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Is tigecycline a suitable option for Clostridium difficile infection? Evidence from the literature
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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
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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 <1% compared with untreated controls [20]. The hypothesis that tigecycline has a low propensity to promote colonisation and toxin production by C. difficile was also evaluated in a mouse model by Jump et al. [23]. Mice received subcutaneous injections of tigecycline alone (two dosages, 0.05 mg/day or 0.6 mg/day) or in combination with clindamycin for 6 days. Growth of and toxin production by C. difficile were measured in caecal contents collected 6 h or 3 days after the final antibiotic dose. The authors observed that tigecycline treatment did not promote overgrowth of C. difficile in caecal contents collected at either time point [23]. Theriot et al. exposed ten mice with established CDI to 5 days of tigecycline given subcutaneously at 6.25 mg/kg every 12 h. The authors also conducted in vitro experiments where C. difficile was grown with subinhibitory concentrations of tigecycline and demonstrated that the drug was able to suppress toxin activity and spore formation [34]. A recent study conducted by Kim et al. used gnotobiotic piglets to evaluate the role of tigecycline in both treating and preventing CDI. In a first experiment, eight gnotobiotic piglets were inoculated with C. difficile spores and after 48 h were started on oral tigecycline for 7 days (2 mg/kg/day) [35]. Four piglets received no treatment and were used as controls. Necropsies performed 10 days post-inoculation revealed characteristic lesions of CDI in control piglets, including dilation and oedema of the gut and pseudomembranes in the rectum. In contrast, seven of the eight tigecycline-treated piglets showed no gross lesions of the gastrointestinal system and normal spiral colon, and six of them had negative C. difficile cultures 10 days after inoculation. The effect of oral tigecycline in predisposing CDI was assessed in a second experiment: gnotobiotic piglets received human microflora transplantation and 5–7 days later were given 2 mg/kg/day of oral tigecycline for 6–8 days of treatment. After 2 more days (i.e. 2 days after the start of the course of tigecycline) the piglets were inoculated with 107 C. difficile spores. No piglets colonised with human gut microflora and treated with tigecycline followed by C. difficile infection developed any signs of CDI. 3. 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%)
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Table 2 Tigecycline for Clostridium difficile infection (CDI): case reports and case series from the literature. Author/Reference
Age (years)/sex
Patient characteristics
Length of tigecycline administration (days)
Concomitant anti-C. difficile treatment
Outcome/follow-up
Bossé et al. [38]
35/M
14
Metronidazole
Episode resolution
Britt et al. [39]
64/F
Vancomycin allergic reaction Severe CDI
10
Resolved/no recurrence
46/M
Refractory CDI
8
38/M 80/F
Severe CDI Refractory CDI
8 6
68/M
Refractory CDI
21
84/F
Refractory CDI
3
73/F 83/F 75/F 89/M
Severe CDI Recurrent CDI Refractory CDI Septic shock
4 14 10 N/S
Herpers et al. [43]
59/M 36/F 36/M 82/F
Refractory CDI Refractory CDI Severe CDI Refractory CDI
Kopterides et al. [44]
70/M
Refractory CDI
21 15 7 24 days followed by two courses of pulse therapy 20
Metronidazole, vancomycin Metronidazole, vancomycin Vancomycin Metronidazole, vancomycin Metronidazole, vancomycin Metronidazole, vancomycin Metronidazole None Rifaximin Metronidazole, vancomycin Vancomycin None Vancomycin None
Lao et al. [45]
68/M
Refractory CDI
14
Lu et al. [26]
55/F
Recurrent CDI
14
Metan et al. [46]
44/M
Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Severe CDI
7
Metronidazole, vancomycin and immunoglobulins Rifaximin, vancomycin Metronidazole, vancomycin Metronidazole
14
Metronidazole
21
Metronidazole
3
Metronidazole
14
Metronidazole
14
Metronidazole
14
Metronidazole
5
Metronidazole
14
Metronidazole
14
Metronidazole
14
Metronidazole
N/S
Metronidazole and/or vancomycin (17 patients); fidaxomicin (1 patient)
Cheong and Gottlieb [40] El-Herte et al. [41] Fantin et al. [42]
23/M 56/M 26/M 25/F 20/M 49/M 21/F 23/M 33/F 26/M Thomas et al. [47]
18 patients; median age 55
Resolved/no recurrence Resolved/no recurrence Resolved/no recurrence Death (not CDI attributable) Clinical failure Resolved/no recurrence No recurrence at 3 months 7 days/diarrhoea resolution 8 days/diarrhoea resolution No recurrence at 3 months No recurrence at 3 months No recurrence at 3 months No recurrence at 3 months
Death
Resolved/no recurrence at 1 month 6 months/no recurrence Resolved/no recurrence at 6 months Resolved/no recurrence at 3 months Resolved/no recurrence at 6 months Skin rash/tigecycline stopped Resolved/no recurrence at 6 months Resolved/no recurrence at 6 months Resolved/no recurrence at 6 months Death Resolved/no recurrence at 4 months Resolved/no recurrence at 4 months Resolved/no recurrence at 3 months 4 deaths; 14 survived (2 colectomies, 2 recurrent CDI); follow-up not specified
N/S, not specified; HSCT, haematopoietic stem cell transplantation.
