA) has approved its use for complicated intra-abdominal infections and complicated skin and skin structure infection (2005), and for community-acquired pneumonia (2009).3, 4 The drug is the 9-t-butylglycylamido derivative of minocycline. Tigecycline enters bacterial cells, reversibly binds to the 30S subunit of the ribosome, and inhibits protein synthesis. By comparison with tetracyclines, tigecycline binds to corresponding ribosomal sites with five-times the affinity, irrespective of the presence of mutations that confer resistance to tetracyclines, and evades tetracycline efflux mechanisms.5, 6 Tigecycline has in-vitro activity against a wide range of bacterial pathogens, including Gram-positive and Gram-negative aerobic and anaerobic species.7, 8

Many studies have assessed tigecycline's pharmacokinetics, in-vitro efficacy against resistant organisms, and clinical efficacy and safety.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Systematic reviews of such studies have been published, but with no synthesis of results,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and a pooled analysis of eight trials was done only in patients with secondary bacteraemia.³⁶ The only effort to assess the efficacy and safety of tigecycline by synthesis of the results of existing trials was done by Cai and colleagues,³⁷ but was limited to eight published randomised controlled trials. Their findings suggested that tigecycline monotherapy might be used as effectively as comparator treatments, but it should be used prudently. However, meta-analyses that ignore the full programme of clinical trials, including unpublished studies, could reach narrow, misleading interpretations.³⁸ Therefore, we aimed to assess the efficacy and safety of tigecycline, compared with other antimicrobial agents, for treatment of infectious disease by updating Cai and colleagues' meta-analysis with inclusion of subsequent trials and unpublished studies. This report follows the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement.³⁹