Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection

Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial... Abstract Background The fully human monoclonal antibody bezlotoxumab binds Clostridioides (Clostridium) difficile toxin B and reduces recurrence rates in patients with C. difficile infection (CDI) receiving antibacterial treatment for a primary or recurrent episode. Objectives To investigate whether the timing of bezlotoxumab administration relative to the onset of antibacterial treatment affected clinical outcome in the Phase 3 trials MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Methods Initial clinical cure and CDI recurrence rates of participants who received bezlotoxumab or placebo were summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI: 0–2, 3–4 and ≥5 days after onset. Results Of 1554 total participants, 649 (41.8%), 469 (30.1%) and 436 (28.1%) received an infusion 0–2, 3–4 and ≥5 days after onset of antibacterial treatment for CDI, respectively. Regardless of timing of administration, there were no differences in initial clinical cure rates between participants receiving bezlotoxumab (range 77.8% to 81.4%) or placebo (77.8% to 81.7%). Bezlotoxumab efficacy was unaffected by timing of administration; rates of CDI recurrence were lower versus placebo in all subgroups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo). Timing of administration also had no effect on time to resolution of diarrhoea, which was achieved by the end of antibacterial treatment in ∼95% of participants in both bezlotoxumab and placebo groups. Conclusions Bezlotoxumab is effective in preventing CDI recurrence and can be administered at any time before ending antibacterial drug treatment. Introduction Clostridioides (Clostridium) difficile infection (CDI) is the most frequent cause of healthcare-associated gastrointestinal (GI) infection in the USA and is also increasingly associated with community-acquired GI infections.1,2 Although clinical treatment of CDI with metronidazole, vancomycin or fidaxomicin is often successful, ∼25% of individuals experience a recurrence of CDI (rCDI) following treatment of a primary episode3–6 and ∼40% experience further recurrences following the first rCDI.5 Bezlotoxumab (MK-6072) is a fully human monoclonal antibody that binds to C. difficile toxin B and is indicated for prevention of rCDI in adults receiving antibacterial drug treatment for CDI who are at high risk for rCDI.7,8 In the Phase 3 MODIFY I/II trials, a single intravenous dose of bezlotoxumab resulted in a significantly lower rate of rCDI versus placebo during the 12 week follow-up period in participants receiving antibacterial drug treatment for primary or rCDI.9 Bezlotoxumab had no effect on initial clinical cure (ICC). Most participants received bezlotoxumab ≥3 days after antibiotic treatment for CDI began.9 It is not known if the timing of administration relative to onset of antibiotic treatment affects clinical outcome. The aim of this post hoc analysis of the MODIFY I/II trials was to evaluate the efficacy of bezlotoxumab summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI. Methods Study design MODIFY I (NCT01241552; P001) and MODIFY II (NCT01513239; P002) were randomized, double-blind, placebo-controlled, multicentre, Phase 3 trials that were conducted from November 2011 to May 2015 at 322 sites in 30 countries.9 MODIFY I and MODIFY II trials were conducted in accordance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki. The protocols and amendments were approved by the institutional review board or independent ethics committee at each study site and written informed consent was obtained from all participants before the trial began. Adults aged ≥18 years who were prescribed oral antibacterial drug treatment for CDI (metronidazole, vancomycin or fidaxomicin) were randomized to receive a single infusion of bezlotoxumab (10 mg/kg of body weight), actoxumab (10 mg/kg; MODIFY I only), bezlotoxumab + actoxumab (10 mg/kg each) or placebo. Investigators were encouraged to administer the study medication as soon as possible relative to the initiation of antibacterial treatment; however, the protocol permitted administration at any time during the antibacterial treatment period, which was specified to be 10 to 14 days. CDI was defined as diarrhoea [≥3 unformed bowel movements (types 5 to 7 on the Bristol stool scale)10 in 24 h], with a stool test result positive for toxigenic C. difficile. In this post hoc analysis, efficacy data from participants who were administered bezlotoxumab or placebo in the MODIFY