- Email: [email protected]
Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis
J Infect Chemother xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis* Hiroyuki Okumura a, *, Ayako Fukushima b, 1, Vanessa Taieb c, Shingo Shoji a, Marci English d a
Astellas Pharma, Inc., Tokyo, Japan Creativ-Ceutical, Paris, France Creativ-Ceutical, London, UK d Astellas Pharma Global Development, Inc., Northbrook, IL, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 March 2019 Received in revised form 17 June 2019 Accepted 1 July 2019 Available online xxx
We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Clostridioides difficile infection Fidaxomicin Vancomycin Metronidazole Meta-analysis
1. Introduction Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of nosocomial bacterial diarrhoea in industrialised countries, and can be serious and life-threatening; its incidence and severity are rising, which impacts all aspects of healthcare
* All authors meet the ICMJE authorship criteria and have made substantial contributions to all the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be submitted. * Corresponding author. Health Economics & Outcomes Research, Medical Affairs, Astellas Pharma, Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan. E-mail address: [email protected] (H. Okumura). 1 Employee of Creativ-Ceutical at the time of the study.
delivery globally [1,2]. The most widely used antibiotics for the management of CDI are vancomycin (VCM) and metronidazole (MTZ) [2]. However, recurrence of CDI is observed in up to 25% of patients treated with VCM or MTZ [3,4]. CDI recurrence is associated with poor clinical outcomes, increased duration of hospitalisation and increased costs [5e7]. The latest guidelines developed by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), updated in 2017, recommend either VCM or fidaxomicin (FDX) for the treatment of an initial episode of mild or moderate CDI in adults [1]. A notable change from the previous IDSA/SHEA guidelines was that MTZ in mild or moderate CDI was downgraded from a first-line treatment to an alternative treatment option recommended when FDX or VCM is not available [1]. The guidance for VCM was based on evidence from head-to-head studies that reported significantly higher cure rates, as well as
https://doi.org/10.1016/j.jiac.2019.07.005 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
2
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
lower recurrence rates, for VCM versus MTZ [8,9]. The guidance for FDX was based on two head-to-head studies of FDX and VCM, which demonstrated the non-inferiority of FDX versus VCM for clinical cure, and showed that the recurrence rate was significantly lower for FDX than for VCM [10,11]. FDX is a narrow-spectrum macrocyclic antibiotic that was approved globally based on the results of two randomised, controlled trials (RCTs) of FDX versus VCM in patients with CDI in the USA, Canada and Europe [10,11]. More recently, a randomised study of nosocomial CDI in Japan showed that although non-inferiority was not demonstrated for FDX versus VCM, the 28-day recurrence rate was 19.5% and 25.3% for FDX and VCM, respectively [12]. To date, there are no comparative studies of FDX versus MTZ in CDI, although in a network meta-analysis (NMA) including data available up to July 2017, FDX was significantly better than MTZ for sustained symptomatic cure (odds ratio [OR]: 0.49; 95% CI: 0.35, 0.68) [2]. In this analysis, we conducted a systematic literature review to identify RCTs of FDX versus VCM and VCM versus MTZ; we then performed an NMA to assess the relative effectiveness of FDX versus MTZ in the treatment of CDI, using VCM as the common arm. 2. Patients and methods 2.1. Design and objectives A systematic evidence-based approach was used to screen the literature and extract RCTs of FDX, VCM or MTZ for the treatment of CDI. An NMA was then conducted to assess the relative effectiveness of FDX versus VCM, and FDX versus MTZ using VCM as the common CDI treatment arm. The effectiveness outcomes of interest, calculated for each treatment, were clinical cure rates during the treatment period, recurrence rates during follow up, and sustained cure rate defined as clinical cure without recurrence during follow up. 2.2. Searches and data extraction A systematic literature search performed on 3 July 2011 identified three articles that were eligible for inclusion; an updated literature search was performed to identify articles published up to 10 March 2014. A further literature search was conducted in September 2016. Search strings were based on ‘Clostridioides (Clostridium) difficile’, ‘CDI’ or ‘CDAD’, and ‘fidaxomicin’, ‘vancomycin’, ‘metronidazole’ or ‘probiotics’. The initial inclusion of probiotics was intended to broaden the subsequent network; however, no such articles were found fulfilling the search criteria. Research articles published in English were identified using the Ovid platform to search Medline, EMBASE and the Cochrane Central Register of Controlled Trials, and articles were identified using the Igaku Chuo Zasshi database, which includes more than 2500 biomedical journals and other serial publications published in Japan. The Japanese Association for Infectious Diseases, the Japanese Society of Environmental Infections and the Japanese Association for Anaerobic Infection Research congress databases were also searched to obtain studies published only as abstracts (published in 2015 and 2016). The Clinicaltrials.gov database was used to identify closed clinical studies in adults from 2013 to 2016, using the search terms ‘Clostridioides (Clostridium) difficile’, ‘CDI’ or ‘CDAD’ with the interventions ‘fidaxomicin’, ‘vancomycin’, ‘metronidazole’ or ‘probiotics’. Articles were eligible for inclusion if they reported RCTs of FDX, VCM or MTZ in adult patients with confirmed CDI of any severity. Articles were excluded if they were studies in patients aged <18
years or receiving treatment other than FDX, VCM, MTZ, or probiotics, or non-randomised studies including reviews, opinions, systematic reviews and editorials. Articles were screened by title and abstract to identify those containing relevant data and the full text of the selected articles was fully assessed to ensure compliance with the inclusion and exclusion criteria. Data extracted into Excel included publication type, title, year of publication, trial name, trial number, sponsor/ funding, country, study objective, study design, population, inclusion/exclusion criteria, sample size, details of intervention/ comparator, outcomes of interest (clinical cure, recurrence rate and sustained cure rate), follow-up time and statistical methods (Table 1). Screening was performed by two independent reviewers, and a quality-control check of the data extraction was performed by a further independent reviewer. 2.3. Data analysis All data used in the analysis were from the intention-to-treat (ITT) study populations. The endpoints of interest were: clinical cure rates during the treatment period; recurrence rates during follow up; and sustained cure rate during follow up. Definitions and endpoints from the published article were used when available, and were otherwise calculated as given in Table 2. Some studies reported recurrence as a proportion of patients who achieved initial clinical cure, while others reported recurrence as a proportion of patients who previously met the criteria for resolution of diarrhoea. Therefore, two definitions of sustained cure were calculated for the studies included in this paper: ‘sustained cure 1’ was defined as initial clinical cure with no recurrence and ‘sustained cure 2’ was defined as resolution of diarrhoea with no recurrence (Table 2). The NMA was performed using a Bayesian framework, using a fixed-effects model and a random-effects model. The fixed-effects and random-effects models were compared using the Deviance Information Criterion (DIC). Differences in DIC of <5 points were not considered meaningful; consequently, the simpler fixed-effects model was selected for the analysis because the difference in DIC between fixed-effects and random-effects models was negligible (see Results). A generalised linear model with a binomial error distribution and logit link function was used, and results were summarised as odds ratios (ORs) with 95% credible intervals (CrI). Forest plots presented the ORs for FDX versus VCM or MTZ: for clinical cure rate and sustained cure rate, an OR>1 favours FDX; for recurrence rate, an OR<1 favours FDX. Between-study heterogeneity was assessed using pairwise comparisons, with the inverse variance-weighted method for the fixed-effects model and either the restricted maximum likelihood or the DerSimonian-Laird method for the random-effects model. Odds ratios and 95% confidence intervals (CIs) were used to summarise the individual and pooled treatment effects (Figure A.1). An I2 score of <25 was considered to indicate low heterogeneity. 3. Results 3.1. Searches In the initial literature search, 1261 publications were identified, of which 44 were selected for full-text evaluation and five publications (reporting data from five studies) met the inclusion criteria. In the updated literature search, 610 articles were identified, of which 118 were duplicates. After screening titles and abstracts of 492 articles, 30 were examined in detail; of these, two publications (reporting from three datasets) fulfilled the inclusion criteria (Fig. 1). From these seven publications, there were eight datasets,
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
Clinical cure, recurrence rate (follow up 28 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 2819-CL-3002 (Mikamo 2018) [12]
a Not included in the NMA. CDI, Clostridioides difficile infection; FA, fusidic acid; FDX, fidaxomicin; IM, intramuscularly; IV, intravenously; MTZ, metronidazole; TEC, teicoplanin; TLV, tolevamer; VCM, vancomycin. Follow-up periods are quoted from the end of treatment.
