The role of tigecycline in the treatment of infections in light of the new black box warning

Abstract

Tigecycline is an antibiotic with a broad spectrum of activity. Similar to tetracycline antibiotics, tigecycline exerts bacteriostatic activity. Earlier studies documented the safety and efficacy of tigecycline for complicated intra-abdominal and complicated skin and skin-structure infections, which led to its approval. Recent systematic reviews and meta-analyses have suggested increased risk of death in patients receiving tigecycline compared to other antibiotics. The Food and Drug Administration has warned clinicians about increased risk for death in patients who received tigecycline with certain severe infections and have issued a black box warning. The increased mortality risk with tigecycline is most apparent in patients treated for hospital-acquired pneumonia, particularly ventilator-associated pneumonia. The cause of excess deaths in these trials is uncertain, but it is likely that most deaths in patients with these severe infections were related to progression of the infection. Further experience with tigecycline for serious infections with drug-resistant pathogens is currently warranted.

Keywords::

• black-box warning
• meta-analysis
• mortality
• severe infection
• tigecycline

Antibiotic-resistant pathogens continue to be a growing concern particularly since the development of new antimicrobial agents is considerably scarce. Tigecycline was intended to meet this need. This agent is a derivative of tetracycline known as glycycline, developed in an effort to overcome resistance to earlier tetracyclines [1]. Perhaps, the most promising characteristic of the drug is its activity against multidrug-resistant Gram-positive and negative pathogens including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, vancomycin-resistant enterococcus, extended-spectrum β-lactamase-producing and Amp C β-lactamase-producing Enterobacteriaceae, anaerobes, atypical pathogens and Clostridium difficile [2]. However, it lacks activity against Proteus mirabilis and Pseudomonas aeruguinosa [2].

Although there are several antibiotics or combination of agents that can be utilized to manage infections, tigecycline is unique for its ability to be used as monotherapy for coverage of several drug-resistant pathogens when first-line therapy fails [3]. Other potential advantages of tigecycline include its value as an alternate treatment option in patients who exhibit true allergies to penicillins or antimicrobial toxicities [1]. Additionally, no adverse effects on kidneys have been observed, thus not requiring an adjustment in patients with impaired renal function.

In 2005, the US FDA allowed priority review status for tigecycline. Within 6 months, the FDA approved the drug for the treatment of complicated intra-abdominal (cIAI) and complicated skin and skin structure infections (cSSSIs). In 2009, tigecycline also received FDA approval for community-acquired bacterial pneumonia (CABP) in adults [2].

Basis of approval: clinical data

The efficacy of tigecycline was evaluated in a multicenter Phase III randomized, double-blinded, clinical trial in hospitalized patients with cSSSI and cIAI. The results demonstrated that tigecycline use was equivalent, but not superior to the combination of vancomycin and aztreonam [1,3]. Additionally, when tigecycline was studied in patients with cIAI, the drug was shown to be equivalent to imipenem/cilastatin with comparable cure rates, and no difference in outcome was identified between monomicrobial and polymicrobial infections [1,3]. The most common side effects reported in the trials included nausea and vomiting, diarrhea and abdominal pain. Though, postmarketing surveillance of tigecycline revealed hepatic dysfunction, liver failure and pancreatitis.

Tigecycline concerns

The US FDA issued a safety alert for tigecycline in September 2010 in reference to an observed increase in mortality risk based upon a meta-analysis of 13 Phase III and Phase IV trials [4]. The pooled results across the studies found an overall mortality rate of 4% (150/3788 patients) with tigecycline and 3% (110/3646 patients) with the comparator antibiotics resulting in an adjusted risk difference of 0.6%. The indications reviewed included hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), diabetic foot infections, infections caused by resistant pathogens along with the approved indications of CABP, cSSSI and cIAI [4].

While mortality differences per indication were not found to be statistically significant, the incidence of mortality was increased in the tigecycline group for each comparison. Among the infections for which tigecycline has FDA approval, there was a risk difference of 0.7, 0.8 and 0.2% for cSSSI, cIAI and CABP, respectively. With HAP infections, death occurred in 14.1% of patients in the tigecycline group and 12.2% of patients in the comparator group. When analyzing the subgroups of HAP, the greatest increase in mortality risk occurred with VAP in 19.1% (25/131) of patients treated with tigecycline and 12.3% (15/122) of patients treated with comparator agents. This led to updates in the ‘Warnings and Precautions’ and ‘Adverse Reaction’ sections of the tigecycline labeling and initiated further scrutiny of safety studies. In light of these findings, the FDA urged healthcare professionals to use alternative therapeutic agents in patients with severe infections.