I/II trials were summarized by timing of study medication administration: 0–2, 3–4 and ≥5 days after onset of antibacterial drug treatment for CDI. Endpoints ICC was defined as no diarrhoea during the two consecutive days following completion of ≤16 calendar days of antibacterial drug treatment for CDI. rCDI was defined as a new episode of diarrhoea associated with a positive stool test for toxigenic C. difficile in participants who had achieved ICC of the baseline CDI episode. Data and statistical analysis The analysis population for ICC was the modified ITT (mITT) population, which included all randomized participants in the overall population of the MODIFY I/II trials who received study infusion, had a positive baseline stool test for toxigenic C. difficile and received antibacterial drug treatment for CDI at the time of randomization. Estimation of rCDI was assessed in participants who achieved ICC (clinical cure population). Baseline demographics and clinical characteristics were summarized descriptively. ICC rates and observed rCDI rates are presented along with adjusted rate differences between the bezlotoxumab and placebo groups and their 95% CIs. Adjusted rate difference was based on the Miettinen and Nurminen11 method and stratified by trial (MODIFY I versus MODIFY II), antibacterial drug treatment for CDI (metronidazole versus vancomycin versus fidaxomicin) and hospitalization status at time of randomization (inpatient versus outpatient). The non-parametric Kaplan–Meier method was used to estimate the distribution of time to resolution of baseline CDI episode for each treatment group and timing of infusion group. Results Participants This post hoc analysis included 1554 participants, of which 781 received bezlotoxumab and 773 received placebo. In total, 649 (41.8%), 469 (30.1%) and 436 (28.1%) participants received an infusion 0–2, 3–4 and ≥5 days after onset of antibacterial treatment for CDI, respectively (Table 1). The number of participants completing the trial through to the end of the 12 week follow-up period was similar in all groups (82.6% to 88.8%), and the baseline characteristics were generally similar between the bezlotoxumab and placebo treatment groups, according to time of infusion initiation (Table 1). Table 1. Baseline demographics and clinical characteristics by timing of infusion (mITT population) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) a Pre-specified risk factors include: ≥1 CDI episodes in the past 6 months; severe CDI at baseline; age ≥65 years; ribotype 027, 078 or 244 at baseline; and/or immunocompromised. b Defined on the basis of medical history or use of immunosuppressive therapy. c Based on the following at time of randomization: (i) age >60 years (1 point); (ii) body temperature >38.3°C (>100°F) (1 point); (iii) albumin level <2.5 g/dL (1 point); (iv) peripheral white blood cell count >15 000 cells/mm3 within 48 h (1 point); (v) endoscopic evidence of pseudomembranous colitis (2 points); and (vi) treatment in an ICU (2 points). d The denominators used to calculate percentages are the numbers of participants who had a positive culture. Table 1. Baseline demographics and clinical characteristics by timing of infusion (mITT population) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) a Pre-specified risk factors include: ≥1 CDI episodes in the past 6 months; severe CDI at baseline; age ≥65 years; ribotype 027, 078 or 244 at baseline; and/or immunocompromised. b Defined on the basis of medical history or use of immunosuppressive therapy. c Based on the following at time of randomization: (i) age >60 years (1 point); (ii) body temperature >38.3°C (>100°F) (1 point); (iii) albumin level <2.5 g/dL (1 point); (iv) peripheral white blood cell count >15 000 cells/mm3 within 48 h (1 point); (v) endoscopic evidence of pseudomembranous colitis (2 points); and (vi) treatment in an ICU (2 points). d The denominators used to calculate percentages are the numbers of participants who had a positive culture. Efficacy ICC rates were similar in all groups, irrespective of treatment administered or timing of administration (range 77.8% to 81.4% for bezlotoxumab and 77.8% to 81.7% for placebo) (Figure 1a). Rates of rCDI were lower with bezlotoxumab compared with placebo across all infusion timing groups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo) (Figure 1b), and the adjusted difference between the bezlotoxumab and placebo groups was similar, regardless of the timing of study medication infusion (–12.3% to –13.1%). Figure 1. View largeDownload slide Proportion of participants (a) achieving ICC (mITT population) and (b) experiencing rCDI (clinical cure population) summarized by timing of infusion after onset of antibacterial treatment for CDI. Figure 1. View largeDownload slide Proportion of participants (a) achieving ICC (mITT population) and (b) experiencing rCDI (clinical cure population) summarized by timing of infusion after onset of antibacterial treatment for CDI. Time to resolution of diarrhoea was similar for both bezlotoxumab and placebo in each subgroup (Figure S1, available as Supplementary data at JAC Online). In both the bezlotoxumab and placebo treatment groups, ∼70% of participants who had been receiving antibacterial treatment for three or more days before infusion of the study medication no longer had diarrhoea at the time of infusion (Study Day 1). By the end of antibacterial treatment, ∼95% of participants had resolved their diarrhoea in both treatment groups, regardless of the timing of infusion. Discussion This post hoc analysis was conducted to evaluate the impact of infusion timing on bezlotoxumab efficacy endpoints. The analysis demonstrated a substantial reduction in the incidence of rCDI with bezlotoxumab compared with placebo, regardless of timing of infusion. Bezlotoxumab did not appear to improve ICC rates when given early during the course of antibiotic treatment and irrespective of timing of infusion relative to the onset of antibacterial treatment, as indicated by the similar point estimates and difference between bezlotoxumab and placebo groups. Moreover, early administration of bezlotoxumab did not appear to improve the time to resolution of the primary symptom of CDI, diarrhoea. While we did not see an effect of bezlotoxumab on ICC or time to resolution of diarrhoea, it is thought that administration early after onset of symptoms could improve outcomes in patients with severe CDI. However, only 17% of participants who were administered study medication within the first two days of onset of antibiotic therapy were classified as having severe CDI; therefore, the sample size was too small to evaluate this hypothesis. These findings suggest that there can be flexibility in the timing of bezlotoxumab administration, facilitating its use in an outpatient setting. This may improve post-hospitalization follow-up and increase the likelihood of reimbursement from third-party payers. The MODIFY trial design required that the study medication be administered before the end of antibiotic therapy. The rationale for this design was to ensure that the antibodies were in the systemic circulation before onset of the at-risk period for rCDI. A previous study demonstrated that fidaxomicin and vancomycin treatment reduced C. difficile toxin B levels as early as 3–5 days after onset of treatment and this effect was sustained until the end of treatment (10–13 days). Toxin B levels began to rise 9–25 days after the end of therapy (the first follow-up visit) following completion of therapy for both antimicrobial agents.12 This illustrates the time course of toxin B levels during antibacterial drug treatment for CDI and highlights that toxin levels begin to rise shortly after finishing a course of antibiotic treatment, representing the start of the rCDI risk period. There was a significant correlation between the presence of vegetative cells and spores and high toxin levels.12 These findings support the theory that it is optimal to administer bezlotoxumab before antibacterial treatment for CDI ends, so that it is in the systemic circulation and available to protect against the damaging effects of new toxin production when the patient is most at risk for relapse or re-infection. Further support for administering bezlotoxumab prior to the end of antibacterial drug treatment is provided by preclinical evidence, which showed that by preventing rCDI during the critical high-risk period, bezlotoxumab treatment allowed the intestinal microbiota time to fully recover its role as a natural defence against C. difficile.13 This post hoc analysis of the effect of bezlotoxumab infusion timing on clinical outcome supports the proposal that administration of bezlotoxumab any time before ending antibacterial treatment is effective in the prevention of rCDI. Limitations of the study include the fact this was a post hoc analysis, which was not powered to assess for statistical significance. As such, the results can only be interpreted as trends rather than taken as conclusive. Despite this, the sample sizes for each subgroup were fairly large and risk factors for rCDI were balanced across treatment groups within each