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ANTAGE-4575; No. of Pages 5

International Journal of Antimicrobial Agents xxx (2015) xxx–xxx

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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Is tigecycline a suitable option for Clostridium difficile infection? Evidence from the literature S. Di Bella a,∗ , C. Nisii b , N. Petrosillo a a b

2nd Infectious Disease Division, National Institute for Infectious Diseases ‘L. Spallanzani’, Via Portuense 292, 00149 Rome, Italy Laboratory of Microbiology, National Institute for Infectious Diseases ‘L. Spallanzani’, Rome, Italy

a r t i c l e

i n f o

Article history: Received 6 March 2015 Received in revised form 21 March 2015 Accepted 24 March 2015 Keywords: Tigecycline Clostridium Clostridium difficile Clostridium difficile infection CDI

a b s t r a c t 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 broadspectrum 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. © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. 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 [8–10]. Therefore, recent guidelines

recommend metronidazole in a minority of cases while they are more in favour of vancomycin, fidaxomicin and faecal microbiota transplantation (FMT) [11–13]. 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’, ‘TBGMINO’, ‘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).

2. Experimental data from in vitro and animal studies ∗ Corresponding author. Tel.: +39 06 5517 0294; fax: +39 06 5517 0486. E-mail address: [email protected] (S. Di Bella).

Besides papers on the in vitro susceptibility of C. difficile to tigecycline listed in Table 1, which showed low MICs never exceeding

http://dx.doi.org/10.1016/j.ijantimicag.2015.03.012 0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Please cite this article in press as: Di Bella S, et al. Is tigecycline a suitable option for Clostridium difficile infection? Evidence from the literature. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2015.03.012

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Table 1 In vitro susceptibility of human Clostridium difficile isolates to tigecycline. Author/Reference

No. of C. difficile strains tested

Isolate origin

MIC (mg/L)

Kundrapu et al. [18] Aldape et al. [19] Garneau et al. [20] Lachowicz et al. [21] Nuding et al. [22] Rashid et al. [17] Jump et al. [23] Lin et al. [24] Hawser [25] Lu et al. [26] Nagy and Dowzicky [16] Noren et al. [27] Hecht et al. [28] Baines et al. [29] Edlund and Nord [30] Petersen et al. [31]

12 1 non NAP1; 1 NAP1 10 83 20 133 3 113 256 1 115 205 110 39 50 10

USA USA Canada Poland Germany Sweden USA Taiwan Europe Taiwan Europe Sweden USAb UK/North America Sweden USA and Canada

≤0.012 0.024; 0.048 0.02a 0.19 ≤0.016 0.125 ≤0.012 0.06 0.25 0.06 0.25 0.064 0.25 0.06 0.032 0.12

MIC range – – 0.016–0.032 0.016–0.25 N/S 0.032–0.25 ≤0.012 0.03–0.25 ≤0.06–2 – ≤0.06–2 ≤0.016–0.25 0.06–1 0.06–0.06 0.016–0.032 ≤0.06–0.25

MIC, minimum inhibitory concentration; N/S, not specified. a Mean of MICs. b Mainly.

2 mg/L [16–31] 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 disruption of the gut microflora have been investigated [19,20,29]. 2.1. Effect of tigecycline on disruption of the gut microflora and establishment of Clostridium difficile infection Three studies have addressed the role of tigecycline in altering the normal microflora of the gut, thereby potentially allowing proliferation of C. difficile. Nord et al. evaluated the effect of 10 days of tigecycline on the oropharyngeal and intestinal microflora of 13 healthy subjects, reporting a transient alteration that was normalised after the end of treatment; only bifidobacteria remained persistently low until the end of the study period (31 days) [32]. Baines et al. used a three-stage gut model to investigate the interplay among tigecycline, the gut microflora and C. difficile ribotypes 001 and 027. Despite a marked decline in numbers of bifidobacteria and Bacteroides (falling below the detection limits after 5–7 days), no germination and/or proliferation of C. difficile was observed in their study after tigecycline instillation [29]. On the other hand, experiments conducted in an animal model by Bassis et al., who investigated the effects of 10 days of tigecycline versus saline on the structure of the gut microbiota, showed that mice challenged with spores of C. difficile 2 days after the end of tigecycline exposure (6.25 mg/kg administered subcutaneously) developed clinical signs of severe CDI after a considerable decrease in Bacteroides levels [33]. 2.2. Effect of tigecycline on sporulation and/or toxin production Some studies have addressed the relationship between treatment with tigecycline and proliferation of C. difficile and toxin production. Aldape et al. demonstrated that although tigecycline stimulates increased expression of cytotoxin- and sporulationrelated genes (tcdA, tcdB and spo0A), its inhibitory effect on protein synthesis also affects the expression of these genes, thereby lowering toxin A and toxin B levels and preventing sporulation [19]. Garneau et al. also studied the effect of tigecycline on sporulation in the presence of sub-MIC concentrations. Ten C. difficile strains (six different PCR ribotypes) were used and spores were counted by microscopy after 48 h and 96 h of growth in the absence or presence of 0.5 × MIC of tigecycline. This study also highlighted a strong

inhibitory effect on sporulation, with a spore count

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

Clostridium difficile infection (CDI) has become the most frequent cause of nosocomial infectious diarrhoea in developed countries, causing an increas...
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