102/110 74.0e75.0 Japan
Clinical cure, recurrence rate (follow up 30 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 101.1.C.004 (Cornely 2012) [10]
III
199/310 63.4 Europe, Canada, US
Clinical cure, recurrence rate (follow up 28 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 101.1.C.003 (Louie 2011) [11]
III
263/333 60.3e62.9 US, Canada
Clinical cure, recurrence rate (follow up 28 days) TLVa, 9 g þ 3 g orally, three times daily for 14 days VCM, 125 mg orally, four times daily for 10 days MTZ, 375 mg orally, four times daily for 10 days Studies 301 and 302 (Johnson 2014) [9]
III
258/279 62e67 US, Canada, Europe, Australia
Clinical cure, recurrence rate (follow up 21 days) VCM, 125 mg orally, four times daily for 10 days MTZ, 250 mg orally, four times daily for 10 days Zar 2007 [8]
III
82/68 (complete treatment only) 56.8e61.9 (complete treatment only) US
Clinical cure, recurrence rate (follow up 30 days) FAa, 500 mg orally, three times daily for 10 days VCM, 500 mg orally, three times daily for 10 days MTZ, 500 mg orally, three times daily for 10 days TECa, 400 mg IV/IM, twice daily for 10 days
N/A
33/29 38e44 Austria
93/1 (complete treatment only)
Wenisch 1996 [14]
N/A
Mean age range (years)
63.6e65.5 (complete treatment only) US
Country
VCM, 500 mg orally, four times daily for 10 days MTZ, 250 mg orally, four times daily for 10 days Teasley 1983 [13]
Phase Outcome measures
Treatment failure, recurrence (follow up 21 days)
Treatments and dosing Trial identifier/reference
Table 1 Summary of randomised controlled trials included in the network meta-analysis.
N/A
Gender (male/female)
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
3
including five datasets for VCM versus MTZ and three datasets for FDX versus VCM (i.e. one article included two RCTs) (Fig. 2). 3.2. FDX and VCM Three randomised, controlled, double-blind phase III studies of FDX versus VCM were identified and met the inclusion criteria for the NMA, each comparing 10 days’ treatment of FDX and VCM in patients with CDI. Two studies were non-inferiority studies conducted in the USA, Canada and Europe, and the third study was a comparative study conducted in Japan (Table 1). The outcomes of these studies demonstrated comparable cure rates for the FDX and VCM treatment arms; however, in the FDX arm, recurrence rates were lower resulting in increased rates of sustained clinical cure compared with VCM [10e12]. In the studies conducted in the USA, Canada, and Europe, the primary endpoint was the non-inferiority of FDX versus VCM for clinical cure. In both RCTs, the primary outcome was clinical cure defined as the resolution of diarrhoea (3 unformed bowel movements [UBMs] for 2 consecutive days), maintenance of resolution for the duration of therapy, and no further requirement (in the investigator's opinion) for CDI therapy at 2 days after end of treatment (EOT) [10,11]. In one study, among 596 patients in the modified ITT population, FDX was non-inferior to VCM for initial clinical cure of CDI (88.2% versus 85.8%, respectively), and the 28day recurrence rates were significantly lower for FDX vs VCM (15.4% versus 25.3%, respectively) [11]. In the other study, among 509 patients in the modified ITT population, FDX was non-inferior to VCM for clinical cure (91.7% versus 90.6%, respectively), and the 28-day recurrence rates were also significantly lower for FDX compared with VCM (12.7% versus 26.9%, respectively) [10]. A further randomised, double-blind, parallel-group study was conducted to assess the efficacy and safety of FDX versus VCM for the treatment of CDI in adult hospitalised patients in Japan [12]. The primary endpoint was the non-inferiority of FDX versus VCM for global cure rate of CDI, defined as the proportion of patients cured at end of treatment with no recurrence during 28-day follow up. Among 212 patients, the global cure rate was 67.3% for FDX and 65.7% for VCM: non-inferiority was not demonstrated. The 28-day recurrence rate was 19.5% for FDX compared with 25.3% for VCM [12]. 3.3. VCM and MTZ Five RCTs of VCM versus MTZ were identified for inclusion in the NMA (Table 1). The earliest prospective, randomised study, conducted in the early 1980s, found that among 101 patients with CDI who received VCM or MTZ for 10 days, the clinical cure rate was about 35% in both treatment groups [13]. In a further trial conducted in the 1990s, 62 patients were randomised 1:1 to receive VCM or MTZ, and the clinical cure rate was 94% in both treatment groups [14]. Larger, more recent randomised trials report significant improvements in CDI clinical outcomes for VCM over MTZ. In a pooled analysis from two trials, reported by Johnson et al., the primary endpoint was the non-inferiority of VCM versus MTZ for clinical success, defined as the resolution of diarrhoea and absence of severe abdominal discomfort due to CDI for more than 2 consecutive days including day 10; resolution of diarrhoea was defined as attainment of bowel movements with a hard or formed consistency on average or 2 or fewer bowel movements/day with a loose or watery consistency on average [9]. Among 289 patients receiving MTZ and 266 patients receiving VCM, the clinical success rate for MTZ was inferior to VCM (72.7% and 81.1%, respectively).