Subsequently, the FDA conducted another meta-analysis in September 2013 with 10 clinical trials including only approved uses of the agent. The analysis indicated an increased mortality in patients treated with tigecycline at 2.5% (66/2650 patients) compared with 1.8% (48/2628 patients) with the other antibiotics yielding an adjusted risk difference of 0.6% [5]. As a result, a boxed warning was issued for the antibiotic, cautioning against its use for approved and unapproved indications unless alternatives were exhausted [5].

The FDA suggested that the increase in mortality was likely due to progression of the infection in conjunction with tigecycline bacteriostatic mode of action. However, in reviewing the studies of tigecycline for FDA-approved indications, the agent demonstrated similar results when evaluated against its bactericidal comparators [6–8]. Further assessment of tigecycline in VAP studies postulated that the mortality risk may actually be attributed to suboptimal dosing of the agent [9]. In a study by Freire et al. pharmacokinetic and pharmacodynamic analyses were conducted comparing tigecycline to imipenem/cilastatin for VAP and non-VAP infections. In VAP patients, tigecycline had a 15% lower mean AUC and 60% lower unbound AUC_0–24/MIC ratio compared with non-VAP patients [9]. Due to these findings, a small Phase II study was conducted by Ramirez et al. which randomized patients to receive imipenem or tigecycline at one of the two doses: 150 mg followed by 75 mg twice daily or 200 mg followed by 100 mg twice daily. The study found that 85% (17/20) of patients in the tigecycline 100 mg group attained a clinical cure compared with 69% (16/23) and 75% (18/24) of patients in the tigecycline 75 mg and imipenem groups, respectively [10].

Role of tigecycline in the treatment of infections

Four systematic reviews and meta-analyses have been published and have reached similar conclusions, highlighting the use of tigecycline and increased overall mortality [11–14].

Cai et al. conducted the first systematic review and meta-analysis of the effectiveness and safety of tigecycline for the treatment of infectious disease [11]. Eight randomized controlled clinical trials were included in this meta-analysis with a total of 4651 patients. For the treatment of cIAIs, CABP and cSSSIs, tigecycline alone was associated with similar clinical and microbiological cures compared with other empiric antibiotic agents in those trials. There was an increased incidence of total adverse effects reported due to tigecycline in this meta-analysis. Significantly, more episodes of adverse effects of the gastrointestinal system, hemic and lymphatic system and body as a whole were reported in tigecycline-treated patients. Although no statistical difference in all-cause mortality and drug-related mortality was found, there were more patients who died in the tigecycline group compared with other antibiotic regimens. The authors of this meta-analysis concluded that clinicians should use caution when tigecycline monotherapy is utilized in severe infections as a higher risk of mortality was observed.

Yahav et al. conducted a systematic review and meta-analysis on efficacy and safety of tigecycline in comparison to other antibiotic regimen for the treatment of any infection [12]. The primary outcome of this study was 30-day mortality, and secondary outcomes included clinical and microbiological failure, superinfections and adverse events. Based on 15 trials, overall mortality was higher with tigecycline compared with other regimens; higher clinical failure was also observed. Septic shock, superinfections and adverse events developed more often in patients who received tigecycline.

Another meta-analysis on efficacy and safety of tigecycline for the treatment of infectious disease was reported by Tasina et al. [13]. Randomized studies that assessed clinical efficacy, safety and eradication efficiency of tigecycline compared with other antibiotics were included in this meta-analysis and comprised 7400 patients. The primary outcome was defined as successful treatment even if patients received one dose of the study drug, had signs and symptoms of disease and had finished the follow-up. The meta-analysis demonstrated that tigecycline was less efficacious and resulted in higher all-cause mortality though the findings were not statistically significant. No difference in eradication efficiency was observed between tigecyline and other antibiotic regimens.

Prasad et al. re-examined the mortality and cure rates using all available data from randomized clinical trials of tigecycline and they reported excess deaths associated with tigecycline after approval based on noninferiority trials [15]. Thirteen randomized controlled trials (10 published and 3 unpublished) were included in this report. Higher mortality and greater noncure rates were observed with tigecycline than comparators. Tigecycline was associated with a 0.7% absolute risk in mortality and 2.9% absolute increase in noncure rates. Increased mortality with tigecycline was seen independent of infection type, trial design and study size as reported in the sub analysis group. This effect of excess mortality with tigecycline was similar when FDA-approved and nonapproved indications were compared. Additionally, increased risk of death was observed in patients with serious life-threatening infections, and the authors concluded that tigecycline was not a durable option in such situations. An editorial commentary accompanied this article, which stated that for every 143 patients treated with tigecyline, there would be one excess death and for every 34 patients treated with tigecycline, one person would experience noncure [16].