subgroup, which will have minimized bias in the results. In conclusion, the results of this post hoc analysis suggest that bezlotoxumab can be administered any time before ending antibacterial drug treatment for CDI in order to prevent rCDI. Acknowledgements Mary Hanson, PhD, of Merck & Co., Inc., Kenilworth, NJ, USA contributed to the concept and design of the analysis but did not otherwise fulfil authorship criteria. Funding Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance was also funded by Merck Sharp & Dohme Corp., in accordance with Good Publication Practice (GPP3) guidelines. Transparency declarations T. B. acted as an investigator for MSD. Y. G. has received research grants from MSD and Allergan, contributed to speakers’ bureaus for MSD, Allergan and Pfizer, and acted as a consultant for MSD, Pfizer, Allergan, Tetraphase, Melinta and Shionogi. G. R. is a board member for MSD and Gilead, received fees from ViiV, Gilead and AbbVie for educational activities and contributed to speakers’ bureaus for ViiV.  E. J., L. G., D. G. and M. B. D. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in the company.  Medical writing assistance, under the direction of the authors, was provided by Edward Rochford, PhD, of CMC AFFINITY, a division of Complete Medical Communications Ltd, Macclesfield, UK. Supplementary data Figure S1 is available as Supplementary data at JAC Online. References 1 Magill SS , Edwards JR , Bamberg W et al. Multistate point-prevalence survey of health care-associated infections . N Engl J Med 2014 ; 370 : 1198 – 208 . Google Scholar CrossRef Search ADS PubMed 2 McDonald LC , Gerding DN , Johnson S 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 ; 66 : e1 – 48 . Google Scholar CrossRef Search ADS PubMed 3 Johnson S , Louie TJ , Gerding DN et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials . Clin Infect Dis 2014 ; 59 : 345 – 54 . Google Scholar CrossRef Search ADS PubMed 4 Louie TJ , Miller MA , Mullane KM et al. Fidaxomicin versus vancomycin for Clostridium difficile infection . N Engl J Med 2011 ; 364 : 422 – 31 . Google Scholar CrossRef Search ADS PubMed 5 Sheitoyan-Pesant C , Abou Chakra CN , Pépin J et al. Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection . Clin Infect Dis 2016 ; 62 : 574 – 80 . Google Scholar CrossRef Search ADS PubMed 6 Cornely OA , Miller MA , Louie TJ et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin . Clin Infect Dis 2012 ; 55 Suppl 2: S154 – 61 . Google Scholar CrossRef Search ADS PubMed 7 Merck Sharp & Dohme Corp . Zinplava (Bezlotoxumab) Prescribing Information. 2016 . https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf. 8 EMA . Zinplava Assessment Report. 2016 . http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004136/WC500222643.pdf. 9 Wilcox MH , Gerding DN , Poxton IR et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection . N Engl J Med 2017 ; 376 : 305 – 17 . Google Scholar CrossRef Search ADS PubMed 10 Lewis SJ , Heaton KW. Stool form scale as a useful guide to intestinal transit time . Scand J Gastroenterol 1997 ; 32 : 920 – 4 . Google Scholar CrossRef Search ADS PubMed 11 Miettinen O , Nurminen M. Comparative analysis of two rates . Stat Med 1985 ; 4 : 213 – 26 . Google Scholar CrossRef Search ADS PubMed 12 Thabit AK , Alam MJ , Khaleduzzaman M et al. A pilot study to assess bacterial and toxin reduction in patients with Clostridium difficile infection given fidaxomicin or vancomycin . Ann Clin Microbiol Antimicrob 2016 ; 15 : 22 . Google Scholar CrossRef Search ADS PubMed 13 Warn P , Thommes P , Sattar A et al. Disease progression and resolution in rodent models of Clostridium difficile infection and impact of antitoxin antibodies and vancomycin . Antimicrob Agents Chemother 2016 ; 60 : 6471 – 82 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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10.1093/jac/dky182
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Abstract