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
4
Source
Outcome
Definition
FDX (n/N)
VCM (n/N)
MTZ (n/N)
Teasley 1983 [13]
Clinical curea
Resolution of diarrhoea (<2 formed stools per day) within 6 days of treatment and completion of 10 days of treatment [inferred]a Recurrence of diarrhoea (4 watery stools per day for 48 h) in patients who had completed 10 days of treatment, had normal stools at the end of the treatment period and had not received additional antibiotics after the treatment period, plus a positive C. difficile stool culture/cytotoxin assay or visible pseudomembranes at endoscopy Resolution of diarrhoea within 6 treatment days, completion of 10 days of treatment and no relapse within the follow-up period [As for SCC 1]
e
51/56
39/45
e
6/51
2/39
e
45/56
37/45
Recurrence (‘relapse’)
Sustained cure 1 (‘cure’) Sustained cure 2 Wenisch 1996 [14]
Zar 2007 [8]
Johnson 2014d (study 301) [9]
e
45/56
37/45
e
29/31
29/31
Recurrence (‘clinical relapse’) Sustained cure 1 Sustained cure 2
Lack of symptoms (no loose stools, gastrointestinal symptoms or fever) and normalisation of serum levels of C-reactive protein and leukocyte counts Reappearance of CDI and other symptoms during the 30-day follow-up period Attainment of clinical cure during treatment with no relapse during the follow-up period [inferred]b [As for SCC 1]
e e e
5/31 24/31 24/31
5/31 24/31 24/31
Clinical cure (‘cure’) Recurrence (‘relapse’) Sustained cure 1 Sustained cure 2
Resolution of diarrhoea by day 6 of treatment and a negative C. difficile toxin assay at days 6 and 10 of treatment Recurrence of C. difficile toxin A-positive diarrhoea by day 21 after initial cure Attainment of clinical cure during treatment with no relapse during the follow-up period [inferred]b [As for SCC 1]
e e e
69/82 5/69 64/82 64/82
66/90 9/66 57/90 57/90
Clinical cure (‘clinical success’)
Resolution of diarrhoea (attainment of bowel movements with a hard/formed consistency on average, or 2 loose/ watery bowel movements per day, on average) and absence of severe abdominal discomfort due to CDI, for >2 consecutive days including day 10 Confirmed diagnosis of CDI during the 4-week follow-up period in patients who previously had resolution of diarrhoea Clinical cure with no recurrence [calculated]b Resolution of diarrhoea with no recurrence [calculated]c
e
109/134
103/143
e e e
25/107 84/134 82/134
29/107 74/143 78/143
e
101/125
99/135
e e e
18/102 83/125 84/125
20/106 79/135 86/135
253/287
265/309
e
39/253
67/265
e
214/287 214/287
198/309 198/309
e e
221/252
223/257
e
Clinical cure
Recurrence Sustained cure 1b Sustained cure 2c Johnson 2014d (study 302) [9]
Clinical cure (‘clinical success’)
Recurrence Sustained cure 1b Sustained cure 2c Louie 2011 (101.1.C.003) [11]
Clinical cure Recurrence (‘clinical recurrence’) Sustained cure (‘global cure’) Sustained cure 2
Cornely 2012 (101.1.C.004) [10]
Clinical cure Recurrence Sustained cure 1 (‘sustained response’) Sustained cure 2
Mikamo 2018 (2819-CL-3002) [12]
Clinical cure Recurrence Sustained cure 1 (‘global cure’) Sustained cure 2
Resolution of diarrhoea (attainment of bowel movements with a hard/formed consistency on average, or 2 loose/ watery bowel movements per day, on average) and absence of severe abdominal discomfort due to CDI, for >2 consecutive days including day 10 Confirmed diagnosis of CDI during the 4-week follow-up period in patients who previously had resolution of diarrhoea Clinical cure with no recurrence [calculated]b Resolution of diarrhoea with no recurrence [calculated]c Resolution of diarrhoea (3 UBMs for 2 consecutive days), maintenance of resolution until EOT and no requirement for further therapy at 2 days after EOT Reappearance of >3 diarrhoeal stools per 24-h period within 4 weeks of end of treatment; presence of C. difficile toxin A/ B in stool; and a requirement for further therapy Resolution of diarrhoea with no recurrence [As for sustained cure (‘global cure’)] Resolution of diarrhoea (3 UBMs per day for 2 consecutive days, or a substantial number of UBMs at EOT) for the duration of treatment and no requirement for further therapy at 2 days after EOT Reappearance of >3 UBMs per 24-h period within 30 days of EOT; positive C. difficile toxin stool test; and a requirement for further therapy Clinical cure with no recurrence
28/221
60/223
e
193/252
163/257
e
[As for SCC 1]
193/252
163/257
e
Resolution of diarrhoea (3 UBMs for 2 consecutive days), maintenance of resolution until EOT, and no requirement for further therapy treatment at EOT More frequent UBMs then at EOT per 24-h period within 4 weeks of EOT, presence of C. difficile toxin A/B in stool; and a requirement for further therapy Clinical cure at EOT with no recurrence during follow up [As for SCC 1]
87/104
95/108
e
17/87
24/95
e
70/104 70/104
71/108 71/108
e e
CDI, Clostridioides difficile infection; EOT, end of treatment; FDX, fidaxomicin; MTZ, metronidazole; SCC, sustained clinical cure; UBM, unformed bowel movement; VCM, vancomycin. Terminology used in the published studies are given in parentheses in the ‘Outcome’ column, where it differs from terminology used in this report. a Not explicitly reported; deduced for this analysis using the reported proportion of patients with relapse. b Not explicitly reported; calculated for this analysis by subtracting the number of patients with recurrence from the number of patients with clinical cure. c Not explicitly reported; calculated for this analysis by subtracting the number of patients with recurrence from the number of patients with resolution of diarrhoea. d Johnson 2014 reports pooled data from Study 301 and 302 for the subgroups; for the total populations, numbers are provided for each study separately.
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
Table 2 Summary of the datasets included and definitions (actual and calculated) used in the NMA.
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
5
Fig. 1. Flow chart of article selection. FDX, fidaxomicin; ICHUSHI, Igaku Chuo Zasshi database; MTZ, metronidazole; VCM, vancomycin.
The RCT reported by Zar et al. compared VCM with MTZ, using the primary outcome of clinical cure defined as the resolution of diarrhoea by day 6 of treatment and a negative result of a C. difficile toxin A assay at days 6 and 10 of treatment [8]. Of 172 patients, 150 completed the study; while clinical cure rates with MTZ and VCM were similar for mild CDI (90% versus 98%, respectively), in patients with severe CDI, the clinical cure rates were significantly lower with MTZ than with VCM (76% versus 97%, respectively). None of the studies provided rates of sustained clinical cure, so these were calculated from clinical cure and recurrence/relapse rates as shown in Table 2.
3.4. Network meta-analysis (NMA) The NMA included three FDX datasets and five MTZ datasets, each compared with VCM (Fig. 2). The total population and outcomes are shown in Table 2. Clinical cure rates were reported using the same methods of evaluation in all eligible studies, although the definition of clinical cure and recurrence differed across studies. For the purpose of evidence synthesis, clinical cure and recurrence definitions were considered similar and data were used as reported in the sources. Heterogeneity of 23.10% between studies was observed for the FDX versus VCM comparison of sustained clinical cure (definitions 1 and 2) (Figures A.3 and A.4). For all other outcomes and for MTZ versus VCM, heterogeneity was 0e0.55% (Figures A.1eA.4). For all the endpoints of interest, there was a negligible difference in DIC between the fixed-effects and random-effects models (Table A.1), so the fixed-effects model was used. 3.5. Fixed-effects model
Fig. 2. Network diagram of treatments in the network meta-analysis. FDX, fidaxomicin; MTZ, metronidazole; VCM, vancomycin.
There was no difference between FDX and VCM in clinical cure rate, and a significant difference in favour of FDX for clinical cure rate compared with MTZ (OR: 1.77 [95% CrI: 1.11, 2.83]) (Fig. 3). For recurrence (defined as clinical cure without recurrence or diarrhoea resolution without recurrence), there was a significant
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
6
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
Fig. 3. Clinical cure for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median logORs with 95% credible intervals.