One of the greatest challenges in weighing the utility of tigecycline against its safety concerns is that most of the data are derived from meta-analyses and is therefore subject to its limitations. The major concerns include bias and heterogeneity of results. Despite the results in a meta-analysis, statistical heterogeneity may be indeterminate and cannot support definitive conclusions [14]. Curcio and Verde questioned the homogeneity of the studies analyzed by Yahav et al. due to a significant difference in mortality among them. Further, they commented that pooling of relative risks among studies and utilizing a fixed-effect meta-analysis led to a misleading determination of tigecycline causing an increase in mortality [17]. They discuss that the predictive interval for relative risk determined by Yahav et al. would not be able to predict 6 of 14 studies included in the analysis, indicating an inappropriate statistical model and questioning its conclusions. The authors suggest that while a specific conclusion may not be possible based upon Yahav et al.’s meta-analysis, underlying mortality of the study population may be a greater determining factor [18].

Role of tigecycline as a combination therapy in the treatment of infections

Poulakou et al. in a small observational retrospective study in critically ill patients with Acinetobacter baumannii and Klebsiella pneumoniae infections where tigecycline was mainly used as a monotherapy reported that 31.8% of their patients in the study had microbiological failure due to development of acquired resistance, breakthrough infection or superinfection [19]. Increase in tigecycline resistance in Gram-negative bacteria especially with A. baumannii and K. pneumoniae has been reported in last few years [20–23]. In most instances, this has been documented as acquired resistance during therapy; patients who were treated with tigecyline as monotherapy with initially susceptible organisms developed resistance to tigecycline during therapy. It has been postulated that the acquired resistance maybe due to overexpression of efflux pumps or attainment of low serum tigecycline levels on treatment, especially if the minimum inhibitory concentration for the infecting organism in a patient is higher than the maximum plasma concentration of tigecyline [24]. Additionally, tigecycline exhibits intrinsic resistance to certain pathogens such as Pseudomonas spp., Proteus spp. and Burkholderia cepacia, and patients on tigecycline monotherapy have developed superinfections with these organisms [24]. To overcome the development of acquired resistance and superinfections during tigecycline monotherapy, it may be best to utilize this antibiotic in combination therapy. In vitro and animal data suggest that no antagonism is observed and increased efficacy or synergy is exhibited when tigecycline is combined with other antibiotics against problematic multidrug-resistant Gram-negative organisms such as A. baumannii and K. pneumonia, among others [25]. In humans, the reports of tigecycline used as combination therapy is derived from case reports and small retrospective studies, which suggests that the use of tigecycline in combination with other antimicrobials may result in better efficacy [20–23]. Hirsch and Tam reviewed 15 papers which had 55 single cases with patients who had carbepenemase-producing K. pneumoniae. They reported that when the polymyxins were combined with tigecycline or aminoglycosides, patients had better clinical success rates [26]. Similar results have been reported in other retrospective studies due to multidrug-resistant organisms where decrease in mortality was observed from 46.7 to 20.2% when combination therapy was utilized [27,28]. Recently, Tumbarello et al. reported a 30-day decrease in mortality when triple combination therapy including colistin, tigecycline and meropenem was utilized to treat bacteremia due to carabenempase-producing K. pneumonia [29].

Conclusion

The results from these systematic reviews and meta-analyses have raised significant issues in the realm of clinical practice, the future of antimicrobial studies, evaluations of antimicrobials by the regulatory agencies like the FDA and marketing strategies by pharmaceutical companies. Although the results are obtained, the black box warning is issued from studies that have systematic reviews and meta-analysis which have its own limitations. Nevertheless, any increase in mortality due to an antimicrobial agent raises a red flag especially in the treatment of serious infections in which administration of ineffective antibiotics can result in death. While the cause of the excess deaths observed in clinical trials is uncertain, it may be related to severity of illness and the activity of tigecycline against organisms that are extremely virulent. An intuitive response for the place of therapy of tigecycline maybe for patients with serious infections with multidrug-resistant organisms susceptible to tigecycline, essentially when there are very limited options for patients. However, the data presented above argue against the use of tigecycline in this patient population. Higher mortality in these meta-analyses was suggested in patients with serious nosocomial infections including HAP, particularly VAP. With the availability of recent data, clinicians should carefully consider place in therapy for tigecycline and use it cautiously when needed as a combination therapy in these serious infections. In infections with highly virulent multidrug-resistant organisms, combination use of tigecycline with polymixins maybe more beneficial as a last resort. Perhaps, tigecycline may have a role in the treatment of complicated skin and soft tissue infections and intra-abdominal infection. As of now, clinicians are left with little direct evidence from well-designed, controlled clinical trials to adequately define the place in therapy for tigecycline.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.