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 clinical failure and one (2%) experienced a skin rash. Follow-up ranged from 0 to 6 months, therefore the recurrence rate reported here could be underestimated.
The usual dosage was 100 mg loading dose followed by 50 mg every 12 h. The duration of treatment ranged from 3 days to 24 days (mean 12 days). These case reports/case series are summarised in Table 2. 4. Discussion CDI is often difficult to treat and is characterised by a high recurrence rate. The treatment options currently available, especially
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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 more effective antibiotics an open issue. Tigecycline is a potential candidate for the treatment of CDI as it showed good in vitro activity against C. difficile (Table 1). However, a potential caveat could be disruption of the normal microflora during its use, thus promoting or worsening CDI. Nevertheless, the experimental conditions of the studies addressing the disrupting effect on the flora mentioned above are quite different, and all together the results suggest that while the ability of tigecycline to promote the overgrowth of C. difficile appears to be dependent on the dosage used [23,32–34], its role as a predisposing factor for CDI appears to be quite limited. In other words, as tigecycline is a broadspectrum antibiotic with proven activity against anaerobes, a mild disrupting effect on the colon microflora is to be expected, but at the appropriate dosage it is counterbalanced by its anti-Clostridium effect. The studies addressing sporulation and toxin production are more conclusive, consistently showing an inhibitory action on both, regardless of dosage or experimental conditions used [19,20,23,34]. Some authors concluded that this could be ascribed to the inhibitory activity of tigecycline on protein synthesis; this evidence was also supported by studies by Ochsner et al. and Mathur et al. [36,37] who noticed that other molecules targeting protein synthesis also have an inhibitory effect on sporulation. The importance of these results lies in the fact that the persistence of spores is likely a major cause of relapses, as standard antibiotic therapy with metronidazole, vancomycin or fidaxomicin is effective on vegetative cells but has poor or no effect on spores. The paper by Kim et al. [35] is very interesting as it shows good anti-CDI activity in piglets treated with an oral formulation of tigecycline (which is not commercially available). However, the specific pharmacokinetics of tigecycline is characterised by a high elimination through faeces, via biliary excretion [15]; it is this property that allowed good activity against C. difficile when given intravenously [26,38–47], whilst the same does not happen for vancomycin. Although not licensed for use against CDI, evidence and clinical reports of successful use of tigecycline for CDI have been published [26,38–41,43–47], mainly examples of good clinical outcomes of severe or refractory cases of CDI or in particular circumstances (e.g. known allergy to vancomycin), but there is a lack of clinical trials. For this reason, the ESCMID guidelines have assigned a recommendation of strength C for tigecycline with a low quality of evidence [12]. Clinical trials comparing tigecycline with other antimicrobials or FMT in cases of recurrent CDI are also needed. All together, the data available so far are encouraging, and although more studies are needed to confirm its usefulness in preventing or treating CDI also in consideration of cost/benefit aspects, the available evidence suggests that tigecycline could be an additional option for critically ill patients or cases of refractory CDI.
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.