difference in favour of FDX versus both VCM (OR: 0.50 [95% CrI: 0.37, 0.68]) and MTZ (OR: 0.44 [95% CrI: 0.27, 0.72]) (Fig. 4). There were significant differences in favour of FDX for sustained cure 1 (clinical cure without recurrence) versus VCM (OR: 1.61 [95% CrI: 1.27, 2.05]) and MTZ (OR: 2.39 [95% CrI: 1.65, 3.47]) (Fig. 5). There were also significant differences in favour of FDX for sustained cure 2 (diarrhoea resolution without recurrence) versus VCM (OR: 1.61 [95% CrI: 1.27, 2.05]) and MTZ (OR 2.12 [95% CrI: 1.46, 3.08]) (Fig. 6). 4. Discussion VCM and MTZ have been the mainstays of CDI treatment for decades, with MTZ used in mild or moderate episodes and VCM in severe CDI. MTZ is recommended as a first-line treatment for mild or moderate CDI in Europe [15], Japan [16] and Australia [17];
however, in the 2017 IDSA/SHEA guidelines, MTZ is recommended only as an alternative treatment option if FDX or VCM is not available [1]. In this NMA comparing the effectiveness of FDX, VCM and MTZ for the treatment of CDI, FDX was more effective than MTZ but comparable to VCM for clinical cure rate, while FDX was more effective than both VCM and MTZ with regard to CDI recurrence and sustained cure rates. The main outcome in our analysis was clinical cure rate, which in the fixed-effects model was significantly higher for FDX versus MTZ, and similar for FDX versus VCM. The result of the comparison with VCM is consistent with a previous meta-analysis that did not include the most recent randomised trial in Japan, and which reported that clinical cure rates were similar for FDX and VCM (OR: 1.17; 95% CI: 0.82, 1.66) [18]. Recurrence rates were assessed during 28- and 30-day followup periods (after end of treatment) in the FDX versus VCM trials
Fig. 4. Recurrence for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median logORs with 95% credible intervals.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
7
Fig. 5. Sustained cure 1 (clinical cure without recurrence) for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median log-ORs with 95% credible intervals.
Fig. 6. Sustained cure 2 (diarrhoea resolution without recurrence) for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median log-ORs with 95% credible intervals.
[10,11], and during 21-, 28-, and 30-day follow-up periods in the VCM versus MTZ trials [8,9,13,14]. Our analysis calculated recurrence rate to be significantly lower, and sustained cure rates to be correspondingly higher, with FDX versus MTZ. With the exception of the Japanese phase III trial [12], FDX was also associated with significant improvements in recurrence rates and sustained cure rates compared with VCM. Our findings are consistent with a recent NMA based on published data available up to 2017 that compared 13 treatments for CDI, including FDX, MTZ and VCM [2]. The estimates reported in the study suggest that for sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death, FDX was better than MTZ (OR: 0.49 [95% CI: 0.35, 0.68]), and better than VCM (OR: 0.67 [95% CI: 0.55, 0.82]) [2]. The authors of
the study concluded that MTZ should not be recommended for treatment of CDI, and that FDX should be considered for initial therapy for mild or moderate CDI [2]. The approach in our analysis allowed the effectiveness of FDX and MTZ to be compared across clinical trials using VCM as the common arm. Our study is primarily limited by variability between the original studies in multiple aspects, including treatment dosage and duration; the definitions of clinical cure, recurrence rate and sustained cure; and the duration of follow up. In particular, sustained cure rates were provided in the FDX versus VCM studies, but were calculated from using clinical cure and recurrence rates for VCM versus MTZ. Lastly, the therapeutic environment or intestinal flora in the studies conducted in the 1980s and 90s may have differed from that in contemporary studies.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
8
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
In summary, our meta-analysis suggests that FDX and VCM, but not MTZ, are effective first-line treatments for CDI, and that FDX may be more effective at preventing CDI recurrence than VCM.
[5]
Conflicts of interest
[6]
A. Fukushima was an employee of Creativ-Ceutical at the time of the study, and V. Taieb is an employee of Creativ-Ceutical, working on behalf of Astellas Pharma, Inc. H. Okumura and S. Shoji are employees of Astellas Pharma, Inc. and M. English is an employee of Astellas Pharma Global Development, Inc.
[7]
Data sharing statement Access to anonymised individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under “Sponsor Specific Details for Astellas”.
[8]
[9]
[10]
[11]
Acknowledgements The study was funded by Astellas Pharma, Inc., Japan, and Astellas Pharma Global Development, Inc., USA. Medical writing support was provided by Annick Moon, PhD, for Cello Health MedErgy, funded by Astellas Pharma, Inc.
[12]
[13]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jiac.2019.07.005. References [1] McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;31:431e55. https://doi.org/10.1093/cid/cix1085. [2] Beinortas T, Burr NE, Wilcox MH, Subramanian V. Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. Lancet Infect Dis 2018;18:1035e44. https://doi.org/10.1016/ S1473-3099(18)30285-8. [3] Vardakas KZ, Polyzos KA, Patouni K, Rafailidis PI, Samonis G, Falagas ME. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents 2012;40:1e8. https://doi.org/10.1016/ j.ijantimicag.2012.01.004. [4] Heimann SM, Vehreschild JJ, Cornely OA, Wisplinghoff H, Hallek M, Goldbrunner R, et al. Economic burden of Clostridium difficile-associated
[14]
[15]
[16]
[17]
[18]
diarrhoea: a cost-of-illness study from a German tertiary care hospital. Infection 2015;43:707e14. https://doi.org/10.1007/s15010-015-0810-x. Bouza E. Consequences of Clostridium difficile infection: understanding the healthcare burden. Clin Microbiol Infect 2012;18(Suppl. 6):5e12. https:// doi.org/10.1111/1469-0691.12064. Olsen MA, Yan Y, Reske KA, Zilberberg M, Dubberke ER. Impact of Clostridium difficile recurrence on hospital readmissions. Am J Infect Contr 2015;43: 318e22. https://doi.org/10.1016/j.ajic.2014.12.020. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect 2015;21:164e70. https://doi.org/10.1016/j.cmi.2014.08.017. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302e7. https:// doi.org/10.1086/519265. Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014;59:345e54. https://doi.org/10.1093/cid/ciu313. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e9. https://doi.org/10.1016/ S1473-3099(11)70374-7. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422e31. https://doi.org/10.1056/NEJMoa0910812. Mikamo H, Tateda K, Yanagihara K, Kusachi S, Takesue Y, Miki T, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan. J Infect Chemother 2018;24:744e52. https://doi.org/10.1016/ j.jiac.2018.05.010. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983;2: 1043e6. https://doi.org/10.1016/S0140-6736(83)91036-X. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996;22:813e8. https://doi.org/10.1093/clinids/22.5.813. Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20(Suppl. 2):1e26. https://doi.org/10.1111/1469-0691.12418. Ohnishi K, Ainoda Y, Imamura A, Iwabuchi S, Okuda M, Nakano T. JAID/JSC guidelines for infection treatment 2015dintestinal infections. J Infect Chemother 2018;24:1e17. https://doi.org/10.1016/j.jiac.2017.09.002. Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May MLA, et al. Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand. Intern Med J 2016;46:479e93. https://doi.org/10.1111/ imj.13027. Cornely OA, Nathwani D, Ivanescu C, Odufowora-Sita O, Retsa P, Odeyemi IAO. Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: a meta-analysis and indirect treatment comparison. J Antimicrob Chemother 2014;69:2892e900. https://doi.org/ 10.1093/jac/dku261.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Original Article
Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis* Hiroyuki Okumura a, *, Ayako Fukushima b, 1, Vanessa Taieb c, Shingo Shoji a, Marci English d a
Astellas Pharma, Inc., Tokyo, Japan Creativ-Ceutical, Paris, France Creativ-Ceutical, London, UK d Astellas Pharma Global Development, Inc., Northbrook, IL, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 March 2019 Received in revised form 17 June 2019 Accepted 1 July 2019 Available online xxx
We conducted a systematic review of the literature and network meta-analysis (NMA) to compare the relative effectiveness of antibiotic treatments for Clostridioides (Clostridium) difficile infection (CDI) including vancomycin (VCM), metronidazole (MTZ) and fidaxomicin (FDX). Eligible studies were randomised controlled trials (RCTs) including adults with any severity of CDI that was treated with VCM, MTZ or FDX. The NMA was performed using a Bayesian framework, using a fixed-effects model. The searches identified seven publications for inclusion, which provided five RCTs for VCM versus MTZ, and three RCTs for FDX versus VCM. The NMA showed that for clinical cure rate, there was no difference for FDX versus VCM, and there was a significant difference in favour of FDX versus MTZ (odds ratio [OR]: 1.77; 95% credible interval [CrI] 1.11, 2.83]). For recurrence rate, there was a significant difference in favour of FDX versus both VCM (OR: 0.50; 95% CrI: 0.37, 0.68) and MTZ (OR: 0.44; 95% CrI: 0.27, 0.72). For sustained cure (clinical cure without recurrence), there was a significant difference in favour of FDX versus VCM (OR: 1.61; 95% CrI: 1.27, 2.05) and MTZ (OR: 2.39; 95% CrI: 1.65, 3.47). These findings suggest that FDX and VCM are effective first-line treatments for mild or moderate CDI, whereas MTZ is not, and FDX may be more effective at preventing CDI recurrence than VCM. © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Clostridioides difficile infection Fidaxomicin Vancomycin Metronidazole Meta-analysis
1. Introduction Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of nosocomial bacterial diarrhoea in industrialised countries, and can be serious and life-threatening; its incidence and severity are rising, which impacts all aspects of healthcare
* All authors meet the ICMJE authorship criteria and have made substantial contributions to all the following: the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be submitted. * Corresponding author. Health Economics & Outcomes Research, Medical Affairs, Astellas Pharma, Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan. E-mail address: [email protected] (H. Okumura). 1 Employee of Creativ-Ceutical at the time of the study.