Abstract Background The fully human monoclonal antibody bezlotoxumab binds Clostridioides (Clostridium) difficile toxin B and reduces recurrence rates in patients with C. difficile infection (CDI) receiving antibacterial treatment for a primary or recurrent episode. Objectives To investigate whether the timing of bezlotoxumab administration relative to the onset of antibacterial treatment affected clinical outcome in the Phase 3 trials MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Methods Initial clinical cure and CDI recurrence rates of participants who received bezlotoxumab or placebo were summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI: 0–2, 3–4 and ≥5 days after onset. Results Of 1554 total participants, 649 (41.8%), 469 (30.1%) and 436 (28.1%) received an infusion 0–2, 3–4 and ≥5 days after onset of antibacterial treatment for CDI, respectively. Regardless of timing of administration, there were no differences in initial clinical cure rates between participants receiving bezlotoxumab (range 77.8% to 81.4%) or placebo (77.8% to 81.7%). Bezlotoxumab efficacy was unaffected by timing of administration; rates of CDI recurrence were lower versus placebo in all subgroups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo). Timing of administration also had no effect on time to resolution of diarrhoea, which was achieved by the end of antibacterial treatment in ∼95% of participants in both bezlotoxumab and placebo groups. Conclusions Bezlotoxumab is effective in preventing CDI recurrence and can be administered at any time before ending antibacterial drug treatment. Introduction Clostridioides (Clostridium) difficile infection (CDI) is the most frequent cause of healthcare-associated gastrointestinal (GI) infection in the USA and is also increasingly associated with community-acquired GI infections.1,2 Although clinical treatment of CDI with metronidazole, vancomycin or fidaxomicin is often successful, ∼25% of individuals experience a recurrence of CDI (rCDI) following treatment of a primary episode3–6 and ∼40% experience further recurrences following the first rCDI.5 Bezlotoxumab (MK-6072) is a fully human monoclonal antibody that binds to C. difficile toxin B and is indicated for prevention of rCDI in adults receiving antibacterial drug treatment for CDI who are at high risk for rCDI.7,8 In the Phase 3 MODIFY I/II trials, a single intravenous dose of bezlotoxumab resulted in a significantly lower rate of rCDI versus placebo during the 12 week follow-up period in participants receiving antibacterial drug treatment for primary or rCDI.9 Bezlotoxumab had no effect on initial clinical cure (ICC). Most participants received bezlotoxumab ≥3 days after antibiotic treatment for CDI began.9 It is not known if the timing of administration relative to onset of antibiotic treatment affects clinical outcome. The aim of this post hoc analysis of the MODIFY I/II trials was to evaluate the efficacy of bezlotoxumab summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI. Methods Study design MODIFY I (NCT01241552; P001) and MODIFY II (NCT01513239; P002) were randomized, double-blind, placebo-controlled, multicentre, Phase 3 trials that were conducted from November 2011 to May 2015 at 322 sites in 30 countries.9 MODIFY I and MODIFY II trials were conducted in accordance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki. The protocols and amendments were approved by the institutional review board or independent ethics committee at each study site and written informed consent was obtained from all participants before the trial began. Adults aged ≥18 years who were prescribed oral antibacterial drug treatment for CDI (metronidazole, vancomycin or fidaxomicin) were randomized to receive a single infusion of bezlotoxumab (10 mg/kg of body weight), actoxumab (10 mg/kg; MODIFY I only), bezlotoxumab + actoxumab (10 mg/kg each) or placebo. Investigators were encouraged to administer the study medication as soon as possible relative to the initiation of antibacterial treatment; however, the protocol permitted administration at any time during the antibacterial treatment period, which was specified to be 10 to 14 days. CDI was defined as diarrhoea [≥3 unformed bowel movements (types 5 to 7 on the Bristol stool scale)10 in 24 h], with a stool test result positive for toxigenic C. difficile. In this post hoc analysis, efficacy data from participants who were administered bezlotoxumab or placebo in the MODIFY I/II trials were summarized by timing of study medication administration: 0–2, 3–4 and ≥5 days after onset of antibacterial drug treatment for CDI. Endpoints ICC was defined as no diarrhoea during the two consecutive days following completion of ≤16 calendar days of antibacterial drug treatment for CDI. rCDI was defined as a new episode of diarrhoea associated with a positive stool test for toxigenic C. difficile in participants who had achieved ICC of the baseline CDI episode. Data and statistical analysis The analysis population for ICC was the modified ITT (mITT) population, which included all randomized participants in the overall population of the MODIFY I/II trials who received study infusion, had a positive baseline stool test for toxigenic