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[37] Mathur T, Kumar M, Barman TK, Kumar GR, Kalia V, Singhal S, et al. Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile. J Antimicrob Chemother 2011;66:1087–95. [38] Bossé D, Lemire C, Ruel J, Cantin AM, Ménard F, Valiquette L. Severe anaphylaxis caused by orally administered vancomycin to a patient with Clostridium difficile infection. Infection 2013;41:579–82. [39] Britt NS, Steed ME, Potter EM, Clough LA. Tigecycline for the treatment of severe and severe complicated Clostridium difficile infection. Infect Dis Ther 2014;3:321–31. [40] Cheong EY, Gottlieb T. Intravenous tigecycline in the treatment of severe recurrent Clostridium difficile colitis. Med J Aust 2011;194:374–5. [41] El-Herte RI, Baban TA, Kanj SS. Recurrent refractory Clostridium difficile colitis treated successfully with rifaximin and tigecycline: a case report and review of the literature. Scand J Infect Dis 2012;44:228–30. [42] Fantin F, Manica A, Soldani F, Bissoli L, Zivelonghi A, Zamboni M. Use of tigecycline in elderly patients for Clostridium difficile infection. Geriatr Gerontol Int 2015;15:230–1. [43] Herpers BL, Vlaminckx B, Burkhardt O, Blom H, Biemond-Moeniralam HS, Hornef M, et al. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis 2009;48:1732–5. [44] Kopterides P, Papageorgiou C, Antoniadou A, Papadomichelakis E, Tsangaris I, Dimopoulou I, et al. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth Intensive Care 2010;38:755–8. [45] Lao 2nd D, Chiang T, Gomez E. Refractory Clostridium difficile infection successfully treated with tigecycline, rifaximin, and vancomycin. Case Rep Med 2012;2012:702910. [46] Metan G, Ture Z, Kaynar L, Berk E, Gursoy S, Alp E, et al. Tigecycline for the treatment of Clostridium difficile infection refractory to metronidazole in haematopoietic stem cell transplant recipients. J Chemother 2014 (1973947814Y0000000225) [Epub ahead of print]. [47] Thomas A, Khan F, Uddin N, Wallace MR. Tigecycline for severe Clostridium difficile infection. Int J Infect Dis 2014;26:171–2.
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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
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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 <1% compared with untreated controls [20]. The hypothesis that tigecycline has a low propensity to promote colonisation and toxin production by C. difficile was also evaluated in a mouse model by Jump et al. [23]. Mice received subcutaneous injections of tigecycline alone (two dosages, 0.05 mg/day or 0.6 mg/day) or in combination with clindamycin for 6 days. Growth of and toxin production by C. difficile were measured in caecal contents collected 6 h or 3 days after the final antibiotic dose. The authors observed that tigecycline treatment did not promote overgrowth of C. difficile in caecal contents collected at either time point [23]. Theriot et al. exposed ten mice with established CDI to 5 days of tigecycline given subcutaneously at 6.25 mg/kg every 12 h. The authors also conducted in vitro experiments where C. difficile was grown with subinhibitory concentrations of tigecycline and demonstrated that the drug was able to suppress toxin activity and spore formation [34]. A recent study conducted by Kim et al. used gnotobiotic piglets to evaluate the role of tigecycline in both treating and preventing CDI. In a first experiment, eight gnotobiotic piglets were inoculated with C. difficile spores and after 48 h were started on oral tigecycline for 7 days (2 mg/kg/day) [35]. Four piglets received no treatment and were used as controls. Necropsies performed 10 days post-inoculation revealed characteristic lesions of CDI in control piglets, including dilation and oedema of the gut and pseudomembranes in the rectum. In contrast, seven of the eight tigecycline-treated piglets showed no gross lesions of the gastrointestinal system and normal spiral colon, and six of them had negative C. difficile cultures 10 days after inoculation. The effect of oral tigecycline in predisposing CDI was assessed in a second experiment: gnotobiotic piglets received human microflora transplantation and 5–7 days later were given 2 mg/kg/day of oral tigecycline for 6–8 days of treatment. After 2 more days (i.e. 2 days after the start of the course of tigecycline) the piglets were inoculated with 107 C. difficile spores. No piglets colonised with human gut microflora and treated with tigecycline followed by C. difficile infection developed any signs of CDI. 3. 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%)
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Table 2 Tigecycline for Clostridium difficile infection (CDI): case reports and case series from the literature. Author/Reference
Age (years)/sex
Patient characteristics
Length of tigecycline administration (days)
Concomitant anti-C. difficile treatment
Outcome/follow-up
Bossé et al. [38]
35/M
14
Metronidazole
Episode resolution
Britt et al. [39]
64/F
Vancomycin allergic reaction Severe CDI
10
Resolved/no recurrence
46/M
Refractory CDI
8
38/M 80/F
Severe CDI Refractory CDI
8 6
68/M
Refractory CDI
21
84/F
Refractory CDI
3
73/F 83/F 75/F 89/M
Severe CDI Recurrent CDI Refractory CDI Septic shock
4 14 10 N/S
Herpers et al. [43]
59/M 36/F 36/M 82/F
Refractory CDI Refractory CDI Severe CDI Refractory CDI
Kopterides et al. [44]
70/M
Refractory CDI
21 15 7 24 days followed by two courses of pulse therapy 20