delivery globally [1,2]. The most widely used antibiotics for the management of CDI are vancomycin (VCM) and metronidazole (MTZ) [2]. However, recurrence of CDI is observed in up to 25% of patients treated with VCM or MTZ [3,4]. CDI recurrence is associated with poor clinical outcomes, increased duration of hospitalisation and increased costs [5e7]. The latest guidelines developed by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), updated in 2017, recommend either VCM or fidaxomicin (FDX) for the treatment of an initial episode of mild or moderate CDI in adults [1]. A notable change from the previous IDSA/SHEA guidelines was that MTZ in mild or moderate CDI was downgraded from a first-line treatment to an alternative treatment option recommended when FDX or VCM is not available [1]. The guidance for VCM was based on evidence from head-to-head studies that reported significantly higher cure rates, as well as
https://doi.org/10.1016/j.jiac.2019.07.005 1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
2
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
lower recurrence rates, for VCM versus MTZ [8,9]. The guidance for FDX was based on two head-to-head studies of FDX and VCM, which demonstrated the non-inferiority of FDX versus VCM for clinical cure, and showed that the recurrence rate was significantly lower for FDX than for VCM [10,11]. FDX is a narrow-spectrum macrocyclic antibiotic that was approved globally based on the results of two randomised, controlled trials (RCTs) of FDX versus VCM in patients with CDI in the USA, Canada and Europe [10,11]. More recently, a randomised study of nosocomial CDI in Japan showed that although non-inferiority was not demonstrated for FDX versus VCM, the 28-day recurrence rate was 19.5% and 25.3% for FDX and VCM, respectively [12]. To date, there are no comparative studies of FDX versus MTZ in CDI, although in a network meta-analysis (NMA) including data available up to July 2017, FDX was significantly better than MTZ for sustained symptomatic cure (odds ratio [OR]: 0.49; 95% CI: 0.35, 0.68) [2]. In this analysis, we conducted a systematic literature review to identify RCTs of FDX versus VCM and VCM versus MTZ; we then performed an NMA to assess the relative effectiveness of FDX versus MTZ in the treatment of CDI, using VCM as the common arm. 2. Patients and methods 2.1. Design and objectives A systematic evidence-based approach was used to screen the literature and extract RCTs of FDX, VCM or MTZ for the treatment of CDI. An NMA was then conducted to assess the relative effectiveness of FDX versus VCM, and FDX versus MTZ using VCM as the common CDI treatment arm. The effectiveness outcomes of interest, calculated for each treatment, were clinical cure rates during the treatment period, recurrence rates during follow up, and sustained cure rate defined as clinical cure without recurrence during follow up. 2.2. Searches and data extraction A systematic literature search performed on 3 July 2011 identified three articles that were eligible for inclusion; an updated literature search was performed to identify articles published up to 10 March 2014. A further literature search was conducted in September 2016. Search strings were based on ‘Clostridioides (Clostridium) difficile’, ‘CDI’ or ‘CDAD’, and ‘fidaxomicin’, ‘vancomycin’, ‘metronidazole’ or ‘probiotics’. The initial inclusion of probiotics was intended to broaden the subsequent network; however, no such articles were found fulfilling the search criteria. Research articles published in English were identified using the Ovid platform to search Medline, EMBASE and the Cochrane Central Register of Controlled Trials, and articles were identified using the Igaku Chuo Zasshi database, which includes more than 2500 biomedical journals and other serial publications published in Japan. The Japanese Association for Infectious Diseases, the Japanese Society of Environmental Infections and the Japanese Association for Anaerobic Infection Research congress databases were also searched to obtain studies published only as abstracts (published in 2015 and 2016). The Clinicaltrials.gov database was used to identify closed clinical studies in adults from 2013 to 2016, using the search terms ‘Clostridioides (Clostridium) difficile’, ‘CDI’ or ‘CDAD’ with the interventions ‘fidaxomicin’, ‘vancomycin’, ‘metronidazole’ or ‘probiotics’. Articles were eligible for inclusion if they reported RCTs of FDX, VCM or MTZ in adult patients with confirmed CDI of any severity. Articles were excluded if they were studies in patients aged <18
years or receiving treatment other than FDX, VCM, MTZ, or probiotics, or non-randomised studies including reviews, opinions, systematic reviews and editorials. Articles were screened by title and abstract to identify those containing relevant data and the full text of the selected articles was fully assessed to ensure compliance with the inclusion and exclusion criteria. Data extracted into Excel included publication type, title, year of publication, trial name, trial number, sponsor/ funding, country, study objective, study design, population, inclusion/exclusion criteria, sample size, details of intervention/ comparator, outcomes of interest (clinical cure, recurrence rate and sustained cure rate), follow-up time and statistical methods (Table 1). Screening was performed by two independent reviewers, and a quality-control check of the data extraction was performed by a further independent reviewer. 2.3. Data analysis All data used in the analysis were from the intention-to-treat (ITT) study populations. The endpoints of interest were: clinical cure rates during the treatment period; recurrence rates during follow up; and sustained cure rate during follow up. Definitions and endpoints from the published article were used when available, and were otherwise calculated as given in Table 2. Some studies reported recurrence as a proportion of patients who achieved initial clinical cure, while others reported recurrence as a proportion of patients who previously met the criteria for resolution of diarrhoea. Therefore, two definitions of sustained cure were calculated for the studies included in this paper: ‘sustained cure 1’ was defined as initial clinical cure with no recurrence and ‘sustained cure 2’ was defined as resolution of diarrhoea with no recurrence (Table 2). The NMA was performed using a Bayesian framework, using a fixed-effects model and a random-effects model. The fixed-effects and random-effects models were compared using the Deviance Information Criterion (DIC). Differences in DIC of <5 points were not considered meaningful; consequently, the simpler fixed-effects model was selected for the analysis because the difference in DIC between fixed-effects and random-effects models was negligible (see Results). A generalised linear model with a binomial error distribution and logit link function was used, and results were summarised as odds ratios (ORs) with 95% credible intervals (CrI). Forest plots presented the ORs for FDX versus VCM or MTZ: for clinical cure rate and sustained cure rate, an OR>1 favours FDX; for recurrence rate, an OR<1 favours FDX. Between-study heterogeneity was assessed using pairwise comparisons, with the inverse variance-weighted method for the fixed-effects model and either the restricted maximum likelihood or the DerSimonian-Laird method for the random-effects model. Odds ratios and 95% confidence intervals (CIs) were used to summarise the individual and pooled treatment effects (Figure A.1). An I2 score of <25 was considered to indicate low heterogeneity. 3. Results 3.1. Searches In the initial literature search, 1261 publications were identified, of which 44 were selected for full-text evaluation and five publications (reporting data from five studies) met the inclusion criteria. In the updated literature search, 610 articles were identified, of which 118 were duplicates. After screening titles and abstracts of 492 articles, 30 were examined in detail; of these, two publications (reporting from three datasets) fulfilled the inclusion criteria (Fig. 1). From these seven publications, there were eight datasets,
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
Clinical cure, recurrence rate (follow up 28 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 2819-CL-3002 (Mikamo 2018) [12]
a Not included in the NMA. CDI, Clostridioides difficile infection; FA, fusidic acid; FDX, fidaxomicin; IM, intramuscularly; IV, intravenously; MTZ, metronidazole; TEC, teicoplanin; TLV, tolevamer; VCM, vancomycin. Follow-up periods are quoted from the end of treatment.