C. difficile and received antibacterial drug treatment for CDI at the time of randomization. Estimation of rCDI was assessed in participants who achieved ICC (clinical cure population). Baseline demographics and clinical characteristics were summarized descriptively. ICC rates and observed rCDI rates are presented along with adjusted rate differences between the bezlotoxumab and placebo groups and their 95% CIs. Adjusted rate difference was based on the Miettinen and Nurminen11 method and stratified by trial (MODIFY I versus MODIFY II), antibacterial drug treatment for CDI (metronidazole versus vancomycin versus fidaxomicin) and hospitalization status at time of randomization (inpatient versus outpatient). The non-parametric Kaplan–Meier method was used to estimate the distribution of time to resolution of baseline CDI episode for each treatment group and timing of infusion group. Results Participants This post hoc analysis included 1554 participants, of which 781 received bezlotoxumab and 773 received placebo. In total, 649 (41.8%), 469 (30.1%) and 436 (28.1%) participants received an infusion 0–2, 3–4 and ≥5 days after onset of antibacterial treatment for CDI, respectively (Table 1). The number of participants completing the trial through to the end of the 12 week follow-up period was similar in all groups (82.6% to 88.8%), and the baseline characteristics were generally similar between the bezlotoxumab and placebo treatment groups, according to time of infusion initiation (Table 1). Table 1. Baseline demographics and clinical characteristics by timing of infusion (mITT population) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) a Pre-specified risk factors include: ≥1 CDI episodes in the past 6 months; severe CDI at baseline; age ≥65 years; ribotype 027, 078 or 244 at baseline; and/or immunocompromised. b Defined on the basis of medical history or use of immunosuppressive therapy. c Based on the following at time of randomization: (i) age >60 years (1 point); (ii) body temperature >38.3°C (>100°F) (1 point); (iii) albumin level <2.5 g/dL (1 point); (iv) peripheral white blood cell count >15 000 cells/mm3 within 48 h (1 point); (v) endoscopic evidence of pseudomembranous colitis (2 points); and (vi) treatment in an ICU (2 points). d The denominators used to calculate percentages are the numbers of participants who had a positive culture. Table 1. Baseline demographics and clinical characteristics by timing of infusion (mITT population) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) Bezlotoxumab timing of infusion Placebo timing of infusion 0–2 days, N = 318 3–4 days, N = 239 ≥5 days, N = 224 0–2 days, N = 331 3–4 days, N = 230 ≥5 days, N = 212 Characteristics, n (%)  female 176 (55.3) 136 (56.9) 130 (58.0) 189 (57.1) 134 (58.3) 126 (59.4)  inpatient 229 (72.0) 164 (68.6) 137 (61.2) 231 (69.8) 153 (66.5) 136 (64.2) Antibacterial treatment for CDI, n (%)  metronidazole 138 (43.4) 126 (52.7) 115 (51.3) 166 (50.2) 108 (47.0) 100 (47.2)  vancomycin 163 (51.3) 108 (45.2) 101 (45.1) 153 (46.2) 112 (48.7) 108 (50.9)  fidaxomicin 17 (5.3) 5 (2.1) 8 (3.6) 12 (3.6) 10 (4.3) 4 (1.9) Risk factors for recurrence, n (%)  ≥1 of 5 pre-specified risk factorsa 244 (76.7) 181 (75.7) 167 (74.6) 241 (72.8) 181 (78.7) 161 (75.9)  ≥1 CDI episodes in past 6 months 92 (28.9) 66 (27.6) 58 (25.9) 82 (24.8) 67 (29.1) 70 (33.0)  ≥2 previous CDI episodes ever 104 (32.7) 73 (30.5) 73 (32.6) 102 (30.8) 77 (33.5) 80 (37.7)  ≥65 years of age 145 (45.6) 124 (51.9) 121 (54.0) 161 (48.6) 126 (54.8) 118 (55.7)  compromised immunityb 72 (22.6) 56 (23.4) 50 (22.3) 71 (21.5) 45 (19.6) 37 (17.5)  severe CDI (Zar score ≥2)c 55 (17.3) 37 (15.5) 30 (13.4) 57 (17.2) 37 (16.1) 31 (14.6) C. difficile straind, n (%)  participants with a positive culture 233 (73.3) 141 (59.0) 116 (51.8) 229 (69.2) 142 (61.7) 115 (54.2)  ribotype 027, 078 or 244d 48 (20.6) 32 (22.7) 22 (19.0) 62 (27.1) 29 (20.4) 24 (20.9)  ribotype 027d 42 (18.0) 30 (21.3) 17 (14.7) 54 (23.6) 25 (17.6) 21 (18.3) a Pre-specified risk factors include: ≥1 CDI episodes in the past 6 months; severe CDI at baseline; age ≥65 years; ribotype 027, 078 or 244 at baseline; and/or immunocompromised. b Defined on the basis of medical history or use of immunosuppressive therapy. c Based on the following at time of randomization: (i) age >60 years (1 point); (ii) body temperature >38.3°C (>100°F) (1 point); (iii) albumin level <2.5 g/dL (1 point); (iv) peripheral white blood cell count >15 000 cells/mm3 within 48 h (1 point); (v) endoscopic evidence of pseudomembranous colitis (2 points); and (vi) treatment in an ICU (2 points). d The denominators used to calculate percentages are the numbers of participants who had a positive culture. Efficacy ICC rates were similar in all groups, irrespective of treatment administered or timing of administration (range 77.8% to 81.4% for bezlotoxumab and 77.8% to 81.7% for placebo) (Figure 1a). Rates of rCDI were lower with bezlotoxumab compared with placebo across all infusion timing groups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo) (Figure 1b), and the adjusted difference between the bezlotoxumab and placebo groups was similar, regardless of the timing of study medication infusion (–12.3% to –13.1%). Figure 1. View largeDownload slide Proportion of participants (a) achieving ICC (mITT population) and (b) experiencing rCDI (clinical cure population) summarized by timing of infusion after onset of antibacterial treatment for CDI. Figure 1. View largeDownload slide Proportion of participants (a) achieving ICC (mITT population) and (b) experiencing rCDI (clinical cure population) summarized by timing of infusion after onset of antibacterial treatment for CDI. Time to resolution of diarrhoea was similar for both bezlotoxumab and placebo in each subgroup (Figure S1, available as Supplementary data at JAC Online). In both the bezlotoxumab and placebo treatment groups, ∼70% of participants who had been receiving antibacterial treatment for three or more days before infusion of the study medication no longer had diarrhoea at the time of infusion (Study Day 1). By the end of antibacterial treatment, ∼95% of participants had resolved their diarrhoea in both treatment groups, regardless of the timing of infusion. Discussion This post hoc analysis was conducted to evaluate the impact of infusion timing on bezlotoxumab efficacy endpoints. The analysis demonstrated a substantial reduction in the incidence of rCDI with bezlotoxumab compared with placebo, regardless of timing of infusion. Bezlotoxumab did not appear to improve ICC rates when given early during the course of antibiotic treatment and irrespective of timing of infusion relative to the onset of antibacterial treatment, as indicated by the similar point estimates and difference between bezlotoxumab and placebo groups. Moreover, early administration of bezlotoxumab did not appear to improve the time to resolution of the primary symptom of CDI, diarrhoea. While we did not see an effect of bezlotoxumab on ICC or time to resolution of diarrhoea, it is thought that administration early after onset of symptoms could improve outcomes in patients with severe CDI. However, only 17% of participants who were administered study medication within the first two days of onset of antibiotic therapy were classified as having severe CDI; therefore, the sample size was too small to evaluate this hypothesis. These findings suggest that there can be flexibility in the timing of bezlotoxumab administration, facilitating its use in an outpatient setting. This may improve post-hospitalization follow-up and increase the likelihood of reimbursement from third-party payers. The MODIFY trial design required that the study medication be administered before the end of antibiotic therapy. The rationale for this design was to ensure that the antibodies were in the systemic circulation before onset of the at-risk period for rCDI. A previous study demonstrated that fidaxomicin and vancomycin treatment reduced C. difficile toxin B levels as early as 3–5 days after onset of treatment and this effect was sustained until the end of treatment (10–13 days). Toxin B levels began to rise 9–25 days after the end of therapy (the first follow-up visit) following completion of therapy for both antimicrobial agents.12 This illustrates the time course of toxin B levels during antibacterial drug treatment for CDI and highlights that toxin levels begin to rise shortly after finishing a course of antibiotic treatment, representing the start of the rCDI risk period. There was a significant correlation between the presence of vegetative cells and spores and high toxin levels.12 These findings support the theory that it is optimal to administer bezlotoxumab before antibacterial treatment for CDI ends, so that it is in the systemic circulation and available to protect against the damaging effects of new toxin production when the patient is most at risk for relapse or re-infection. Further support for administering bezlotoxumab prior to the end of antibacterial drug treatment is provided by preclinical evidence, which showed that by preventing rCDI during the critical high-risk period, bezlotoxumab