Review
Is tigecycline a suitable option for Clostridium difficile infection? Evidence from the literature

https://doi.org/10.1016/j.ijantimicag.2015.03.012Get rights and content

Highlights

  • Tigecycline has shown in vitro activity against Clostridium difficile.

  • Tigecycline's disrupting effect on the microflora is counterbalanced by its anti-Clostridium effect.

  • Tigecycline plays a role in reducing C. difficile sporulation and toxin production.

  • Clinical reports on the use of tigecycline for C. difficile infection in humans mainly show good clinical outcomes.

Abstract

Clostridium difficile infection (CDI) has become the most frequent cause of nosocomial infectious diarrhoea in developed countries, causing an increase in mortality, recurrences or treatment failure. In the search for new and more effective drugs, researchers recently turned their attention to tigecycline, a broad-spectrum antibiotic of the glycylglycine class available as an intravenous formulation for human use, which has also shown in vitro activity against C. difficile. We performed a literature review of articles addressing in vitro as well as in vivo studies and case reports on the effectiveness of tigecycline, whose use is promising especially in light of its high faecal excretion. The available evidence suggests that tigecycline could play a role as an alternative therapeutic option for critically ill patients or cases of refractory CDI.

Introduction

Clostridium difficile infection (CDI) is an emerging problem in most developed countries [1], [2] where it has become the most frequent cause of nosocomial infectious diarrhoea [3]. Over the past few years, an increase in incidence, morbidity, mortality and recurrent/refractory cases has been reported [4] and, more recently, a survey conducted in 183 US hospitals demonstrated that C. difficile was the most common cause of healthcare-associated infection, replacing the role that once belonged to Staphylococcus aureus [5].

The increasing incidence observed over the last 15 years has been mainly attributed to the changing epidemiology of CDI, in association with the emergence and spreading of ribotypes with particular characteristics such as increased toxin production and increased antibiotic resistance patterns (e.g. ribotype 027) [2], [6]. Although antibiotic resistance may only have a marginal role in the spread of C. difficile, a trend towards reduced susceptibility to metronidazole has been reported by Baines et al. who compared C. difficile ribotype 001 strains collected in 1995–2001 with strains collected in 2005–2006, finding an increase in geometric mean minimum inhibitory concentrations (MICs) from 1.03 mg/L (range 0.25–2 mg/L) to 5.94 mg/L (4–8 mg/L) [7]. Cases of metronidazole failure have also been reported [8], [9], [10]. Therefore, recent guidelines recommend metronidazole in a minority of cases while they are more in favour of vancomycin, fidaxomicin and faecal microbiota transplantation (FMT) [11], [12], [13].

In the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines, in addition to the abovementioned antibiotics, tigecycline is also mentioned with a recommendation grade C-III (marginally supported recommendation for use—expert opinion evidence) for severe CDI cases when oral treatment is not feasible, despite its use being currently off-label [12].

Approved in 2005 for the treatment of complicated skin and soft-tissue infections and complicated intra-abdominal infections, and later for community-acquired pneumonia [14], tigecycline is a broad-spectrum protein synthesis inhibitor of the glycylglycine class, active against Gram-positive and Gram-negative bacteria and anaerobes, including C. difficile, Fusobacterium spp., Prevotella spp., Porphyromonas spp. and Bacteroides fragilis group [15].

In this manuscript, we present studies on tigecycline and C. difficile, updated to February 2015. Keywords used for the literature search on PubMed were as follows: ‘tigecycline’, ‘Tygacil’, ‘TBG-MINO’, ‘WAY-GAR-936’, ‘GAR-936’, ‘Clostridium difficile’, ‘C. difficile’ and ‘CDI’. MICs reported throughout this paper refer to the MIC90 (MIC required to inhibit 90% of the isolates).

Section snippets

Experimental data from in vitro and animal studies

Besides papers on the in vitro susceptibility of C. difficile to tigecycline listed in Table 1, which showed low MICs never exceeding 2 mg/L [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31] for more than 1000 human isolates, some studies have investigated the role of tigecycline in preventing or treating CDI in in vitro experiments or in animal models. In particular, the effects of tigecycline on sporulation and toxin production as well as on

Results from clinical case reports/case series in humans

The literature search retrieved 11 articles describing cases of CDI patients treated with tigecycline (47 subjects in total). The majority of them were refractory cases and in most instances (94%) tigecycline was administered together or following treatment with another drug. In all cases tigecycline was administered intravenously.

Tigecycline alone was administered in three patients (6%). Thirty-five patients (74%) were cured, whilst seven died (15%), two had recurrences (4%), one (2%) had a

Discussion

CDI is often difficult to treat and is characterised by a high recurrence rate. The treatment options currently available, especially when the oral route is not possible, are limited to a few drugs whose use is frequently hampered by the emergence of resistance (e.g. metronidazole). Whilst FMT appears to be a valid solution, it is not routinely used in clinical practice. The importance of C. difficile as a nosocomial infectious agent and the frequency of recurrences leave the search for new and

Funding

Funded by the Ministry of Health [grant RF 2011-02347608].

Competing interests

NP has received speaker's honoraria from Pfizer, Astellas, Sanofi Aventis, Wyeth, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, CareFusion, Johnson & Johnson, Janssen-Cilag and Bristol-Myers Squibb. All other authors declare no competing interests.

Ethical approval

Not required.

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