102/110 74.0e75.0 Japan
Clinical cure, recurrence rate (follow up 30 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 101.1.C.004 (Cornely 2012) [10]
III
199/310 63.4 Europe, Canada, US
Clinical cure, recurrence rate (follow up 28 days) FDX, 200 mg orally, twice daily for 10 days VCM, 125 mg orally, four times daily for 10 days Study 101.1.C.003 (Louie 2011) [11]
III
263/333 60.3e62.9 US, Canada
Clinical cure, recurrence rate (follow up 28 days) TLVa, 9 g þ 3 g orally, three times daily for 14 days VCM, 125 mg orally, four times daily for 10 days MTZ, 375 mg orally, four times daily for 10 days Studies 301 and 302 (Johnson 2014) [9]
III
258/279 62e67 US, Canada, Europe, Australia
Clinical cure, recurrence rate (follow up 21 days) VCM, 125 mg orally, four times daily for 10 days MTZ, 250 mg orally, four times daily for 10 days Zar 2007 [8]
III
82/68 (complete treatment only) 56.8e61.9 (complete treatment only) US
Clinical cure, recurrence rate (follow up 30 days) FAa, 500 mg orally, three times daily for 10 days VCM, 500 mg orally, three times daily for 10 days MTZ, 500 mg orally, three times daily for 10 days TECa, 400 mg IV/IM, twice daily for 10 days
N/A
33/29 38e44 Austria
93/1 (complete treatment only)
Wenisch 1996 [14]
N/A
Mean age range (years)
63.6e65.5 (complete treatment only) US
Country
VCM, 500 mg orally, four times daily for 10 days MTZ, 250 mg orally, four times daily for 10 days Teasley 1983 [13]
Phase Outcome measures
Treatment failure, recurrence (follow up 21 days)
Treatments and dosing Trial identifier/reference
Table 1 Summary of randomised controlled trials included in the network meta-analysis.
N/A
Gender (male/female)
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
3
including five datasets for VCM versus MTZ and three datasets for FDX versus VCM (i.e. one article included two RCTs) (Fig. 2). 3.2. FDX and VCM Three randomised, controlled, double-blind phase III studies of FDX versus VCM were identified and met the inclusion criteria for the NMA, each comparing 10 days’ treatment of FDX and VCM in patients with CDI. Two studies were non-inferiority studies conducted in the USA, Canada and Europe, and the third study was a comparative study conducted in Japan (Table 1). The outcomes of these studies demonstrated comparable cure rates for the FDX and VCM treatment arms; however, in the FDX arm, recurrence rates were lower resulting in increased rates of sustained clinical cure compared with VCM [10e12]. In the studies conducted in the USA, Canada, and Europe, the primary endpoint was the non-inferiority of FDX versus VCM for clinical cure. In both RCTs, the primary outcome was clinical cure defined as the resolution of diarrhoea (3 unformed bowel movements [UBMs] for 2 consecutive days), maintenance of resolution for the duration of therapy, and no further requirement (in the investigator's opinion) for CDI therapy at 2 days after end of treatment (EOT) [10,11]. In one study, among 596 patients in the modified ITT population, FDX was non-inferior to VCM for initial clinical cure of CDI (88.2% versus 85.8%, respectively), and the 28day recurrence rates were significantly lower for FDX vs VCM (15.4% versus 25.3%, respectively) [11]. In the other study, among 509 patients in the modified ITT population, FDX was non-inferior to VCM for clinical cure (91.7% versus 90.6%, respectively), and the 28-day recurrence rates were also significantly lower for FDX compared with VCM (12.7% versus 26.9%, respectively) [10]. A further randomised, double-blind, parallel-group study was conducted to assess the efficacy and safety of FDX versus VCM for the treatment of CDI in adult hospitalised patients in Japan [12]. The primary endpoint was the non-inferiority of FDX versus VCM for global cure rate of CDI, defined as the proportion of patients cured at end of treatment with no recurrence during 28-day follow up. Among 212 patients, the global cure rate was 67.3% for FDX and 65.7% for VCM: non-inferiority was not demonstrated. The 28-day recurrence rate was 19.5% for FDX compared with 25.3% for VCM [12]. 3.3. VCM and MTZ Five RCTs of VCM versus MTZ were identified for inclusion in the NMA (Table 1). The earliest prospective, randomised study, conducted in the early 1980s, found that among 101 patients with CDI who received VCM or MTZ for 10 days, the clinical cure rate was about 35% in both treatment groups [13]. In a further trial conducted in the 1990s, 62 patients were randomised 1:1 to receive VCM or MTZ, and the clinical cure rate was 94% in both treatment groups [14]. Larger, more recent randomised trials report significant improvements in CDI clinical outcomes for VCM over MTZ. In a pooled analysis from two trials, reported by Johnson et al., the primary endpoint was the non-inferiority of VCM versus MTZ for clinical success, defined as the resolution of diarrhoea and absence of severe abdominal discomfort due to CDI for more than 2 consecutive days including day 10; resolution of diarrhoea was defined as attainment of bowel movements with a hard or formed consistency on average or 2 or fewer bowel movements/day with a loose or watery consistency on average [9]. Among 289 patients receiving MTZ and 266 patients receiving VCM, the clinical success rate for MTZ was inferior to VCM (72.7% and 81.1%, respectively).