treatment allowed the intestinal microbiota time to fully recover its role as a natural defence against C. difficile.13 This post hoc analysis of the effect of bezlotoxumab infusion timing on clinical outcome supports the proposal that administration of bezlotoxumab any time before ending antibacterial treatment is effective in the prevention of rCDI. Limitations of the study include the fact this was a post hoc analysis, which was not powered to assess for statistical significance. As such, the results can only be interpreted as trends rather than taken as conclusive. Despite this, the sample sizes for each subgroup were fairly large and risk factors for rCDI were balanced across treatment groups within each subgroup, which will have minimized bias in the results. In conclusion, the results of this post hoc analysis suggest that bezlotoxumab can be administered any time before ending antibacterial drug treatment for CDI in order to prevent rCDI. Acknowledgements Mary Hanson, PhD, of Merck & Co., Inc., Kenilworth, NJ, USA contributed to the concept and design of the analysis but did not otherwise fulfil authorship criteria. Funding Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance was also funded by Merck Sharp & Dohme Corp., in accordance with Good Publication Practice (GPP3) guidelines. Transparency declarations T. B. acted as an investigator for MSD. Y. G. has received research grants from MSD and Allergan, contributed to speakers’ bureaus for MSD, Allergan and Pfizer, and acted as a consultant for MSD, Pfizer, Allergan, Tetraphase, Melinta and Shionogi. G. R. is a board member for MSD and Gilead, received fees from ViiV, Gilead and AbbVie for educational activities and contributed to speakers’ bureaus for ViiV.  E. J., L. G., D. G. and M. B. D. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in the company.  Medical writing assistance, under the direction of the authors, was provided by Edward Rochford, PhD, of CMC AFFINITY, a division of Complete Medical Communications Ltd, Macclesfield, UK. Supplementary data Figure S1 is available as Supplementary data at JAC Online. References 1 Magill SS , Edwards JR , Bamberg W et al. Multistate point-prevalence survey of health care-associated infections . N Engl J Med 2014 ; 370 : 1198 – 208 . Google Scholar CrossRef Search ADS PubMed 2 McDonald LC , Gerding DN , Johnson S 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 ; 66 : e1 – 48 . Google Scholar CrossRef Search ADS PubMed 3 Johnson S , Louie TJ , Gerding DN et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials . Clin Infect Dis 2014 ; 59 : 345 – 54 . Google Scholar CrossRef Search ADS PubMed 4 Louie TJ , Miller MA , Mullane KM et al. Fidaxomicin versus vancomycin for Clostridium difficile infection . N Engl J Med 2011 ; 364 : 422 – 31 . Google Scholar CrossRef Search ADS PubMed 5 Sheitoyan-Pesant C , Abou Chakra CN , Pépin J et al. Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection . Clin Infect Dis 2016 ; 62 : 574 – 80 . Google Scholar CrossRef Search ADS PubMed 6 Cornely OA , Miller MA , Louie TJ et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin . Clin Infect Dis 2012 ; 55 Suppl 2: S154 – 61 . Google Scholar CrossRef Search ADS PubMed 7 Merck Sharp & Dohme Corp . Zinplava (Bezlotoxumab) Prescribing Information. 2016 . https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf. 8 EMA . Zinplava Assessment Report. 2016 . http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004136/WC500222643.pdf. 9 Wilcox MH , Gerding DN , Poxton IR et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection . N Engl J Med 2017 ; 376 : 305 – 17 . Google Scholar CrossRef Search ADS PubMed 10 Lewis SJ , Heaton KW. Stool form scale as a useful guide to intestinal transit time . Scand J Gastroenterol 1997 ; 32 : 920 – 4 . Google Scholar CrossRef Search ADS PubMed 11 Miettinen O , Nurminen M. Comparative analysis of two rates . Stat Med 1985 ; 4 : 213 – 26 . Google Scholar CrossRef Search ADS PubMed 12 Thabit AK , Alam MJ , Khaleduzzaman M et al. A pilot study to assess bacterial and toxin reduction in patients with Clostridium difficile infection given fidaxomicin or vancomycin . Ann Clin Microbiol Antimicrob 2016 ; 15 : 22 . Google Scholar CrossRef Search ADS PubMed 13 Warn P , Thommes P , Sattar A et al. Disease progression and resolution in rodent models of Clostridium difficile infection and impact of antitoxin antibodies and vancomycin . Antimicrob Agents Chemother 2016 ; 60 : 6471 – 82 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 16, 2018

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