Metronidazole, vancomycin Metronidazole, vancomycin Vancomycin Metronidazole, vancomycin Metronidazole, vancomycin Metronidazole, vancomycin Metronidazole None Rifaximin Metronidazole, vancomycin Vancomycin None Vancomycin None
Lao et al. [45]
68/M
Refractory CDI
14
Lu et al. [26]
55/F
Recurrent CDI
14
Metan et al. [46]
44/M
Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Refractory CDI/HSCT Severe CDI
7
Metronidazole, vancomycin and immunoglobulins Rifaximin, vancomycin Metronidazole, vancomycin Metronidazole
14
Metronidazole
21
Metronidazole
3
Metronidazole
14
Metronidazole
14
Metronidazole
14
Metronidazole
5
Metronidazole
14
Metronidazole
14
Metronidazole
14
Metronidazole
N/S
Metronidazole and/or vancomycin (17 patients); fidaxomicin (1 patient)
Cheong and Gottlieb [40] El-Herte et al. [41] Fantin et al. [42]
23/M 56/M 26/M 25/F 20/M 49/M 21/F 23/M 33/F 26/M Thomas et al. [47]
18 patients; median age 55
Resolved/no recurrence Resolved/no recurrence Resolved/no recurrence Death (not CDI attributable) Clinical failure Resolved/no recurrence No recurrence at 3 months 7 days/diarrhoea resolution 8 days/diarrhoea resolution No recurrence at 3 months No recurrence at 3 months No recurrence at 3 months No recurrence at 3 months
Death
Resolved/no recurrence at 1 month 6 months/no recurrence Resolved/no recurrence at 6 months Resolved/no recurrence at 3 months Resolved/no recurrence at 6 months Skin rash/tigecycline stopped Resolved/no recurrence at 6 months Resolved/no recurrence at 6 months Resolved/no recurrence at 6 months Death Resolved/no recurrence at 4 months Resolved/no recurrence at 4 months Resolved/no recurrence at 3 months 4 deaths; 14 survived (2 colectomies, 2 recurrent CDI); follow-up not specified
N/S, not specified; HSCT, haematopoietic stem cell transplantation.
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 clinical failure and one (2%) experienced a skin rash. Follow-up ranged from 0 to 6 months, therefore the recurrence rate reported here could be underestimated.
The usual dosage was 100 mg loading dose followed by 50 mg every 12 h. The duration of treatment ranged from 3 days to 24 days (mean 12 days). These case reports/case series are summarised in Table 2. 4. Discussion CDI is often difficult to treat and is characterised by a high recurrence rate. The treatment options currently available, especially
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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 more effective antibiotics an open issue. Tigecycline is a potential candidate for the treatment of CDI as it showed good in vitro activity against C. difficile (Table 1). However, a potential caveat could be disruption of the normal microflora during its use, thus promoting or worsening CDI. Nevertheless, the experimental conditions of the studies addressing the disrupting effect on the flora mentioned above are quite different, and all together the results suggest that while the ability of tigecycline to promote the overgrowth of C. difficile appears to be dependent on the dosage used [23,32–34], its role as a predisposing factor for CDI appears to be quite limited. In other words, as tigecycline is a broadspectrum antibiotic with proven activity against anaerobes, a mild disrupting effect on the colon microflora is to be expected, but at the appropriate dosage it is counterbalanced by its anti-Clostridium effect. The studies addressing sporulation and toxin production are more conclusive, consistently showing an inhibitory action on both, regardless of dosage or experimental conditions used [19,20,23,34]. Some authors concluded that this could be ascribed to the inhibitory activity of tigecycline on protein synthesis; this evidence was also supported by studies by Ochsner et al. and Mathur et al. [36,37] who noticed that other molecules targeting protein synthesis also have an inhibitory effect on sporulation. The importance of these results lies in the fact that the persistence of spores is likely a major cause of relapses, as standard antibiotic therapy with metronidazole, vancomycin or fidaxomicin is effective on vegetative cells but has poor or no effect on spores. The paper by Kim et al. [35] is very interesting as it shows good anti-CDI activity in piglets treated with an oral formulation of tigecycline (which is not commercially available). However, the specific pharmacokinetics of tigecycline is characterised by a high elimination through faeces, via biliary excretion [15]; it is this property that allowed good activity against C. difficile when given intravenously [26,38–47], whilst the same does not happen for vancomycin. Although not licensed for use against CDI, evidence and clinical reports of successful use of tigecycline for CDI have been published [26,38–41,43–47], mainly examples of good clinical outcomes of severe or refractory cases of CDI or in particular circumstances (e.g. known allergy to vancomycin), but there is a lack of clinical trials. For this reason, the ESCMID guidelines have assigned a recommendation of strength C for tigecycline with a low quality of evidence [12]. Clinical trials comparing tigecycline with other antimicrobials or FMT in cases of recurrent CDI are also needed. All together, the data available so far are encouraging, and although more studies are needed to confirm its usefulness in preventing or treating CDI also in consideration of cost/benefit aspects, the available evidence suggests that tigecycline could be an additional option for critically ill patients or cases of refractory CDI.
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.
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