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
4
Source
Outcome
Definition
FDX (n/N)
VCM (n/N)
MTZ (n/N)
Teasley 1983 [13]
Clinical curea
Resolution of diarrhoea (<2 formed stools per day) within 6 days of treatment and completion of 10 days of treatment [inferred]a Recurrence of diarrhoea (4 watery stools per day for 48 h) in patients who had completed 10 days of treatment, had normal stools at the end of the treatment period and had not received additional antibiotics after the treatment period, plus a positive C. difficile stool culture/cytotoxin assay or visible pseudomembranes at endoscopy Resolution of diarrhoea within 6 treatment days, completion of 10 days of treatment and no relapse within the follow-up period [As for SCC 1]
e
51/56
39/45
e
6/51
2/39
e
45/56
37/45
Recurrence (‘relapse’)
Sustained cure 1 (‘cure’) Sustained cure 2 Wenisch 1996 [14]
Zar 2007 [8]
Johnson 2014d (study 301) [9]
e
45/56
37/45
e
29/31
29/31
Recurrence (‘clinical relapse’) Sustained cure 1 Sustained cure 2
Lack of symptoms (no loose stools, gastrointestinal symptoms or fever) and normalisation of serum levels of C-reactive protein and leukocyte counts Reappearance of CDI and other symptoms during the 30-day follow-up period Attainment of clinical cure during treatment with no relapse during the follow-up period [inferred]b [As for SCC 1]
e e e
5/31 24/31 24/31
5/31 24/31 24/31
Clinical cure (‘cure’) Recurrence (‘relapse’) Sustained cure 1 Sustained cure 2
Resolution of diarrhoea by day 6 of treatment and a negative C. difficile toxin assay at days 6 and 10 of treatment Recurrence of C. difficile toxin A-positive diarrhoea by day 21 after initial cure Attainment of clinical cure during treatment with no relapse during the follow-up period [inferred]b [As for SCC 1]
e e e
69/82 5/69 64/82 64/82
66/90 9/66 57/90 57/90
Clinical cure (‘clinical success’)
Resolution of diarrhoea (attainment of bowel movements with a hard/formed consistency on average, or 2 loose/ watery bowel movements per day, on average) and absence of severe abdominal discomfort due to CDI, for >2 consecutive days including day 10 Confirmed diagnosis of CDI during the 4-week follow-up period in patients who previously had resolution of diarrhoea Clinical cure with no recurrence [calculated]b Resolution of diarrhoea with no recurrence [calculated]c
e
109/134
103/143
e e e
25/107 84/134 82/134
29/107 74/143 78/143
e
101/125
99/135
e e e
18/102 83/125 84/125
20/106 79/135 86/135
253/287
265/309
e
39/253
67/265
e
214/287 214/287
198/309 198/309
e e
221/252
223/257
e
Clinical cure
Recurrence Sustained cure 1b Sustained cure 2c Johnson 2014d (study 302) [9]
Clinical cure (‘clinical success’)
Recurrence Sustained cure 1b Sustained cure 2c Louie 2011 (101.1.C.003) [11]
Clinical cure Recurrence (‘clinical recurrence’) Sustained cure (‘global cure’) Sustained cure 2
Cornely 2012 (101.1.C.004) [10]
Clinical cure Recurrence Sustained cure 1 (‘sustained response’) Sustained cure 2
Mikamo 2018 (2819-CL-3002) [12]
Clinical cure Recurrence Sustained cure 1 (‘global cure’) Sustained cure 2
Resolution of diarrhoea (attainment of bowel movements with a hard/formed consistency on average, or 2 loose/ watery bowel movements per day, on average) and absence of severe abdominal discomfort due to CDI, for >2 consecutive days including day 10 Confirmed diagnosis of CDI during the 4-week follow-up period in patients who previously had resolution of diarrhoea Clinical cure with no recurrence [calculated]b Resolution of diarrhoea with no recurrence [calculated]c Resolution of diarrhoea (3 UBMs for 2 consecutive days), maintenance of resolution until EOT and no requirement for further therapy at 2 days after EOT Reappearance of >3 diarrhoeal stools per 24-h period within 4 weeks of end of treatment; presence of C. difficile toxin A/ B in stool; and a requirement for further therapy Resolution of diarrhoea with no recurrence [As for sustained cure (‘global cure’)] Resolution of diarrhoea (3 UBMs per day for 2 consecutive days, or a substantial number of UBMs at EOT) for the duration of treatment and no requirement for further therapy at 2 days after EOT Reappearance of >3 UBMs per 24-h period within 30 days of EOT; positive C. difficile toxin stool test; and a requirement for further therapy Clinical cure with no recurrence
28/221
60/223
e
193/252
163/257
e
[As for SCC 1]
193/252
163/257
e
Resolution of diarrhoea (3 UBMs for 2 consecutive days), maintenance of resolution until EOT, and no requirement for further therapy treatment at EOT More frequent UBMs then at EOT per 24-h period within 4 weeks of EOT, presence of C. difficile toxin A/B in stool; and a requirement for further therapy Clinical cure at EOT with no recurrence during follow up [As for SCC 1]
87/104
95/108
e
17/87
24/95
e
70/104 70/104
71/108 71/108
e e
CDI, Clostridioides difficile infection; EOT, end of treatment; FDX, fidaxomicin; MTZ, metronidazole; SCC, sustained clinical cure; UBM, unformed bowel movement; VCM, vancomycin. Terminology used in the published studies are given in parentheses in the ‘Outcome’ column, where it differs from terminology used in this report. a Not explicitly reported; deduced for this analysis using the reported proportion of patients with relapse. b Not explicitly reported; calculated for this analysis by subtracting the number of patients with recurrence from the number of patients with clinical cure. c Not explicitly reported; calculated for this analysis by subtracting the number of patients with recurrence from the number of patients with resolution of diarrhoea. d Johnson 2014 reports pooled data from Study 301 and 302 for the subgroups; for the total populations, numbers are provided for each study separately.
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
Table 2 Summary of the datasets included and definitions (actual and calculated) used in the NMA.
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
5
Fig. 1. Flow chart of article selection. FDX, fidaxomicin; ICHUSHI, Igaku Chuo Zasshi database; MTZ, metronidazole; VCM, vancomycin.
The RCT reported by Zar et al. compared VCM with MTZ, using the primary outcome of clinical cure defined as the resolution of diarrhoea by day 6 of treatment and a negative result of a C. difficile toxin A assay at days 6 and 10 of treatment [8]. Of 172 patients, 150 completed the study; while clinical cure rates with MTZ and VCM were similar for mild CDI (90% versus 98%, respectively), in patients with severe CDI, the clinical cure rates were significantly lower with MTZ than with VCM (76% versus 97%, respectively). None of the studies provided rates of sustained clinical cure, so these were calculated from clinical cure and recurrence/relapse rates as shown in Table 2.
3.4. Network meta-analysis (NMA) The NMA included three FDX datasets and five MTZ datasets, each compared with VCM (Fig. 2). The total population and outcomes are shown in Table 2. Clinical cure rates were reported using the same methods of evaluation in all eligible studies, although the definition of clinical cure and recurrence differed across studies. For the purpose of evidence synthesis, clinical cure and recurrence definitions were considered similar and data were used as reported in the sources. Heterogeneity of 23.10% between studies was observed for the FDX versus VCM comparison of sustained clinical cure (definitions 1 and 2) (Figures A.3 and A.4). For all other outcomes and for MTZ versus VCM, heterogeneity was 0e0.55% (Figures A.1eA.4). For all the endpoints of interest, there was a negligible difference in DIC between the fixed-effects and random-effects models (Table A.1), so the fixed-effects model was used. 3.5. Fixed-effects model
Fig. 2. Network diagram of treatments in the network meta-analysis. FDX, fidaxomicin; MTZ, metronidazole; VCM, vancomycin.
