In 2010 and 2013, the US Food and Drug Administration (FDA) reported an increased risk of mortality associated with tigecycline use in comparison with other drugs in the treatment of serious infections. The analysis used a pooled group of randomized clinical trials including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), and diabetic foot infections [1, 2]. On the basis of the pooled data analysis, the FDA recommended that alternatives to tigecycline should be considered in patients with severe infections. After the FDA warning several meta-analysis were published; obviously using different methodologies and selecting different studies. Yahav et al. [3] meta-analysis reported statistically higher all-cause 30-day mortality in the tigecycline arms. On the other hand, Cai et al. [4] found no difference in all-cause mortality and drug-related mortality between tigecycline and the comparators, whereas Tasina et al. [5] demonstrated reduced clinical efficacy and increased mortality for tigecycline, but the difference was not statistically significant. The FDA alert has been further jeopardized by two more studies. McGovern et al. [6] performed an all-cause mortality analysis by use of logistic regression and classification and regression tree analyses on study-level and patient-level data in an effort to find a reason for the increase in mortality. Deaths were attributed to infections or underlying co-morbidities and not to tigecycline. Subsequently, Vardakas et al. [7] separately analyzed studies involving infections for which tigecycline has approval and reported no statistical difference in clinical efficacy and no significant increase in mortality. On the other hand, analyzed data from non-approved indications showed that the tigecycline arm was statistically less effective. Finally, meta-analyses of study-level data suggested decreased clinical efficacy as a possible explanation for the demonstrated imbalance in mortality [3, 8].

In their interesting and welcome article published in the current issue of intensive care medicine, Montravers et al. [9] conclude that tigecycline success rates in patients in ICU with severe infections appear comparable to those reported with other antibiotics; the overall success rate was 60 % at the end of treatment, and 53 % 7 days later. Furthermore, they report a survival rate of 85 % at day 28. Historically, clinical trials concerning management of critically ill and particularly ICU-admitted patients with tigecycline are limited. A few large observational studies have been set up to determine the outcomes of ICU tigecycline-treated patients in clinical practice and a recent multicenter European surveillance study encompassing 1,782 patients (56 % from ICU), who received tigecycline under real-life conditions of daily clinical practice. In this study tigecycline was used to treat a variety of infections, including some for which tigecycline was not granted approval for use, and the efficacy and safety profile support the use of this drug in complicated infections in critically ill patients [10]. Studies of clinical experience with tigecycline in non-approved indications suffer significant heterogeneity and report a variety of clinical and microbiological endpoints with diverse rates of efficacy and mortality ranging from 12 % to more than 80 %. In the majority of them, the true contribution of tigecycline to the outcome is confounded by the use of various combination regimens. These studies are summarised in Table 1.

Table 1 Clinical studies of tigecycline encompassing non-approved indications
Full size table

Furthermore, recent published reports of infections caused by multidrug-resistant (MDR) pathogens with limited therapeutic options, including bacteria from the ESKAPE group, have highlighted an encouraging role of tigecycline in off-label use as part of a combination regimen. Specifically, tigecycline has been successfully used against life-threatening infections due to carbapenemase-producing Klebsiella pneumoniae (KPC) and MDR Acinetobacter baumannii in combination with other agents [11, 12]. In a large retrospective multicenter study significant reduction of 30-day mortality was demonstrated by logistic regression analysis when combination therapy (i.e., tigecycline, colistin, and meropenem) was used instead of monotherapy against KPC [12].

Almost 10 years after the launching of tigecycline, microbiological issues still exist. Although considerable in vitro activity has been shown for tigecycline against difficult-to-treat bacteria, the results are not universally consistent and may have varied according to different microbiological breakpoints. Furthermore, Vitek automated systems seem to overestimate resistance to K. pneumoniae KPC(+) strains, compared to E-test, therefore discouraging its use in a proportion of infections by almost untreatable pathogens [13]. In vitro interaction synergy studies against KPC or carbapenem-resistant Acinetobacter spp. have revealed promising effects of tigecycline in combination [14, 15]. Despite the demonstration of an adequate activity against Acinetobacter species of clinical significance [14], the question regarding whether tigecycline constitutes an effective option against resistant Acinetobacter spp. has not been comprehensively confirmed.

Another important issue is whether the dosage used so far was adequate from a PK/PD standpoint. A recent phase 2 study in HAP and VAP investigated the use of two high-dosage (HD) tigecycline regimens (200 mg initial, and then 100 mg twice daily or 150 mg initial and then 75 mg twice daily) showing higher cure rates when the “highest” HD was used compared to lower dosage and imipenem/cilastatin [16]. The study hypothesized that a higher area under the concentration–time divided by the MIC (AUC/MIC ratio) above one was necessary on the basis of a previous phase 3 study demonstrating lower cure rates in patients with HAP treated with conventional dose of tigecycline; this effect was attributed to a lower exposure to the drug on the lung tissue level [16]. This undermines the necessity of high doses when the MIC of the pathogen exceeds 0.5 mg/L. Similarly, another study encompassing 100 ICU patients treated with either standard or HD tigecycline showed no differences in terms of ICU mortality but numerically higher clinical cure rate and microbiological eradication in the HD arm compared to the tigecycline standard dose group. In the multivariate model HD tigecycline was a predictor of clinical cure [36]. Furthermore, compared to colistin that did not reach sufficient drug levels in the lung tissue, HD tigecycline was efficacious for treating experimental pneumonia due to metallo-beta-lactamase (NDM-1)-producing Enterobacteriaceae [17].

Although no major issues of toxicity have been displayed at high doses so far, the tolerability of these regimens in large trials still needs to be assessed [16]. Finally, tigecycline’s propensity to select for resistant strains (e.g., MDR Acinetobacter spp.) and to induce Pseudomonas aeruginosa or Proteus spp. superinfections requires further investigation.

In conclusion, despite the obscure vision provided by an impressive number of meta-analyses, tigecycline is expected to be used more often in approved indications and in off-label combination regimens for the treatment of MDR gram-negative infections in routine clinical practice. This is greatly supported by the large observational studies from five European countries and by the Montravers study mentioned above [9, 10]. Well-controlled prospective studies are necessary to evaluate tigecycline’s efficacy and safety profile at high doses.

The increased medical need represented by the growing impact of multiresistant infections and the current lack of alternative or new antibiotics suggests that tigecycline benefit–risk continues to be positive.