There was no difference between FDX and VCM in clinical cure rate, and a significant difference in favour of FDX for clinical cure rate compared with MTZ (OR: 1.77 [95% CrI: 1.11, 2.83]) (Fig. 3). For recurrence (defined as clinical cure without recurrence or diarrhoea resolution without recurrence), there was a significant
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
6
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
Fig. 3. Clinical cure for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median logORs with 95% credible intervals.
difference in favour of FDX versus both VCM (OR: 0.50 [95% CrI: 0.37, 0.68]) and MTZ (OR: 0.44 [95% CrI: 0.27, 0.72]) (Fig. 4). There were significant differences in favour of FDX for sustained cure 1 (clinical cure without recurrence) versus VCM (OR: 1.61 [95% CrI: 1.27, 2.05]) and MTZ (OR: 2.39 [95% CrI: 1.65, 3.47]) (Fig. 5). There were also significant differences in favour of FDX for sustained cure 2 (diarrhoea resolution without recurrence) versus VCM (OR: 1.61 [95% CrI: 1.27, 2.05]) and MTZ (OR 2.12 [95% CrI: 1.46, 3.08]) (Fig. 6). 4. Discussion VCM and MTZ have been the mainstays of CDI treatment for decades, with MTZ used in mild or moderate episodes and VCM in severe CDI. MTZ is recommended as a first-line treatment for mild or moderate CDI in Europe [15], Japan [16] and Australia [17];
however, in the 2017 IDSA/SHEA guidelines, MTZ is recommended only as an alternative treatment option if FDX or VCM is not available [1]. In this NMA comparing the effectiveness of FDX, VCM and MTZ for the treatment of CDI, FDX was more effective than MTZ but comparable to VCM for clinical cure rate, while FDX was more effective than both VCM and MTZ with regard to CDI recurrence and sustained cure rates. The main outcome in our analysis was clinical cure rate, which in the fixed-effects model was significantly higher for FDX versus MTZ, and similar for FDX versus VCM. The result of the comparison with VCM is consistent with a previous meta-analysis that did not include the most recent randomised trial in Japan, and which reported that clinical cure rates were similar for FDX and VCM (OR: 1.17; 95% CI: 0.82, 1.66) [18]. Recurrence rates were assessed during 28- and 30-day followup periods (after end of treatment) in the FDX versus VCM trials
Fig. 4. Recurrence for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median logORs with 95% credible intervals.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
7
Fig. 5. Sustained cure 1 (clinical cure without recurrence) for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median log-ORs with 95% credible intervals.
Fig. 6. Sustained cure 2 (diarrhoea resolution without recurrence) for fidaxomicin versus metronidazole and vancomycin. FDX, fidaxomicin; MTZ, metronidazole; OR, odds ratio; VCM, vancomycin. Data are shown as median log-ORs with 95% credible intervals.
[10,11], and during 21-, 28-, and 30-day follow-up periods in the VCM versus MTZ trials [8,9,13,14]. Our analysis calculated recurrence rate to be significantly lower, and sustained cure rates to be correspondingly higher, with FDX versus MTZ. With the exception of the Japanese phase III trial [12], FDX was also associated with significant improvements in recurrence rates and sustained cure rates compared with VCM. Our findings are consistent with a recent NMA based on published data available up to 2017 that compared 13 treatments for CDI, including FDX, MTZ and VCM [2]. The estimates reported in the study suggest that for sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death, FDX was better than MTZ (OR: 0.49 [95% CI: 0.35, 0.68]), and better than VCM (OR: 0.67 [95% CI: 0.55, 0.82]) [2]. The authors of
the study concluded that MTZ should not be recommended for treatment of CDI, and that FDX should be considered for initial therapy for mild or moderate CDI [2]. The approach in our analysis allowed the effectiveness of FDX and MTZ to be compared across clinical trials using VCM as the common arm. Our study is primarily limited by variability between the original studies in multiple aspects, including treatment dosage and duration; the definitions of clinical cure, recurrence rate and sustained cure; and the duration of follow up. In particular, sustained cure rates were provided in the FDX versus VCM studies, but were calculated from using clinical cure and recurrence rates for VCM versus MTZ. Lastly, the therapeutic environment or intestinal flora in the studies conducted in the 1980s and 90s may have differed from that in contemporary studies.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005
8
H. Okumura et al. / J Infect Chemother xxx (xxxx) xxx
In summary, our meta-analysis suggests that FDX and VCM, but not MTZ, are effective first-line treatments for CDI, and that FDX may be more effective at preventing CDI recurrence than VCM.
[5]
Conflicts of interest
[6]
A. Fukushima was an employee of Creativ-Ceutical at the time of the study, and V. Taieb is an employee of Creativ-Ceutical, working on behalf of Astellas Pharma, Inc. H. Okumura and S. Shoji are employees of Astellas Pharma, Inc. and M. English is an employee of Astellas Pharma Global Development, Inc.
[7]
Data sharing statement Access to anonymised individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under “Sponsor Specific Details for Astellas”.
[8]
[9]
[10]
[11]
Acknowledgements The study was funded by Astellas Pharma, Inc., Japan, and Astellas Pharma Global Development, Inc., USA. Medical writing support was provided by Annick Moon, PhD, for Cello Health MedErgy, funded by Astellas Pharma, Inc.
[12]
[13]
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jiac.2019.07.005. References [1] McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;31:431e55. https://doi.org/10.1093/cid/cix1085. [2] Beinortas T, Burr NE, Wilcox MH, Subramanian V. Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. Lancet Infect Dis 2018;18:1035e44. https://doi.org/10.1016/ S1473-3099(18)30285-8. [3] Vardakas KZ, Polyzos KA, Patouni K, Rafailidis PI, Samonis G, Falagas ME. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents 2012;40:1e8. https://doi.org/10.1016/ j.ijantimicag.2012.01.004. [4] Heimann SM, Vehreschild JJ, Cornely OA, Wisplinghoff H, Hallek M, Goldbrunner R, et al. Economic burden of Clostridium difficile-associated
[14]
[15]
[16]
[17]
[18]
diarrhoea: a cost-of-illness study from a German tertiary care hospital. Infection 2015;43:707e14. https://doi.org/10.1007/s15010-015-0810-x. Bouza E. Consequences of Clostridium difficile infection: understanding the healthcare burden. Clin Microbiol Infect 2012;18(Suppl. 6):5e12. https:// doi.org/10.1111/1469-0691.12064. Olsen MA, Yan Y, Reske KA, Zilberberg M, Dubberke ER. Impact of Clostridium difficile recurrence on hospital readmissions. Am J Infect Contr 2015;43: 318e22. https://doi.org/10.1016/j.ajic.2014.12.020. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect 2015;21:164e70. https://doi.org/10.1016/j.cmi.2014.08.017. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302e7. https:// doi.org/10.1086/519265. Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014;59:345e54. https://doi.org/10.1093/cid/ciu313. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e9. https://doi.org/10.1016/ S1473-3099(11)70374-7. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422e31. https://doi.org/10.1056/NEJMoa0910812. Mikamo H, Tateda K, Yanagihara K, Kusachi S, Takesue Y, Miki T, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan. J Infect Chemother 2018;24:744e52. https://doi.org/10.1016/ j.jiac.2018.05.010. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983;2: 1043e6. https://doi.org/10.1016/S0140-6736(83)91036-X. Wenisch C, Parschalk B, Hasenhundl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996;22:813e8. https://doi.org/10.1093/clinids/22.5.813. Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20(Suppl. 2):1e26. https://doi.org/10.1111/1469-0691.12418. Ohnishi K, Ainoda Y, Imamura A, Iwabuchi S, Okuda M, Nakano T. JAID/JSC guidelines for infection treatment 2015dintestinal infections. J Infect Chemother 2018;24:1e17. https://doi.org/10.1016/j.jiac.2017.09.002. Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May MLA, et al. Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand. Intern Med J 2016;46:479e93. https://doi.org/10.1111/ imj.13027. Cornely OA, Nathwani D, Ivanescu C, Odufowora-Sita O, Retsa P, Odeyemi IAO. Clinical efficacy of fidaxomicin compared with vancomycin and metronidazole in Clostridium difficile infections: a meta-analysis and indirect treatment comparison. J Antimicrob Chemother 2014;69:2892e900. https://doi.org/ 10.1093/jac/dku261.
Please cite this article as: Okumura H et al., Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis, J Infect Chemother, https://doi.org/10.1016/j.jiac.2019.07.005